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2f9b7f88bae3a6d1f5e23e36ab5feaa521ab06d1 | wikidoc | Pemetrexed | Pemetrexed
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# Overview
Pemetrexed is a antineoplastic agent that is FDA approved for the treatment of non-squamous non-small cell lung cancer, mesothelioma. Common adverse reactions include itching, peeling of skin, constipation, diarrhea, loss of appetite, nausea, pharyngitis, stomatitis, vomiting, anemia, leukopenia, neutropenia, thrombocytopenia, fatigue.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
The recommended dose of pemetrexed is 500 mg/m2 administered as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle. The recommended dose of cisplatin is 75 mg/m2 infused over 2 hours beginning approximately 30 minutes after the end of pemetrexed administration. See cisplatin package insert for more information.
The recommended dose of pemetrexed is 500 mg/m2 administered as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle.
- Instruct patients to initiate folic acid 400 mcg to 1000 mcg orally once daily beginning 7 days before the first dose of pemetrexed. Continue folic acid during the full course of therapy and for 21 days after the last dose of pemetrexed.
- Administer vitamin B12 1 mg intramuscularly 1 week prior to the first dose of pemetrexed and every 3 cycles thereafter. Subsequent vitamin B12 injections may be given the same day as treatment with pemetrexed.
Administer dexamethasone 4 mg by mouth twice daily the day before, the day of, and the day after pemetrexed administration.
Complete blood cell counts, including platelet counts, should be performed on all patients receiving pemetrexed. Patients should be monitored for nadir and recovery, which were tested in the clinical study before each dose and on days 8 and 15 of each cycle. Patients should not begin a new cycle of treatment unless the ANC is ≥1500 cells/mm3, the platelet count is ≥100,000 cells/mm3, and creatinine clearance is ≥45 mL/min. Periodic chemistry tests should be performed to evaluate renal and hepatic function.
Dose adjustments at the start of a subsequent cycle should be based on nadir hematologic counts or maximum nonhematologic toxicity from the preceding cycle of therapy. Treatment may be delayed to allow sufficient time for recovery. Upon recovery, patients should be retreated using the guidelines in Tables 1-3, which are suitable for using pemetrexed as a single-agent or in combination with cisplatin.
If patients develop nonhematologic toxicities (excluding neurotoxicity) ≥Grade 3, treatment should be withheld until resolution to less than or equal to the patient's pre-therapy value. Treatment should be resumed according to guidelines in Table 2.
In the event of neurotoxicity, the recommended dose adjustments for pemetrexed and cisplatin are described in Table 3. Patients should discontinue therapy if Grade 3 or 4 neurotoxicity is experienced.
ALIMTA therapy should be discontinued if a patient experiences any hematologic or nonhematologic Grade 3 or 4 toxicity after 2 dose reductions or immediately if Grade 3 or 4 neurotoxicity is observed.
In clinical studies, patients with creatinine clearance ≥45 mL/min required no dose adjustments other than those recommended for all patients. Insufficient numbers of patients with creatinine clearance below 45 mL/min have been treated to make dosage recommendations for this group of patients. Therefore, pemetrexed should not be administered to patients whose creatinine clearance is <45 mL/min using the standard Cockcroft and Gault formula (below) or GFR measured by Tc99m-DTPA serum clearance method:
Caution should be exercised when administering pemetrexed concurrently with NSAIDs to patients whose creatinine clearance is <80 mL/min .
As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of infusion solutions of pemetrexed. The use of gloves is recommended. If a solution of pemetrexed contacts the skin, wash the skin immediately and thoroughly with soap and water. If pemetrexed contacts the mucous membranes, flush thoroughly with water. Several published guidelines for handling and disposal of anticancer agents are available.
pemetrexed is not a vesicant. There is no specific antidote for extravasation of pemetrexed. To date, there have been few reported cases of pemetrexed extravasation, which were not assessed as serious by the investigator. Pemetrexed extravasation should be managed with local standard practice for extravasation as with other non-vesicants.
- Use aseptic technique during the reconstitution and further dilution of pemetrexed for intravenous infusion administration.
- Calculate the dose of pemetrexed and determine the number of vials needed. Vials contain either 100 mg or 500 mg of pemetrexed. The vials contain an excess of pemetrexed to facilitate delivery of label amount.
- Reconstitute each 100-mg vial with 4.2 ml of 0.9% Sodium Chloride Injection (preservative free). Reconstitute each 500-mg vial with 20 mL of 0.9% Sodium Chloride Injection (preservative free). Reconstitution of either size vial gives a solution containing 25 mg/mL pemetrexed. Gently swirl each vial until the powder is completely dissolved. The resulting solution is clear and ranges in color from colorless to yellow or green-yellow without adversely affecting product quality. The pH of the reconstituted pemetrexed solution is between 6.6 and 7.8. FURTHER DILUTION IS REQUIRED.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If particulate matter is observed, do not administer.
- An appropriate quantity of the reconstituted pemetrexed solution must be further diluted into a solution of 0.9% Sodium Chloride Injection (preservative free), so that the total volume of solution is 100 ml. pemetrexed is administered as an intravenous infusion over 10 minutes.
- Chemical and physical stability of reconstituted and infusion solutions of pemetrexed were demonstrated for up to 24 hours following initial reconstitution, when stored refrigerated. When prepared as directed, reconstitution and infusion solutions of pemetrexed contain no antimicrobial preservatives. Discard any unused portion.
Reconstitution and further dilution prior to intravenous infusion is only recommended with 0.9% Sodium Chloride Injection (preservative free). pemetrexed is physically incompatible with diluents containing calcium, including Lactated Ringer's Injection, USP and Ringer's Injection, USP and therefore these should not be used. Coadministration of pemetrexed with other drugs and diluents has not been studied, and therefore is not recommended. Pemetrexed is compatible with standard polyvinyl chloride (PVC) administration sets and intravenous solution bags.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pemetrexed in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- First-line therapy pemetrexed + carboplatin: Pemetrexed 500 mg/m2 IV infusion over 10 min, followed by carboplatin AUC 5 administered during 30 min, 0.5 h after premetexed infusion.
- Monotherapy: 500 mg/m2 administered as IV infusion over 10 minutes with 3 week intervals.
- Dosing Information
- 500-900 mg/m2.
- Pemetrexed + carboplatin combination therapy: pemetrexed 500 mg/m2 infusion administered over 10 min, followed by carboplatin AUC 6 over 30 min, 0.5 h after pemetrexed infusion.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Pemetrexed FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pemetrexed in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Pemetrexed in pediatric patients.
# Contraindications
Pemetrexed is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed.
# Warnings
Prior to treatment with pemetrxed, initiate supplementation with oral folic acid and intramuscular vitamin B12 to reduce the severity of hematologic and gastrointestinal toxicity of pemetrxed. Do not substitute oral vitamin B12 for intramuscular vitamin B12. In clinical studies, the incidence of the following Grade 3-4 toxicities were higher in patients with mesothelioma who were never supplemented as compared to patients who were fully supplemented with folic acid and vitamin B12 prior to and throughout pemetrxed treatment: neutropenia , thrombocytopenia , febrile neutropenia , and infection with neutropenia .
Administer dexamethasone the day before, the day of, and the day after pemetrxed administration.
Pemetrxed can suppress bone marrow function, as manifested by neutropenia, thrombocytopenia, and anemia (or pancytopenia); myelosuppression is usually the dose-limiting toxicity. Dose reductions for subsequent cycles are based on nadir ANC, platelet count, and maximum nonhematologic toxicity seen in the previous cycle.
Pemetrxed is primarily eliminated unchanged by renal excretion. No dosage adjustment is needed in patients with creatinine clearance ≥45 mL/min. Insufficient numbers of patients have been studied with creatinine clearance <45 mL/min to give a dose recommendation. Therefore, pemetrxed should not be administered to patients whose creatinine clearance is < 45 mL/min.
One patient with severe renal impairment (creatinine clearance 19 mL/min) who did not receive folic acid and vitamin B12 died of drug-related toxicity following administration of pemetrxed alone.
Caution should be used when administering NSAIDs concurrently with pemetrxed to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min).
Obtain a complete blood count and renal function tests at the beginning of each cycle and as needed. Do not initiate a cycle of treatment unless the ANC is ≥1500 cells/mm3, the platelet count is ≥100,000 cells/mm3, and creatinine clearance is ≥45 mL/min.
Based on its mechanism of action, pemetrxed can cause fetal harm when administered to a pregnant woman. Pemetrexed administered intraperitoneally to mice during organogenesis was embryotoxic, fetotoxic and teratogenic in mice at greater than 1/833rd the recommended human dose. If pemetrxed is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant. Women should be advised to use effective contraceptive measures to prevent pregnancy during treatment with pemetrxed.
# Adverse Reactions
## Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reactions rates cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice.
In clinical trials, the most common adverse reactions (incidence ≥20%) during therapy with pemetrexed as a single-agent were fatigue, nausea, and anorexia. Additional common adverse reactions (incidence ≥20%) during therapy with pemetrexed when used in combination with cisplatin included vomiting, neutropenia, leukopenia, anemia, stomatitis/pharyngitis, thrombocytopenia, and constipation.
- Table 4 provides the frequency and severity of adverse reactions that have been reported in > 5% of 839 patients with NSCLC who were randomized to study and received pemetrexed plus cisplatin and 830 patients with NSCLC who were randomized to study and received gemcitabine plus cisplatin. All patients received study therapy as initial treatment for locally advanced or metastatic NSCLC and patients in both treatment groups were fully supplemented with folic acid and vitamin B12.
- No clinically relevant differences in adverse reactions were seen in patients based on histology.
- In addition to the lower incidence of hematologic toxicity on the pemetrexed and cisplatin arm, use of transfusions (RBC and platelet) and hematopoietic growth factors was lower in the pemetrexed and cisplatin arm compared to the gemcitabine and cisplatin arm.
Incidence 1% to 5%
- Body as a Whole: febrile neutropenia, infection, pyrexia
- General Disorders: dehydration
- Metabolism and Nutrition: increased AST, increased ALT
- Renal: creatinine clearance decrease, renal failure
- Special Senses: conjunctivitis
Incidence Less than 1%
- Cardiovascular: arrhythmia
- General Disorders: chest pain
- Metabolism and Nutrition: increased GGT
- Neurology: motor neuropathy
- Table 5 provides the frequency and severity of adverse reactions reported in >5% of the 438 patients with NSCLC who received pemetrexed maintenance and the 218 patients with NSCLC who received placebo following a platinum-based induction therapy.
- All patients received study therapy immediately following 4 cycles of platinum-based treatment for locally advanced or metastatic NSCLC. Patients in both study arms were fully supplemented with folic acid and vitamin B12.
- No clinically relevant differences in Grade 3/4 adverse reactions were seen in patients based on age, gender, ethnic origin, or histology except a higher incidence of Grade 3/4 fatigue for Caucasian patients compared to non-Caucasian patients (6.5% versus 0.6%).
- Safety was assessed by exposure for patients who received at least one dose of pemetrexed (N=438). The incidence of adverse reactions was evaluated for patients who received ≤6 cycles of pemetrexed, and compared to patients who received >6 cycles of pemetrexed. Increases in adverse reactions (all grades) were observed with longer exposure; however no clinically relevant differences in Grade 3/4 adverse reactions were seen.
- Consistent with the higher incidence of anemia (all grades) on the pemetrexed arm, use of transfusions (mainly RBC) and erythropoiesis stimulating agents (ESAs; erythropoietin and darbepoetin) were higher in the pemetrexed arm compared to the placebo arm (transfusions 9.5% versus 3.2%, ESAs 5.9% versus 1.8%).
Incidence 1% to 5%
- Dermatology/Skin: alopecia, pruritis/itching
- Gastrointestinal: constipation
- General Disorders: edema, fever (in the absence of neutropenia)
- Hematologic: thrombocytopenia
- Renal: decreased creatinine clearance, increased creatinine, decreased glomerular filtration rate
- Special Senses: ocular surface disease (including conjunctivitis), increased lacrimation
Incidence Less than 1%
- Cardiovascular: supraventricular arrhythmia
- Dermatology/Skin: erythema multiforme
- General Disorders: febrile neutropenia, allergic reaction/hypersensitivity
- Neurology: motor neuropathy
- Renal: renal failure
- Table 6 provides the frequency and severity of adverse reactions reported in >5% of the 500 patients with non-squamous NSCLC who received at least one cycle of pemetrexed maintenance (n=333) or placebo (n=167) on the continuation maintenance trial.
- The median of maintenance cycles administered to patients receiving one or more doses of maintenance therapy was 4 on both the pemetrexed and placebo arms. Dose reductions for adverse events occurred in 3.3% of patients in the pemetrexed arm and 0.6% in the placebo arm. Dose delays for adverse events occurred in 22% of patients in the pemetrexed arm and 16% in the placebo arm. Patients in both study arms were supplemented with folic acid and vitamin B12.
- Administration of RBC (13% versus 4.8%) and platelet (1.5% versus 0.6%) transfusions, erythropoiesis stimulating agents (12% versus 7%), and granulocyte colony stimulating factors (6% versus 0) were higher in the pemetrexed arm compared to the placebo arm.
Incidence 1% to 5%
- Blood/Bone Marrow: thrombocytopenia
- General Disorders: febrile neutropenia
Incidence Less than 1%
- Cardiovascular: ventricular tachycardia, syncope
- General Disorders: pain
- Gastrointestinal: gastrointestinal obstruction
- Neurologic: depression
- Renal: renal failure
- Vascular: pulmonary embolism
- Table 7 provides the frequency and severity of adverse reactions that have been reported in >5% of 265 patients randomly assigned to receive single-agent pemetrexed with folic acid and vitamin B12 supplementation and 276 patients randomly assigned to receive single-agent docetaxel. All patients were diagnosed with locally advanced or metastatic NSCLC and received prior chemotherapy.
- No clinically relevant differences in adverse reactions were seen in patients based on histology.
- Clinically relevant adverse reactions occurring in 5% of patients that received docetaxel include CTC Grade 3/4 febrile neutropenia (1.9% pemetrexed, 12.7% docetaxel).
Incidence 1% to 5%
- Body as a Whole: abdominal pain, allergic reaction/hypersensitivity, febrile neutropenia, infection
- Dermatology/Skin: erythema multiforme
- Neurology: motor neuropathy, sensory neuropathy
- Renal: increased creatinine
Incidence Less than 1%
- Cardiovascular: supraventricular arrhythmias
- Table 8 provides the frequency and severity of adverse reactions that have been reported in >5% of 168 patients with mesothelioma who were randomly assigned to receive cisplatin and pemetrexed and 163 patients with mesothelioma randomly assigned to receive single-agent cisplatin. In both treatment arms, these chemonaive patients were fully supplemented with folic acid and vitamin B12.
The following additional adverse reactions were observed in patients with malignant pleural mesothelioma randomly assigned to receive pemetrexed plus cisplatin.
Incidence 1% to 5%
Body as a Whole: febrile neutropenia, infection, pyrexia
Dermatology/Skin: urticaria
General Disorders: chest pain
Metabolism and Nutrition: increased AST, increased ALT, increased GGT
Renal: renal failure
Incidence Less than 1%
Cardiovascular: arrhythmia
Neurology: motor neuropathy
- Table 9 compares the incidence (percentage of patients) of CTC Grade 3/4 toxicities in patients who received vitamin supplementation with daily folic acid and vitamin B12 from the time of enrollment in the study (fully supplemented) with the incidence in patients who never received vitamin supplementation (never supplemented) during the study in the pemetrexed plus cisplatin arm.
- The following adverse events were greater in the fully supplemented group compared to the never supplemented group: hypertension (11%, 3%), chest pain (8%, 6%), and thrombosis/embolism (6%, 3%).
- No relevant effect for pemetrexed safety due to gender or race was identified, except an increased incidence of rash in men (24%) compared to women (16%).
- Sepsis, which in some cases was fatal, occurred in approximately 1% of patients.
- Esophagitis occurred in less than 1% of patients.
## Postmarketing Experience
The following adverse reactions have been identified during post-approval use of pemetrexed. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
These reactions occurred with pemetrexed when used as a single-agent and in combination therapies:
- Blood and Lymphatic System: immune-mediated hemolytic anemia
- Gastrointestinal: colitis, pancreatitis
- General Disorders and Administration Site Conditions: edema
- Injury, poisoning, and procedural complications: Radiation recall has been reported in patients who have previously received radiotherapy.
- Respiratory: interstitial pneumonitis
- Skin: Bullous conditions, including Stevens-Johnson syndrome and toxic epidermal necrolysis. Some cases were fatal.
# Drug Interactions
- Although ibuprofen (400 mg four times a day) can decrease the clearance of pemetrexed, it can be administered with pemetrexed in patients with normal renal function (creatinine clearance ≥80 mL/min). No dose adjustment of pemetrexed is needed with concomitant NSAIDs in patients with normal renal function.
- Caution should be used when administering NSAIDs concurrently with pemetrexed to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min). NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of 2 days before, the day of, and 2 days following administration of pemetrexed.
- In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least 5 days before, the day of, and 2 days following pemetrexed administration. If concomitant administration of NSAIDs is necessary, patients should be monitored closely for toxicity, especially myelosuppression, renal, and gastrointestinal toxicity.
- Pemetrexed is primarily eliminated unchanged renally as a result of glomerular filtration and tubular secretion. Concomitant administration of nephrotoxic drugs could result in delayed clearance of pemetrexed. Concomitant administration of substances that are also tubularly secreted (e.g., probenecid) could potentially result in delayed clearance of pemetrexed.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
Based on its mechanism of action, pemetrexed can cause fetal harm when administered to a pregnant woman. There are no adequate and well controlled studies of pemetrexed in pregnant women. Pemetrexed was embryotoxic, fetotoxic, and teratogenic in mice. In mice, repeated intraperitoneal doses of pemetrexed when given during organogenesis caused fetal malformations (incomplete ossification of talus and skull bone; about 1/833rd the recommended intravenous human dose on a mg/m2 basis), and cleft palate (1/33rd the recommended intravenous human dose on a mg/m2 basis). Embryotoxicity was characterized by increased embryo-fetal deaths and reduced litter sizes. If pemetrexed is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to use effective contraceptive measures to prevent pregnancy during the treatment with pemetrexed.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Pemetrexed in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Pemetrexed during labor and delivery.
### Nursing Mothers
It is not known whether pemetrexed or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from pemetrexed, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug for the mother.
### Pediatric Use
Efficacy of pemetrexed in pediatric patients has not been demonstrated. Pemetrexed was administered as an intravenous infusion over 10 minutes on Day 1 of a 21 day cycle to pediatric patients with recurrent solid tumors in a Phase 1 study (32 patients) and a Phase 2 study (72 patients). All patients received pretreatment with vitamin B12 and folic acid supplementation and dexamethasone. The dose escalation in the Phase 1 study determined the maximum tolerated dose was 1910 mg/m2 and this dose (or 60 mg/kg for patients <12 months old) was evaluated in the Phase 2 study of patients with relapsed or refractory osteosarcoma, Ewing sarcoma/peripheral PNET, rhabdomyosarcoma, neuroblastoma, ependymoma, medulloblastoma/supratentorial PNET, or non-brainstem high grade glioma. No responses were observed among the 72 patients in this Phase 2 trial. The most common toxicities reported were hematological (leukopenia, neutropenia/granulocytopenia, anemia, thrombocytopenia, and lymphopenia), liver function abnormalities (increased ALT/AST), fatigue, and nausea.
The single dose pharmacokinetics of pemetrexed administered in doses ranging from 400 to 2480 mg/m2 were evaluated in the Phase 1 trial in 22 patients (13 males and 9 females) aged 4 to 18 years (average age 12 years). Pemetrexed exposure (AUC and Cmax) appeared to increase proportionally with dose. The average pemetrexed clearance (2.30 L/h/m2) and half-life (2.3 hours) in pediatric patients were comparable to values reported in adults.
### Geriatic Use
Pemetrexed is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Renal function monitoring is recommended with administration of pemetrexed. No dose reductions other than those recommended for all patients are necessary for patients 65 years of age or older
Of 3,946 patients (34.0% ≥65) studied across the five clinical trials, the effect of pemetrexed on survival was similar in patients <65 compared to ≥65 years of age. There were no differences in safety with the exception of the following Grade 3-4 adverse reactions, which were noted in at least one of the five trials to be greater in patients 65 years of age and older as compared to younger patients: anemia, fatigue, thrombocytopenia, hypertension, and neutropenia.
### Gender
Of 3,946 patients (Male 70.5%) studied across the five registration studies for pemetrexed indications, the effect of pemetrexed on survival was similar in female and male patients.
### Race
Of 3,946 patients (Caucasian 78.6%) studied across the five registration studies for pemetrexed indications, the effect of pemetrexed on survival was similar in the Caucasian and non-Caucasian patients.
### Renal Impairment
Pemetrexed is known to be primarily excreted by the kidneys. Decreased renal function will result in reduced clearance and greater exposure (AUC) to pemetrexed compared with patients with normal renal function. Cisplatin coadministration with pemetrexed has not been studied in patients with moderate renal impairment.
### Hepatic Impairment
There was no effect of elevated AST, ALT, or total bilirubin on the pharmacokinetics of pemetrexed. However, no formal studies have been conducted to examine the pharmacokinetics of pemetrexed in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Pemetrexed in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Pemetrexed in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Intravenous
### Monitoring
Complete blood cell counts, including platelet counts, should be performed on all patients receiving pemetrexed. Patients should be monitored for nadir and recovery, which were tested in the clinical study before each dose and on days 8 and 15 of each cycle. Patients should not begin a new cycle of treatment unless the ANC is ≥1500 cells/mm3, the platelet count is ≥100,000 cells/mm3, and creatinine clearance is ≥45 mL/min. Periodic chemistry tests should be performed to evaluate renal and hepatic function.
# IV Compatibility
Reconstitution and further dilution prior to intravenous infusion is only recommended with 0.9% Sodium Chloride Injection (preservative free). Pemetrexed is physically incompatible with diluents containing calcium, including Lactated Ringer's Injection, USP and Ringer's Injection, USP and therefore these should not be used. Coadministration of pemetrexed with other drugs and diluents has not been studied, and therefore is not recommended. Pemetrexed is compatible with standard polyvinyl chloride (PVC) administration sets and intravenous solution bags.
# Overdosage
- There have been few cases of pemetrexed overdose. Reported toxicities included neutropenia, anemia, thrombocytopenia, mucositis, and rash. Anticipated complications of overdose include bone marrow suppression as manifested by neutropenia, thrombocytopenia, and anemia. In addition, infection with or without fever, diarrhea, and mucositis may be seen. If an overdose occurs, general supportive measures should be instituted as deemed necessary by the treating physician.
- In clinical trials, leucovorin was permitted for CTC Grade 4 leukopenia lasting ≥3 days, CTC Grade 4 neutropenia lasting ≥3 days, and immediately for CTC Grade 4 thrombocytopenia, bleeding associated with Grade 3 thrombocytopenia, or Grade 3 or 4 mucositis. The following intravenous doses and schedules of leucovorin were recommended for intravenous use: 100 mg/m2, intravenously once, followed by leucovorin, 50 mg/m2, intravenously every 6 hours for 8 days.
- The ability of pemetrexed to be dialyzed is unknown.
# Pharmacology
## Mechanism of Action
Pemetrexed for injection, is a folate analog metabolic inhibitor that exerts its action by disrupting folate-dependent metabolic processes essential for cell replication. In vitro studies have shown that pemetrexed inhibits thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT), which are folate-dependent enzymes involved in the de novo biosynthesis of thymidine and purine nucleotides. Pemetrexed is taken into cells by membrane carriers such as the reduced folate carrier and membrane folate binding protein transport systems. Once in the cell, pemetrexed is converted to polyglutamate forms by the enzyme folylpolyglutamate synthetase. The polyglutamate forms are retained in cells and are inhibitors of TS and GARFT. Polyglutamation is a time- and concentration-dependent process that occurs in tumor cells and, is thought to occur to a lesser extent, in normal tissues. Polyglutamated metabolites are thought to have an increased intracellular half-life resulting in prolonged drug action in malignant cells.
## Structure
Pemetrexed disodium heptahydrate has the chemical name L-Glutamic acid, N-pyrimidin-5-yl)ethyl]benzoyl]-, disodium salt, heptahydrate. It is a white to almost-white solid with a molecular formula of C20H19N5Na2O67H2O and a molecular weight of 597.49. The structural formula is as follows:
Pemetrexed is supplied as a sterile lyophilized powder for intravenous infusion available in single-dose vials. The product is a white to either light yellow or green-yellow lyophilized solid. Each 100-mg or 500-mg vial of pemetrexed contains pemetrexed disodium equivalent to 100 mg pemetrexed and 106 mg mannitol or 500 mg pemetrexed and 500 mg mannitol, respectively. Hydrochloric acid and/or sodium hydroxide may have been added to adjust pH.
## Pharmacodynamics
- Preclinical studies have shown that pemetrexed inhibits the in vitro growth of mesothelioma cell lines (MSTO-211H, NCI-H2052). Studies with the MSTO-211H mesothelioma cell line showed synergistic effects when pemetrexed was combined concurrently with cisplatin.
- Absolute neutrophil counts (ANC) following single-agent administration of pemetrexed to patients not receiving folic acid and vitamin B12 supplementation were characterized using population pharmacodynamic analyses. Severity of hematologic toxicity, as measured by the depth of the ANC nadir, correlates with the systemic exposure, or area under the curve (AUC) of pemetrexed. It was also observed that lower ANC nadirs occurred in patients with elevated baseline cystathionine or homocysteine concentrations. The levels of these substances can be reduced by folic acid and vitamin B12 supplementation. There is no cumulative effect of pemetrexed exposure on ANC nadir over multiple treatment cycles.
- Time to ANC nadir with pemetrexed systemic exposure (AUC), varied between 8 to 9.6 days over a range of exposures from 38.3 to 316.8 mcghr/mL. Return to baseline ANC occurred 4.2 to 7.5 days after the nadir over the same range of exposures.
## Pharmacokinetics
- The pharmacokinetics of pemetrexed administered as a single-agent in doses ranging from 0.2 to 838 mg/m2 infused over a 10-minute period have been evaluated in 426 cancer patients with a variety of solid tumors. Pemetrexed total systemic exposure (AUC) and maximum plasma concentration (Cmax) increase proportionally with dose. The pharmacokinetics of pemetrexed do not change over multiple treatment cycles.
- Pemetrexed has a steady-state volume of distribution of 16.1 liters. In vitro studies indicate that pemetrexed is approximately 81% bound to plasma proteins. Binding is not affected by degree of renal impairment.
- Pemetrexed is not metabolized to an appreciable extent and is primarily eliminated in the urine, with 70% to 90% of the dose recovered unchanged within the first 24 hours following administration. The clearance decreases, and exposure (AUC) increases, as renal function decreases. The total systemic clearance of pemetrexed is 91.8 mL/min and the elimination half-life of pemetrexed is 3.5 hours in patients with normal renal function (creatinine clearance of 90 mL/min).
- The pharmacokinetics of pemetrexed in special populations were examined in about 400 patients in controlled and single arm studies.
- In vitro studies indicate that pemetrexed is a substrate of OAT3 (organic anion transporter 3), a transporter that may play a role in active secretion of pemetrexed.
- No effect of age on the pharmacokinetics of pemetrexed was observed over a range of 26 to 80 years.
- The pharmacokinetics of pemetrexed were not different in male and female patients.
- The pharmacokinetics of pemetrexed were similar in Caucasians and patients of African descent. Insufficient data are available to compare pharmacokinetics for other ethnic groups.
- There was no effect of elevated AST, ALT, or total bilirubin on the pharmacokinetics of pemetrexed. However, studies of hepatically impaired patients have not been conducted.
- Pharmacokinetic analyses of pemetrexed included 127 patients with reduced renal function. Plasma clearance of pemetrexed decreases as renal function decreases, with a resultant increase in systemic exposure. Patients with creatinine clearances of 45, 50, and 80 mL/min had 65%, 54%, and 13% increases, respectively in pemetrexed total systemic exposure (AUC) compared to patients with creatinine clearance of 100 mL/min.
- The effect of third space fluid, such as pleural effusion and ascites, on pemetrexed is not fully defined. A study of pemetrexed 500 mg/m2 was performed in 31 solid tumor patients with stable third space fluid (All but 2 of the 31 patients included in study had mild or moderate amounts of third space fluid). Moderate pleural effusion was defined in the study as less than 1/3 the way up on one side with obscuring of the entire hemidiaphragm. Moderate ascites was defined as that detectable on physical exam. The pemetrexed plasma concentrations in these patients were comparable to those observed in previous clinical trials in patients without third space fluid collections. Thus, drainage of mild or moderate third space fluid collection prior to pemetrexed treatment should be considered, but is probably not necessary. The effect of severe third space fluid on pharmacokinetics is not known.
- Ibuprofen doses of 400 mg four times a day reduce pemetrexed's clearance by about 20% (and increase AUC by 20%) in patients with normal renal function. The effect of greater doses of ibuprofen on pemetrexed pharmacokinetics is unknown.
- Aspirin, administered in low to moderate doses (325 mg every 6 hours), does not affect the pharmacokinetics of pemetrexed. The effect of greater doses of aspirin on pemetrexed pharmacokinetics is unknown.
- Cisplatin does not affect the pharmacokinetics of pemetrexed and the pharmacokinetics of total platinum are unaltered by pemetrexed.
- Coadministration of oral folic acid or intramuscular vitamin B12 does not affect the pharmacokinetics of pemetrexed.
- Results from in vitro studies with human liver microsomes predict that pemetrexed would not cause clinically significant inhibition of metabolic clearance of drugs metabolized by CYP3A, CYP2D6, CYP2C9, and CYP1A2.
## Nonclinical Toxicology
No carcinogenicity studies have been conducted with pemetrexed. Pemetrexed was clastogenic in the in vivo micronucleus assay in mouse bone marrow but was not mutagenic in multiple in vitro tests (Ames assay, CHO cell assay). Pemetrexed administered at i.v. doses of 0.1 mg/kg/day or greater to male mice (about 1/1666 the recommended human dose on a mg/m2 basis) resulted in reduced fertility, hypospermia, and testicular atrophy.
# Clinical Studies
A multi-center, randomized, open-label study in 1725 chemonaive patients with Stage IIIb/IV NSCLC was conducted to compare the overall survival following treatment with pemetrexed in combination with cisplatin (AC) versus gemcitabine in combination with cisplatin (GC). Pemetrexed was administered intravenously over 10 minutes at a dose of 500 mg/m2 with cisplatin administered intravenously at a dose of 75 mg/m2 after pemetrexed administration, on Day 1 of each 21-day cycle. Gemcitabine was administered at a dose of 1250 mg/m2 on Day 1 and Day 8, and cisplatin was administered intravenously at a dose of 75 mg/m2 after administration of gemcitabine, on Day 1 of each 21-day cycle. Treatment was administered up to a total of 6 cycles, and patients in both treatment arms received folic acid, vitamin B12, and dexamethasone.
Patient demographics of the intent to treat (ITT) population are shown in Table 10. The demographics and disease characteristics were well balanced.
Patients received a median of 5 cycles of treatment in both study arms. Patients treated with pemetrexed plus cisplatin received a relative dose intensity of 94.8% of the protocol-specified pemetrexed dose intensity and 95.0% of the protocol-specified cisplatin dose intensity. Patients treated with gemcitabine plus cisplatin received a relative dose intensity of 85.8% of the protocol-specified gemcitabine dose intensity and 93.5% of the protocol-specified cisplatin dose intensity.
The primary endpoint in this study was overall survival. The median survival time was 10.3 months in the pemetrexed plus cisplatin treatment arm and 10.3 months in the gemcitabine plus cisplatin arm, with an adjusted hazard ratio of 0.94.
A pre-specified analysis of the impact of NSCLC histology on overall survival was examined. Clinically relevant differences in survival according to histology were observed and are shown in Table 12. This difference in treatment effect for pemetrexed based on histology demonstrating a lack of efficacy in squamous cell histology was also observed in the single-agent, second-line study and the maintenance study.
A multi-center, randomized, double-blind, placebo-controlled study was conducted in 663 patients with Stage IIIb/IV NSCLC who did not progress after four cycles of platinum-based chemotherapy. Patients who did not progress were randomized 2:1 to receive pemetrexed or placebo immediately following platinum-based chemotherapy. Of the randomized patients, 47.2% versus 52.7% achieved a complete or partial response to induction therapy and 51.9% versus 47.3% had stable disease after induction therapy in the pemetrexed and placebo arms, respectively. Pemetrexed was administered intravenously over 10 minutes at a dose of 500 mg/m2 on Day 1 of each 21-day cycle, until disease progression. Patients in both study arms received folic acid, vitamin B12, and dexamethasone.
The study was designed to demonstrate superior progression-free survival and overall survival of pemetrexed over placebo. Progression-free survival (PFS) was assessed by independent review. Patient characteristics of the intent to treat (ITT) population are shown in Table 13. The demographics and baseline disease characteristics were well balanced between study arms.
Patients received a median of 5 cycles of pemetrexed and 3.5 cycles of placebo. Patients randomized to ALIMTA received a relative dose intensity of 95.7%. A total of 213 patients (48.3%) completed ≥6 cycles and a total of 98 patients (22.6%) completed ≥10 cycles of treatment with ALIMTA.
In the overall study population, pemetrexed was statistically superior to placebo in terms of overall survival (OS) (median 13.4 months versus 10.6 months, HR=0.79 (95% CI: 0.65-0.95), p-value=0.012) and PFS (median 4.0 months versus 2.0 months, HR=0.60 (95% CI: 0.49-0.73), p-value<0.00001). A difference in treatment outcomes was observed according to histologic classification. For the population of patients with nonsquamous NSCLC, pemetrexed was superior to placebo for OS (median 15.5 months versus 10.3 months, HR=0.70 (95% CI: 0.56-0.88)) and PFS (median 4.4 months versus 1.8 months, HR=0.47 (95% CI: 0.37-0.60)). For the population of patients with squamous NSCLC, pemetrexed did not improve OS compared to placebo (median 9.9 months versus 10.8 months, HR=1.07 (95% CI: 0.77-1.50)) or PFS (median 2.4 months versus 2.5 months, HR=1.03 (95% CI: 0.71-1.49)). This difference in treatment effect for pemetrexed based on histology demonstrating lack of benefit in squamous cell histology was also observed in the first-line and second-line studies.
Efficacy results for the overall patient population are presented in Table 14 and Figure 3, and efficacy results by pre-specified histologic subgroups are presented in Table 15 and Figure 4, below.
A multi-center, randomized, double-blind, placebo-controlled study was conducted to evaluate continuation of pemetrexed in patients with Stage IIIb/IV nonsquamous NSCLC. Patients completing induction treatment of four cycles of pemetrexed plus cisplatin with stable disease or better and PS 0/1 were randomized (2:1) to maintenance treatment with pemetrexed or placebo. Randomization was stratified by response to induction (complete response (CR)/partial response (PR) versus stable disease (SD)), disease stage (IIIb versus IV), and ECOG performance status (0 versus 1). Pemetrexed was administered intravenously over 10 minutes at a dose of 500 mg/m2 on Day 1 of each 21-day cycle and continued until disease progression. Patients in both study arms received folic acid, vitamin B12, and dexamethasone. The main efficacy outcome was investigator-assessed progression-free survival.
A total of 539 patients were randomized; all completed four cycles of pemetrexed and cisplatin induction prior to randomization. Of the randomized patients, 44% versus 42% achieved a complete or partial response to induction therapy and 53% versus 53% had stable disease after induction treatment in the pemetrexed or the placebo arms respectively.
Patient demographics of the intent to treat (ITT) population are shown in Table 16.
Patients received a median of four cycles of pemetrexed maintenance or placebo. The percentages of patients that received post-study treatment were similar (64% in the pemetrexed arm and 72% in the placebo arm).
The trial showed a statistically significant improvement in progression-free survival and in overall survival for patients randomized to pemetrexed maintenance. Efficacy results are presented in Table 17 and Figure 5.
A multi-center, randomized, open label study was conducted in patients with Stage III or IV NSCLC after prior chemotherapy to compare the overall survival following treatment with pemetrexed versus docetaxel. Pemetrexed was administered intravenously over 10 minutes at a dose of 500 mg/m2 and docetaxel was administered at 75 mg/m2 as a 1-hour intravenous infusion. Both drugs were given on Day 1 of each 21-day cycle. All patients treated with pemetrexed received vitamin supplementation with folic acid and vitamin B12. The study was intended to show either an overall survival superiority or non-inferiority of pemetrexed to docetaxel. Patient demographics of the intent to treat (ITT) population are shown in Table 18.
The primary endpoint in this study was overall survival. The median survival time was 8.3 months in the pemetrexed treatment arm and 7.9 months in the docetaxel arm, with a hazard ratio of 0.99 (see Table 19). The study did not show an overall survival superiority of pemetrexed.
A retrospective analysis of the impact of NSCLC histology on overall survival was examined. Clinically relevant differences in survival according to histology were observed and are shown in Table 20. This difference in treatment effect for pemetrexed based on histology demonstrating a lack of efficacy in squamous cell histology was also observed in the first-line combination study and in the maintenance study.
A multi-center, randomized, single-blind study in 448 chemonaive patients with malignant pleural mesothelioma (MPM) compared survival in patients treated with pemetrexed in combination with cisplatin to survival in patients receiving cisplatin alone. Pemetrexed was administered intravenously over 10 minutes at a dose of 500 mg/m2 and cisplatin was administered intravenously over 2 hours at a dose of 75 mg/m2 beginning approximately 30 minutes after the end of administration of pemetrexed. Both drugs were given on Day 1 of each 21-day cycle. After 117 patients were treated, white cell and GI toxicity led to a change in protocol whereby all patients were given folic acid and vitamin B12 supplementation.
The primary analysis of this study was performed on the population of all patients randomly assigned to treatment who received study drug (randomized and treated). An analysis was also performed on patients who received folic acid and vitamin B12 supplementation during the entire course of study therapy (fully supplemented), as supplementation is recommended. Results in all patients and those fully supplemented were similar. Patient demographics are shown in Table 21.
Table 22 and Figure 6 summarize the survival results for all randomized and treated patients regardless of vitamin supplementation status and those patients receiving vitamin supplementation from the time of enrollment in the trial.
Similar results were seen in the analysis of patients (N=303) with confirmed histologic diagnosis of malignant pleural mesothelioma. There were too few non-white patients to assess possible ethnic differences. The effect in women (median survival 15.7 months with the combination versus 7.5 months on cisplatin alone), however, was larger than the effect in males (median survival 11 versus 9.4 respectively). As with any exploratory analysis, it is not clear whether this difference is real or is a chance finding.
Objective tumor response for malignant pleural mesothelioma is difficult to measure and response criteria are not universally agreed upon. However, based upon prospectively defined criteria, the objective tumor response rate for pemetrexed plus cisplatin was greater than the objective tumor response rate for cisplatin alone. There was also improvement in lung function (forced vital capacity) in the pemetrexed plus cisplatin arm compared to the control arm.
Patients who received full supplementation with folic acid and vitamin B12 during study therapy received a median of 6 and 4 cycles in the pemetrexed/cisplatin (N=168) and cisplatin (N=163) arms, respectively. Patients who never received folic acid and vitamin B12 during study therapy received a median of 2 cycles in both treatment arms (N=32 and N=38 for the pemetrexed/cisplatin and cisplatin arm, respectively). Patients receiving pemetrexed in the fully supplemented group received a relative dose intensity of 93% of the protocol specified pemetrexed dose intensity; patients treated with cisplatin in the same group received 94% of the projected dose intensity. Patients treated with cisplatin alone had a dose intensity of 96%.
# How Supplied
- ALIMTA, pemetrexed for injection, is available in sterile single-use vials containing 100 mg pemetrexed. NDC 0002-7640-01 (VL7640): single-use vial with ivory flip-off cap individually packaged in a carton.
- ALIMTA, pemetrexed for injection, is available in sterile single-use vials containing 500 mg pemetrexed. NDC 0002-7623-01 (VL7623): single-use vial with ivory flip-off cap individually packaged in a carton.
## Storage
- Pemetrexed for injection, should be stored at 25°C (77°F); excursions permitted to 15-30°C (59-86°F).
- Chemical and physical stability of reconstituted and infusion solutions of pemetrexed were demonstrated for up to 24 hours following initial reconstitution, when stored refrigerated, 2-8°C (36-46°F).
- When prepared as directed, reconstituted and infusion solutions of pemetrexed contain no antimicrobial preservatives.
- Discard unused portion
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Instruct patients to read the patient package insert before initiating pemetrexed.
- Instruct patients on the need for folic acid and vitamin B12 supplementation to reduce treatment-related hematologic and gastrointestinal toxicity and of the need for corticosteroids to reduce treatment-related dermatologic toxicity.
- Inform patients of the risk of low blood cell counts and instruct them to immediately contact their physician for signs of infection, including fever, bleeding or symptoms of anemia.
- Instruct patients to contact their physician if persistent vomiting, diarrhea, or signs of dehydration appear.
- Instruct patients to inform their physician of all concomitant prescription or over-the-counter medications they are taking, particularly those for pain or inflammation such as non-steroidal anti-inflammatory drugs.
# Precautions with Alcohol
Alcohol-Pemetrexed interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Alimta
# Look-Alike Drug Names
- Pemetrexed - Pralatrexate
# Drug Shortage Status
Drug Shortage
# Price | Pemetrexed
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alonso Alvarado, M.D. [2]
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# Overview
Pemetrexed is a antineoplastic agent that is FDA approved for the treatment of non-squamous non-small cell lung cancer, mesothelioma. Common adverse reactions include itching, peeling of skin, constipation, diarrhea, loss of appetite, nausea, pharyngitis, stomatitis, vomiting, anemia, leukopenia, neutropenia, thrombocytopenia, fatigue.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
The recommended dose of pemetrexed is 500 mg/m2 administered as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle. The recommended dose of cisplatin is 75 mg/m2 infused over 2 hours beginning approximately 30 minutes after the end of pemetrexed administration. See cisplatin package insert for more information.
The recommended dose of pemetrexed is 500 mg/m2 administered as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle.
- Instruct patients to initiate folic acid 400 mcg to 1000 mcg orally once daily beginning 7 days before the first dose of pemetrexed. Continue folic acid during the full course of therapy and for 21 days after the last dose of pemetrexed.
- Administer vitamin B12 1 mg intramuscularly 1 week prior to the first dose of pemetrexed and every 3 cycles thereafter. Subsequent vitamin B12 injections may be given the same day as treatment with pemetrexed.
Administer dexamethasone 4 mg by mouth twice daily the day before, the day of, and the day after pemetrexed administration.
Complete blood cell counts, including platelet counts, should be performed on all patients receiving pemetrexed. Patients should be monitored for nadir and recovery, which were tested in the clinical study before each dose and on days 8 and 15 of each cycle. Patients should not begin a new cycle of treatment unless the ANC is ≥1500 cells/mm3, the platelet count is ≥100,000 cells/mm3, and creatinine clearance is ≥45 mL/min. Periodic chemistry tests should be performed to evaluate renal and hepatic function.
Dose adjustments at the start of a subsequent cycle should be based on nadir hematologic counts or maximum nonhematologic toxicity from the preceding cycle of therapy. Treatment may be delayed to allow sufficient time for recovery. Upon recovery, patients should be retreated using the guidelines in Tables 1-3, which are suitable for using pemetrexed as a single-agent or in combination with cisplatin.
If patients develop nonhematologic toxicities (excluding neurotoxicity) ≥Grade 3, treatment should be withheld until resolution to less than or equal to the patient's pre-therapy value. Treatment should be resumed according to guidelines in Table 2.
In the event of neurotoxicity, the recommended dose adjustments for pemetrexed and cisplatin are described in Table 3. Patients should discontinue therapy if Grade 3 or 4 neurotoxicity is experienced.
ALIMTA therapy should be discontinued if a patient experiences any hematologic or nonhematologic Grade 3 or 4 toxicity after 2 dose reductions or immediately if Grade 3 or 4 neurotoxicity is observed.
In clinical studies, patients with creatinine clearance ≥45 mL/min required no dose adjustments other than those recommended for all patients. Insufficient numbers of patients with creatinine clearance below 45 mL/min have been treated to make dosage recommendations for this group of patients. Therefore, pemetrexed should not be administered to patients whose creatinine clearance is <45 mL/min using the standard Cockcroft and Gault formula (below) or GFR measured by Tc99m-DTPA serum clearance method:
Caution should be exercised when administering pemetrexed concurrently with NSAIDs to patients whose creatinine clearance is <80 mL/min [see Drug Interactions (7.1)].
As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of infusion solutions of pemetrexed. The use of gloves is recommended. If a solution of pemetrexed contacts the skin, wash the skin immediately and thoroughly with soap and water. If pemetrexed contacts the mucous membranes, flush thoroughly with water. Several published guidelines for handling and disposal of anticancer agents are available.
pemetrexed is not a vesicant. There is no specific antidote for extravasation of pemetrexed. To date, there have been few reported cases of pemetrexed extravasation, which were not assessed as serious by the investigator. Pemetrexed extravasation should be managed with local standard practice for extravasation as with other non-vesicants.
- Use aseptic technique during the reconstitution and further dilution of pemetrexed for intravenous infusion administration.
- Calculate the dose of pemetrexed and determine the number of vials needed. Vials contain either 100 mg or 500 mg of pemetrexed. The vials contain an excess of pemetrexed to facilitate delivery of label amount.
- Reconstitute each 100-mg vial with 4.2 ml of 0.9% Sodium Chloride Injection (preservative free). Reconstitute each 500-mg vial with 20 mL of 0.9% Sodium Chloride Injection (preservative free). Reconstitution of either size vial gives a solution containing 25 mg/mL pemetrexed. Gently swirl each vial until the powder is completely dissolved. The resulting solution is clear and ranges in color from colorless to yellow or green-yellow without adversely affecting product quality. The pH of the reconstituted pemetrexed solution is between 6.6 and 7.8. FURTHER DILUTION IS REQUIRED.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If particulate matter is observed, do not administer.
- An appropriate quantity of the reconstituted pemetrexed solution must be further diluted into a solution of 0.9% Sodium Chloride Injection (preservative free), so that the total volume of solution is 100 ml. pemetrexed is administered as an intravenous infusion over 10 minutes.
- Chemical and physical stability of reconstituted and infusion solutions of pemetrexed were demonstrated for up to 24 hours following initial reconstitution, when stored refrigerated. When prepared as directed, reconstitution and infusion solutions of pemetrexed contain no antimicrobial preservatives. Discard any unused portion.
Reconstitution and further dilution prior to intravenous infusion is only recommended with 0.9% Sodium Chloride Injection (preservative free). pemetrexed is physically incompatible with diluents containing calcium, including Lactated Ringer's Injection, USP and Ringer's Injection, USP and therefore these should not be used. Coadministration of pemetrexed with other drugs and diluents has not been studied, and therefore is not recommended. Pemetrexed is compatible with standard polyvinyl chloride (PVC) administration sets and intravenous solution bags.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pemetrexed in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- First-line therapy pemetrexed + carboplatin: Pemetrexed 500 mg/m2 IV infusion over 10 min, followed by carboplatin AUC 5 administered during 30 min, 0.5 h after premetexed infusion.[1]
- Monotherapy: 500 mg/m2 administered as IV infusion over 10 minutes with 3 week intervals.[2]
- Dosing Information
- 500-900 mg/m2.[3][4]
- Pemetrexed + carboplatin combination therapy: pemetrexed 500 mg/m2 infusion administered over 10 min, followed by carboplatin AUC 6 over 30 min, 0.5 h after pemetrexed infusion.[5]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Pemetrexed FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pemetrexed in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Pemetrexed in pediatric patients.
# Contraindications
Pemetrexed is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed.
# Warnings
Prior to treatment with pemetrxed, initiate supplementation with oral folic acid and intramuscular vitamin B12 to reduce the severity of hematologic and gastrointestinal toxicity of pemetrxed. Do not substitute oral vitamin B12 for intramuscular vitamin B12. In clinical studies, the incidence of the following Grade 3-4 toxicities were higher in patients with mesothelioma who were never supplemented as compared to patients who were fully supplemented with folic acid and vitamin B12 prior to and throughout pemetrxed treatment: neutropenia [38% versus 23%], thrombocytopenia [9% versus 5%], febrile neutropenia [9% versus 0.6%], and infection with neutropenia [6% versus. 0].
Administer dexamethasone the day before, the day of, and the day after pemetrxed administration.
Pemetrxed can suppress bone marrow function, as manifested by neutropenia, thrombocytopenia, and anemia (or pancytopenia); myelosuppression is usually the dose-limiting toxicity. Dose reductions for subsequent cycles are based on nadir ANC, platelet count, and maximum nonhematologic toxicity seen in the previous cycle.
Pemetrxed is primarily eliminated unchanged by renal excretion. No dosage adjustment is needed in patients with creatinine clearance ≥45 mL/min. Insufficient numbers of patients have been studied with creatinine clearance <45 mL/min to give a dose recommendation. Therefore, pemetrxed should not be administered to patients whose creatinine clearance is < 45 mL/min.
One patient with severe renal impairment (creatinine clearance 19 mL/min) who did not receive folic acid and vitamin B12 died of drug-related toxicity following administration of pemetrxed alone.
Caution should be used when administering NSAIDs concurrently with pemetrxed to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min).
Obtain a complete blood count and renal function tests at the beginning of each cycle and as needed. Do not initiate a cycle of treatment unless the ANC is ≥1500 cells/mm3, the platelet count is ≥100,000 cells/mm3, and creatinine clearance is ≥45 mL/min.
Based on its mechanism of action, pemetrxed can cause fetal harm when administered to a pregnant woman. Pemetrexed administered intraperitoneally to mice during organogenesis was embryotoxic, fetotoxic and teratogenic in mice at greater than 1/833rd the recommended human dose. If pemetrxed is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant. Women should be advised to use effective contraceptive measures to prevent pregnancy during treatment with pemetrxed.
# Adverse Reactions
## Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reactions rates cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice.
In clinical trials, the most common adverse reactions (incidence ≥20%) during therapy with pemetrexed as a single-agent were fatigue, nausea, and anorexia. Additional common adverse reactions (incidence ≥20%) during therapy with pemetrexed when used in combination with cisplatin included vomiting, neutropenia, leukopenia, anemia, stomatitis/pharyngitis, thrombocytopenia, and constipation.
- Table 4 provides the frequency and severity of adverse reactions that have been reported in > 5% of 839 patients with NSCLC who were randomized to study and received pemetrexed plus cisplatin and 830 patients with NSCLC who were randomized to study and received gemcitabine plus cisplatin. All patients received study therapy as initial treatment for locally advanced or metastatic NSCLC and patients in both treatment groups were fully supplemented with folic acid and vitamin B12.
- No clinically relevant differences in adverse reactions were seen in patients based on histology.
- In addition to the lower incidence of hematologic toxicity on the pemetrexed and cisplatin arm, use of transfusions (RBC and platelet) and hematopoietic growth factors was lower in the pemetrexed and cisplatin arm compared to the gemcitabine and cisplatin arm.
Incidence 1% to 5%
- Body as a Whole: febrile neutropenia, infection, pyrexia
- General Disorders: dehydration
- Metabolism and Nutrition: increased AST, increased ALT
- Renal: creatinine clearance decrease, renal failure
- Special Senses: conjunctivitis
Incidence Less than 1%
- Cardiovascular: arrhythmia
- General Disorders: chest pain
- Metabolism and Nutrition: increased GGT
- Neurology: motor neuropathy
- Table 5 provides the frequency and severity of adverse reactions reported in >5% of the 438 patients with NSCLC who received pemetrexed maintenance and the 218 patients with NSCLC who received placebo following a platinum-based induction therapy.
- All patients received study therapy immediately following 4 cycles of platinum-based treatment for locally advanced or metastatic NSCLC. Patients in both study arms were fully supplemented with folic acid and vitamin B12.
- No clinically relevant differences in Grade 3/4 adverse reactions were seen in patients based on age, gender, ethnic origin, or histology except a higher incidence of Grade 3/4 fatigue for Caucasian patients compared to non-Caucasian patients (6.5% versus 0.6%).
- Safety was assessed by exposure for patients who received at least one dose of pemetrexed (N=438). The incidence of adverse reactions was evaluated for patients who received ≤6 cycles of pemetrexed, and compared to patients who received >6 cycles of pemetrexed. Increases in adverse reactions (all grades) were observed with longer exposure; however no clinically relevant differences in Grade 3/4 adverse reactions were seen.
- Consistent with the higher incidence of anemia (all grades) on the pemetrexed arm, use of transfusions (mainly RBC) and erythropoiesis stimulating agents (ESAs; erythropoietin and darbepoetin) were higher in the pemetrexed arm compared to the placebo arm (transfusions 9.5% versus 3.2%, ESAs 5.9% versus 1.8%).
Incidence 1% to 5%
- Dermatology/Skin: alopecia, pruritis/itching
- Gastrointestinal: constipation
- General Disorders: edema, fever (in the absence of neutropenia)
- Hematologic: thrombocytopenia
- Renal: decreased creatinine clearance, increased creatinine, decreased glomerular filtration rate
- Special Senses: ocular surface disease (including conjunctivitis), increased lacrimation
Incidence Less than 1%
- Cardiovascular: supraventricular arrhythmia
- Dermatology/Skin: erythema multiforme
- General Disorders: febrile neutropenia, allergic reaction/hypersensitivity
- Neurology: motor neuropathy
- Renal: renal failure
- Table 6 provides the frequency and severity of adverse reactions reported in >5% of the 500 patients with non-squamous NSCLC who received at least one cycle of pemetrexed maintenance (n=333) or placebo (n=167) on the continuation maintenance trial.
- The median of maintenance cycles administered to patients receiving one or more doses of maintenance therapy was 4 on both the pemetrexed and placebo arms. Dose reductions for adverse events occurred in 3.3% of patients in the pemetrexed arm and 0.6% in the placebo arm. Dose delays for adverse events occurred in 22% of patients in the pemetrexed arm and 16% in the placebo arm. Patients in both study arms were supplemented with folic acid and vitamin B12.
- Administration of RBC (13% versus 4.8%) and platelet (1.5% versus 0.6%) transfusions, erythropoiesis stimulating agents (12% versus 7%), and granulocyte colony stimulating factors (6% versus 0) were higher in the pemetrexed arm compared to the placebo arm.
Incidence 1% to 5%
- Blood/Bone Marrow: thrombocytopenia
- General Disorders: febrile neutropenia
Incidence Less than 1%
- Cardiovascular: ventricular tachycardia, syncope
- General Disorders: pain
- Gastrointestinal: gastrointestinal obstruction
- Neurologic: depression
- Renal: renal failure
- Vascular: pulmonary embolism
- Table 7 provides the frequency and severity of adverse reactions that have been reported in >5% of 265 patients randomly assigned to receive single-agent pemetrexed with folic acid and vitamin B12 supplementation and 276 patients randomly assigned to receive single-agent docetaxel. All patients were diagnosed with locally advanced or metastatic NSCLC and received prior chemotherapy.
- No clinically relevant differences in adverse reactions were seen in patients based on histology.
- Clinically relevant adverse reactions occurring in <5% of patients that received pemetrexed treatment but >5% of patients that received docetaxel include CTC Grade 3/4 febrile neutropenia (1.9% pemetrexed, 12.7% docetaxel).
Incidence 1% to 5%
- Body as a Whole: abdominal pain, allergic reaction/hypersensitivity, febrile neutropenia, infection
- Dermatology/Skin: erythema multiforme
- Neurology: motor neuropathy, sensory neuropathy
- Renal: increased creatinine
Incidence Less than 1%
- Cardiovascular: supraventricular arrhythmias
- Table 8 provides the frequency and severity of adverse reactions that have been reported in >5% of 168 patients with mesothelioma who were randomly assigned to receive cisplatin and pemetrexed and 163 patients with mesothelioma randomly assigned to receive single-agent cisplatin. In both treatment arms, these chemonaive patients were fully supplemented with folic acid and vitamin B12.
The following additional adverse reactions were observed in patients with malignant pleural mesothelioma randomly assigned to receive pemetrexed plus cisplatin.
Incidence 1% to 5%
Body as a Whole: febrile neutropenia, infection, pyrexia
Dermatology/Skin: urticaria
General Disorders: chest pain
Metabolism and Nutrition: increased AST, increased ALT, increased GGT
Renal: renal failure
Incidence Less than 1%
Cardiovascular: arrhythmia
Neurology: motor neuropathy
- Table 9 compares the incidence (percentage of patients) of CTC Grade 3/4 toxicities in patients who received vitamin supplementation with daily folic acid and vitamin B12 from the time of enrollment in the study (fully supplemented) with the incidence in patients who never received vitamin supplementation (never supplemented) during the study in the pemetrexed plus cisplatin arm.
- The following adverse events were greater in the fully supplemented group compared to the never supplemented group: hypertension (11%, 3%), chest pain (8%, 6%), and thrombosis/embolism (6%, 3%).
- No relevant effect for pemetrexed safety due to gender or race was identified, except an increased incidence of rash in men (24%) compared to women (16%).
- Sepsis, which in some cases was fatal, occurred in approximately 1% of patients.
- Esophagitis occurred in less than 1% of patients.
## Postmarketing Experience
The following adverse reactions have been identified during post-approval use of pemetrexed. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
These reactions occurred with pemetrexed when used as a single-agent and in combination therapies:
- Blood and Lymphatic System: immune-mediated hemolytic anemia
- Gastrointestinal: colitis, pancreatitis
- General Disorders and Administration Site Conditions: edema
- Injury, poisoning, and procedural complications: Radiation recall has been reported in patients who have previously received radiotherapy.
- Respiratory: interstitial pneumonitis
- Skin: Bullous conditions, including Stevens-Johnson syndrome and toxic epidermal necrolysis. Some cases were fatal.
# Drug Interactions
- Although ibuprofen (400 mg four times a day) can decrease the clearance of pemetrexed, it can be administered with pemetrexed in patients with normal renal function (creatinine clearance ≥80 mL/min). No dose adjustment of pemetrexed is needed with concomitant NSAIDs in patients with normal renal function.
- Caution should be used when administering NSAIDs concurrently with pemetrexed to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min). NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of 2 days before, the day of, and 2 days following administration of pemetrexed.
- In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least 5 days before, the day of, and 2 days following pemetrexed administration. If concomitant administration of NSAIDs is necessary, patients should be monitored closely for toxicity, especially myelosuppression, renal, and gastrointestinal toxicity.
- Pemetrexed is primarily eliminated unchanged renally as a result of glomerular filtration and tubular secretion. Concomitant administration of nephrotoxic drugs could result in delayed clearance of pemetrexed. Concomitant administration of substances that are also tubularly secreted (e.g., probenecid) could potentially result in delayed clearance of pemetrexed.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
Based on its mechanism of action, pemetrexed can cause fetal harm when administered to a pregnant woman. There are no adequate and well controlled studies of pemetrexed in pregnant women. Pemetrexed was embryotoxic, fetotoxic, and teratogenic in mice. In mice, repeated intraperitoneal doses of pemetrexed when given during organogenesis caused fetal malformations (incomplete ossification of talus and skull bone; about 1/833rd the recommended intravenous human dose on a mg/m2 basis), and cleft palate (1/33rd the recommended intravenous human dose on a mg/m2 basis). Embryotoxicity was characterized by increased embryo-fetal deaths and reduced litter sizes. If pemetrexed is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to use effective contraceptive measures to prevent pregnancy during the treatment with pemetrexed.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Pemetrexed in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Pemetrexed during labor and delivery.
### Nursing Mothers
It is not known whether pemetrexed or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from pemetrexed, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug for the mother.
### Pediatric Use
Efficacy of pemetrexed in pediatric patients has not been demonstrated. Pemetrexed was administered as an intravenous infusion over 10 minutes on Day 1 of a 21 day cycle to pediatric patients with recurrent solid tumors in a Phase 1 study (32 patients) and a Phase 2 study (72 patients). All patients received pretreatment with vitamin B12 and folic acid supplementation and dexamethasone. The dose escalation in the Phase 1 study determined the maximum tolerated dose was 1910 mg/m2 and this dose (or 60 mg/kg for patients <12 months old) was evaluated in the Phase 2 study of patients with relapsed or refractory osteosarcoma, Ewing sarcoma/peripheral PNET, rhabdomyosarcoma, neuroblastoma, ependymoma, medulloblastoma/supratentorial PNET, or non-brainstem high grade glioma. No responses were observed among the 72 patients in this Phase 2 trial. The most common toxicities reported were hematological (leukopenia, neutropenia/granulocytopenia, anemia, thrombocytopenia, and lymphopenia), liver function abnormalities (increased ALT/AST), fatigue, and nausea.
The single dose pharmacokinetics of pemetrexed administered in doses ranging from 400 to 2480 mg/m2 were evaluated in the Phase 1 trial in 22 patients (13 males and 9 females) aged 4 to 18 years (average age 12 years). Pemetrexed exposure (AUC and Cmax) appeared to increase proportionally with dose. The average pemetrexed clearance (2.30 L/h/m2) and half-life (2.3 hours) in pediatric patients were comparable to values reported in adults.
### Geriatic Use
Pemetrexed is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Renal function monitoring is recommended with administration of pemetrexed. No dose reductions other than those recommended for all patients are necessary for patients 65 years of age or older
.
Of 3,946 patients (34.0% ≥65) studied across the five clinical trials, the effect of pemetrexed on survival was similar in patients <65 compared to ≥65 years of age. There were no differences in safety with the exception of the following Grade 3-4 adverse reactions, which were noted in at least one of the five trials to be greater in patients 65 years of age and older as compared to younger patients: anemia, fatigue, thrombocytopenia, hypertension, and neutropenia.
### Gender
Of 3,946 patients (Male 70.5%) studied across the five registration studies for pemetrexed indications, the effect of pemetrexed on survival was similar in female and male patients.
### Race
Of 3,946 patients (Caucasian 78.6%) studied across the five registration studies for pemetrexed indications, the effect of pemetrexed on survival was similar in the Caucasian and non-Caucasian patients.
### Renal Impairment
Pemetrexed is known to be primarily excreted by the kidneys. Decreased renal function will result in reduced clearance and greater exposure (AUC) to pemetrexed compared with patients with normal renal function. Cisplatin coadministration with pemetrexed has not been studied in patients with moderate renal impairment.
### Hepatic Impairment
There was no effect of elevated AST, ALT, or total bilirubin on the pharmacokinetics of pemetrexed. However, no formal studies have been conducted to examine the pharmacokinetics of pemetrexed in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Pemetrexed in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Pemetrexed in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Intravenous
### Monitoring
Complete blood cell counts, including platelet counts, should be performed on all patients receiving pemetrexed. Patients should be monitored for nadir and recovery, which were tested in the clinical study before each dose and on days 8 and 15 of each cycle. Patients should not begin a new cycle of treatment unless the ANC is ≥1500 cells/mm3, the platelet count is ≥100,000 cells/mm3, and creatinine clearance is ≥45 mL/min. Periodic chemistry tests should be performed to evaluate renal and hepatic function.
# IV Compatibility
Reconstitution and further dilution prior to intravenous infusion is only recommended with 0.9% Sodium Chloride Injection (preservative free). Pemetrexed is physically incompatible with diluents containing calcium, including Lactated Ringer's Injection, USP and Ringer's Injection, USP and therefore these should not be used. Coadministration of pemetrexed with other drugs and diluents has not been studied, and therefore is not recommended. Pemetrexed is compatible with standard polyvinyl chloride (PVC) administration sets and intravenous solution bags.
# Overdosage
- There have been few cases of pemetrexed overdose. Reported toxicities included neutropenia, anemia, thrombocytopenia, mucositis, and rash. Anticipated complications of overdose include bone marrow suppression as manifested by neutropenia, thrombocytopenia, and anemia. In addition, infection with or without fever, diarrhea, and mucositis may be seen. If an overdose occurs, general supportive measures should be instituted as deemed necessary by the treating physician.
- In clinical trials, leucovorin was permitted for CTC Grade 4 leukopenia lasting ≥3 days, CTC Grade 4 neutropenia lasting ≥3 days, and immediately for CTC Grade 4 thrombocytopenia, bleeding associated with Grade 3 thrombocytopenia, or Grade 3 or 4 mucositis. The following intravenous doses and schedules of leucovorin were recommended for intravenous use: 100 mg/m2, intravenously once, followed by leucovorin, 50 mg/m2, intravenously every 6 hours for 8 days.
- The ability of pemetrexed to be dialyzed is unknown.
# Pharmacology
## Mechanism of Action
Pemetrexed for injection, is a folate analog metabolic inhibitor that exerts its action by disrupting folate-dependent metabolic processes essential for cell replication. In vitro studies have shown that pemetrexed inhibits thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT), which are folate-dependent enzymes involved in the de novo biosynthesis of thymidine and purine nucleotides. Pemetrexed is taken into cells by membrane carriers such as the reduced folate carrier and membrane folate binding protein transport systems. Once in the cell, pemetrexed is converted to polyglutamate forms by the enzyme folylpolyglutamate synthetase. The polyglutamate forms are retained in cells and are inhibitors of TS and GARFT. Polyglutamation is a time- and concentration-dependent process that occurs in tumor cells and, is thought to occur to a lesser extent, in normal tissues. Polyglutamated metabolites are thought to have an increased intracellular half-life resulting in prolonged drug action in malignant cells.
## Structure
Pemetrexed disodium heptahydrate has the chemical name L-Glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-, disodium salt, heptahydrate. It is a white to almost-white solid with a molecular formula of C20H19N5Na2O6•7H2O and a molecular weight of 597.49. The structural formula is as follows:
Pemetrexed is supplied as a sterile lyophilized powder for intravenous infusion available in single-dose vials. The product is a white to either light yellow or green-yellow lyophilized solid. Each 100-mg or 500-mg vial of pemetrexed contains pemetrexed disodium equivalent to 100 mg pemetrexed and 106 mg mannitol or 500 mg pemetrexed and 500 mg mannitol, respectively. Hydrochloric acid and/or sodium hydroxide may have been added to adjust pH.
## Pharmacodynamics
- Preclinical studies have shown that pemetrexed inhibits the in vitro growth of mesothelioma cell lines (MSTO-211H, NCI-H2052). Studies with the MSTO-211H mesothelioma cell line showed synergistic effects when pemetrexed was combined concurrently with cisplatin.
- Absolute neutrophil counts (ANC) following single-agent administration of pemetrexed to patients not receiving folic acid and vitamin B12 supplementation were characterized using population pharmacodynamic analyses. Severity of hematologic toxicity, as measured by the depth of the ANC nadir, correlates with the systemic exposure, or area under the curve (AUC) of pemetrexed. It was also observed that lower ANC nadirs occurred in patients with elevated baseline cystathionine or homocysteine concentrations. The levels of these substances can be reduced by folic acid and vitamin B12 supplementation. There is no cumulative effect of pemetrexed exposure on ANC nadir over multiple treatment cycles.
- Time to ANC nadir with pemetrexed systemic exposure (AUC), varied between 8 to 9.6 days over a range of exposures from 38.3 to 316.8 mcg•hr/mL. Return to baseline ANC occurred 4.2 to 7.5 days after the nadir over the same range of exposures.
## Pharmacokinetics
- The pharmacokinetics of pemetrexed administered as a single-agent in doses ranging from 0.2 to 838 mg/m2 infused over a 10-minute period have been evaluated in 426 cancer patients with a variety of solid tumors. Pemetrexed total systemic exposure (AUC) and maximum plasma concentration (Cmax) increase proportionally with dose. The pharmacokinetics of pemetrexed do not change over multiple treatment cycles.
- Pemetrexed has a steady-state volume of distribution of 16.1 liters. In vitro studies indicate that pemetrexed is approximately 81% bound to plasma proteins. Binding is not affected by degree of renal impairment.
- Pemetrexed is not metabolized to an appreciable extent and is primarily eliminated in the urine, with 70% to 90% of the dose recovered unchanged within the first 24 hours following administration. The clearance decreases, and exposure (AUC) increases, as renal function decreases. The total systemic clearance of pemetrexed is 91.8 mL/min and the elimination half-life of pemetrexed is 3.5 hours in patients with normal renal function (creatinine clearance of 90 mL/min).
- The pharmacokinetics of pemetrexed in special populations were examined in about 400 patients in controlled and single arm studies.
- In vitro studies indicate that pemetrexed is a substrate of OAT3 (organic anion transporter 3), a transporter that may play a role in active secretion of pemetrexed.
- No effect of age on the pharmacokinetics of pemetrexed was observed over a range of 26 to 80 years.
- The pharmacokinetics of pemetrexed were not different in male and female patients.
- The pharmacokinetics of pemetrexed were similar in Caucasians and patients of African descent. Insufficient data are available to compare pharmacokinetics for other ethnic groups.
- There was no effect of elevated AST, ALT, or total bilirubin on the pharmacokinetics of pemetrexed. However, studies of hepatically impaired patients have not been conducted.
- Pharmacokinetic analyses of pemetrexed included 127 patients with reduced renal function. Plasma clearance of pemetrexed decreases as renal function decreases, with a resultant increase in systemic exposure. Patients with creatinine clearances of 45, 50, and 80 mL/min had 65%, 54%, and 13% increases, respectively in pemetrexed total systemic exposure (AUC) compared to patients with creatinine clearance of 100 mL/min.
- The effect of third space fluid, such as pleural effusion and ascites, on pemetrexed is not fully defined. A study of pemetrexed 500 mg/m2 was performed in 31 solid tumor patients with stable third space fluid (All but 2 of the 31 patients included in study had mild or moderate amounts of third space fluid). Moderate pleural effusion was defined in the study as less than 1/3 the way up on one side with obscuring of the entire hemidiaphragm. Moderate ascites was defined as that detectable on physical exam. The pemetrexed plasma concentrations in these patients were comparable to those observed in previous clinical trials in patients without third space fluid collections. Thus, drainage of mild or moderate third space fluid collection prior to pemetrexed treatment should be considered, but is probably not necessary. The effect of severe third space fluid on pharmacokinetics is not known.
- Ibuprofen doses of 400 mg four times a day reduce pemetrexed's clearance by about 20% (and increase AUC by 20%) in patients with normal renal function. The effect of greater doses of ibuprofen on pemetrexed pharmacokinetics is unknown.
- Aspirin, administered in low to moderate doses (325 mg every 6 hours), does not affect the pharmacokinetics of pemetrexed. The effect of greater doses of aspirin on pemetrexed pharmacokinetics is unknown.
- Cisplatin does not affect the pharmacokinetics of pemetrexed and the pharmacokinetics of total platinum are unaltered by pemetrexed.
- Coadministration of oral folic acid or intramuscular vitamin B12 does not affect the pharmacokinetics of pemetrexed.
- Results from in vitro studies with human liver microsomes predict that pemetrexed would not cause clinically significant inhibition of metabolic clearance of drugs metabolized by CYP3A, CYP2D6, CYP2C9, and CYP1A2.
## Nonclinical Toxicology
No carcinogenicity studies have been conducted with pemetrexed. Pemetrexed was clastogenic in the in vivo micronucleus assay in mouse bone marrow but was not mutagenic in multiple in vitro tests (Ames assay, CHO cell assay). Pemetrexed administered at i.v. doses of 0.1 mg/kg/day or greater to male mice (about 1/1666 the recommended human dose on a mg/m2 basis) resulted in reduced fertility, hypospermia, and testicular atrophy.
# Clinical Studies
A multi-center, randomized, open-label study in 1725 chemonaive patients with Stage IIIb/IV NSCLC was conducted to compare the overall survival following treatment with pemetrexed in combination with cisplatin (AC) versus gemcitabine in combination with cisplatin (GC). Pemetrexed was administered intravenously over 10 minutes at a dose of 500 mg/m2 with cisplatin administered intravenously at a dose of 75 mg/m2 after pemetrexed administration, on Day 1 of each 21-day cycle. Gemcitabine was administered at a dose of 1250 mg/m2 on Day 1 and Day 8, and cisplatin was administered intravenously at a dose of 75 mg/m2 after administration of gemcitabine, on Day 1 of each 21-day cycle. Treatment was administered up to a total of 6 cycles, and patients in both treatment arms received folic acid, vitamin B12, and dexamethasone.
Patient demographics of the intent to treat (ITT) population are shown in Table 10. The demographics and disease characteristics were well balanced.
Patients received a median of 5 cycles of treatment in both study arms. Patients treated with pemetrexed plus cisplatin received a relative dose intensity of 94.8% of the protocol-specified pemetrexed dose intensity and 95.0% of the protocol-specified cisplatin dose intensity. Patients treated with gemcitabine plus cisplatin received a relative dose intensity of 85.8% of the protocol-specified gemcitabine dose intensity and 93.5% of the protocol-specified cisplatin dose intensity.
The primary endpoint in this study was overall survival. The median survival time was 10.3 months in the pemetrexed plus cisplatin treatment arm and 10.3 months in the gemcitabine plus cisplatin arm, with an adjusted hazard ratio of 0.94.
A pre-specified analysis of the impact of NSCLC histology on overall survival was examined. Clinically relevant differences in survival according to histology were observed and are shown in Table 12. This difference in treatment effect for pemetrexed based on histology demonstrating a lack of efficacy in squamous cell histology was also observed in the single-agent, second-line study and the maintenance study.
A multi-center, randomized, double-blind, placebo-controlled study was conducted in 663 patients with Stage IIIb/IV NSCLC who did not progress after four cycles of platinum-based chemotherapy. Patients who did not progress were randomized 2:1 to receive pemetrexed or placebo immediately following platinum-based chemotherapy. Of the randomized patients, 47.2% versus 52.7% achieved a complete or partial response to induction therapy and 51.9% versus 47.3% had stable disease after induction therapy in the pemetrexed and placebo arms, respectively. Pemetrexed was administered intravenously over 10 minutes at a dose of 500 mg/m2 on Day 1 of each 21-day cycle, until disease progression. Patients in both study arms received folic acid, vitamin B12, and dexamethasone.
The study was designed to demonstrate superior progression-free survival and overall survival of pemetrexed over placebo. Progression-free survival (PFS) was assessed by independent review. Patient characteristics of the intent to treat (ITT) population are shown in Table 13. The demographics and baseline disease characteristics were well balanced between study arms.
Patients received a median of 5 cycles of pemetrexed and 3.5 cycles of placebo. Patients randomized to ALIMTA received a relative dose intensity of 95.7%. A total of 213 patients (48.3%) completed ≥6 cycles and a total of 98 patients (22.6%) completed ≥10 cycles of treatment with ALIMTA.
In the overall study population, pemetrexed was statistically superior to placebo in terms of overall survival (OS) (median 13.4 months versus 10.6 months, HR=0.79 (95% CI: 0.65-0.95), p-value=0.012) and PFS (median 4.0 months versus 2.0 months, HR=0.60 (95% CI: 0.49-0.73), p-value<0.00001). A difference in treatment outcomes was observed according to histologic classification. For the population of patients with nonsquamous NSCLC, pemetrexed was superior to placebo for OS (median 15.5 months versus 10.3 months, HR=0.70 (95% CI: 0.56-0.88)) and PFS (median 4.4 months versus 1.8 months, HR=0.47 (95% CI: 0.37-0.60)). For the population of patients with squamous NSCLC, pemetrexed did not improve OS compared to placebo (median 9.9 months versus 10.8 months, HR=1.07 (95% CI: 0.77-1.50)) or PFS (median 2.4 months versus 2.5 months, HR=1.03 (95% CI: 0.71-1.49)). This difference in treatment effect for pemetrexed based on histology demonstrating lack of benefit in squamous cell histology was also observed in the first-line and second-line studies.
Efficacy results for the overall patient population are presented in Table 14 and Figure 3, and efficacy results by pre-specified histologic subgroups are presented in Table 15 and Figure 4, below.
A multi-center, randomized, double-blind, placebo-controlled study was conducted to evaluate continuation of pemetrexed in patients with Stage IIIb/IV nonsquamous NSCLC. Patients completing induction treatment of four cycles of pemetrexed plus cisplatin with stable disease or better and PS 0/1 were randomized (2:1) to maintenance treatment with pemetrexed or placebo. Randomization was stratified by response to induction (complete response (CR)/partial response (PR) versus stable disease (SD)), disease stage (IIIb versus IV), and ECOG performance status (0 versus 1). Pemetrexed was administered intravenously over 10 minutes at a dose of 500 mg/m2 on Day 1 of each 21-day cycle and continued until disease progression. Patients in both study arms received folic acid, vitamin B12, and dexamethasone. The main efficacy outcome was investigator-assessed progression-free survival.
A total of 539 patients were randomized; all completed four cycles of pemetrexed and cisplatin induction prior to randomization. Of the randomized patients, 44% versus 42% achieved a complete or partial response to induction therapy and 53% versus 53% had stable disease after induction treatment in the pemetrexed or the placebo arms respectively.
Patient demographics of the intent to treat (ITT) population are shown in Table 16.
Patients received a median of four cycles of pemetrexed maintenance or placebo. The percentages of patients that received post-study treatment were similar (64% in the pemetrexed arm and 72% in the placebo arm).
The trial showed a statistically significant improvement in progression-free survival and in overall survival for patients randomized to pemetrexed maintenance. Efficacy results are presented in Table 17 and Figure 5.
A multi-center, randomized, open label study was conducted in patients with Stage III or IV NSCLC after prior chemotherapy to compare the overall survival following treatment with pemetrexed versus docetaxel. Pemetrexed was administered intravenously over 10 minutes at a dose of 500 mg/m2 and docetaxel was administered at 75 mg/m2 as a 1-hour intravenous infusion. Both drugs were given on Day 1 of each 21-day cycle. All patients treated with pemetrexed received vitamin supplementation with folic acid and vitamin B12. The study was intended to show either an overall survival superiority or non-inferiority of pemetrexed to docetaxel. Patient demographics of the intent to treat (ITT) population are shown in Table 18.
The primary endpoint in this study was overall survival. The median survival time was 8.3 months in the pemetrexed treatment arm and 7.9 months in the docetaxel arm, with a hazard ratio of 0.99 (see Table 19). The study did not show an overall survival superiority of pemetrexed.
A retrospective analysis of the impact of NSCLC histology on overall survival was examined. Clinically relevant differences in survival according to histology were observed and are shown in Table 20. This difference in treatment effect for pemetrexed based on histology demonstrating a lack of efficacy in squamous cell histology was also observed in the first-line combination study and in the maintenance study.
A multi-center, randomized, single-blind study in 448 chemonaive patients with malignant pleural mesothelioma (MPM) compared survival in patients treated with pemetrexed in combination with cisplatin to survival in patients receiving cisplatin alone. Pemetrexed was administered intravenously over 10 minutes at a dose of 500 mg/m2 and cisplatin was administered intravenously over 2 hours at a dose of 75 mg/m2 beginning approximately 30 minutes after the end of administration of pemetrexed. Both drugs were given on Day 1 of each 21-day cycle. After 117 patients were treated, white cell and GI toxicity led to a change in protocol whereby all patients were given folic acid and vitamin B12 supplementation.
The primary analysis of this study was performed on the population of all patients randomly assigned to treatment who received study drug (randomized and treated). An analysis was also performed on patients who received folic acid and vitamin B12 supplementation during the entire course of study therapy (fully supplemented), as supplementation is recommended. Results in all patients and those fully supplemented were similar. Patient demographics are shown in Table 21.
Table 22 and Figure 6 summarize the survival results for all randomized and treated patients regardless of vitamin supplementation status and those patients receiving vitamin supplementation from the time of enrollment in the trial.
Similar results were seen in the analysis of patients (N=303) with confirmed histologic diagnosis of malignant pleural mesothelioma. There were too few non-white patients to assess possible ethnic differences. The effect in women (median survival 15.7 months with the combination versus 7.5 months on cisplatin alone), however, was larger than the effect in males (median survival 11 versus 9.4 respectively). As with any exploratory analysis, it is not clear whether this difference is real or is a chance finding.
Objective tumor response for malignant pleural mesothelioma is difficult to measure and response criteria are not universally agreed upon. However, based upon prospectively defined criteria, the objective tumor response rate for pemetrexed plus cisplatin was greater than the objective tumor response rate for cisplatin alone. There was also improvement in lung function (forced vital capacity) in the pemetrexed plus cisplatin arm compared to the control arm.
Patients who received full supplementation with folic acid and vitamin B12 during study therapy received a median of 6 and 4 cycles in the pemetrexed/cisplatin (N=168) and cisplatin (N=163) arms, respectively. Patients who never received folic acid and vitamin B12 during study therapy received a median of 2 cycles in both treatment arms (N=32 and N=38 for the pemetrexed/cisplatin and cisplatin arm, respectively). Patients receiving pemetrexed in the fully supplemented group received a relative dose intensity of 93% of the protocol specified pemetrexed dose intensity; patients treated with cisplatin in the same group received 94% of the projected dose intensity. Patients treated with cisplatin alone had a dose intensity of 96%.
# How Supplied
- ALIMTA, pemetrexed for injection, is available in sterile single-use vials containing 100 mg pemetrexed. NDC 0002-7640-01 (VL7640): single-use vial with ivory flip-off cap individually packaged in a carton.
- ALIMTA, pemetrexed for injection, is available in sterile single-use vials containing 500 mg pemetrexed. NDC 0002-7623-01 (VL7623): single-use vial with ivory flip-off cap individually packaged in a carton.
## Storage
- Pemetrexed for injection, should be stored at 25°C (77°F); excursions permitted to 15-30°C (59-86°F).
- Chemical and physical stability of reconstituted and infusion solutions of pemetrexed were demonstrated for up to 24 hours following initial reconstitution, when stored refrigerated, 2-8°C (36-46°F).
- When prepared as directed, reconstituted and infusion solutions of pemetrexed contain no antimicrobial preservatives.
- Discard unused portion
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Instruct patients to read the patient package insert before initiating pemetrexed.
- Instruct patients on the need for folic acid and vitamin B12 supplementation to reduce treatment-related hematologic and gastrointestinal toxicity and of the need for corticosteroids to reduce treatment-related dermatologic toxicity.
- Inform patients of the risk of low blood cell counts and instruct them to immediately contact their physician for signs of infection, including fever, bleeding or symptoms of anemia.
- Instruct patients to contact their physician if persistent vomiting, diarrhea, or signs of dehydration appear.
- Instruct patients to inform their physician of all concomitant prescription or over-the-counter medications they are taking, particularly those for pain or inflammation such as non-steroidal anti-inflammatory drugs.
# Precautions with Alcohol
Alcohol-Pemetrexed interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Alimta
# Look-Alike Drug Names
- Pemetrexed - Pralatrexate
# Drug Shortage Status
Drug Shortage
# Price | https://www.wikidoc.org/index.php/Pemetrexed | |
f4b4d00d277e5edd4ddb011a7821580189c17c81 | wikidoc | Pemphigoid | Pemphigoid
Pemphigoid is a group of uncommon and rare autoimmune blistering skin diseases. As its name indicates, pemphigoid is similar to pemphigus, but unlike pemphigus, pemphigoid does not feature acantholysis.
Pemphigoid is less common than pemphigus, and is slightly more common in women than in men. It is also more common in people over 60 years of age than it is in younger people.
# Classificiation
There are three types:
- Gestational pemphigoid or Pemphigoid gestationis (PG) (formerly called Herpes gestationis)
- Bullous pemphigoid (BP)
- Mucous membrane pemphigoid, also known as Cicatricial pemphigoid (CP)
They are considered connective tissue autoimmune skin diseases. Bullous and Cicatricial pemphigoids usually affect persons who are above age 60. Gestational pemphigoid occurs during pregnancy, typically in the second or third trimester, and/or immediately following pregnancy. | Pemphigoid
Template:Search infobox
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Pemphigoid is a group of uncommon and rare autoimmune blistering skin diseases. As its name indicates, pemphigoid is similar to pemphigus,[1] but unlike pemphigus, pemphigoid does not feature acantholysis.[2]
Pemphigoid is less common than pemphigus, and is slightly more common in women than in men. It is also more common in people over 60 years of age than it is in younger people.
# Classificiation
There are three types:
- Gestational pemphigoid or Pemphigoid gestationis (PG) (formerly called Herpes gestationis)
- Bullous pemphigoid (BP)
- Mucous membrane pemphigoid, also known as Cicatricial pemphigoid (CP)
They are considered connective tissue autoimmune skin diseases. Bullous and Cicatricial pemphigoids usually affect persons who are above age 60.[3][4] Gestational pemphigoid occurs during pregnancy,[5] typically in the second or third trimester, and/or immediately following pregnancy. | https://www.wikidoc.org/index.php/Pemphigoid | |
bb8ad9c5039f44f49f01ffeb253c8b4e24333921 | wikidoc | Peppermint | Peppermint
Peppermint (Mentha × piperita) is a (usually) sterile hybrid mint, a cross between watermint (Mentha aquatica) and spearmint (Mentha spicata). It is occasionally found wild with its parent species in central and southern Europe, but the first intentional crossbreed of watermint and spearmint was done in England. Being sterile, it spreads by rooting.
The stems are from 30-70 cm tall, rarely up to 100 cm, smooth, and square in cross section. The leaves are from 4-9 cm long and 1.5-4 cm broad, dark green with reddish veins, and with an acute apex and coarsely toothed margins. The flowers are purple, 6-8 mm long, with a four-lobed corolla about 5 mm diameter; they are produced in whorls around the stem, forming thick, blunt spikes. The roots are fibrous. Flowering is from July to September.
Peppermint is generally regarded as 'the world's oldest medicine', with archeological evidence placing its use at least as far back as ten thousand years ago.
# Uses
Peppermint has a high menthol content, and is often used as a flavoring in tea, ice cream, confectionery, chewing gum, and toothpaste. The oil also contains menthone and menthyl esters. It is the oldest and most popular flavor of mint-flavored confectionery. Peppermint can also be found in some shampoos and soaps, which give the hair a minty scent and produce a cooling sensation on the skin.
Peppermint, like many spices and herbs, is believed to have medicinal properties when consumed. It is said that it helps against upset stomachs, inhibits the growth of certain bacteria, and can help soothe and relax muscles when inhaled or applied to the skin. Other health benefits are attributed to the high manganese, vitamin C and vitamin A content, as well as trace amounts of various other nutrients such as fiber, iron, calcium, folate, potassium, tryptophan, magnesium, omega-3 fatty acids, riboflavin, and copper.
In 2007, Italian investigators reported that 75% of the patients in their study who took peppermint oil capsules for four weeks had a major reduction in irritable bowel syndrome (IBS) symptoms, compared with just 38% of those who took a placebo pill.
Similarly, some poorly-designed earlier trials found that peppermint oil has the ability to reduce colicky abdominal pain due to IBS with an NNT (number needed to treat) around 3.1, but the oil is an irritant to the stomach in the quantity required and therefore needs wrapping for delayed release in the intestine. Peppermint relaxes the gastro-oesophageal sphincter, thus promoting belching.
Peppermint Oil is also an all-natural way to deter ants from being inside and outside the home, though it will need to be reapplied every few days (in sparse amounts) until the ants are fully discouraged. This natural substance seems to work on most species of ant.
Peppermint flowers are large nectar producers and honey bees as well as other nectar harvesting organisms forage them heavily. A mild, pleasant varietal honey can be produced if there is a sufficient area of plants.
Areas of North America where peppermint was formerly grown for oil often have an abundance of feral plants, and it is considered somewhat invasive.
In the United States, Washington ranks number one in production of Peppermint Oil.
# Cultivation
Peppermint generally thrives in shade and expands quickly by underground rhizomes. If you choose to grow peppermint, it is advisable to plant it in a container, otherwise it can rapidly take over a whole garden. It needs a good water supply, and is ideal for planting in part-sun to shade areas.
The leaves and flowering tops are the usable portion of the plant. They are collected as soon as the flowers begin to open and then are carefully dried. The wild form of the plant is less suitable for this purpose, with cultivated plants having been selected for more and better oil content. Seeds sold at stores labeled peppermint generally will not germinate into true peppermint, but into a particularly poor-scented spearmint plant. The true peppermint might rarely produce seeds, but only by fertilization from a spearmint plant, and contribute only their own spearmint genes, as is true of female mules that have babies, contributing only their maternal horse genes.
# Varieties & Cultivars
- Mentha × piperita citrata – Eau De Cologne Mint
- Mentha × piperita officinalis - White Peppermint
- Mentha × piperita vulgaris - Black Peppermint
- Mentha × piperita cultivar Chocolate mint - Grows just like peppermint with dark purple runners with purple lined dark green leaves. | Peppermint
Peppermint (Mentha × piperita) is a (usually) sterile hybrid mint, a cross between watermint (Mentha aquatica) and spearmint (Mentha spicata). It is occasionally found wild with its parent species in central and southern Europe, but the first intentional crossbreed of watermint and spearmint was done in England. Being sterile, it spreads by rooting.
The stems are from 30-70 cm tall, rarely up to 100 cm, smooth, and square in cross section. The leaves are from 4-9 cm long and 1.5-4 cm broad, dark green with reddish veins, and with an acute apex and coarsely toothed margins. The flowers are purple, 6-8 mm long, with a four-lobed corolla about 5 mm diameter; they are produced in whorls around the stem, forming thick, blunt spikes. The roots are fibrous. Flowering is from July to September.
Peppermint is generally regarded as 'the world's oldest medicine', with archeological evidence placing its use at least as far back as ten thousand years ago.
## Uses
Peppermint has a high menthol content, and is often used as a flavoring in tea, ice cream, confectionery, chewing gum, and toothpaste. The oil also contains menthone and menthyl esters. It is the oldest and most popular flavor of mint-flavored confectionery. Peppermint can also be found in some shampoos and soaps, which give the hair a minty scent and produce a cooling sensation on the skin.
Peppermint, like many spices and herbs, is believed to have medicinal properties when consumed. It is said that it helps against upset stomachs, inhibits the growth of certain bacteria, and can help soothe and relax muscles when inhaled or applied to the skin. Other health benefits are attributed to the high manganese, vitamin C and vitamin A content, as well as trace amounts of various other nutrients such as fiber, iron, calcium, folate, potassium, tryptophan, magnesium, omega-3 fatty acids, riboflavin, and copper.
In 2007, Italian investigators reported that 75% of the patients in their study who took peppermint oil capsules for four weeks had a major reduction in irritable bowel syndrome (IBS) symptoms, compared with just 38% of those who took a placebo pill.[1]
Similarly, some poorly-designed earlier trials found that peppermint oil has the ability to reduce colicky abdominal pain due to IBS with an NNT (number needed to treat) around 3.1[2], but the oil is an irritant to the stomach in the quantity required and therefore needs wrapping for delayed release in the intestine. Peppermint relaxes the gastro-oesophageal sphincter, thus promoting belching.
Peppermint Oil is also an all-natural way to deter ants from being inside and outside the home, though it will need to be reapplied every few days (in sparse amounts) until the ants are fully discouraged. This natural substance seems to work on most species of ant.
Peppermint flowers are large nectar producers and honey bees as well as other nectar harvesting organisms forage them heavily. A mild, pleasant varietal honey can be produced if there is a sufficient area of plants.
Areas of North America where peppermint was formerly grown for oil often have an abundance of feral plants, and it is considered somewhat invasive[citation needed].
In the United States, Washington ranks number one in production of Peppermint Oil.[3]
## Cultivation
Peppermint generally thrives in shade and expands quickly by underground rhizomes. If you choose to grow peppermint, it is advisable to plant it in a container, otherwise it can rapidly take over a whole garden. It needs a good water supply, and is ideal for planting in part-sun to shade areas.
The leaves and flowering tops are the usable portion of the plant. They are collected as soon as the flowers begin to open and then are carefully dried. The wild form of the plant is less suitable for this purpose, with cultivated plants having been selected for more and better oil content. Seeds sold at stores labeled peppermint generally will not germinate into true peppermint, but into a particularly poor-scented spearmint plant. The true peppermint might rarely produce seeds, but only by fertilization from a spearmint plant, and contribute only their own spearmint genes, as is true of female mules that have babies, contributing only their maternal horse genes.
## Varieties & Cultivars
- Mentha × piperita citrata – Eau De Cologne Mint
- Mentha × piperita officinalis - White Peppermint
- Mentha × piperita vulgaris - Black Peppermint
- Mentha × piperita cultivar Chocolate mint - Grows just like peppermint with dark purple runners with purple lined dark green leaves.[citation needed] | https://www.wikidoc.org/index.php/Peppermint | |
40de26fbc276e799741411ce75e2dc80d2223139 | wikidoc | Perampanel | Perampanel
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# Black Box Warning
# Overview
Perampanel is a non-competitive AMPA glutamate receptor antagonist that is FDA approved for the {{{indicationType}}} of partial-onset seizures with or without secondarily generalized seizures in patients with epilepsy aged 12 years and older. There is a Black Box Warning for this drug as shown here. Common adverse reactions include dizziness, somnolence, fatigue, irritability, falls, nausea, weight gain, vertigo, ataxia, gait disturbance, and balance disorder.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- In the Absence of Enzyme-Inducing AEDs
- The recommended starting dosage of FYCOMPA is 2 mg once daily taken orally at bedtime. Increase dosage by 2 mg per day increments no more frequently than every week to a dose of 4 mg to 8 mg once daily taken at bedtime. In elderly patients, dosage increases during titration are recommended no more frequently than every two weeks.
- The recommended dose range is 8 mg to 12 mg once daily. A dose of 12 mg once daily resulted in somewhat greater reductions in seizure rates than the dose of 8 mg once daily, but with a substantial increase in adverse reactions. Individual dosing should be adjusted based on clinical response and tolerability
- In the Presence of Enzyme-Inducing AEDs
- The recommended starting dosage of FYCOMPA in the presence of enzyme-inducing AEDs, including phenytoin, carbamazepine, and oxcarbazepine, is 4 mg and patients should be monitored closely for response. Clinical trials revealed a substantially reduced effect on seizure rates in these patients. The reduction in seizure frequency was somewhat greater at 12 mg than at 8 mg.
- When these enzyme-inducing AEDs are introduced or withdrawn from a patient’s treatment regimen, patient should be closely monitored for clinical response and tolerability. Dose adjustment of FYCOMPA may be necessary.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Perampanel in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Perampanel in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- In the Absence of Enzyme-Inducing AEDs
- The recommended starting dosage of FYCOMPA is 2 mg once daily taken orally at bedtime. Increase dosage by 2 mg per day increments no more frequently than every week to a dose of 4 mg to 8 mg once daily taken at bedtime. In elderly patients, dosage increases during titration are recommended no more frequently than every two weeks.
- The recommended dose range is 8 mg to 12 mg once daily. A dose of 12 mg once daily resulted in somewhat greater reductions in seizure rates than the dose of 8 mg once daily, but with a substantial increase in adverse reactions. Individual dosing should be adjusted based on clinical response and tolerability
- In the Presence of Enzyme-Inducing AEDs
- The recommended starting dosage of FYCOMPA in the presence of enzyme-inducing AEDs, including phenytoin, carbamazepine, and oxcarbazepine, is 4 mg and patients should be monitored closely for response. Clinical trials revealed a substantially reduced effect on seizure rates in these patients. The reduction in seizure frequency was somewhat greater at 12 mg than at 8 mg.
- When these enzyme-inducing AEDs are introduced or withdrawn from a patient’s treatment regimen, patient should be closely monitored for clinical response and tolerability. Dose adjustment of FYCOMPA may be necessary.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Perampanel in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Perampanel in pediatric patients.
# Contraindications
- None.
# Warnings
### Precautions
- Serious Psychiatric and Behavioral Reactions
- In the controlled Phase 3 epilepsy clinical trials, hostility- and aggression-related adverse reactions occurred in 12% and 20% of patients randomized to receive FYCOMPA at doses of 8 mg and 12 mg/day, respectively, compared to 6% of patients in the placebo group. These effects were dose-related and generally appeared within the first 6 weeks of treatment, although new events continued to be observed through more than 37 weeks. FYCOMPA-treated patients experienced more hostility- and aggression - related adverse reactions that were serious, severe, and led to dose reduction, interruption, and discontinuation more frequently than placebo-treated patients.
- In general, in placebo-controlled Phase 3 epilepsy trials, neuropsychiatric events were reported more frequently in patients being treated with FYCOMPA than in patients taking placebo. These events included irritability, aggression, anger, and anxiety which occurred in 2% or greater of perampanel treated patients and twice as frequently as in placebo-treated patients. Other symptoms that were observed with perampanel treatment and more commonly than with placebo, included belligerence, affect lability, agitation, and physical assault. Some of these events were reported as serious and life-threatening. Homicidal ideation and/or threat were exhibited in 0.1% of 4,368 perampanel treated patients in controlled and open label studies, including non-epilepsy studies.
- In the Phase 3 epilepsy trials these events occurred in patients with and without prior psychiatric history, prior aggressive behavior, or concomitant use of medications associated with hostility and aggression. Some patients experienced worsening of their pre-existing psychiatric conditions. Patients with active psychotic disorders and unstable recurrent affective disorders were excluded from the clinical trials. The combination of alcohol and perampanel significantly worsened mood and increased anger. Patients taking FYCOMPA should avoid the use of alcohol.
- In healthy volunteers taking FYCOMPA, observed psychiatric events included paranoia, euphoric mood, agitation, anger, mental status changes, and disorientation/confusional state.
- In the non-epilepsy trials, psychiatric events that occurred in perampanel-treated subjects more often than placebo-treated subjects included disorientation, delusion, and paranoia.
- Patients, their caregivers, and families should be informed that FYCOMPA may increase the risk of psychiatric events. Patients should be monitored during treatment and for at least one month after the last dose of FYCOMPA, and especially when taking higher doses and during the initial few weeks of drug therapy (titration period) or at other times of dose increases. Dose of FYCOMPA should be reduced if these symptoms occur. Permanently discontinue FYCOMPA for persistent severe or worsening psychiatric symptoms or behaviors and refer for psychiatric evaluation.
- Suicidal Behavior and Ideation
- Antiepileptic drugs (AEDs), including FYCOMPA, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
- Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI: 1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.
- The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
- The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed.
- Table 1 shows absolute and relative risk by indication for all evaluated AEDs.
- The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.
- Anyone considering prescribing FYCOMPA or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
- Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.
- Neurologic Effects
- Dizziness and Gait Disturbance
- FYCOMPA caused dose-related increases in events related to dizziness and disturbance in gait or coordination. In the controlled Phase 3 epilepsy clinical trials, dizziness and vertigo were reported in 35% and 47% of patients randomized to receive FYCOMPA at doses of 8 mg and 12 mg/day, respectively, compared to 10% of placebo-treated patients. The gait disturbance related events (including ataxia, gait disturbance, balance disorder, and coordination abnormal) were reported in 12% and 16% of patients randomized to receive FYCOMPA at doses of 8 mg and 12 mg/day, respectively, compared to 2% of placebo-treated patients.
- These adverse reactions occurred mostly during the titration phase and led to discontinuation in 3% of perampanel-treated subjects compared to 1% of placebo-treated patients. Elderly patients had an increased risk of these adverse reactions compared to younger adults and adolescents.
- Somnolence and Fatigue
- FYCOMPA caused dose-dependent increases in somnolence and fatigue-related events (including fatigue, asthenia, and lethargy).
- In the controlled Phase 3 epilepsy clinical trials, 16% and 18% of patients randomized to receive FYCOMPA at doses of 8 mg and 12 mg/day, respectively, reported somnolence compared to 7% of placebo patients. In the controlled Phase 3 epilepsy clinical trials, 12% and 15% of patients randomized to receive FYCOMPA at doses of 8 mg and 12 mg/day, respectively, reported fatigue-related events compared to 5% of placebo patients. Somnolence or fatigue-related events led to discontinuation in 2% of perampanel-treated patients and 0.5% of placebo-treated patients. Elderly patients had an increased risk of these adverse reactions compared to younger adults and adolescents.
- Risk Amelioration
- Prescribers should advise patients against engaging in hazardous activities requiring mental alertness, such as operating motor vehicles or dangerous machinery, until the effect of FYCOMPA is known.
- In the controlled Phase 3 epilepsy clinical trials these adverse reactions occurred mostly during the titration phase.
- Falls
- An increased risk of falls, in some cases leading to serious injuries including head injuries and bone fracture, occurred in patients being treated with FYCOMPA (with and without concurrent seizures). In the controlled Phase 3 epilepsy clinical trials, falls were reported in 5% and 10% of patients randomized to receive FYCOMPA at doses of 8 mg and 12 mg/day, respectively, compared to 3% of placebo-treated patients. Falls were reported as serious and led to discontinuation more frequently in FYCOMPA-treated patients than placebo-treated patients. Elderly patients had an increased risk of falls compared to younger adults and adolescents.
- Withdrawal of Antiepileptic Drugs
- There is the potential of increased seizure frequency in patients with seizure disorders when antiepileptic drugs are withdrawn abruptly. FYCOMPA has a half-life of approximately 105 hours so that even after abrupt cessation, blood levels fall gradually. In antiepileptic clinical trials FYCOMPA was withdrawn without down-titration. Although a small number of patients exhibited seizures following discontinuation, the data were not sufficient to allow any recommendations regarding appropriate withdrawal regimens. A gradual withdrawal is generally recommended with antiepileptic drugs, but if withdrawal is a response to adverse events, prompt withdrawal can be considered.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
- A total of 1,038 patients on perampanel (2, 4, 8, or 12 mg once daily) constituted the safety population in the pooled analysis of Phase 3 placebo controlled studies (Studies 1, 2, and 3) in patients with partial onset seizures. Approximately 51% of patients were female and the mean age was 35 years.
- Adverse Reactions Leading to Discontinuation
- In controlled Phase 3 clinical trials (Studies 1, 2, and 3), the rate of discontinuation as a result of an adverse reaction was 3%, 8% and 19% in patients randomized to receive FYCOMPA at the recommended doses of 4 mg, 8 mg and 12 mg/day, respectively, and 5% in patients randomized to receive placebo . The adverse events most commonly leading to discontinuation (≥1% in the 8 mg or 12 mg FYCOMPA group and greater than placebo) were dizziness, somnolence, vertigo, aggression, anger, ataxia, blurred vision, irritability, and dysarthria.
- Most Common Adverse Reactions
- Table 2 gives the incidence in the Phase 3 controlled trials (Studies 1, 2, and 3) of the adverse reactions that occurred in ≥2% of patients with partial-onset seizures in any FYCOMPA dose group. Overall, the most frequently reported dose-related adverse reactions in patients receiving FYCOMPA at doses of 8 mg or 12 mg (≥4% and occurring at least 1% higher than the placebo group) included dizziness (36%), somnolence (16%), fatigue (10%), irritability (9%), falls (7%), nausea (7%), ataxia (5%), balance disorder (4%), gait disturbance (4%), vertigo (4%), and weight gain (4%). For almost every adverse reaction, rates were higher on 12 mg and more often led to dose reduction or discontinuation.
- Weight Gain
- Weight gain has been observed with FYCOMPA use in adults.
- In the controlled Phase 3 epilepsy clinical trials, FYCOMPA-treated adults gained an average of 1.1 kg (2.5 lbs) compared to an average of 0.3 kg (0.7 lbs) in placebo-treated adults with a median exposure of 19 weeks. The percentages of adults who gained at least 7% and 15% of their baseline body weight in FYCOMPA-treated patients were 9.1% and 0.9%, respectively, as compared to 4.5% and 0.2% of placebo-treated patients, respectively.
- Clinical monitoring of weight is recommended.
- Comparison of Sex and Race
- No significant sex differences were noted in the incidence of adverse reactions.
- Although there were few non-Caucasian patients, no differences in the incidences of adverse reactions compared to Caucasian patients were observed.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Perampanel in the drug label.
# Drug Interactions
- Contraceptives
- With concomitant use, FYCOMPA at a dose of 12 mg/day reduced levonorgestrel exposure by approximately 40%. Use of FYCOMPA with oral or implant contraceptives containing levonorgestrel may render them less effective. Additional non-hormonal forms of contraception are recommended.
- Cytochrome P450 (CYP) Inducers
- The concomitant use of known CYP enzyme inducers including carbamazepine, phenytoin, or oxcarbazepine with FYCOMPA decreased the plasma levels of perampanel by approximately 50~67%. The starting doses for FYCOMPA should be increased in the presence of enzyme-inducing AEDs.
- When these enzyme-inducing AEDs are introduced or withdrawn from a patient’s treatment regimen, patient should be closely monitored for clinical response and tolerability. Dose adjustment of FYCOMPA may be necessary. As noted, however, the decrease in the therapeutic effect seen in patients on concomitant treatment was not affected by use of higher doses (8 mg to 12 mg).
- Concomitant use of FYCOMPA with other strong CYP3A inducers (e.g., rifampin, St. John’s wort) should be avoided.
- Alcohol and Other CNS Depressants
- The concomitant use of FYCOMPA and CNS depressants including alcohol may increase CNS depression. A pharmacodynamic interaction study in healthy subjects found that the effects of FYCOMPA on complex tasks such as driving ability were additive or supra-additive to the impairment effects of alcohol. Multiple dosing of FYCOMPA 12 mg/day also enhanced the effects of alcohol to interfere with vigilance and alertness, and increased levels of anger, confusion, and depression. These effects may also be seen when FYCOMPA is used in combination with other CNS depressants. Care should be taken when administering FYCOMPA with these agents. Patients should limit activity until they have experience with concomitant use of CNS depressants (e.g., benzodiazepines, narcotics, barbiturates, sedating antihistamines). Advise patients not to drive or operate machinery until they have gained sufficient experience on FYCOMPA to gauge whether it adversely affects these activities.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- There are no adequate and well-controlled studies in pregnant women. In animal studies, perampanel induced developmental toxicity in pregnant rat and rabbit at clinically relevant doses. FYCOMPA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Oral administration of perampanel (1, 3, or 10 mg/kg/day) to pregnant rats throughout organogenesis resulted in an increase in visceral abnormalities (diverticulum of the intestine) at all doses tested. In a dose-ranging study at higher oral doses (10, 30, or 60 mg/kg/day), embryo lethality and reduced fetal body weight were observed at the mid and high doses tested. The lowest dose tested (1 mg/kg/day) is similar to a human dose of 8 mg/day based on body surface area (mg/m2).
- Upon oral administration of perampanel (1, 3, or 10 mg/kg/day) to pregnant rabbits throughout organogenesis, embryo lethality was observed at the mid and high doses tested; the no effect dose for embryo-fetal developmental toxicity in rabbit (1 mg/kg/day) is approximately 2 times a human dose of 8 mg/day based on body surface area (mg/m2).
- Oral administration of perampanel (1, 3, or 10 mg/kg/day) to rats throughout gestation and lactation resulted in fetal and pup deaths at the mid and high doses and delayed sexual maturation in males and females at the highest dose tested. No effects were observed on measures of neurobehavioral or reproductive function in the offspring. The no-effect dose for pre- and postnatal developmental toxicity in rat (1 mg/kg/day) is similar to a human dose of 8 mg/day based on body surface area (mg/m2).
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Perampanel in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Perampanel during labor and delivery.
### Nursing Mothers
- Perampanel and/or its metabolites are excreted in rat milk, and are detected at concentrations higher than that in maternal plasma. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when FYCOMPA is administered to a nursing woman.
### Pediatric Use
- The safety and efficacy of FYCOMPA for the adjunctive therapy of partial-onset seizures was established by three randomized double blind, placebo-controlled, multicenter studies which included 72 pediatric patients between 12 and 16 years old exposed to perampanel. The safety and effectiveness of FYCOMPA in pediatric patients <12 years old have not been established.
- Juvenile Animal Data
- Oral administration of perampanel (1, 3, 3/10/30 mg/kg/day; high dose increased on postnatal days 28 and 56) to young rats for 12 weeks starting on PND 7 resulted in reduced body weight, reduced growth, neurobehavioral impairment (water maze performance and auditory startle habituation) at the mid and high doses, and delayed sexual maturation at the high doses. CNS signs (reduced activity, incoordination, excessive grooming/scratching), pup death, decreased hindlimb splay, and decreased hindlimb grip strength were observed at all doses. Effects on pup body weight, pup growth, hindlimb splay, impairment in the water maze performance and auditory startle persisted after dosing was stopped. A no-effect dose for postnatal developmental toxicity was not identified in this study.
- Oral administration of perampanel (1, 5, 5/10 mg/kg/day; high dose increased on PND 56) to juvenile dogs for 33 weeks, starting on PND 42, resulted in CNS signs (incoordination, excessive grooming/licking/scratching, spatial disorientation, and/or ataxic gait) at all doses tested.
### Geriatic Use
- Clinical studies of FYCOMPA did not include sufficient numbers of patients aged 65 and over to determine the safety and efficacy of FYCOMPA in the elderly population. Because of increased likelihood for adverse reactions in the elderly, dosing titration should proceed slowly in patients aged 65 years and older.
### Gender
There is no FDA guidance on the use of Perampanel with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Perampanel with respect to specific racial populations.
### Renal Impairment
- Dose adjustment is not required in patients with mild renal impairment. FYCOMPA should be used with caution in patients with moderate renal impairment and slower titration may be considered. Use in patients with severe renal impairment or patients undergoing hemodialysis is not recommended.
### Hepatic Impairment
- Use of FYCOMPA in patients with severe hepatic impairment is not recommended and dosage adjustments are recommended in patients with mild or moderate hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Perampanel in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Perampanel in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Perampanel in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Perampanel in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- There is limited clinical experience with FYCOMPA overdose. The highest reported overdose (approximately 264 mg) was intentional. This patient experienced serious adverse reactions of altered mental status, agitation, and aggressive behavior and recovered without sequelae. In general, the adverse reactions associated with overdoses were similar to the reactions at therapeutic doses with dizziness reported most frequently. There were no reported sequelae.
### Management
- There is no available specific antidote to the overdose reactions of FYCOMPA. In the event of overdose, standard medical practice for the management of any overdose should be used. An adequate airway, oxygenation, and ventilation should be ensured; monitoring of cardiac rhythm and vital sign measurement is recommended. A certified poison control center should be contacted for updated information on the management of overdose with FYCOMPA. Due to its long half-life, the reactions caused by FYCOMPA could be prolonged.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Perampanel in the drug label.
# Pharmacology
## Mechanism of Action
- Perampanel is a non-competitive antagonist of the ionotropic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor on postsynaptic neurons. Glutamate is the primary excitatory neurotransmitter in the central nervous system and is implicated in a number of neurological disorders caused by neuronal over excitation.
- The precise mechanism by which FYCOMPA exerts its antiepileptic effects in humans has not been fully elucidated.
## Structure
- FYCOMPA tablets contain perampanel, a non-competitive AMPA receptor antagonist. Perampanel is described chemically as 2-(2-oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl) benzonitrile hydrate (4:3).
- The molecular formula is C23H15N3O - 3/4H2O, and the molecular weight is 362.90 (3/4 hydrate). The chemical structure of perampanel is:
- Perampanel is a white to yellowish white powder. It is freely soluble in N-methylpyrrolidone, sparingly soluble in acetonitrile and acetone, slightly soluble in methanol, ethanol and ethyl acetate, very slightly soluble in 1-octanol and diethyl ether and practically insoluble in heptane and water.
- FYCOMPA (perampanel) tablets are round, bi-convex, film coated tablets containing 2 mg, 4 mg, 6 mg, 8 mg, 10 mg or 12 mg of perampanel. Tablets contain the following inactive ingredients: lactose monohydrate, low substituted hydroxypropyl cellulose, povidone, microcrystalline cellulose, magnesium stearate, hypromellose, polyethylene glycol, talc and titanium dioxide. Tablets of different strengths also may contain yellow ferric oxide (10 mg and 2 mg), red ferric oxide (2 mg, 4 mg, 6 mg, 8 mg), black ferric oxide (8 mg) and FD&C blue # 2 indigo carmine aluminum lake (10 mg and 12 mg).
## Pharmacodynamics
- Psychomotor Performance
- In a healthy volunteer study to assess the effects of FYCOMPA on psychomotor performance using a standard battery of assessments including simulated driving, single and multiple daily doses of FYCOMPA 4 mg did not impair simple psychomotor tasks, driving performance or sensori-motor coordination. Single and multiple doses of 8 mg and 12 mg impaired psychomotor performance in a dose-related manner. Car handling ability was impaired after dosing of FYCOMPA 12 mg, but postural stability was not significantly impaired. Performance testing returned to baseline within 2 weeks of cessation of FYCOMPA dosing.
- Interactions with Alcohol
- In the above study, when administered to healthy subjects receiving alcohol to achieve a blood concentration of 80-100mg/100mL, FYCOMPA consistently impaired simple psychomotor performance after single doses of 4 to 12 mg, and after 21 days of multiple 12 mg/day doses. The effects of FYCOMPA on complex tasks such as driving ability were additive or supra-additive to the impairment effects of alcohol. FYCOMPA enhanced the effects of alcohol on vigilance and alertness, and increased levels of anger, confusion, and depression.
- Potential to Prolong QT Interval
- In a placebo-controlled thorough QT study perampanel in healthy subjects, there was no evidence that perampanel caused QT interval prolongation of clinical significance at doses of 6 or 12 mg (i.e., the upper bound of the 95% confidence interval for the largest placebo-adjusted baseline-corrected QTc was below 10 msec). The exposures observed with the 12 mg dose in this study will not cover the exposures expected in patients with hepatic impairment taking doses over 6 mg/day. At the maximum recommended dose (12 mg), perampanel did not prolong the QTc interval to any clinically relevant extent.
## Pharmacokinetics
- Pharmacokinetics of perampanel are similar in healthy subjects and patients with partial-onset seizures. The half-life of perampanel is about 105 hours, so that steady state is reached in about 2-3 weeks. AUC of perampanel increased in a dose-proportional manner after single-dose administration of 0.2-12 mg and after multiple-dose administration of 1-12 mg once daily.
- Absorption
- Perampanel is rapidly and completely absorbed after oral administration with negligible first-pass metabolism. Median Tmax ranged from 0.5 to 2.5 hours under fasted condition. Food does not affect the extent of absorption (AUC), but slows the rate of absorption. Under fed conditions, Cmax of perampanel was decreased by 28-40% and Tmax was delayed by 2-3 hours compared to that under fasted conditions.
- Distribution
- Data from in vitro studies indicate that, in the concentration range of 20 to 2000 ng/mL, perampanel is approximately 95-96% bound to plasma proteins, mainly bound to albumin and α1-acid glycoprotein. Blood to plasma ratio of perampanel is 0.55-0.59.
- Metabolism
- Perampanel is extensively metabolized via primary oxidation and sequential glucuronidation. Oxidative metabolism is primarily mediated by CYP3A4/5 and to a lesser extent by CYP1A2 and CYP2B6, based on results of in vitro studies using recombinant human CYPs and human liver microsomes. Other CYP enzymes may also be involved.
- Following administration of radiolabeled perampanel, unchanged perampanel accounted for 74-80% of total radioactivity in systemic circulation, whereas only trace amounts of individual perampanel metabolites were detected in plasma.
- Elimination
- Following administration of a radiolabeled perampanel dose to 8 healthy elderly subjects, 22% of administered radioactivity was recovered in the urine and 48% in the feces. In urine and feces, recovered radioactivity was primarily composed of a mixture of oxidative and conjugated metabolites. Population pharmacokinetic analysis of pooled data from 19 Phase 1 studies reported that t1/2 of perampanel was 105 hours on average. Apparent clearance of perampanel in healthy subjects and patients was approximately 12 mL/min.
- Specific Populations
- Hepatic Impairment
- The pharmacokinetics of perampanel following a single 1 mg dose were evaluated in 12 subjects with mild and moderate hepatic impairment (Child-Pugh A and B, respectively) compared with 12 demographically matched healthy subjects. The total (free and protein bound) exposure (AUC0-inf) of perampanel was 50% greater in subjects with mild hepatic impairment and more than doubled (2.55-fold) in subjects with moderate hepatic impairment compared to their healthy controls. The AUC0-inf of free perampanel in subjects with mild and moderate hepatic impairment was 1.8-fold and 3.3-fold, respectively, of those in matched healthy controls. The t1/2 was prolonged in subjects with mild impairment (306 vs. 125 hours) and moderate impairment (295 vs. 139 hours). Perampanel has not been studied in subjects with severe hepatic impairment.
- Renal Impairment
- A dedicated study has not been conducted to evaluate the pharmacokinetics of perampanel in patients with renal impairment. Population pharmacokinetic analysis was performed on pooled data from patients with partial-onset seizures and receiving FYCOMPA up to 12 mg/day in placebo-controlled clinical trials. Results showed that perampanel apparent clearance was decreased by 27% in patients with mild renal impairment (creatinine clearance 50-80 mL/min) compared to patients with normal renal function (creatinine clearance >80 mL/min), with a corresponding 37% increase in AUC. Considering the substantial overlap in the exposure between normal and mildly impaired patients, no dosage adjustment is necessary for patients with mild renal impairment. Perampanel has not been studied in patients with severe renal impairment and patients undergoing hemodialysis.
- Sex
- In a population pharmacokinetic analysis of patients with partial-onset seizures receiving FYCOMPA in placebo-controlled clinical trials, perampanel apparent clearance in females (0.605 L/hr) was 17% lower than in males (0.730 L/hr). No dosage adjustment is necessary based on sex.
- Pediatric Patients
- FYCOMPA has not been studied in patients <12 years old. In a population pharmacokinetic analysis of patients with partial-onset seizures ranging in age from 12 to 74 years receiving FYCOMPA in placebo-controlled trials, apparent clearance of perampanel in adolescents (0.787 L/hr) was slightly, but not significantly, higher than that in adults. Pediatric patients above 12 years old can be dosed similarly to adults.
- Geriatrics
- In a population pharmacokinetic analysis of patients with partial-onset seizures ranging in age from 12 to 74 years receiving FYCOMPA in placebo-controlled trials, no significant effect of age on perampanel apparent clearance was found.
- Race
- In a population pharmacokinetic analysis of patients with partial-onset seizures which included 576 Caucasians, 14 Blacks, 97 non-Chinese Asians, and 62 Chinese receiving FYCOMPA in placebo-controlled trials, no significant effect of race on perampanel apparent clearance was found. No dosage adjustment is necessary.
- Drug Interaction Studies
- In Vitro Assessment of Drug Interactions
- Drug Metabolizing Enzymes
- In human liver microsomes, perampanel at a concentration of 30 μmol/L, about 10 fold the steady state Cmax at a 12 mg dose, had a weak inhibitory effect on CYP2C8, CYP3A4, UGT1A9 and UGT2B7. Perampanel did not inhibit CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, UGT1A1, UGT1A4, and UGT1A6 at a concentration of 30 µmol/L.
- Compared with positive controls (including phenobarbital and rifampin), perampanel was found to weakly induce CYP2B6 (30µmol/L) and CYP3A4/5 (≥ 3µmol/L) in cultured human hepatocytes. Perampanel also induced UGT1A1 (≥ 3µmol/L) and UGT1A4 (30µmol/L). Perampanel did not induce CYP1A2 at concentrations up to 30 µmol/L.
- Transporters
- In vitro studies showed that perampanel is not a substrate or significant inhibitor of the following: organic anion transporting polypeptides 1B1 and 1B3; organic anion transporters 1, 2, 3, and 4; organic cation transporters 1, 2, and 3; efflux transporters P-glycoprotein and Breast Cancer Resistance Protein.
- In Vivo Assessment of Drug Interactions
- Drug Interactions with AEDs
- Effect of concomitant AEDs on FYCOMPA:
- Carbamazepine. As an inducer of CYP enzymes, carbamazepine increases perampanel clearance. Steady state administration of carbamazepine at 300 mg BID in healthy subjects reduced the Cmax and AUC0-inf of a single 2 mg dose of perampanel by 26% and 67% respectively. The t1/2 of perampanel was shortened from 56.8 hours to 25 hours. In clinical studies examining partial-onset seizures, a population pharmacokinetic analysis showed that perampanel AUC was reduced by 67% in patients on carbamazepine compared to the AUC in patients not on enzyme-inducing AEDs.
- Oxcarbazepine. In clinical studies examining partial-onset seizures, a population pharmacokinetic analysis showed that perampanel AUC was reduced by half in patients on oxcarbazepine compared to patients not on enzyme-inducing AEDs.
- Phenytoin. In clinical studies examining partial-onset seizures, a population pharmacokinetic analysis showed that perampanel AUC was reduced by half in patients on phenytoin compared to patients not on enzyme-inducing AEDs.
- Phenobarbital and Primidone: In a population pharmacokinetic analysis of patients with partial-onset seizures in clinical trials (37 patients coadministered phenobarbital and 9 patients coadministered primidone) no significant effect on perampanel AUC was found. A modest effect of phenobarbital and primidone on perampanel concentrations cannot be excluded.
- Topiramate: Population pharmacokinetic analysis of patients with partial-onset seizures in clinical trials showed that perampanel AUC was reduced by approximately 20% in patients on topiramate compared to patients not on enzyme-inducing AEDs.
- Other AEDs: Population pharmacokinetic analysis of patients with partial-onset seizures in clinical trials showed that clobazam, clonazepam, lamotrigine, levetiracetam, valproate, and zonisamide did not have an effect on perampanel clearance.
- Other strong CYP3A inducers (e.g., rifampin, St. John’s wort) may also greatly increase clearance of perampanel and reduce perampanel plasma concentrations.
- Effect of FYCOMPA on concomitant AEDs:
- FYCOMPA up to 12 mg/day did not significantly affect the clearance of clonazepam, levetiracetam, phenobarbital, phenytoin, topiramate, or zonisamide based on a population pharmacokinetic analysis of patients with partial-onset seizures in clinical trials. FYCOMPA had a statistically significant effect on the clearance of carbamazepine, clobazam, lamotrigine, and valproic acid, but the increases in clearance of these drugs were each less than 10% at the highest perampanel dose evaluated (12 mg/day). FYCOMPA coadministration resulted in a 26% decrease in oxcarbazepine clearance and increased its concentrations. The concentrations of 10-monohydroxy metabolite (MHD), the active metabolite of oxcarbazepine, were not measured.
- Drug-drug interaction studies with other drugs
- Effect of other drugs on FYCOMPA
- Ketoconazole. Coadministration of single 1-mg dose of perampanel with 400 mg once daily doses of ketoconazole, a strong CYP3A4 inhibitor, for 8 days in healthy subjects prolonged perampanel t1/2 by 15% (67.8 vs. 58.4 hours) and increased AUC0-inf by 20%.
- Oral contraceptives. Perampanel Cmax and AUC0-72h were not altered when a single 6-mg dose of perampanel was administered to healthy female subjects following a 21-day course of oral contraceptives containing ethinylestradiol 30 µg and levonorgestrel 150 µg.
- Effect of FYCOMPA on other drugs
- Midazolam. Perampanel administered as 6 mg once daily doses for 20 days decreased AUC0-inf and Cmax of midazolam (a CYP3A4 substrate) by 13% and 15%, respectively, in healthy subjects.
- Oral Contraceptives. Coadministration of perampanel 4 mg once daily with an oral contraceptive containing ethinylestradiol 30 µg and levonorgestrel 150 µg for 21 days did not alter Cmax or AUC0-24h of either ethinylestradiol or levonorgestrel in healthy female subjects. In another study, a single dose of the oral contraceptive was administered following 21-day once daily dosing of FYCOMPA 12 mg or 8 mg in healthy females. FYCOMPA at 12 mg did not alter AUC0-24h of ethinylestradiol but decreased its Cmax by 18%, and also decreased Cmax and AUC0-24h of levonorgestrel by 42% and 40%, respectively. FYCOMPA at 8 mg did not have significant effect on Cmax or AUC0-24h of either ethinylestradiol or levonorgestrel, with a small decrease in AUC0-24h of levonorgestrel (9%).
- Levodopa. Perampanel administered as 4 mg once daily doses for 19 days had no effect on Cmax and AUC0-inf of levodopa in healthy subjects.
## Nonclinical Toxicology
- Carcinogenesis
- Perampanel was administered orally to mice (1, 3, 10, or 30 mg/kg/day) and rats (10, 30, or 100 mg/kg/day in males; 3, 10, or 30 mg/kg/day in females) for up to 104 weeks. There was no evidence of drug-related tumors in either species. Plasma perampanel exposures (AUC) at the highest doses tested were less than that in humans dosed at 8 mg/day.
- Mutagenesis
- Perampanel was negative in the in vitro Ames and mouse lymphoma tk assays, and in the in vivo rat micronucleus assay.
- Impairment of Fertility
- In male and female rats administered perampanel (oral doses of 1, 10, or 30 mg/kg/day) prior to and throughout mating and continuing in females to gestation day 6, there were no clear effects on fertility. Prolonged and/or irregular estrus cycles were observed at all doses but particularly at the highest dose tested. Plasma perampanel exposures (AUC) at all doses were lower than that in humans dosed at 8 mg/day.
# Clinical Studies
- The efficacy of FYCOMPA in partial-onset seizures, with or without secondary generalization, was studied in patients who were not adequately controlled with 1 to 3 concomitant AEDs in 3 randomized, double-blind, placebo-controlled, multicenter trials (Studies 1, 2, and 3) in adult and adolescent patients (aged 12 years and older). All trials had an initial 6-week Baseline Period, during which patients were required to have more than five seizures in order to be randomized. The Baseline Period was followed by a 19-week Treatment Period consisting of a 6-week Titration Phase and a 13-week Maintenance Phase. Patients in these 3 trials had a mean duration of epilepsy of approximately 21 years and a median baseline seizure frequency ranging from 9.3 to 14.3 seizures per 28 days. During the trials, more than 85% of patients were taking 2 to 3 concomitant AEDs with or without concurrent vagal nerve stimulation, and approximately 50% were on at least one AED known to induce CYP3A4, an enzyme critical to the metabolism of FYCOMPA (i.e., carbamazepine, oxcarbazepine, or phenytoin), resulting in a significant reduction in FYCOMPA’s serum concentration.
- Each study evaluated placebo and multiple FYCOMPA dosages (see Figure 1). During the Titration period in all 3 trials, patients on FYCOMPA received an initial 2 mg once daily dose, which was subsequently increased in weekly increments of 2 mg per day to the final target dose. Patients experiencing intolerable adverse reactions were permitted to have their dose reduced to the previously tolerated dose.
- The primary endpoint in Studies 1, 2, and 3 was the percent change in seizure frequency per 28 days during the Treatment Period as compared to the Baseline Period. The criterion for statistical significance was p<0.05. Table 3 shows the results of these studies. A statistically significant decrease in seizure rate was observed at doses of 4 to 12 mg per day. Dose response was apparent at 4 to 8 mg with little additional reduction in frequency at 12 mg per day.
- Table 4 presents an analysis combining data from all 3 studies, grouping patients based upon whether or not concomitant AED inducers (carbamazepine, oxcarbazepine, or phenytoin) were used. The analysis revealed a substantially reduced effect in the presence of inducers.
- Figure 1 shows the proportion of patients with different percent reductions during the maintenance phase over baseline across all three trials. Patients in whom the seizure frequency increased are shown at left as “worse.” Patients in whom the seizure frequency decreased are shown in the remaining five categories. Thus, the percentages of patients with a 40 to <60% reduction in seizure frequency were 13.2%, 17.4%, 19.0%, and 15.8% for placebo, 4, 8, and 12 mg, respectively.
- The percentages of patients with a 50% or greater reduction in seizure frequency were 19.3%, 28.5%, 35.3%, 35.0% for placebo, 4, 8, and 12 mg, respectively.
# How Supplied
- FYCOMPA (perampanel) Tablets 2 mg are orange, round, biconvex, film-coated tablets debossed with "2" on one side and "Є 275" on the other. They are supplied as follows:
- Bottles of 30 NDC 62856-272-30
- Bottles of 90 NDC 62856-272-90
- FYCOMPA (perampanel) Tablets 4 mg are red, round, biconvex, film-coated tablets debossed with "4" on one side and "Є 277" on the other. They are supplied as follows:
- Bottles of 30 NDC 62856-274-30
- Bottles of 90 NDC 62856-274-90
- FYCOMPA (perampanel) Tablets 6 mg are pink, round, biconvex, film-coated tablets debossed with "6" on one side and "Є 294" on the other. They are supplied as follows:
- Bottles of 30 NDC 62856-276-30
- Bottles of 90 NDC 62856-276-90
- FYCOMPA (perampanel) Tablets 8 mg are purple, round, biconvex, film-coated tablets debossed with "8" on one side and "Є 295" on the other. They are supplied as follows:
- Bottles of 30 NDC 62856-278-30
- Bottles of 90 NDC 62856-278-90
- FYCOMPA (perampanel) Tablets 10 mg are green, round, biconvex, film-coated tablets debossed with "10" on one side and "Є 296" on the other. They are supplied as follows:
- Bottles of 30 NDC 62856-280-30
- Bottles of 90 NDC 62856-280-90
- FYCOMPA (perampanel) Tablets 12 mg are blue, round, biconvex, film-coated tablets debossed with "12" on one side and "Є 297" on the other. They are supplied as follows:
- Bottles of 30 NDC 62856-282-30
- Bottles of 90 NDC 62856-282-90
- Storage
- Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F).
## Storage
There is limited information regarding Perampanel Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Inform patients of the availability of a Medication Guide, and instruct them to read the Medication Guide prior to taking FYCOMPA. Instruct patients to take FYCOMPA only as prescribed.
- Serious Psychiatric and Behavioral Reactions
- Counsel patients, families and caregivers of patients of the need to monitor for the emergence of anger, aggression, hostility, unusual changes in mood, personality, or behavior, and other behavioral symptoms. Advise them to report any such symptoms immediately to their health care providers.
- Suicidal Thinking and Behavior
- Counsel patients, their caregivers, and families that AEDs, including FYCOMPA, may increase the risk of suicidal thinking and behavior and advise them of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Instruct patients, caregivers and families to report behaviors of concern immediately to healthcare providers.
- Neurologic Effects: Dizziness, Gait Disturbance, Somnolence, and Fatigue
- Counsel patients that FYCOMPA may cause dizziness, gait disturbance, somnolence, and fatigue. Advise patients taking FYCOMPA not to drive, operate complex machinery, or engage in other hazardous activities until they have become accustomed to any such effects associated with FYCOMPA.
- Falls
- Counsel patients that FYCOMPA may cause falls and injuries.
- Withdrawal of Antiepileptic Drugs
- Counsel patients that abrupt discontinuation of FYCOMPA may increase seizure frequency.
- Contraceptives
- Counsel patients that FYCOMPA may decrease efficacy of contraceptives containing levonorgestrel.
- Alcohol and Other CNS Depressants
- Counsel patients that FYCOMPA may enhance the impairment effects of alcohol. These effects may also be seen if FYCOMPA is taken with other CNS depressants.
- Missed Doses
- Counsel patients that if they miss a dose, they should resume dosing the following day at their prescribed daily dose. Instruct patients to contact their physician if more than one day of dosing is missed.
- Controlled Substance
- Counsel patients that FYCOMPA is a controlled substance that can be misused and abused.
- Pregnancy Registry
- To provide information regarding the effects of in utero exposure to FYCOMPA, recommend pregnant patients treated with FYCOMPA to enroll in the NAAED Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website .
# Precautions with Alcohol
- Alcohol-Perampanel interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- FYCOMPA®
# Look-Alike Drug Names
There is limited information regarding Perampanel Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Perampanel
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2]
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# Black Box Warning
# Overview
Perampanel is a non-competitive AMPA glutamate receptor antagonist that is FDA approved for the {{{indicationType}}} of partial-onset seizures with or without secondarily generalized seizures in patients with epilepsy aged 12 years and older. There is a Black Box Warning for this drug as shown here. Common adverse reactions include dizziness, somnolence, fatigue, irritability, falls, nausea, weight gain, vertigo, ataxia, gait disturbance, and balance disorder.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- In the Absence of Enzyme-Inducing AEDs
- The recommended starting dosage of FYCOMPA is 2 mg once daily taken orally at bedtime. Increase dosage by 2 mg per day increments no more frequently than every week to a dose of 4 mg to 8 mg once daily taken at bedtime. In elderly patients, dosage increases during titration are recommended no more frequently than every two weeks.
- The recommended dose range is 8 mg to 12 mg once daily. A dose of 12 mg once daily resulted in somewhat greater reductions in seizure rates than the dose of 8 mg once daily, but with a substantial increase in adverse reactions. Individual dosing should be adjusted based on clinical response and tolerability
- In the Presence of Enzyme-Inducing AEDs
- The recommended starting dosage of FYCOMPA in the presence of enzyme-inducing AEDs, including phenytoin, carbamazepine, and oxcarbazepine, is 4 mg and patients should be monitored closely for response. Clinical trials revealed a substantially reduced effect on seizure rates in these patients. The reduction in seizure frequency was somewhat greater at 12 mg than at 8 mg.
- When these enzyme-inducing AEDs are introduced or withdrawn from a patient’s treatment regimen, patient should be closely monitored for clinical response and tolerability. Dose adjustment of FYCOMPA may be necessary.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Perampanel in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Perampanel in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- In the Absence of Enzyme-Inducing AEDs
- The recommended starting dosage of FYCOMPA is 2 mg once daily taken orally at bedtime. Increase dosage by 2 mg per day increments no more frequently than every week to a dose of 4 mg to 8 mg once daily taken at bedtime. In elderly patients, dosage increases during titration are recommended no more frequently than every two weeks.
- The recommended dose range is 8 mg to 12 mg once daily. A dose of 12 mg once daily resulted in somewhat greater reductions in seizure rates than the dose of 8 mg once daily, but with a substantial increase in adverse reactions. Individual dosing should be adjusted based on clinical response and tolerability
- In the Presence of Enzyme-Inducing AEDs
- The recommended starting dosage of FYCOMPA in the presence of enzyme-inducing AEDs, including phenytoin, carbamazepine, and oxcarbazepine, is 4 mg and patients should be monitored closely for response. Clinical trials revealed a substantially reduced effect on seizure rates in these patients. The reduction in seizure frequency was somewhat greater at 12 mg than at 8 mg.
- When these enzyme-inducing AEDs are introduced or withdrawn from a patient’s treatment regimen, patient should be closely monitored for clinical response and tolerability. Dose adjustment of FYCOMPA may be necessary.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Perampanel in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Perampanel in pediatric patients.
# Contraindications
- None.
# Warnings
### Precautions
- Serious Psychiatric and Behavioral Reactions
- In the controlled Phase 3 epilepsy clinical trials, hostility- and aggression-related adverse reactions occurred in 12% and 20% of patients randomized to receive FYCOMPA at doses of 8 mg and 12 mg/day, respectively, compared to 6% of patients in the placebo group. These effects were dose-related and generally appeared within the first 6 weeks of treatment, although new events continued to be observed through more than 37 weeks. FYCOMPA-treated patients experienced more hostility- and aggression - related adverse reactions that were serious, severe, and led to dose reduction, interruption, and discontinuation more frequently than placebo-treated patients.
- In general, in placebo-controlled Phase 3 epilepsy trials, neuropsychiatric events were reported more frequently in patients being treated with FYCOMPA than in patients taking placebo. These events included irritability, aggression, anger, and anxiety which occurred in 2% or greater of perampanel treated patients and twice as frequently as in placebo-treated patients. Other symptoms that were observed with perampanel treatment and more commonly than with placebo, included belligerence, affect lability, agitation, and physical assault. Some of these events were reported as serious and life-threatening. Homicidal ideation and/or threat were exhibited in 0.1% of 4,368 perampanel treated patients in controlled and open label studies, including non-epilepsy studies.
- In the Phase 3 epilepsy trials these events occurred in patients with and without prior psychiatric history, prior aggressive behavior, or concomitant use of medications associated with hostility and aggression. Some patients experienced worsening of their pre-existing psychiatric conditions. Patients with active psychotic disorders and unstable recurrent affective disorders were excluded from the clinical trials. The combination of alcohol and perampanel significantly worsened mood and increased anger. Patients taking FYCOMPA should avoid the use of alcohol.
- In healthy volunteers taking FYCOMPA, observed psychiatric events included paranoia, euphoric mood, agitation, anger, mental status changes, and disorientation/confusional state.
- In the non-epilepsy trials, psychiatric events that occurred in perampanel-treated subjects more often than placebo-treated subjects included disorientation, delusion, and paranoia.
- Patients, their caregivers, and families should be informed that FYCOMPA may increase the risk of psychiatric events. Patients should be monitored during treatment and for at least one month after the last dose of FYCOMPA, and especially when taking higher doses and during the initial few weeks of drug therapy (titration period) or at other times of dose increases. Dose of FYCOMPA should be reduced if these symptoms occur. Permanently discontinue FYCOMPA for persistent severe or worsening psychiatric symptoms or behaviors and refer for psychiatric evaluation.
- Suicidal Behavior and Ideation
- Antiepileptic drugs (AEDs), including FYCOMPA, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
- Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI: 1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.
- The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
- The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed.
- Table 1 shows absolute and relative risk by indication for all evaluated AEDs.
- The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.
- Anyone considering prescribing FYCOMPA or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
- Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.
- Neurologic Effects
- Dizziness and Gait Disturbance
- FYCOMPA caused dose-related increases in events related to dizziness and disturbance in gait or coordination. In the controlled Phase 3 epilepsy clinical trials, dizziness and vertigo were reported in 35% and 47% of patients randomized to receive FYCOMPA at doses of 8 mg and 12 mg/day, respectively, compared to 10% of placebo-treated patients. The gait disturbance related events (including ataxia, gait disturbance, balance disorder, and coordination abnormal) were reported in 12% and 16% of patients randomized to receive FYCOMPA at doses of 8 mg and 12 mg/day, respectively, compared to 2% of placebo-treated patients.
- These adverse reactions occurred mostly during the titration phase and led to discontinuation in 3% of perampanel-treated subjects compared to 1% of placebo-treated patients. Elderly patients had an increased risk of these adverse reactions compared to younger adults and adolescents.
- Somnolence and Fatigue
- FYCOMPA caused dose-dependent increases in somnolence and fatigue-related events (including fatigue, asthenia, and lethargy).
- In the controlled Phase 3 epilepsy clinical trials, 16% and 18% of patients randomized to receive FYCOMPA at doses of 8 mg and 12 mg/day, respectively, reported somnolence compared to 7% of placebo patients. In the controlled Phase 3 epilepsy clinical trials, 12% and 15% of patients randomized to receive FYCOMPA at doses of 8 mg and 12 mg/day, respectively, reported fatigue-related events compared to 5% of placebo patients. Somnolence or fatigue-related events led to discontinuation in 2% of perampanel-treated patients and 0.5% of placebo-treated patients. Elderly patients had an increased risk of these adverse reactions compared to younger adults and adolescents.
- Risk Amelioration
- Prescribers should advise patients against engaging in hazardous activities requiring mental alertness, such as operating motor vehicles or dangerous machinery, until the effect of FYCOMPA is known.
- In the controlled Phase 3 epilepsy clinical trials these adverse reactions occurred mostly during the titration phase.
- Falls
- An increased risk of falls, in some cases leading to serious injuries including head injuries and bone fracture, occurred in patients being treated with FYCOMPA (with and without concurrent seizures). In the controlled Phase 3 epilepsy clinical trials, falls were reported in 5% and 10% of patients randomized to receive FYCOMPA at doses of 8 mg and 12 mg/day, respectively, compared to 3% of placebo-treated patients. Falls were reported as serious and led to discontinuation more frequently in FYCOMPA-treated patients than placebo-treated patients. Elderly patients had an increased risk of falls compared to younger adults and adolescents.
- Withdrawal of Antiepileptic Drugs
- There is the potential of increased seizure frequency in patients with seizure disorders when antiepileptic drugs are withdrawn abruptly. FYCOMPA has a half-life of approximately 105 hours so that even after abrupt cessation, blood levels fall gradually. In antiepileptic clinical trials FYCOMPA was withdrawn without down-titration. Although a small number of patients exhibited seizures following discontinuation, the data were not sufficient to allow any recommendations regarding appropriate withdrawal regimens. A gradual withdrawal is generally recommended with antiepileptic drugs, but if withdrawal is a response to adverse events, prompt withdrawal can be considered.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
- A total of 1,038 patients on perampanel (2, 4, 8, or 12 mg once daily) constituted the safety population in the pooled analysis of Phase 3 placebo controlled studies (Studies 1, 2, and 3) in patients with partial onset seizures. Approximately 51% of patients were female and the mean age was 35 years.
- Adverse Reactions Leading to Discontinuation
- In controlled Phase 3 clinical trials (Studies 1, 2, and 3), the rate of discontinuation as a result of an adverse reaction was 3%, 8% and 19% in patients randomized to receive FYCOMPA at the recommended doses of 4 mg, 8 mg and 12 mg/day, respectively, and 5% in patients randomized to receive placebo [see Clinical Studies (14)]. The adverse events most commonly leading to discontinuation (≥1% in the 8 mg or 12 mg FYCOMPA group and greater than placebo) were dizziness, somnolence, vertigo, aggression, anger, ataxia, blurred vision, irritability, and dysarthria.
- Most Common Adverse Reactions
- Table 2 gives the incidence in the Phase 3 controlled trials (Studies 1, 2, and 3) of the adverse reactions that occurred in ≥2% of patients with partial-onset seizures in any FYCOMPA dose group. Overall, the most frequently reported dose-related adverse reactions in patients receiving FYCOMPA at doses of 8 mg or 12 mg (≥4% and occurring at least 1% higher than the placebo group) included dizziness (36%), somnolence (16%), fatigue (10%), irritability (9%), falls (7%), nausea (7%), ataxia (5%), balance disorder (4%), gait disturbance (4%), vertigo (4%), and weight gain (4%). For almost every adverse reaction, rates were higher on 12 mg and more often led to dose reduction or discontinuation.
- Weight Gain
- Weight gain has been observed with FYCOMPA use in adults.
- In the controlled Phase 3 epilepsy clinical trials, FYCOMPA-treated adults gained an average of 1.1 kg (2.5 lbs) compared to an average of 0.3 kg (0.7 lbs) in placebo-treated adults with a median exposure of 19 weeks. The percentages of adults who gained at least 7% and 15% of their baseline body weight in FYCOMPA-treated patients were 9.1% and 0.9%, respectively, as compared to 4.5% and 0.2% of placebo-treated patients, respectively.
- Clinical monitoring of weight is recommended.
- Comparison of Sex and Race
- No significant sex differences were noted in the incidence of adverse reactions.
- Although there were few non-Caucasian patients, no differences in the incidences of adverse reactions compared to Caucasian patients were observed.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Perampanel in the drug label.
# Drug Interactions
- Contraceptives
- With concomitant use, FYCOMPA at a dose of 12 mg/day reduced levonorgestrel exposure by approximately 40%. Use of FYCOMPA with oral or implant contraceptives containing levonorgestrel may render them less effective. Additional non-hormonal forms of contraception are recommended.
- Cytochrome P450 (CYP) Inducers
- The concomitant use of known CYP enzyme inducers including carbamazepine, phenytoin, or oxcarbazepine with FYCOMPA decreased the plasma levels of perampanel by approximately 50~67%. The starting doses for FYCOMPA should be increased in the presence of enzyme-inducing AEDs.
- When these enzyme-inducing AEDs are introduced or withdrawn from a patient’s treatment regimen, patient should be closely monitored for clinical response and tolerability. Dose adjustment of FYCOMPA may be necessary. As noted, however, the decrease in the therapeutic effect seen in patients on concomitant treatment was not affected by use of higher doses (8 mg to 12 mg).
- Concomitant use of FYCOMPA with other strong CYP3A inducers (e.g., rifampin, St. John’s wort) should be avoided.
- Alcohol and Other CNS Depressants
- The concomitant use of FYCOMPA and CNS depressants including alcohol may increase CNS depression. A pharmacodynamic interaction study in healthy subjects found that the effects of FYCOMPA on complex tasks such as driving ability were additive or supra-additive to the impairment effects of alcohol. Multiple dosing of FYCOMPA 12 mg/day also enhanced the effects of alcohol to interfere with vigilance and alertness, and increased levels of anger, confusion, and depression. These effects may also be seen when FYCOMPA is used in combination with other CNS depressants. Care should be taken when administering FYCOMPA with these agents. Patients should limit activity until they have experience with concomitant use of CNS depressants (e.g., benzodiazepines, narcotics, barbiturates, sedating antihistamines). Advise patients not to drive or operate machinery until they have gained sufficient experience on FYCOMPA to gauge whether it adversely affects these activities.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- There are no adequate and well-controlled studies in pregnant women. In animal studies, perampanel induced developmental toxicity in pregnant rat and rabbit at clinically relevant doses. FYCOMPA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Oral administration of perampanel (1, 3, or 10 mg/kg/day) to pregnant rats throughout organogenesis resulted in an increase in visceral abnormalities (diverticulum of the intestine) at all doses tested. In a dose-ranging study at higher oral doses (10, 30, or 60 mg/kg/day), embryo lethality and reduced fetal body weight were observed at the mid and high doses tested. The lowest dose tested (1 mg/kg/day) is similar to a human dose of 8 mg/day based on body surface area (mg/m2).
- Upon oral administration of perampanel (1, 3, or 10 mg/kg/day) to pregnant rabbits throughout organogenesis, embryo lethality was observed at the mid and high doses tested; the no effect dose for embryo-fetal developmental toxicity in rabbit (1 mg/kg/day) is approximately 2 times a human dose of 8 mg/day based on body surface area (mg/m2).
- Oral administration of perampanel (1, 3, or 10 mg/kg/day) to rats throughout gestation and lactation resulted in fetal and pup deaths at the mid and high doses and delayed sexual maturation in males and females at the highest dose tested. No effects were observed on measures of neurobehavioral or reproductive function in the offspring. The no-effect dose for pre- and postnatal developmental toxicity in rat (1 mg/kg/day) is similar to a human dose of 8 mg/day based on body surface area (mg/m2).
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Perampanel in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Perampanel during labor and delivery.
### Nursing Mothers
- Perampanel and/or its metabolites are excreted in rat milk, and are detected at concentrations higher than that in maternal plasma. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when FYCOMPA is administered to a nursing woman.
### Pediatric Use
- The safety and efficacy of FYCOMPA for the adjunctive therapy of partial-onset seizures was established by three randomized double blind, placebo-controlled, multicenter studies which included 72 pediatric patients between 12 and 16 years old exposed to perampanel. The safety and effectiveness of FYCOMPA in pediatric patients <12 years old have not been established.
- Juvenile Animal Data
- Oral administration of perampanel (1, 3, 3/10/30 mg/kg/day; high dose increased on postnatal days [PND] 28 and 56) to young rats for 12 weeks starting on PND 7 resulted in reduced body weight, reduced growth, neurobehavioral impairment (water maze performance and auditory startle habituation) at the mid and high doses, and delayed sexual maturation at the high doses. CNS signs (reduced activity, incoordination, excessive grooming/scratching), pup death, decreased hindlimb splay, and decreased hindlimb grip strength were observed at all doses. Effects on pup body weight, pup growth, hindlimb splay, impairment in the water maze performance and auditory startle persisted after dosing was stopped. A no-effect dose for postnatal developmental toxicity was not identified in this study.
- Oral administration of perampanel (1, 5, 5/10 mg/kg/day; high dose increased on PND 56) to juvenile dogs for 33 weeks, starting on PND 42, resulted in CNS signs (incoordination, excessive grooming/licking/scratching, spatial disorientation, and/or ataxic gait) at all doses tested.
### Geriatic Use
- Clinical studies of FYCOMPA did not include sufficient numbers of patients aged 65 and over to determine the safety and efficacy of FYCOMPA in the elderly population. Because of increased likelihood for adverse reactions in the elderly, dosing titration should proceed slowly in patients aged 65 years and older.
### Gender
There is no FDA guidance on the use of Perampanel with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Perampanel with respect to specific racial populations.
### Renal Impairment
- Dose adjustment is not required in patients with mild renal impairment. FYCOMPA should be used with caution in patients with moderate renal impairment and slower titration may be considered. Use in patients with severe renal impairment or patients undergoing hemodialysis is not recommended.
### Hepatic Impairment
- Use of FYCOMPA in patients with severe hepatic impairment is not recommended and dosage adjustments are recommended in patients with mild or moderate hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Perampanel in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Perampanel in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Perampanel in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Perampanel in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- There is limited clinical experience with FYCOMPA overdose. The highest reported overdose (approximately 264 mg) was intentional. This patient experienced serious adverse reactions of altered mental status, agitation, and aggressive behavior and recovered without sequelae. In general, the adverse reactions associated with overdoses were similar to the reactions at therapeutic doses with dizziness reported most frequently. There were no reported sequelae.
### Management
- There is no available specific antidote to the overdose reactions of FYCOMPA. In the event of overdose, standard medical practice for the management of any overdose should be used. An adequate airway, oxygenation, and ventilation should be ensured; monitoring of cardiac rhythm and vital sign measurement is recommended. A certified poison control center should be contacted for updated information on the management of overdose with FYCOMPA. Due to its long half-life, the reactions caused by FYCOMPA could be prolonged.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Perampanel in the drug label.
# Pharmacology
## Mechanism of Action
- Perampanel is a non-competitive antagonist of the ionotropic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor on postsynaptic neurons. Glutamate is the primary excitatory neurotransmitter in the central nervous system and is implicated in a number of neurological disorders caused by neuronal over excitation.
- The precise mechanism by which FYCOMPA exerts its antiepileptic effects in humans has not been fully elucidated.
## Structure
- FYCOMPA tablets contain perampanel, a non-competitive AMPA receptor antagonist. Perampanel is described chemically as 2-(2-oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl) benzonitrile hydrate (4:3).
- The molecular formula is C23H15N3O • 3/4H2O, and the molecular weight is 362.90 (3/4 hydrate). The chemical structure of perampanel is:
- Perampanel is a white to yellowish white powder. It is freely soluble in N-methylpyrrolidone, sparingly soluble in acetonitrile and acetone, slightly soluble in methanol, ethanol and ethyl acetate, very slightly soluble in 1-octanol and diethyl ether and practically insoluble in heptane and water.
- FYCOMPA (perampanel) tablets are round, bi-convex, film coated tablets containing 2 mg, 4 mg, 6 mg, 8 mg, 10 mg or 12 mg of perampanel. Tablets contain the following inactive ingredients: lactose monohydrate, low substituted hydroxypropyl cellulose, povidone, microcrystalline cellulose, magnesium stearate, hypromellose, polyethylene glycol, talc and titanium dioxide. Tablets of different strengths also may contain yellow ferric oxide (10 mg and 2 mg), red ferric oxide (2 mg, 4 mg, 6 mg, 8 mg), black ferric oxide (8 mg) and FD&C blue # 2 indigo carmine aluminum lake (10 mg and 12 mg).
## Pharmacodynamics
- Psychomotor Performance
- In a healthy volunteer study to assess the effects of FYCOMPA on psychomotor performance using a standard battery of assessments including simulated driving, single and multiple daily doses of FYCOMPA 4 mg did not impair simple psychomotor tasks, driving performance or sensori-motor coordination. Single and multiple doses of 8 mg and 12 mg impaired psychomotor performance in a dose-related manner. Car handling ability was impaired after dosing of FYCOMPA 12 mg, but postural stability was not significantly impaired. Performance testing returned to baseline within 2 weeks of cessation of FYCOMPA dosing.
- Interactions with Alcohol
- In the above study, when administered to healthy subjects receiving alcohol to achieve a blood concentration of 80-100mg/100mL, FYCOMPA consistently impaired simple psychomotor performance after single doses of 4 to 12 mg, and after 21 days of multiple 12 mg/day doses. The effects of FYCOMPA on complex tasks such as driving ability were additive or supra-additive to the impairment effects of alcohol. FYCOMPA enhanced the effects of alcohol on vigilance and alertness, and increased levels of anger, confusion, and depression.
- Potential to Prolong QT Interval
- In a placebo-controlled thorough QT study perampanel in healthy subjects, there was no evidence that perampanel caused QT interval prolongation of clinical significance at doses of 6 or 12 mg (i.e., the upper bound of the 95% confidence interval for the largest placebo-adjusted baseline-corrected QTc was below 10 msec). The exposures observed with the 12 mg dose in this study will not cover the exposures expected in patients with hepatic impairment taking doses over 6 mg/day. At the maximum recommended dose (12 mg), perampanel did not prolong the QTc interval to any clinically relevant extent.
## Pharmacokinetics
- Pharmacokinetics of perampanel are similar in healthy subjects and patients with partial-onset seizures. The half-life of perampanel is about 105 hours, so that steady state is reached in about 2-3 weeks. AUC of perampanel increased in a dose-proportional manner after single-dose administration of 0.2-12 mg and after multiple-dose administration of 1-12 mg once daily.
- Absorption
- Perampanel is rapidly and completely absorbed after oral administration with negligible first-pass metabolism. Median Tmax ranged from 0.5 to 2.5 hours under fasted condition. Food does not affect the extent of absorption (AUC), but slows the rate of absorption. Under fed conditions, Cmax of perampanel was decreased by 28-40% and Tmax was delayed by 2-3 hours compared to that under fasted conditions.
- Distribution
- Data from in vitro studies indicate that, in the concentration range of 20 to 2000 ng/mL, perampanel is approximately 95-96% bound to plasma proteins, mainly bound to albumin and α1-acid glycoprotein. Blood to plasma ratio of perampanel is 0.55-0.59.
- Metabolism
- Perampanel is extensively metabolized via primary oxidation and sequential glucuronidation. Oxidative metabolism is primarily mediated by CYP3A4/5 and to a lesser extent by CYP1A2 and CYP2B6, based on results of in vitro studies using recombinant human CYPs and human liver microsomes. Other CYP enzymes may also be involved.
- Following administration of radiolabeled perampanel, unchanged perampanel accounted for 74-80% of total radioactivity in systemic circulation, whereas only trace amounts of individual perampanel metabolites were detected in plasma.
- Elimination
- Following administration of a radiolabeled perampanel dose to 8 healthy elderly subjects, 22% of administered radioactivity was recovered in the urine and 48% in the feces. In urine and feces, recovered radioactivity was primarily composed of a mixture of oxidative and conjugated metabolites. Population pharmacokinetic analysis of pooled data from 19 Phase 1 studies reported that t1/2 of perampanel was 105 hours on average. Apparent clearance of perampanel in healthy subjects and patients was approximately 12 mL/min.
- Specific Populations
- Hepatic Impairment
- The pharmacokinetics of perampanel following a single 1 mg dose were evaluated in 12 subjects with mild and moderate hepatic impairment (Child-Pugh A and B, respectively) compared with 12 demographically matched healthy subjects. The total (free and protein bound) exposure (AUC0-inf) of perampanel was 50% greater in subjects with mild hepatic impairment and more than doubled (2.55-fold) in subjects with moderate hepatic impairment compared to their healthy controls. The AUC0-inf of free perampanel in subjects with mild and moderate hepatic impairment was 1.8-fold and 3.3-fold, respectively, of those in matched healthy controls. The t1/2 was prolonged in subjects with mild impairment (306 vs. 125 hours) and moderate impairment (295 vs. 139 hours). Perampanel has not been studied in subjects with severe hepatic impairment.
- Renal Impairment
- A dedicated study has not been conducted to evaluate the pharmacokinetics of perampanel in patients with renal impairment. Population pharmacokinetic analysis was performed on pooled data from patients with partial-onset seizures and receiving FYCOMPA up to 12 mg/day in placebo-controlled clinical trials. Results showed that perampanel apparent clearance was decreased by 27% in patients with mild renal impairment (creatinine clearance 50-80 mL/min) compared to patients with normal renal function (creatinine clearance >80 mL/min), with a corresponding 37% increase in AUC. Considering the substantial overlap in the exposure between normal and mildly impaired patients, no dosage adjustment is necessary for patients with mild renal impairment. Perampanel has not been studied in patients with severe renal impairment and patients undergoing hemodialysis.
- Sex
- In a population pharmacokinetic analysis of patients with partial-onset seizures receiving FYCOMPA in placebo-controlled clinical trials, perampanel apparent clearance in females (0.605 L/hr) was 17% lower than in males (0.730 L/hr). No dosage adjustment is necessary based on sex.
- Pediatric Patients
- FYCOMPA has not been studied in patients <12 years old. In a population pharmacokinetic analysis of patients with partial-onset seizures ranging in age from 12 to 74 years receiving FYCOMPA in placebo-controlled trials, apparent clearance of perampanel in adolescents (0.787 L/hr) was slightly, but not significantly, higher than that in adults. Pediatric patients above 12 years old can be dosed similarly to adults.
- Geriatrics
- In a population pharmacokinetic analysis of patients with partial-onset seizures ranging in age from 12 to 74 years receiving FYCOMPA in placebo-controlled trials, no significant effect of age on perampanel apparent clearance was found.
- Race
- In a population pharmacokinetic analysis of patients with partial-onset seizures which included 576 Caucasians, 14 Blacks, 97 non-Chinese Asians, and 62 Chinese receiving FYCOMPA in placebo-controlled trials, no significant effect of race on perampanel apparent clearance was found. No dosage adjustment is necessary.
- Drug Interaction Studies
- In Vitro Assessment of Drug Interactions
- Drug Metabolizing Enzymes
- In human liver microsomes, perampanel at a concentration of 30 μmol/L, about 10 fold the steady state Cmax at a 12 mg dose, had a weak inhibitory effect on CYP2C8, CYP3A4, UGT1A9 and UGT2B7. Perampanel did not inhibit CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, UGT1A1, UGT1A4, and UGT1A6 at a concentration of 30 µmol/L.
- Compared with positive controls (including phenobarbital and rifampin), perampanel was found to weakly induce CYP2B6 (30µmol/L) and CYP3A4/5 (≥ 3µmol/L) in cultured human hepatocytes. Perampanel also induced UGT1A1 (≥ 3µmol/L) and UGT1A4 (30µmol/L). Perampanel did not induce CYP1A2 at concentrations up to 30 µmol/L.
- Transporters
- In vitro studies showed that perampanel is not a substrate or significant inhibitor of the following: organic anion transporting polypeptides 1B1 and 1B3; organic anion transporters 1, 2, 3, and 4; organic cation transporters 1, 2, and 3; efflux transporters P-glycoprotein and Breast Cancer Resistance Protein.
- In Vivo Assessment of Drug Interactions
- Drug Interactions with AEDs
- Effect of concomitant AEDs on FYCOMPA:
- Carbamazepine. As an inducer of CYP enzymes, carbamazepine increases perampanel clearance. Steady state administration of carbamazepine at 300 mg BID in healthy subjects reduced the Cmax and AUC0-inf of a single 2 mg dose of perampanel by 26% and 67% respectively. The t1/2 of perampanel was shortened from 56.8 hours to 25 hours. In clinical studies examining partial-onset seizures, a population pharmacokinetic analysis showed that perampanel AUC was reduced by 67% in patients on carbamazepine compared to the AUC in patients not on enzyme-inducing AEDs.
- Oxcarbazepine. In clinical studies examining partial-onset seizures, a population pharmacokinetic analysis showed that perampanel AUC was reduced by half in patients on oxcarbazepine compared to patients not on enzyme-inducing AEDs.
- Phenytoin. In clinical studies examining partial-onset seizures, a population pharmacokinetic analysis showed that perampanel AUC was reduced by half in patients on phenytoin compared to patients not on enzyme-inducing AEDs.
- Phenobarbital and Primidone: In a population pharmacokinetic analysis of patients with partial-onset seizures in clinical trials (37 patients coadministered phenobarbital and 9 patients coadministered primidone) no significant effect on perampanel AUC was found. A modest effect of phenobarbital and primidone on perampanel concentrations cannot be excluded.
- Topiramate: Population pharmacokinetic analysis of patients with partial-onset seizures in clinical trials showed that perampanel AUC was reduced by approximately 20% in patients on topiramate compared to patients not on enzyme-inducing AEDs.
- Other AEDs: Population pharmacokinetic analysis of patients with partial-onset seizures in clinical trials showed that clobazam, clonazepam, lamotrigine, levetiracetam, valproate, and zonisamide did not have an effect on perampanel clearance.
- Other strong CYP3A inducers (e.g., rifampin, St. John’s wort) may also greatly increase clearance of perampanel and reduce perampanel plasma concentrations.
- Effect of FYCOMPA on concomitant AEDs:
- FYCOMPA up to 12 mg/day did not significantly affect the clearance of clonazepam, levetiracetam, phenobarbital, phenytoin, topiramate, or zonisamide based on a population pharmacokinetic analysis of patients with partial-onset seizures in clinical trials. FYCOMPA had a statistically significant effect on the clearance of carbamazepine, clobazam, lamotrigine, and valproic acid, but the increases in clearance of these drugs were each less than 10% at the highest perampanel dose evaluated (12 mg/day). FYCOMPA coadministration resulted in a 26% decrease in oxcarbazepine clearance and increased its concentrations. The concentrations of 10-monohydroxy metabolite (MHD), the active metabolite of oxcarbazepine, were not measured.
- Drug-drug interaction studies with other drugs
- Effect of other drugs on FYCOMPA
- Ketoconazole. Coadministration of single 1-mg dose of perampanel with 400 mg once daily doses of ketoconazole, a strong CYP3A4 inhibitor, for 8 days in healthy subjects prolonged perampanel t1/2 by 15% (67.8 vs. 58.4 hours) and increased AUC0-inf by 20%.
- Oral contraceptives. Perampanel Cmax and AUC0-72h were not altered when a single 6-mg dose of perampanel was administered to healthy female subjects following a 21-day course of oral contraceptives containing ethinylestradiol 30 µg and levonorgestrel 150 µg.
- Effect of FYCOMPA on other drugs
- Midazolam. Perampanel administered as 6 mg once daily doses for 20 days decreased AUC0-inf and Cmax of midazolam (a CYP3A4 substrate) by 13% and 15%, respectively, in healthy subjects.
- Oral Contraceptives. Coadministration of perampanel 4 mg once daily with an oral contraceptive containing ethinylestradiol 30 µg and levonorgestrel 150 µg for 21 days did not alter Cmax or AUC0-24h of either ethinylestradiol or levonorgestrel in healthy female subjects. In another study, a single dose of the oral contraceptive was administered following 21-day once daily dosing of FYCOMPA 12 mg or 8 mg in healthy females. FYCOMPA at 12 mg did not alter AUC0-24h of ethinylestradiol but decreased its Cmax by 18%, and also decreased Cmax and AUC0-24h of levonorgestrel by 42% and 40%, respectively. FYCOMPA at 8 mg did not have significant effect on Cmax or AUC0-24h of either ethinylestradiol or levonorgestrel, with a small decrease in AUC0-24h of levonorgestrel (9%).
- Levodopa. Perampanel administered as 4 mg once daily doses for 19 days had no effect on Cmax and AUC0-inf of levodopa in healthy subjects.
## Nonclinical Toxicology
- Carcinogenesis
- Perampanel was administered orally to mice (1, 3, 10, or 30 mg/kg/day) and rats (10, 30, or 100 mg/kg/day in males; 3, 10, or 30 mg/kg/day in females) for up to 104 weeks. There was no evidence of drug-related tumors in either species. Plasma perampanel exposures (AUC) at the highest doses tested were less than that in humans dosed at 8 mg/day.
- Mutagenesis
- Perampanel was negative in the in vitro Ames and mouse lymphoma tk assays, and in the in vivo rat micronucleus assay.
- Impairment of Fertility
- In male and female rats administered perampanel (oral doses of 1, 10, or 30 mg/kg/day) prior to and throughout mating and continuing in females to gestation day 6, there were no clear effects on fertility. Prolonged and/or irregular estrus cycles were observed at all doses but particularly at the highest dose tested. Plasma perampanel exposures (AUC) at all doses were lower than that in humans dosed at 8 mg/day.
# Clinical Studies
- The efficacy of FYCOMPA in partial-onset seizures, with or without secondary generalization, was studied in patients who were not adequately controlled with 1 to 3 concomitant AEDs in 3 randomized, double-blind, placebo-controlled, multicenter trials (Studies 1, 2, and 3) in adult and adolescent patients (aged 12 years and older). All trials had an initial 6-week Baseline Period, during which patients were required to have more than five seizures in order to be randomized. The Baseline Period was followed by a 19-week Treatment Period consisting of a 6-week Titration Phase and a 13-week Maintenance Phase. Patients in these 3 trials had a mean duration of epilepsy of approximately 21 years and a median baseline seizure frequency ranging from 9.3 to 14.3 seizures per 28 days. During the trials, more than 85% of patients were taking 2 to 3 concomitant AEDs with or without concurrent vagal nerve stimulation, and approximately 50% were on at least one AED known to induce CYP3A4, an enzyme critical to the metabolism of FYCOMPA (i.e., carbamazepine, oxcarbazepine, or phenytoin), resulting in a significant reduction in FYCOMPA’s serum concentration.
- Each study evaluated placebo and multiple FYCOMPA dosages (see Figure 1). During the Titration period in all 3 trials, patients on FYCOMPA received an initial 2 mg once daily dose, which was subsequently increased in weekly increments of 2 mg per day to the final target dose. Patients experiencing intolerable adverse reactions were permitted to have their dose reduced to the previously tolerated dose.
- The primary endpoint in Studies 1, 2, and 3 was the percent change in seizure frequency per 28 days during the Treatment Period as compared to the Baseline Period. The criterion for statistical significance was p<0.05. Table 3 shows the results of these studies. A statistically significant decrease in seizure rate was observed at doses of 4 to 12 mg per day. Dose response was apparent at 4 to 8 mg with little additional reduction in frequency at 12 mg per day.
- Table 4 presents an analysis combining data from all 3 studies, grouping patients based upon whether or not concomitant AED inducers (carbamazepine, oxcarbazepine, or phenytoin) were used. The analysis revealed a substantially reduced effect in the presence of inducers.
- Figure 1 shows the proportion of patients with different percent reductions during the maintenance phase over baseline across all three trials. Patients in whom the seizure frequency increased are shown at left as “worse.” Patients in whom the seizure frequency decreased are shown in the remaining five categories. Thus, the percentages of patients with a 40 to <60% reduction in seizure frequency were 13.2%, 17.4%, 19.0%, and 15.8% for placebo, 4, 8, and 12 mg, respectively.
- The percentages of patients with a 50% or greater reduction in seizure frequency were 19.3%, 28.5%, 35.3%, 35.0% for placebo, 4, 8, and 12 mg, respectively.
# How Supplied
- FYCOMPA (perampanel) Tablets 2 mg are orange, round, biconvex, film-coated tablets debossed with "2" on one side and "Є 275" on the other. They are supplied as follows:
- Bottles of 30 NDC 62856-272-30
- Bottles of 90 NDC 62856-272-90
- FYCOMPA (perampanel) Tablets 4 mg are red, round, biconvex, film-coated tablets debossed with "4" on one side and "Є 277" on the other. They are supplied as follows:
- Bottles of 30 NDC 62856-274-30
- Bottles of 90 NDC 62856-274-90
- FYCOMPA (perampanel) Tablets 6 mg are pink, round, biconvex, film-coated tablets debossed with "6" on one side and "Є 294" on the other. They are supplied as follows:
- Bottles of 30 NDC 62856-276-30
- Bottles of 90 NDC 62856-276-90
- FYCOMPA (perampanel) Tablets 8 mg are purple, round, biconvex, film-coated tablets debossed with "8" on one side and "Є 295" on the other. They are supplied as follows:
- Bottles of 30 NDC 62856-278-30
- Bottles of 90 NDC 62856-278-90
- FYCOMPA (perampanel) Tablets 10 mg are green, round, biconvex, film-coated tablets debossed with "10" on one side and "Є 296" on the other. They are supplied as follows:
- Bottles of 30 NDC 62856-280-30
- Bottles of 90 NDC 62856-280-90
- FYCOMPA (perampanel) Tablets 12 mg are blue, round, biconvex, film-coated tablets debossed with "12" on one side and "Є 297" on the other. They are supplied as follows:
- Bottles of 30 NDC 62856-282-30
- Bottles of 90 NDC 62856-282-90
- Storage
- Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F).
## Storage
There is limited information regarding Perampanel Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Inform patients of the availability of a Medication Guide, and instruct them to read the Medication Guide prior to taking FYCOMPA. Instruct patients to take FYCOMPA only as prescribed.
- Serious Psychiatric and Behavioral Reactions
- Counsel patients, families and caregivers of patients of the need to monitor for the emergence of anger, aggression, hostility, unusual changes in mood, personality, or behavior, and other behavioral symptoms. Advise them to report any such symptoms immediately to their health care providers.
- Suicidal Thinking and Behavior
- Counsel patients, their caregivers, and families that AEDs, including FYCOMPA, may increase the risk of suicidal thinking and behavior and advise them of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Instruct patients, caregivers and families to report behaviors of concern immediately to healthcare providers.
- Neurologic Effects: Dizziness, Gait Disturbance, Somnolence, and Fatigue
- Counsel patients that FYCOMPA may cause dizziness, gait disturbance, somnolence, and fatigue. Advise patients taking FYCOMPA not to drive, operate complex machinery, or engage in other hazardous activities until they have become accustomed to any such effects associated with FYCOMPA.
- Falls
- Counsel patients that FYCOMPA may cause falls and injuries.
- Withdrawal of Antiepileptic Drugs
- Counsel patients that abrupt discontinuation of FYCOMPA may increase seizure frequency.
- Contraceptives
- Counsel patients that FYCOMPA may decrease efficacy of contraceptives containing levonorgestrel.
- Alcohol and Other CNS Depressants
- Counsel patients that FYCOMPA may enhance the impairment effects of alcohol. These effects may also be seen if FYCOMPA is taken with other CNS depressants.
- Missed Doses
- Counsel patients that if they miss a dose, they should resume dosing the following day at their prescribed daily dose. Instruct patients to contact their physician if more than one day of dosing is missed.
- Controlled Substance
- Counsel patients that FYCOMPA is a controlled substance that can be misused and abused.
- Pregnancy Registry
- To provide information regarding the effects of in utero exposure to FYCOMPA, recommend pregnant patients treated with FYCOMPA to enroll in the NAAED Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org.
# Precautions with Alcohol
- Alcohol-Perampanel interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- FYCOMPA®[2]
# Look-Alike Drug Names
There is limited information regarding Perampanel Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Perampanel | |
170c8535b66b699cf45e9b75d34c61c20203c29d | wikidoc | Percentile | Percentile
# Overview
A percentile is the value of a variable below which a certain percent of observations fall. So the 20th percentile is the value (or score) below which 20 percent of the observations may be found. The term percentile and the related term percentile rank are often used in descriptive statistics as well as in the reporting of scores from norm-referenced tests.
The 25th percentile is also known as the first quartile; the 50th percentile as the median.
There is no standard definition of percentile
, however all definitions yield similar results when the number of observations is large. One definition is that the p-th percentile of N ordered values is obtained by first calculating the rank n = \frac{N}{100}\,p+\frac{1}{2}, rounding to the nearest integer, and taking the value that corresponds to that rank.
An alternative method, used in many applications, is to use linear interpolation between the two nearest ranks instead of rounding. Specifically, if we have N values v_1, v_2, v_3,...,v_N , ranked from least to greatest, define the percentile corresponding to the n-th value as p_n=\frac{100}{N}(n-\frac{1}{2}). In this way, for example, if N=5 the percentile corresponding to the third value is p_3=\frac{100}{5}(3-\frac{1}{2})=50.
Suppose we now want to calculate the value v corresponding to a percentile p. If p or p>p_N, we take v=v_1 or v=v_N respectively. Otherwise, we find an integer k such that p_k\le p \le p_{k+1} , and take v=v_k+\frac{N}{100}(p-p_k)(v_{k+1}-v_k).
When p=50, the formula gives the median. When N is even and p=25, the formula gives the median of the first \frac{N}{2} values.
Linked with the percentile function, there is also a weighted percentile, where the percentage in the total weight is counted instead of the total number. In most spreadsheet applications there is no standard function for a weighted percentile. One method for weighted percentile extends the method described above. Suppose we have positive weights w_1, w_2, w_3,...,w_N , associated respectively with our N sample values. Let S_n=\sum_{k=1}^{n}w_k be the n-th partial sum of these weights. Then the formulas above are generalized by taking p_n=\frac{100}{S_N}(S_n-\frac{w_n}{2}) and v=v_k+\frac{p-p_k}{p_{k+1}-p_k}(v_{k+1}-v_k).
# Relation between percentile, decile and quartile
- P25 = Q1
- P50 = D5 = Q2 = median value
- P75 = Q3
- P100 = D10 = Q4
- P10 = D1
- P20 = D2
- P30 = D3
- P40 = D4
- P60 = D6
- P70 = D7
- P80 = D8
- P90 = D9
Note: One quartile is equivalent to 25 percentile while 1 decile is equal to 10 percentile.
# Examples
When ISPs bill "Burstable" Internet bandwidth, the 95th or 98th percentile usually cuts off the top 5% or 2% of bandwidth peaks in each month, and then bills at the nearest rate. In this way infrequent peaks are ignored, and the customer is charged in a fairer way.
Physicians will often use infant and children's weight and height percentile as a gauge of relative health. | Percentile
# Overview
A percentile is the value of a variable below which a certain percent of observations fall. So the 20th percentile is the value (or score) below which 20 percent of the observations may be found. The term percentile and the related term percentile rank are often used in descriptive statistics as well as in the reporting of scores from norm-referenced tests.
The 25th percentile is also known as the first quartile; the 50th percentile as the median.
There is no standard definition of percentile
[1]
[2]
, however all definitions yield similar results when the number of observations is large. One definition is that the <math>p</math>-th percentile of <math>N</math> ordered values is obtained by first calculating the rank <math> n = \frac{N}{100}\,p+\frac{1}{2}</math>, rounding to the nearest integer, and taking the value that corresponds to that rank.
An alternative method, used in many applications, is to use linear interpolation between the two nearest ranks instead of rounding. Specifically, if we have <math>N</math> values <math>v_1</math>, <math> v_2</math>, <math>v_3</math>,...,<math>v_N</math> , ranked from least to greatest, define the percentile corresponding to the <math>n</math>-th value as <math>p_n=\frac{100}{N}(n-\frac{1}{2}).</math> In this way, for example, if <math>N=5</math> the percentile corresponding to the third value is <math>p_3=\frac{100}{5}(3-\frac{1}{2})=50.</math>
Suppose we now want to calculate the value <math> v </math> corresponding to a percentile <math>p</math>. If <math>p<p_1</math> or <math>p>p_N</math>, we take <math>v=v_1</math> or <math>v=v_N</math> respectively. Otherwise, we find an integer <math>k</math> such that <math>p_k\le p \le p_{k+1}</math> , and take <math>v=v_k+\frac{N}{100}(p-p_k)(v_{k+1}-v_k).</math>
[3]
When <math>p=50</math>, the formula gives the median. When <math>N</math> is even and <math>p=25</math>, the formula gives the median of the first <math>\frac{N}{2}</math> values.
Linked with the percentile function, there is also a weighted percentile, where the percentage in the total weight is counted instead of the total number. In most spreadsheet applications there is no standard function for a weighted percentile. One method for weighted percentile extends the method described above. Suppose we have positive weights <math>w_1</math>, <math> w_2</math>, <math>w_3</math>,...,<math>w_N</math> , associated respectively with our <math>N</math> sample values. Let <math>S_n=\sum_{k=1}^{n}w_k</math> be the <math>n</math>-th partial sum of these weights. Then the formulas above are generalized by taking <math>p_n=\frac{100}{S_N}(S_n-\frac{w_n}{2})</math> and <math>v=v_k+\frac{p-p_k}{p_{k+1}-p_k}(v_{k+1}-v_k).</math>
# Relation between percentile, decile and quartile
- P25 = Q1
- P50 = D5 = Q2 = median value
- P75 = Q3
- P100 = D10 = Q4
- P10 = D1
- P20 = D2
- P30 = D3
- P40 = D4
- P60 = D6
- P70 = D7
- P80 = D8
- P90 = D9
Note: One quartile is equivalent to 25 percentile while 1 decile is equal to 10 percentile.
# Examples
When ISPs bill "Burstable" Internet bandwidth, the 95th or 98th percentile usually cuts off the top 5% or 2% of bandwidth peaks in each month, and then bills at the nearest rate. In this way infrequent peaks are ignored, and the customer is charged in a fairer way.
Physicians will often use infant and children's weight and height percentile as a gauge of relative health. | https://www.wikidoc.org/index.php/Percentile | |
682b43cf566cb87dbd0128895eaada79ffd4021a | wikidoc | Perception | Perception
# Overview
In psychology and the cognitive sciences, perception is the process of acquiring, interpreting, selecting, and organizing sensory information. It is a task far more complex than was imagined in the 1950s and 1960s, when it was proclaimed that building perceiving machines would take about a decade, but, needless to say, that is still very far from reality. The word perception comes from the Latin perception-, percepio, , meaning "receiving, collecting, action of taking possession, apprehension with the mind or senses." --OED.com. Methods of studying perception range from essentially biological or physiological approaches, through psychological approaches through the philosophy of mind and in empiricist epistemology, such as that of David Hume, John Locke, George Berkeley, or as in Merleau Ponty's affirmation of perception as the basis of all science and knowledge.
There are two basic theories of perception: Passive Perception (PP) and Active Perception (PA). The passive perception (conceived by René Descartes) is addressed in this article and could be surmised as the following sequence of events: surrounding - > input (senses) - > processing (brain) - > output (re-action). Although still supported by mainstream philosophers, psychologists and neurologists, this theory is nowadays losing momentum. The theory of active perception has emerged from extensive research of sensory illusions with works of Professor Emeritus Richard L Gregory in a lead. This theory is increasingly gaining experimental support and could be surmised as dynamic relationship between “description” (in the brain) senses surrounding.
# History of the study of perception
Perception is one of the oldest fields within scientific psychology, and there are correspondingly many theories about its underlying processes. The oldest quantitative law in psychology is the Weber-Fechner law, which quantifies the relationship between the intensity of physical stimuli and their perceptual effects. It was the study of perception that gave rise to the Gestalt school of psychology, with its emphasis on holistic approach. .
# Perception and reality
Many cognitive psychologists hold that, as we move about in the world, we create a model of how the world works. That is, we sense the objective world, but our sensations map to percepts, and these percepts are provisional, in the same sense that scientific hypotheses are provisional (cf. in the scientific method).
As we acquire new information, our percepts shift, thus solidifying the idea that perception is a matter of belief. Abraham Pais' biography refers to the 'esemplastic' nature of imagination. In the case of visual perception, some people can actually see the percept shift in their mind's eye. Others who are not picture thinkers, may not necessarily perceive the 'shape-shifting' as their world changes. The 'esemplastic' nature has been shown by experiment: an ambiguous image has multiple interpretations on the perceptual level.
Just as one object can give rise to multiple percepts, so an object may fail to give rise to any percept at all: if the percept has no grounding in a person's experience, the person may literally not perceive it.
This confusing ambiguity of perception is exploited in human technologies such as camouflage, and also in biological mimicry, for example by Peacock butterflies, whose wings bear eye markings that birds respond to as though they were the eyes of a dangerous predator. Perceptual ambiguity is not restricted to vision. For example, recent touch perception research (Robles-De-La-Torre & Hayward 2001) found that kinesthesia-based haptic perception strongly relies on the forces experienced during touch. This makes it possible to produce illusory touch percepts (see also the MIT Technology Review article The Cutting Edge of Haptics).
Cognitive theories of perception assume there is a poverty of stimulus. This (with reference to perception) is the claim that sensations are, by themselves, unable to provide a unique description of the world. Sensations require 'enriching', which is the role of the mental model. A different type of theory is the perceptual ecology approach of James J. Gibson. Gibson rejected the assumption of a poverty of stimulus by rejecting the notion that perception is based in sensations. Instead, he investigated what information is actually presented to the perceptual systems. He (and the psychologists who work within this paradigm) detailed how the world could be specified to a mobile, exploring organism via the lawful projection of information about the world into energy arrays. Specification is a 1:1 mapping of some aspect of the world into a perceptual array; given such a mapping, no enrichment is required and perception is direct.
# Perception-in-Action
The ecological understanding of perception advanced from Gibson's early work is perception-in-action, the notion that perception is a requisite property of animate action, without perception action would not be guided and without action perception would be pointless. Animate actions require perceiving and moving together. In a sense, "perception and movement are two sides of the same coin, the coin is action." (D.N. Lee) A mathematical theory of perception-in-action has been devised and investigated in many forms of controlled movement by many different species of organism, General Tau Theory. According to this theory, tau information, or time-to-goal information is the fundamental 'percept' in perception.-
# Perception and action
We gather information about the world and interact with it through our actions. Perceptual information is critical for action. Perceptual deficits may lead to profound deficits in action (for touch-perception-related deficits, see Robles-De-La-Torre 2006).
# Types of perception
- Amodal perception
- Color perception
- Depth perception
- Visual perception
- Form perception
- Haptic perception
- Speech perception
- Perception as Interpretation
- Numeric Value of Perception
- Pitch perception
- Harmonic perception
- Rhythmic perception
# References and Further Reading
- Flanagan, J.R., Lederman, S.J. Neurobiology: Feeling bumps and holes, News and Views, Nature, 412(6845):389-91 (2001).
- James.J.Gibson, The Senses Considered as Perceptual Systems. Boston 1966.
- James J. Gibson. The Ecological Approach to Visual Perception. Lawrence Erlbaum Associates, 1987. ISBN 0898599598
- Hayward V, Astley OR, Cruz-Hernandez M, Grant D, Robles-De-La-Torre G. Haptic interfaces and devices. Sensor Review 24(1), pp. 16-29 (2004).
- Robles-De-La-Torre G. & Hayward V. Force Can Overcome Object Geometry In the perception of Shape Through Active Touch. Nature 412 (6845):445-8 (2001).
- Robles-De-La-Torre G. The Importance of the Sense of Touch in Virtual and Real Environments. IEEE Multimedia 13(3), Special issue on Haptic User Interfaces for Multimedia Systems, pp. 24-30 (2006). | Perception
Template:Psychology
Template:Neuropsychology
# Overview
In psychology and the cognitive sciences, perception is the process of acquiring, interpreting, selecting, and organizing sensory information. It is a task far more complex than was imagined in the 1950s and 1960s, when it was proclaimed that building perceiving machines would take about a decade, but, needless to say, that is still very far from reality. The word perception comes from the Latin perception-, percepio, , meaning "receiving, collecting, action of taking possession, apprehension with the mind or senses." --OED.com. Methods of studying perception range from essentially biological or physiological approaches, through psychological approaches through the philosophy of mind and in empiricist epistemology, such as that of David Hume, John Locke, George Berkeley, or as in Merleau Ponty's affirmation of perception as the basis of all science and knowledge.
There are two basic theories of perception: Passive Perception (PP) and Active Perception (PA). The passive perception (conceived by René Descartes) is addressed in this article and could be surmised as the following sequence of events: surrounding - > input (senses) - > processing (brain) - > output (re-action). Although still supported by mainstream philosophers, psychologists and neurologists, this theory is nowadays losing momentum. The theory of active perception has emerged from extensive research of sensory illusions with works of Professor Emeritus Richard L Gregory in a lead. This theory is increasingly gaining experimental support and could be surmised as dynamic relationship between “description” (in the brain) < - > senses < - > surrounding.
# History of the study of perception
Perception is one of the oldest fields within scientific psychology, and there are correspondingly many theories about its underlying processes. The oldest quantitative law in psychology is the Weber-Fechner law, which quantifies the relationship between the intensity of physical stimuli and their perceptual effects. It was the study of perception that gave rise to the Gestalt school of psychology, with its emphasis on holistic approach. .
# Perception and reality
Many cognitive psychologists hold that, as we move about in the world, we create a model of how the world works. That is, we sense the objective world, but our sensations map to percepts, and these percepts are provisional, in the same sense that scientific hypotheses are provisional (cf. in the scientific method).
As we acquire new information, our percepts shift, thus solidifying the idea that perception is a matter of belief. Abraham Pais' biography refers to the 'esemplastic' nature of imagination. In the case of visual perception, some people can actually see the percept shift in their mind's eye. Others who are not picture thinkers, may not necessarily perceive the 'shape-shifting' as their world changes. The 'esemplastic' nature has been shown by experiment: an ambiguous image has multiple interpretations on the perceptual level.
Just as one object can give rise to multiple percepts, so an object may fail to give rise to any percept at all: if the percept has no grounding in a person's experience, the person may literally not perceive it.
This confusing ambiguity of perception is exploited in human technologies such as camouflage, and also in biological mimicry, for example by Peacock butterflies, whose wings bear eye markings that birds respond to as though they were the eyes of a dangerous predator. Perceptual ambiguity is not restricted to vision. For example, recent touch perception research (Robles-De-La-Torre & Hayward 2001) found that kinesthesia-based haptic perception strongly relies on the forces experienced during touch. This makes it possible to produce illusory touch percepts (see also the MIT Technology Review article The Cutting Edge of Haptics).
Cognitive theories of perception assume there is a poverty of stimulus. This (with reference to perception) is the claim that sensations are, by themselves, unable to provide a unique description of the world. Sensations require 'enriching', which is the role of the mental model. A different type of theory is the perceptual ecology approach of James J. Gibson. Gibson rejected the assumption of a poverty of stimulus by rejecting the notion that perception is based in sensations. Instead, he investigated what information is actually presented to the perceptual systems. He (and the psychologists who work within this paradigm) detailed how the world could be specified to a mobile, exploring organism via the lawful projection of information about the world into energy arrays. Specification is a 1:1 mapping of some aspect of the world into a perceptual array; given such a mapping, no enrichment is required and perception is direct.
# Perception-in-Action
The ecological understanding of perception advanced from Gibson's early work is perception-in-action, the notion that perception is a requisite property of animate action, without perception action would not be guided and without action perception would be pointless. Animate actions require perceiving and moving together. In a sense, "perception and movement are two sides of the same coin, the coin is action." (D.N. Lee) A mathematical theory of perception-in-action has been devised and investigated in many forms of controlled movement by many different species of organism, General Tau Theory. According to this theory, tau information, or time-to-goal information is the fundamental 'percept' in perception.-
# Perception and action
We gather information about the world and interact with it through our actions. Perceptual information is critical for action. Perceptual deficits may lead to profound deficits in action (for touch-perception-related deficits, see Robles-De-La-Torre 2006).
# Types of perception
- Amodal perception
- Color perception
- Depth perception
- Visual perception
- Form perception
- Haptic perception
- Speech perception
- Perception as Interpretation
- Numeric Value of Perception
- Pitch perception
- Harmonic perception
- Rhythmic perception
# References and Further Reading
- Flanagan, J.R., Lederman, S.J. Neurobiology: Feeling bumps and holes, News and Views, Nature, 412(6845):389-91 (2001).
- James.J.Gibson, The Senses Considered as Perceptual Systems. Boston 1966.
- James J. Gibson. The Ecological Approach to Visual Perception. Lawrence Erlbaum Associates, 1987. ISBN 0898599598
- Hayward V, Astley OR, Cruz-Hernandez M, Grant D, Robles-De-La-Torre G. Haptic interfaces and devices. Sensor Review 24(1), pp. 16-29 (2004).
- Robles-De-La-Torre G. & Hayward V. Force Can Overcome Object Geometry In the perception of Shape Through Active Touch. Nature 412 (6845):445-8 (2001).
- Robles-De-La-Torre G. The Importance of the Sense of Touch in Virtual and Real Environments. IEEE Multimedia 13(3), Special issue on Haptic User Interfaces for Multimedia Systems, pp. 24-30 (2006).
# External links
- Online papers on perception, by various authors, compiled by David Chalmers
- Paradoxical haptic objects. An example of touch illusions of shape. See also the MIT Technology Review article:
- The Cutting Edge of Haptics, by Duncan Graham-Rowe.
- Theories of Perception
- Richard L Gregory | https://www.wikidoc.org/index.php/Perception | |
2a2c24f666c1d4b0bef47ede6df04f4135c08589 | wikidoc | Periosteum | Periosteum
The periosteum is a thin layer of dense, irregular connective tissue membrane that covers the outer surface of a bone in all places except at joints. (The outer surface of bone at joints is covered with "articular cartilage", a type of hyaline cartilage.) As opposed to osseous tissue itself, periosteum has nociceptive nerve endings, making it very sensitive to manipulation. It also provides nourishment by providing the blood supply. Periosteum is attached to bone by strong collagenous fibers called Sharpey's fibres, which extend to the outer circumferential and interstitial lamellae.
Periosteum consists of an outer "fibrous layer" and inner "cambium layer". The fibrous layer contains fibroblasts while the cambium layer contains progenitor cells which develop into osteoblasts that are responsible for increasing the width of a long bone. (The length of a long bone is controlled by the epiphyseal plate.) After a bone fracture the progenitor cells develop into osteoblasts and chondroblasts which are essential to the healing process. Periosteum provides an attatchment for muscles and tendons.
Periosteum that covers the outer surface of the skull is known as "pericranium". | Periosteum
Template:Infobox Anatomy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
The periosteum is a thin layer of dense, irregular connective tissue membrane that covers the outer surface of a bone in all places except at joints. (The outer surface of bone at joints is covered with "articular cartilage", a type of hyaline cartilage.) As opposed to osseous tissue itself, periosteum has nociceptive nerve endings, making it very sensitive to manipulation. It also provides nourishment by providing the blood supply. Periosteum is attached to bone by strong collagenous fibers called Sharpey's fibres, which extend to the outer circumferential and interstitial lamellae.
Periosteum consists of an outer "fibrous layer" and inner "cambium layer". The fibrous layer contains fibroblasts while the cambium layer contains progenitor cells which develop into osteoblasts that are responsible for increasing the width of a long bone. (The length of a long bone is controlled by the epiphyseal plate.) After a bone fracture the progenitor cells develop into osteoblasts and chondroblasts which are essential to the healing process. Periosteum provides an attatchment for muscles and tendons.
Periosteum that covers the outer surface of the skull is known as "pericranium". | https://www.wikidoc.org/index.php/Pericranium | |
70dca11c719b14d10f09f2f5de637d500d7ae065 | wikidoc | Peripherin | Peripherin
Peripherin is a type III intermediate filament protein expressed mainly in neurons of the peripheral nervous system. It is also found in neurons of the central nervous system that have projections toward peripheral structures, such as spinal motor neurons. Its size, structure, and sequence/location of protein motifs is similar to other type III intermediate filament proteins such as desmin, vimentin and glial fibrillary acidic protein. Like these proteins, peripherin can self-assemble to form homopolymeric filamentous networks (networks formed from peripherin protein dimers), but it can also heteropolymerize with neurofilaments in several neuronal types. This protein in humans is encoded by the PRPH gene. Peripherin is thought to play a role in neurite elongation during development and axonal regeneration after injury, but its exact function is unknown. It is also associated with some of the major neuropathologies that characterize amyotropic lateral sclerosis (ALS), but despite extensive research into how neurofilaments and peripherin contribute to ALS, their role in this disease is still unidentified.
# History
Peripherin, first named such in 1984, was also known as 57 kDa neuronal intermediate filament prior to 1990. In 1987, a second distinct peripherally located retinal rod protein was also given the name peripherin. To distinguish between the two, this second protein is referred to peripherin 2 or peripherin/RDS (retinal degeneration slow) for its location and role in retinal disease.
# Structure and properties
Peripherin was discovered as being the major intermediate filament in neuroblastoma cell lines and in rat pheochromocytoma cells. It is classified by gene structure and coding sequence as a type III intermediate filament protein because of its homology with vimentin, glial fibrillary acidic protein, and desmin. All intermediate filament proteins share a common secondary structure consisting of three main domains, the most conserved of which is the central α-helical rod domain. This central coil is capped by non-helical head (N-terminal) and tail (C-terminal) domains. The α-helical rod domain contains repeating segments of hydrophobic amino acids, such that the first and fourth residues of every set of seven amino acids are usually nonpolar. This specific structure enables two intermediate filament polypeptides to coil together and create a "hydrophobic seal". The rod also contains specific placement of alternating acidic and basic residues, many of which are spaced 4 amino acids apart. This spacing is optimal for the formation of ionic salt bridges, which serve to stabilize the α-helical rod through intrachain interactions. A switch from intrachain salt bridges to interchain ionic associations may assist in intermediate filament assembly by utilizing electrostatic interactions to stabilize coiled-coil dimers. The head and tail regions of intermediate filament proteins vary in length and amino acid composition, with greater variations in length occurring in the tail regions.
Peripherin, unlike keratin IFs, can self-assemble and exist as homopolymers (see polymer). They can also heteropolymerize, or co-assemble, with other type III proteins or the light neurofilament subunit (NF-L) to form intermediate filament networks. Type III proteins like peripherin can exist in different states within a cell. These states include nonfilamentous particles which combine to firm short IFs, or squiggles. These squiggles come together to form long IFs that make up cytoskeletal networks. Studies of network assembly in spreading fibroblasts and differentiating nerve cells show that particles move along microtubules in a kinesin and dynein-dependent manner, and as spreading continues, the particles polymerize into intermediate filaments.
In addition to the main species of peripherin, 57 kDa, two other forms have been identified in mice: Per 61 and Per 56. These two alternatives are both made by alternative splicing. Per 61 is created by introducing a 32 amino acid insertion within coil 2b of the α-helical rod domain of peripherin. Per 56 is made by a receptor on exon 9 of the peripherin gene transcript which induces a frameshift and replacement of a 21 amino acid sequence in the C-terminal found on the dominant 57 form with a new 8 amino acid sequence. The functions of these two alternative forms of peripherin are unknown. Per 57 and 56 are normally co-expressed, whereas Per 61 is not found in normal peripherin expression in adult motor neurons.
## Tissue distribution
Peripherin is widely expressed in the cell body and axons of neurons in the peripheral nervous system. These include small-sized root ganglion neurons, lower motor neurons, sensory and motor neurons of the cranial nerves, and autonomic neurons in ganglia and the enteric nervous system. It is also expressed in the central nervous system in a small set of brainstem and spinal cord neurons that have projections toward peripheral structures. Some of these structures include the hypothalamic magnocellular nuclei, pontine cholinergic nuclei, some cerebellar nuclei, and scattered neurons in the cerebral cortex. They can also be found in the ventral horn neurons and in the cholinergic laterodorsal tegmentum (LDT) and pedunculopontine tegmentum (PPT) nuclei.
A comparison of peripherin expression in the posterior and lateral hypothalamus in mice showed a sixty-fold higher expression in the posterior hypothalamus. This higher expression is due to the presence of peripherin in the tuberomammillary neurons of the mouse posterior hypothalamus.
# Function
The diverse properties of intermediate filaments, compared with the conserved microtubule and actin filament proteins, could be responsible for the distinguishing molecular shapes of different cell types. In nerve cells, for example, the expressions of different types of IFs relates to the change in shape during development. Early stages of development in neurons is marked by the outgrowth of neurites and axons contributing to the cells asymmetric shape. During these transitions in cell shape, only homopolymer type III intermediate filaments, such as those with peripherin, are made. As the nerve cell matures, these type III IFs are replaced by more complex type IV neurofilaments expanding the diameter of axons in order to attain normal velocities of action potentials.
The exact function of peripherin is unknown. Expression of peripherin in development is greatest during the axonal growth phase and decreases postnatally, which suggests a role in neurite elongation and axonal guidance during development. Expression is also increased after axonal injury, such as peripheral axotomy in motor neurons and dorsal root ganglia. This upregulation implies that peripherin may also play a role in axon regeneration. However, experiments using peripherin depleted PC12 cells and peripherin knockout mice provide proof that the majority of neurons have no requirement of peripherin for axonal guidance and regrowth. PC12 cells lacking peripherin showed no defects in neurite outgrowth and peripherin knockout mice develop normally with no anatomical abnormalities or different phenotypes. In these experiments, peripherin deficiency did produce an upregulation of α-internexin, indicating the possibility that this type IV intermediate filament makes up for the loss of peripherin. Future studies of double knockout mice for both the peripherin and α-internexin genes might address this theory. However, while most peripherin knockout mice displayed normal neuron growth, its absence did affect development of a subset of unmyelinated sensory axons. In such mice, there was a "34% reduction in the number of L5 unmyelinated sensory fibers that correlated with a decreased binding of the lectin IB4."
# Gene (PRPH)
The complete sequence of the human (GenBank L14565), rat (GenBank M26232) and mouse (EMBL X59840) peripherin genes (PRPH) have been reported and complementary DNAs (cDNA) thus far described are those for rat, mouse and Xenopus peripherin. The use of a mouse cDNA probe during the in situ hybridization procedure allowed for the localization of the PRPH gene to the E-F region of mouse chromosome 15 and the q12-q13 region of human chromosome 12.
The overall structure of the peripherin gene is nine exons separated by eight introns. This configuration is conserved among the three known mammalian species with known coding for peripherin, namely human, rat and mouse. The nucleotide sequences of human and rat exons were 90% identical and produced a predicted protein that differed at only 18 of 475 amino acid residues. Comparison of introns 1 and 2 also yielded high homology of conserved segments. The 5' flanking regions and regulatory sequences were also very similar and a nerve growth factor negative regulatory element, a Hox protein (See Hox gene) binding site, and a heat shock element were found in all known peripherin genes.
## Regulatory mechanisms
Nerve growth factor (NGF) plays the major role in the regulation of peripherin. It is both a transcriptional inducer and post-translational regulator of peripherin expression in PC12 and neuroblastoma cells. The mechanism of NGF-induced activation occurs through 5' flanking elements and intragenic sequences involving the TATA box and other upstream elements as well as depression at a negative element. The specific signals regulating peripherin expression in vivo are unknown. The peripherin gene is transcriptionally activated in both small and large sized sensory neurons of the dorsal root ganglion at about day E10, and mRNA is present in these cells after postnatal day 2 and throughout adulthood. Post transcriptional mechanisms reduce detectable peripherin to only the small sized cells; however, crushing of the peripheral processes in dorsal root ganglion neurons lead to mRNA and detectable peripherin in the large sized cells.
The proinflammatory cytokines, interleukin-6 and leukemia inhibitory factor, can also induce peripherin expression through the JAK-STAT signaling pathway. This specific upregulation is linked to neuronal regeneration.
# Potential role in the pathogenesis of amyotrophic lateral sclerosis
Protein and neurofilamentous aggregates are characteristic of patients with amyotrophic lateral sclerosis, a progressive, fatal neurodegenerative disease. Spheroids, specifically, which are protein aggregates of neuronal intermediate filaments, have been found in patients with amyotrophic lateral sclerosis. Peripherin has been found in such spheroids in conjunction with other neurofilaments in other neuronal diseases, thus suggesting that peripherin may play a role in the pathogenesis of amyotrophic lateral sclerosis.
## Alternative splicing
An alternatively spliced mouse peripherin variant was identified that includes intron 4, a region that is spliced out of the abundant peripherin forms. Because of the change in reading frame, this variant produces a larger form of peripherin (Per61). In human peripherin, the inclusion of introns 3 and 4, regions that are similarly spliced out of the abundant peripherin protein forms, results in the generation of a truncated peripherin protein (Per28). In both cases, an antibody specific to a peptide coded by the intron regions stained the filamentous inclusions of in tissues affected by amyotrophic lateral sclerosis. These studies suggest that such alternative splicing could play a role in the disease and lend themselves to further investigation.
## Mutations
Experiments examining peripherin overexpression in mice have suggested that PRPH mutations play a role in the pathogenesis of amyotrophic lateral sclerosis, with more recent studies investigating the prevalence of such mutations in humans. Though many polymorphic variants of PRPH exist, two variants of PRPH were seen uniquely in patients with ALS, both of which consisted of a frameshift mutation. In the first variant, a single base pair deletion in exon 1 of PRPH was predictive of a peripherin species truncated to 85 amino acids. This truncation negatively impacted the ability of the neurofilament network to assemble, thus suggesting that mutations in PRPH may play a role in at least a small percentage of human cases of amyotrophic lateral sclerosis.
The second variant consisted of an amino acid substitution from aspartate to tyrosine as a result of a single point mutation in exon 1. This was also shown to adversely affect the assembly of the neurofilament network. The PRPH mutations observed in amyotrophic lateral sclerosis cause a change in the 3D structure of the protein. Consequently, the mutant peripherin forms aggregates instead of the filamentous network that it usually forms.
# Other clinical significance
Peripherin may be involved in the pathology of insulin-dependent diabetes mellitus (or diabetes mellitus type 1) in animals; however, no direct linkage has been found in human patients. In a nonobese diabetic mouse model, peripherin has been found as a known autoantigen (See antigen). B cell clones reactive to peripherin have also been found in early stages of the disease. Since peripherin is expressed in both the peripheral nervous system and, in young animals, by islet beta cells, it is possible that the destruction of both peripheral nervous system elements and islet β-cells in insulin-dependent diabetes mellitus is due to the immune response to autoreactive peripherin.
Peripherin can also play a role in the definitive diagnosis of Hirschsprung disease. Patients suspected of having the disease undergo rectal biopsy to look for the presence or absence of ganglion cells. However, the identification of these cells can be very difficult, especially in newborns where immature ganglion cells are easily confused with endothelial, mesenchyme and inflammatory cells. To aid in identification, a protocol utilizing peripherin and S-100 immunohistochemistry staining was developed to assist in the recognition of ganglion cells in rectal biopsies.
# Potential applications
Possible involvement of intermediate filaments such as peripherin in neurodegenerative diseases is currently being investigated. Interactions between intermediate filaments and other proteins are also being pursued. Peripherin has been shown to associate with protein kinase Cε, inducing its aggregation and leading to increased apoptosis. It may be possible to regulate this aggregation and apoptosis using siRNAs and protein kinase Cε. Pinpointing the source and possible resolution of protein aggregates is a promising direction for potential therapeutics. | Peripherin
Peripherin is a type III intermediate filament protein expressed mainly in neurons of the peripheral nervous system. It is also found in neurons of the central nervous system that have projections toward peripheral structures, such as spinal motor neurons. Its size, structure, and sequence/location of protein motifs is similar to other type III intermediate filament proteins such as desmin, vimentin and glial fibrillary acidic protein. Like these proteins, peripherin can self-assemble to form homopolymeric filamentous networks (networks formed from peripherin protein dimers), but it can also heteropolymerize with neurofilaments in several neuronal types. This protein in humans is encoded by the PRPH gene.[1][2] Peripherin is thought to play a role in neurite elongation during development and axonal regeneration after injury, but its exact function is unknown. It is also associated with some of the major neuropathologies that characterize amyotropic lateral sclerosis (ALS), but despite extensive research into how neurofilaments and peripherin contribute to ALS, their role in this disease is still unidentified.[3]
# History
Peripherin, first named such in 1984, was also known as 57 kDa neuronal intermediate filament prior to 1990. In 1987, a second distinct peripherally located retinal rod protein was also given the name peripherin. To distinguish between the two, this second protein is referred to peripherin 2 or peripherin/RDS (retinal degeneration slow) for its location and role in retinal disease.[4]
# Structure and properties
Peripherin was discovered as being the major intermediate filament in neuroblastoma cell lines and in rat pheochromocytoma cells. It is classified by gene structure and coding sequence as a type III intermediate filament protein because of its homology with vimentin, glial fibrillary acidic protein, and desmin.[5] All intermediate filament proteins share a common secondary structure consisting of three main domains, the most conserved of which is the central α-helical rod domain. This central coil is capped by non-helical head (N-terminal) and tail (C-terminal) domains. The α-helical rod domain contains repeating segments of hydrophobic amino acids, such that the first and fourth residues of every set of seven amino acids are usually nonpolar. This specific structure enables two intermediate filament polypeptides to coil together and create a "hydrophobic seal".[6] The rod also contains specific placement of alternating acidic and basic residues, many of which are spaced 4 amino acids apart. This spacing is optimal for the formation of ionic salt bridges, which serve to stabilize the α-helical rod through intrachain interactions.[6] A switch from intrachain salt bridges to interchain ionic associations may assist in intermediate filament assembly by utilizing electrostatic interactions to stabilize coiled-coil dimers.[6] The head and tail regions of intermediate filament proteins vary in length and amino acid composition, with greater variations in length occurring in the tail regions.[6]
Peripherin, unlike keratin IFs, can self-assemble and exist as homopolymers (see polymer). They can also heteropolymerize, or co-assemble, with other type III proteins or the light neurofilament subunit (NF-L) to form intermediate filament networks.[6] Type III proteins like peripherin can exist in different states within a cell. These states include nonfilamentous particles which combine to firm short IFs, or squiggles. These squiggles come together to form long IFs that make up cytoskeletal networks.[7] Studies of network assembly in spreading fibroblasts and differentiating nerve cells show that particles move along microtubules in a kinesin and dynein-dependent manner, and as spreading continues, the particles polymerize into intermediate filaments.[7]
In addition to the main species of peripherin, 57 kDa, two other forms have been identified in mice: Per 61 and Per 56. These two alternatives are both made by alternative splicing. Per 61 is created by introducing a 32 amino acid insertion within coil 2b of the α-helical rod domain of peripherin. Per 56 is made by a receptor on exon 9 of the peripherin gene transcript which induces a frameshift and replacement of a 21 amino acid sequence in the C-terminal found on the dominant 57 form with a new 8 amino acid sequence. The functions of these two alternative forms of peripherin are unknown. Per 57 and 56 are normally co-expressed, whereas Per 61 is not found in normal peripherin expression in adult motor neurons.[8]
## Tissue distribution
Peripherin is widely expressed in the cell body and axons of neurons in the peripheral nervous system. These include small-sized root ganglion neurons, lower motor neurons, sensory and motor neurons of the cranial nerves, and autonomic neurons in ganglia and the enteric nervous system. It is also expressed in the central nervous system in a small set of brainstem and spinal cord neurons that have projections toward peripheral structures. Some of these structures include the hypothalamic magnocellular nuclei, pontine cholinergic nuclei, some cerebellar nuclei, and scattered neurons in the cerebral cortex.[4] They can also be found in the ventral horn neurons and in the cholinergic laterodorsal tegmentum (LDT) and pedunculopontine tegmentum (PPT) nuclei.[9]
A comparison of peripherin expression in the posterior and lateral hypothalamus in mice showed a sixty-fold higher expression in the posterior hypothalamus. This higher expression is due to the presence of peripherin in the tuberomammillary neurons of the mouse posterior hypothalamus.[9]
# Function
The diverse properties of intermediate filaments, compared with the conserved microtubule and actin filament proteins, could be responsible for the distinguishing molecular shapes of different cell types. In nerve cells, for example, the expressions of different types of IFs relates to the change in shape during development. Early stages of development in neurons is marked by the outgrowth of neurites and axons contributing to the cells asymmetric shape. During these transitions in cell shape, only homopolymer type III intermediate filaments, such as those with peripherin, are made. As the nerve cell matures, these type III IFs are replaced by more complex type IV neurofilaments expanding the diameter of axons in order to attain normal velocities of action potentials.[10]
The exact function of peripherin is unknown. Expression of peripherin in development is greatest during the axonal growth phase and decreases postnatally, which suggests a role in neurite elongation and axonal guidance during development. Expression is also increased after axonal injury, such as peripheral axotomy in motor neurons and dorsal root ganglia. This upregulation implies that peripherin may also play a role in axon regeneration.[9] However, experiments using peripherin depleted PC12 cells and peripherin knockout mice provide proof that the majority of neurons have no requirement of peripherin for axonal guidance and regrowth. PC12 cells lacking peripherin showed no defects in neurite outgrowth and peripherin knockout mice develop normally with no anatomical abnormalities or different phenotypes.[5] In these experiments, peripherin deficiency did produce an upregulation of α-internexin, indicating the possibility that this type IV intermediate filament makes up for the loss of peripherin. Future studies of double knockout mice for both the peripherin and α-internexin genes might address this theory.[5] However, while most peripherin knockout mice displayed normal neuron growth, its absence did affect development of a subset of unmyelinated sensory axons. In such mice, there was a "34% reduction in the number of L5 unmyelinated sensory fibers that correlated with a decreased binding of the lectin IB4."[5]
# Gene (PRPH)
The complete sequence of the human (GenBank L14565), rat (GenBank M26232) and mouse (EMBL X59840) peripherin genes (PRPH) have been reported and complementary DNAs (cDNA) thus far described are those for rat, mouse and Xenopus peripherin.[4] The use of a mouse cDNA probe during the in situ hybridization procedure allowed for the localization of the PRPH gene to the E-F region of mouse chromosome 15 and the q12-q13 region of human chromosome 12.[2]
The overall structure of the peripherin gene is nine exons separated by eight introns. This configuration is conserved among the three known mammalian species with known coding for peripherin, namely human, rat and mouse. The nucleotide sequences of human and rat exons were 90% identical and produced a predicted protein that differed at only 18 of 475 amino acid residues. Comparison of introns 1 and 2 also yielded high homology of conserved segments. The 5' flanking regions and regulatory sequences were also very similar and a nerve growth factor negative regulatory element, a Hox protein (See Hox gene) binding site, and a heat shock element were found in all known peripherin genes.[11]
## Regulatory mechanisms
Nerve growth factor (NGF) plays the major role in the regulation of peripherin. It is both a transcriptional inducer and post-translational regulator of peripherin expression in PC12 and neuroblastoma cells. The mechanism of NGF-induced activation occurs through 5' flanking elements and intragenic sequences involving the TATA box and other upstream elements as well as depression at a negative element. The specific signals regulating peripherin expression in vivo are unknown. The peripherin gene is transcriptionally activated in both small and large sized sensory neurons of the dorsal root ganglion at about day E10, and mRNA is present in these cells after postnatal day 2 and throughout adulthood. Post transcriptional mechanisms reduce detectable peripherin to only the small sized cells; however, crushing of the peripheral processes in dorsal root ganglion neurons lead to mRNA and detectable peripherin in the large sized cells.[4]
The proinflammatory cytokines, interleukin-6 and leukemia inhibitory factor, can also induce peripherin expression through the JAK-STAT signaling pathway. This specific upregulation is linked to neuronal regeneration.[8]
# Potential role in the pathogenesis of amyotrophic lateral sclerosis
Protein and neurofilamentous aggregates are characteristic of patients with amyotrophic lateral sclerosis, a progressive, fatal neurodegenerative disease. Spheroids, specifically, which are protein aggregates of neuronal intermediate filaments, have been found in patients with amyotrophic lateral sclerosis. Peripherin has been found in such spheroids in conjunction with other neurofilaments in other neuronal diseases, thus suggesting that peripherin may play a role in the pathogenesis of amyotrophic lateral sclerosis.[3]
## Alternative splicing
An alternatively spliced mouse peripherin variant was identified that includes intron 4, a region that is spliced out of the abundant peripherin forms. Because of the change in reading frame, this variant produces a larger form of peripherin (Per61). In human peripherin, the inclusion of introns 3 and 4, regions that are similarly spliced out of the abundant peripherin protein forms, results in the generation of a truncated peripherin protein (Per28). In both cases, an antibody specific to a peptide coded by the intron regions stained the filamentous inclusions of in tissues affected by amyotrophic lateral sclerosis. These studies suggest that such alternative splicing could play a role in the disease and lend themselves to further investigation.[3]
## Mutations
Experiments examining peripherin overexpression in mice have suggested that PRPH mutations play a role in the pathogenesis of amyotrophic lateral sclerosis, with more recent studies investigating the prevalence of such mutations in humans. Though many polymorphic variants of PRPH exist, two variants of PRPH were seen uniquely in patients with ALS, both of which consisted of a frameshift mutation. In the first variant, a single base pair deletion in exon 1 of PRPH was predictive of a peripherin species truncated to 85 amino acids. This truncation negatively impacted the ability of the neurofilament network to assemble, thus suggesting that mutations in PRPH may play a role in at least a small percentage of human cases of amyotrophic lateral sclerosis.[12]
The second variant consisted of an amino acid substitution from aspartate to tyrosine as a result of a single point mutation in exon 1. This was also shown to adversely affect the assembly of the neurofilament network. The PRPH mutations observed in amyotrophic lateral sclerosis cause a change in the 3D structure of the protein. Consequently, the mutant peripherin forms aggregates instead of the filamentous network that it usually forms.[13]
# Other clinical significance
Peripherin may be involved in the pathology of insulin-dependent diabetes mellitus (or diabetes mellitus type 1) in animals; however, no direct linkage has been found in human patients. In a nonobese diabetic mouse model, peripherin has been found as a known autoantigen (See antigen). B cell clones reactive to peripherin have also been found in early stages of the disease. Since peripherin is expressed in both the peripheral nervous system and, in young animals, by islet beta cells, it is possible that the destruction of both peripheral nervous system elements and islet β-cells in insulin-dependent diabetes mellitus is due to the immune response to autoreactive peripherin.[9]
Peripherin can also play a role in the definitive diagnosis of Hirschsprung disease. Patients suspected of having the disease undergo rectal biopsy to look for the presence or absence of ganglion cells. However, the identification of these cells can be very difficult, especially in newborns where immature ganglion cells are easily confused with endothelial, mesenchyme and inflammatory cells. To aid in identification, a protocol utilizing peripherin and S-100 immunohistochemistry staining was developed to assist in the recognition of ganglion cells in rectal biopsies.[14]
# Potential applications
Possible involvement of intermediate filaments such as peripherin in neurodegenerative diseases is currently being investigated. Interactions between intermediate filaments and other proteins are also being pursued. Peripherin has been shown to associate with protein kinase Cε, inducing its aggregation and leading to increased apoptosis. It may be possible to regulate this aggregation and apoptosis using siRNAs and protein kinase Cε.[15] Pinpointing the source and possible resolution of protein aggregates is a promising direction for potential therapeutics.[3] | https://www.wikidoc.org/index.php/Peripherin | |
842bac475f66491a907c123ca1f92ac51e0ef65a | wikidoc | Periplakin | Periplakin
Periplakin is a protein that in humans is encoded by the PPL gene.
The protein encoded by this gene is a component of desmosomes and of the epidermal cornified envelope in keratinocytes. The N-terminal domain of this protein interacts with the plasma membrane and its C-terminus interacts with intermediate filaments. Through its rod domain, this protein forms complexes with envoplakin. This protein may serve as a link between the cornified envelope and desmosomes as well as intermediate filaments. AKT1/PKB, a protein kinase mediating a variety of cell growth and survival signaling processes, is reported to interact with this protein, suggesting a possible role for this protein as a localization signal in AKT1-mediated signaling.
# Interactions
PPL (gene) has been shown to interact with Keratin 8 and Envoplakin. | Periplakin
Periplakin is a protein that in humans is encoded by the PPL gene.[1][2][3]
The protein encoded by this gene is a component of desmosomes and of the epidermal cornified envelope in keratinocytes. The N-terminal domain of this protein interacts with the plasma membrane and its C-terminus interacts with intermediate filaments. Through its rod domain, this protein forms complexes with envoplakin. This protein may serve as a link between the cornified envelope and desmosomes as well as intermediate filaments. AKT1/PKB, a protein kinase mediating a variety of cell growth and survival signaling processes, is reported to interact with this protein, suggesting a possible role for this protein as a localization signal in AKT1-mediated signaling.[3]
# Interactions
PPL (gene) has been shown to interact with Keratin 8[4] and Envoplakin.[5][6] | https://www.wikidoc.org/index.php/Periplakin | |
0cf3ed9bbe50315f56c23652b40250fe29a76b16 | wikidoc | Pertuzumab | Pertuzumab
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Black Box Warning
# Overview
Pertuzumab is a monoclonal antibody that is FDA approved for the treatment of metastatic breast cancer and as a neoadjuvant treatment of breast cancer. There is a Black Box Warning for this drug as shown here. Common adverse reactions include diarrhea, alopecia, neutropenia, nausea, vomiting, fatigue, rash, and peripheral neuropathy in combination with trastuzumab and docetaxel.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Metastatic Breast Cancer
- Indicated for use in combination with trastuzumab and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease.
- Recommended initial dose of docetaxel is 75 mg/m2 administered as an intravenous infusion.
- The dose may be escalated to 100 mg/m2 administered every 3 weeks if the initial dose is well tolerated
### Neoadjuvant Treatment of Breast Cancer
- Pertuzumab is indicated for use in combination with trastuzumab and docetaxel for the neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer (either greater than 2 cm in diameter or node positive) as part of a complete treatment regimen for early breast cancer. This indication is based on demonstration of an improvement in pathological complete response rate. No data are available demonstrating improvement in event-free survival or overall survival.
- Pertuzumab should be administered every 3 weeks for 3 to 6 cycles as part of one of the following treatment regimens for early breast cancer:
- Four preoperative cycles of pertuzumab in combination with trastuzumab and docetaxel followed by 3 postoperative cycles of fluorouracil, epirubicin, and cyclophosphamide (FEC) as given in Study 2
- Three preoperative cycles of FEC alone followed by 3 preoperative cycles of pertuzumab in combination with docetaxel and trastuzumab as given in Study 3
- Six preoperative cycles of pertuzumab in combination with docetaxel, carboplatin, and trastuzumab (TCH) (escalation of docetaxel above 75 mg/m2 is not recommended) as given in Study 3
- Following surgery, patients should continue to receive trastuzumab to complete 1 year of treatment. There is insufficient evidence to recommend continued use of pertuzumab for greater than 6 cycles for early breast cancer. There is insufficient evidence to recommend concomitant administration of an anthracycline with pertuzumab, and there are no safety data to support sequential use of doxorubicin with pertuzumab.
### Recommended Doses and Schedules
- The initial dose of pertuzumab is 840 mg administered as a 60-minute intravenous infusion, followed every 3 weeks by a dose of 420 mg administered as an intravenous infusion over 30 to 60 minutes.
- When administered with pertuzumab, the recommended initial dose of trastuzumab is 8 mg/kg administered as a 90-minute intravenous infusion, followed every 3 weeks by a dose of 6 mg/kg administered as an intravenous infusion over 30 to 90 minutes.
- Pertuzumab, trastuzumab, and docetaxel should be administered sequentially. Pertuzumab and trastuzumab can be given in any order. Docetaxel should be administered after pertuzumab and trastuzumab. An observation period of 30 to 60 minutes is recommended after each pertuzumab infusion and before commencement of any subsequent infusion of trastuzumab or docetaxel.
### Dose Modification
- For delayed or missed doses, if the time between two sequential infusions is less than 6 weeks, the 420 mg dose of pertuzumab should be administered. Do not wait until the next planned dose. If the time between two sequential infusions is 6 weeks or more, the initial dose of 840 mg pertuzumab should be re-administered as a 60-minute intravenous infusion followed every 3 weeks thereafter by a dose of 420 mg administered as an intravenous infusion over 30 to 60 minutes.
- Pertuzumab should be discontinued if trastuzumab treatment is discontinued.
- Dose reductions are not recommended for pertuzumab.
- For docetaxel dose modifications, see relevant prescribing information.
Left Ventricular Ejection Fraction (LVEF):
- Withhold pertuzumab and trastuzumab dosing for at least 3 weeks for either:
- A drop in LVEF to less than 45% or
- LVEF of 45% to 49% with a 10% or greater absolute decrease below pretreatment values.
- Pertuzumab may be resumed if the LVEF has recovered to greater than 49% or to 45% to 49% associated with less than a 10% absolute decrease below pretreatment values.
- If after a repeat assessment within approximately 3 weeks, the LVEF has not improved, or has declined further, pertuzumab and trastuzumab should be discontinued, unless the benefits for the individual patient are deemed to outweigh the risks.
Infusion-Related Reactions
- The infusion rate of pertuzumab may be slowed or interrupted if the patient develops an infusion-related reaction.
Hypersensitivity Reactions/Anaphylaxis
- The infusion should be discontinued immediately if the patient experiences a serious hypersensitivity reaction
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pertuzumab in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Pertuzumab in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Pertuzumab FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pertuzumab in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Pertuzumab in pediatric patients.
# Contraindications
- Pertuzumab is contraindicated in patients with known hypersensitivity to pertuzumab or to any of its excipients.
# Warnings
### Embryo-Fetal Toxicity
- Pertuzumab can cause fetal harm when administered to a pregnant woman.
- Treatment of pregnant cynomolgus monkeys with pertuzumab resulted in oligohydramnios, delayed fetal kidney development, and embryo-fetal death.
- If pertuzumab is administered during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to a fetus.
- Verify pregnancy status prior to the initiation of pertuzumab.
- Advise patients of the risks of embryo-fetal death and birth defects and the need for contraception during and after treatment.
- Advise patients to contact their healthcare provider immediately if they suspect they may be pregnant.
- Monitor patients who become pregnant during pertuzumab therapy for oligohydramnios. If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and consistent with community standards of care.
- The efficacy of intravenous hydration in the management of oligohydramnios due to pertuzumab exposure is not known.
### Left Ventricular Dysfunction
- Decreases in LVEF have been reported with drugs that block HER2 activity, including pertuzumab.
- In Study 1, for patients with MBC, pertuzumab in combination with trastuzumab and docetaxel was not associated with increases in the incidence of symptomatic left ventricular systolic dysfunction (LVSD) or decreases in LVEF compared with placebo in combination with trastuzumab and docetaxel. Left ventricular dysfunction occurred in 4.4% of patients in the pertuzumab-treated group and 8.3% of patients in the placebo-treated group. Symptomatic left ventricular systolic dysfunction (congestive heart failure) occurred in 1.0% of patients in the pertuzumab-treated group and 1.8% of patients in the placebo-treated group.
- Patients who have received prior anthracyclines or prior radiotherapy to the chest area may be at higher risk of decreased LVEF.
- In patients receiving neoadjuvant treatment in Study 2, the incidence of LVSD was higher in the pertuzumab-treated groups compared to the trastuzumab- and docetaxel-treated group.
- An increased incidence of LVEF declines was observed in patients treated with pertuzumab in combination with trastuzumab and docetaxel. In the overall treatment period, LVEF decline > 10% and a drop to less than 50% occurred in 1.9% of patients treated with neoadjuvant trastuzumab and docetaxel as compared to 8.4% of patients treated with neoadjuvant pertuzumab in combination with trastuzumab and docetaxel.
- Symptomatic LVSD occurred in 0.9% of patients treated with neoadjuvant pertuzumab in combination with trastuzumab and no patients in the other 3 arms. LVEF recovered to ≥ 50% in all patients.
- In patients receiving neoadjuvant pertuzumab in Study 3, in the overall treatment period, LVEF decline > 10% and a drop to less than 50% occurred in 6.9% of patients treated with pertuzumab plus trastuzumab and FEC followed by pertuzumab plus trastuzumab and docetaxel, 16.0% of patients treated with pertuzumab plus trastuzumab and docetaxel following FEC, and 10.5% of patients treated with pertuzumab in combination with TCH.
- Symptomatic LVSD occurred in 4.0% of patients treated with pertuzumab plus trastuzumab and docetaxel following FEC, 1.3% of patients treated with pertuzumab in combination with TCH, and none of the patients treated with pertuzumab plus trastuzumab and FEC followed by pertuzumab plus trastuzumab and docetaxel.
- LVEF recovered to ≥ 50% in all but one patient.
- Pertuzumab has not been studied in patients with a pretreatment LVEF value of ≤ 50%, a prior history of CHF, decreases in LVEF to 360 mg/m2 of doxorubicin or its equivalent.
- Assess LVEF prior to initiation of pertuzumab and at regular intervals (e.g., every three months in the metastatic setting and every six weeks in the neoadjuvant setting) during treatment to ensure that LVEF is within the institution's normal limits. If LVEF is < 45%, or is 45% to 49% with a 10% or greater absolute decrease below the pretreatment value, withhold pertuzumab and trastuzumab and repeat LVEF assessment within approximately 3 weeks.
- Discontinue pertuzumab and trastuzumab if the LVEF has not improved or has declined further, unless the benefits for the individual patient outweigh the risks.
### Infusion-Related Reactions
- Pertuzumab has been associated with infusion reactions.
- An infusion reactions was defined in Study 1 as any event described as hypersensitivity, anaphylactic reaction, acute infusion reaction, or cytokine release syndrome occurring during an infusion or on the same day as the infusion.
- The initial dose of pertuzumab was given the day before trastuzumab and docetaxel to allow for the examination of pertuzumab-associated reactions.
- On the first day, when only pertuzumab was administered, the overall frequency of infusion reactions was 13.0% in the pertuzumab-treated group and 9.8% in the placebo-treated group. Less than 1% were Grade 3 or 4. The most common infusion reactions (≥ 1.0%) were pyrexia, chills, fatigue, headache, asthenia, hypersensitivity, and vomiting.
- During the second cycle when all drugs were administered on the same day, the most common infusion reactions in the pertuzumab-treated group (≥ 1.0%) were fatigue, dysgeusia, hypersensitivity, myalgia, and vomiting.
- In Study 2 and Study 3, pertuzumab was administered on the same day as the other study treatment drugs.
- Infusion reactions were consistent with those observed in Study 1, with a majority of reactions being National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI - CTCAE v3.0) Grade 1 – 2.
- Observe patients closely for 60 minutes after the first infusion and for 30 minutes after subsequent infusions of pertuzumab.
- If a significant infusion-related reaction occurs, slow or interrupt the infusion, and administer appropriate medical therapies.
- Monitor patients carefully until complete resolution of signs and symptoms.
- Consider permanent discontinuation in patients with severe infusion reactions.
### Hypersensitivity Reactions/Anaphylaxis
- In Study 1, the overall frequency of hypersensitivity/anaphylaxis reactions was 10.8% in the pertuzumab-treated group and 9.1% in the placebo-treated group. The incidence of Grade 3 – 4 hypersensitivity/anaphylaxis reactions was 2.0% in the pertuzumab-treated group and 2.5% in the placebo-treated group according to NCI - CTCAE v3.0.
- Overall, 4 patients in pertuzumab-treated group and 2 patients in the placebo-treated group experienced anaphylaxis.
- In Study 2 and Study 3, hypersensitivity/anaphylaxis events were consistent with those observed in Study 1. In Study 2, two patients in the pertuzumab- and docetaxel-treated group experienced anaphylaxis. In Study 3, the overall frequency of hypersensitivity/anaphylaxis was highest in the pertuzumab plus TCH treated group (13.2%), of which 2.6% were NCI-CTCAE (version 3) Grade 3 – 4.
- Patients should be observed closely for hypersensitivity reactions. Severe hypersensitivity, including anaphylaxis, has been observed in clinical trials with treatment of pertuzumab. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use.
- Pertuzumab is contraindicated in patients with known hypersensitivity to pertuzumab or to any of its excipients.
### HER2 Testing
- Detection of HER2 protein overexpression is necessary for selection of patients appropriate for pertuzumab therapy because these are the only patients studied and for whom benefit has been shown.
- Patients with breast cancer were required to have evidence of HER2 overexpression defined as 3+ IHC or FISH amplification ratio ≥ 2.0 in the clinical studies.
- Only limited data were available for patients whose breast cancer was positive by FISH, but did not demonstrate protein overexpression by IHC.
- Assessment of HER2 status should be performed by laboratories using FDA-approved tests with demonstrated proficiency in the specific technology being utilized.
- Improper assay performance, including use of sub-optimally fixed tissue, failure to utilize specified reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results.
# Adverse Reactions
## Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
### Metastatic Breast Cancer (MBC)
The adverse reactions described in TABLE 1 were identified in 804 patients with HER2-positive metastatic breast cancer treated in Study 1. Patients were randomized to receive either pertuzumab in combination with trastuzumab and docetaxel or placebo in combination with trastuzumab and docetaxel.
- The median duration of study treatment was 18.1 months for patients in the pertuzumab-treated group and 11.8 months for patients in the placebo-treated group. No dose adjustment was permitted for pertuzumab or trastuzumab. The rates of adverse events resulting in permanent discontinuation of all study therapy were 6.1% for patients in the pertuzumab-treated group and 5.3% for patients in the placebo-treated group. Adverse events led to discontinuation of docetaxel alone in 23.6% of patients in the pertuzumab-treated group and 23.2% of patients in the placebo-treated group. TABLE 1 reports the adverse reactions that occurred in at least 10% of patients in the pertuzumab-treated group. The safety profile of pertuzumab remained unchanged with an additional year of follow-up (median total follow-up of 30 months) in Study 1.
The most common adverse reactions (> 30%) seen with pertuzumab in combination with trastuzumab and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy.
- The most common NCI - CTCAE v3.0 Grade 3 – 4 adverse reactions (> 2%) were neutropenia, febrile neutropenia, leukopenia, diarrhea, peripheral neuropathy, anemia, asthenia, and fatigue.
- An increased incidence of febrile neutropenia was observed for Asian patients in both treatment arms compared with patients of other races and from other geographic regions.
- Among Asian patients, the incidence of febrile neutropenia was higher in the pertuzumab-treated group (26%) compared with the placebo-treated group (12%).
The following clinically relevant adverse reactions were reported in < 10% of patients in the pertuzumab-treated group in Study 1:
Skin and subcutaneous tissue disorders: Paronychia (7.1% in the pertuzumab-treated group vs. 3.5% in the placebo-treated group)
Respiratory, thoracic and mediastinal disorders: Pleural effusion (5.2% in the pertuzumab-treated group vs. 5.8% in the placebo-treated group)
Cardiac disorders: Left ventricular dysfunction (4.4% in the pertuzumab-treated group vs. 8.3% in the placebo-treated group) including symptomatic left ventricular systolic dysfunction (CHF) (1.0% in the pertuzumab-treated group vs. 1.8% in the placebo-treated group)
Immune system disorders: Hypersensitivity (10.1% in the pertuzumab-treated group vs. 8.6% in placebo-treated group)
Adverse Reactions Reported in Patients Receiving pertuzumab and Trastuzumab after Discontinuation of Docetaxel
In Study 1, adverse reactions were reported less frequently after discontinuation of docetaxel treatment. All adverse reactions in the pertuzumab and trastuzumab treatment group occurred in < 10% of patients with the exception of diarrhea (19.1%), upper respiratory tract infection (12.8%), rash (11.7%), headache (11.4%), and fatigue (11.1%).
Neoadjuvant Treatment of Breast Cancer (Study 2)
In Study 2, the most common adverse reactions seen with pertuzumab in combination with trastuzumab and docetaxel administered for 4 cycles were similar to those seen in the pertuzumab-treated group in Study 1.
- The most common adverse reactions (> 30%) were alopecia, neutropenia, diarrhea, and nausea.
- The most common NCI – CTCAE v3.0 Grade 3 – 4 adverse reactions (> 2%) were neutropenia, febrile neutropenia, leukopenia, and diarrhea.
- In this group, one patient permanently discontinued neoadjuvant treatment due to an adverse event.
- TABLE 2 reports the adverse reactions that occurred in patients who received neoadjuvant treatment with pertuzumab for breast cancer in Study 2.
- The following adverse reactions were reported in < 10% of patients receiving neoadjuvant treatment and occurred more frequently in pertuzumab-treated groups in Study 2: (Ptz=pertuzumab; T=trastuzumab; D=docetaxel)
Blood and lymphatic system disorders:
- Anemia (6.5% in the T+D arm, 2.8% in the Ptz+T+D arm, 4.6% in the Ptz+T arm and 8.5% in the Ptz+D arm)
- Febrile neutropenia (6.5% in the T+D arm, 8.4% in the Ptz+T+D arm, 0.0% in the Ptz+T arm and 7.4% in the Ptz+D arm)
Immune system disorders:
- Hypersensitivity (1.9% in the T+D arm, 5.6% in the Ptz+T+D arm, 5.6% in the Ptz+T arm and 5.3% in the Ptz+D arm)
Nervous system disorders:
- Dizziness (3.7% in the T+D arm, 2.8% in the Ptz+T+D arm, 5.6% in the Ptz+T arm and 3.2% in the Ptz+D arm)
Infections and infestations:
- Upper respiratory tract infection (2.8% in the T+D arm, 4.7% in the Ptz+T+D arm, 1.9% in the Ptz+T arm and 7.4% in the Ptz+D arm)
Respiratory, thoracic and mediastinal disorders:
- Dyspnea (3.7% in the T+D arm, 4.7% in the Ptz+T+D arm, 2.8% in the Ptz+T arm and 2.1% in the Ptz+D arm)
Cardiac disorders:
- Left ventricular dysfunction (0.9% in the T+D arm, 2.8% in the Ptz+T+D arm, 0.0% in the Ptz+T arm, and 1.1% in the Ptz+D arm) including symptomatic left ventricular dysfunction (CHF) (0.9% in the Ptz+T arm and 0.0% in the T+D arm, Ptz+T+D arm, and Ptz+D arm)
Eye disorders:
- Lacrimation increased (1.9% in the T+D arm, 3.7% in the Ptz+T+D arm, 0.9% in the Ptz+T arm, and 4.3% in the Ptz+D arm)
Neoadjuvant Treatment of Breast Cancer (Study 3)
- In Study 3, when pertuzumab was administered in combination with trastuzumab and docetaxel for 3 cycles following 3 cycles of FEC, the most common adverse reactions (> 30%) were diarrhea, nausea, alopecia, neutropenia, vomiting, and fatigue.
- The most common NCI-CTCAE (version 3) Grade 3 – 4 adverse reactions (> 2%) were neutropenia, leukopenia, febrile neutropenia, diarrhea, left ventricular dysfunction, anemia, dyspnea, nausea, and vomiting.
Similarly, when pertuzumab was administered in combination with docetaxel, carboplatin, and trastuzumab (TCH) for 6 cycles, the most common adverse reactions (> 30%) were diarrhea, alopecia, neutropenia, nausea, fatigue, vomiting, anemia, and thrombocytopenia.
- The most common NCI-CTCAE (version 3) Grade 3 – 4 adverse reactions (> 2%) were neutropenia, febrile neutropenia, anemia, leukopenia, diarrhea, thrombocytopenia, vomiting, fatigue, ALT increased, hypokalemia, and hypersensitivity.
- The rates of adverse events resulting in permanent discontinuation of any component of neoadjuvant treatment were 6.7% for patients receiving pertuzumab in combination with trastuzumab and docetaxel following FEC and 7.9% for patients receiving pertuzumab in combination with TCH.
- TABLE 3 reports the adverse reactions that occurred in patients who received neoadjuvant treatment with pertuzumab for breast cancer in Study 3.
The following selected adverse reactions were reported in < 10% of patients receiving neoadjuvant treatment in Study 3: (Ptz=pertuzumab; T=trastuzumab; D=docetaxel; FEC= fluorouracil, epirubicin, and cyclophosphamide; TCH=docetaxel, carboplatin, and trastuzumab)
Skin and subcutaneous tissue disorders: Nail disorder (9.7% in the Ptz+T+FEC/Ptz+T+D arm, 6.7% in the FEC/Ptz+T+D arm, and 9.2% in the Ptz+TCH arm), Paronychia (0% in the Ptz+T+FEC/Ptz+T+D and 1.3% in both the FEC/Ptz+T+D and Ptz+TCH arms), Pruritis (2.8% in the Ptz+T+FEC/Ptz+T+D arm, 4.0% in the FEC/Ptz+T+D arm, and 3.9% in the Ptz+TCH arm)
Infections and infestations:
- Upper respiratory tract infection (8.3% in the Ptz+T+FEC/Ptz+T+D arm, 4.0% in the FEC/Ptz+T+D arm, and 2.6% in the Ptz+TCH arm), Nasopharyngitis (6.9% in the Ptz+T+FEC/Ptz+T+D arm, 6.7% in the FEC/Ptz+T+D arm, and 7.9% in the Ptz+TCH arm)
Respiratory, thoracic, and mediastinal disorders:
- Pleural effusion (1.4% in the Ptz+T+FEC/Ptz+T+D arm and 0% in the FEC/Ptz+T+D and Ptz+TCH arm)
Cardiac disorders:
- Left ventricular dysfunction (5.6% in the Ptz+T+FEC/PTZ+T+D arm, 4.0% in the FEC/Ptz+T+D arm, and 2.6% in the Ptz+TCH arm) including symptomatic left ventricular systolic dysfunction (CHF) (2.7% in the FEC/Ptz+T+D arm and 0% in the Ptz+T+FEC/Ptz+T+D and Ptz+TCH arms)
### Immunogenicity
- As with all therapeutic proteins, there is the potential for an immune response to pertuzumab.
- Patients in Study 1 were tested at multiple time-points for antibodies to pertuzumab.
- Approximately 2.8% (11/386) of patients in the pertuzumab-treated group and 6.2% (23/372) of patients in the placebo-treated group tested positive for anti-pertuzumab antibodies.
- Of these 34 patients, none experienced anaphylactic/hypersensitivity reactions that were clearly related to the anti-therapeutic antibodies (ATA).
- The presence of pertuzumab in patient serum at the levels expected at the time of ATA sampling can interfere with the ability of this assay to detect anti-pertuzumab antibodies.
- In addition, the assay may be detecting antibodies to trastuzumab.
- As a result, data may not accurately reflect the true incidence of anti-pertuzumab antibody development.
- Immunogenicity data are highly dependent on the sensitivity and specificity of the test methods used.
- Additionally, the observed incidence of a positive result in a test method may be influenced by several factors, including sample handling, timing of sample collection, drug interference, concomitant medication, and the underlying disease. For these reasons, comparison of the incidence of antibodies to pertuzumab with the incidence of antibodies to other products may be misleading.
## Postmarketing Experience
There is limited information regarding Pertuzumab Postmarketing Experience in the drug label.
# Drug Interactions
No drug-drug interactions were observed between pertuzumab and trastuzumab, or between pertuzumab and docetaxel.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
- There are no adequate and well-controlled studies of pertuzumab in pregnant women. Based on findings in animal studies, pertuzumab can cause fetal harm when administered to a pregnant woman. The effects of pertuzumab are likely to be present during all trimesters of pregnancy. Pertuzumab administered to pregnant cynomolgus monkeys resulted in oligohydramnios, delayed fetal kidney development, and embryo-fetal deaths at clinically relevant exposures of 2.5 to 20-fold greater than the recommended human dose, based on Cmax. If pertuzumab is administered during pregnancy, or if a patient becomes pregnant while receiving pertuzumab, the patient should be apprised of the potential hazard to the fetus.
### Animal Data
- Reproductive toxicology studies have been conducted in cynomolgus monkeys. Pregnant monkeys were treated on Gestational Day (GD)19 with loading doses of 30 to 150 mg/kg pertuzumab, followed by bi-weekly doses of 10 to 100 mg/kg. These dose levels resulted in clinically relevant exposures of 2.5 to 20-fold greater than the recommended human dose, based on Cmax. Intravenous administration of pertuzumab from GD19 through GD50 (period of organogenesis) was embryotoxic, with dose-dependent increases in embryo-fetal death between GD25 to GD70. The incidences of embryo-fetal loss were 33, 50, and 85% for dams treated with bi-weekly pertuzumab doses of 10, 30, and 100 mg/kg, respectively (2.5 to 20-fold greater than the recommended human dose, based on Cmax). At Caesarean section on GD100, oligohydramnios, decreased relative lung and kidney weights, and microscopic evidence of renal hypoplasia consistent with delayed renal development were identified in all pertuzumab dose groups. Pertuzumab exposure was reported in offspring from all treated groups, at levels of 29% to 40% of maternal serum levels at GD100.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Pertuzumab in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Pertuzumab during labor and delivery.
### Nursing Mothers
- It is not known whether pertuzumab is excreted in human milk, but human IgG is excreted in human milk. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from pertuzumab, a decision should be made whether to discontinue nursing, or discontinue drug, taking into account the elimination half-life of pertuzumab and the importance of the drug to the mother
### Pediatric Use
- The safety and effectiveness of pertuzumab have not been established in pediatric patients.
### Geriatic Use
- Of 402 patients who received pertuzumab in Study 1, 60 patients (15%) were ≥ 65 years of age and 5 patients (1%) were ≥ 75 years of age. No overall differences in efficacy and safety of pertuzumab were observed between these patients and younger patients.
Based on a population pharmacokinetic analysis, no significant difference was observed in the pharmacokinetics of pertuzumab between patients < 65 years (n=306) and patients ≥ 65 years (n=175).
### Gender
There is no FDA guidance on the use of Pertuzumab with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Pertuzumab with respect to specific racial populations.
### Renal Impairment
Dose adjustments of pertuzumab are not needed in patients with mild (creatinine clearance ]] 60 to 90 mL/min) or moderate (CLcr 30 to 60 mL/min) renal impairment. No dose adjustment can be recommended for patients with severe renal impairment (CLcr less than 30 mL/min) because of the limited pharmacokinetic data available
### Hepatic Impairment
- No clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of pertuzumab.
### Females of Reproductive Potential and Males
- Pertuzumab can cause embryo-fetal harm when administered during pregnancy. Counsel patients regarding pregnancy prevention and planning. *Advise females of reproductive potential to use effective contraception while receiving pertuzumab and for 6 months following the last dose of pertuzumab.
### Immunocompromised Patients
There is no FDA guidance one the use of Pertuzumab in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous infusion
### Monitoring
- Infusion-Related Reactions: Monitor for signs and symptoms. If a significant infusion-associated reaction occurs, slow or interrupt the infusion and administer appropriate medical therapies.
- Hypersensitivity Reactions/Anaphylaxis: Monitor for signs and symptoms
- Monitor patients who become pregnant during pertuzumab therapy for oligohydramnios.
# IV Compatibility
### Preparation for Administration
Administer as an intravenous infusion only. Do not administer as an intravenous push or bolus. Do not mix pertuzumab with other drugs.
### Preparation
Prepare the solution for infusion, using aseptic technique, as follows:
- Parenteral drug products should be inspected visually for particulates and discoloration prior to administration.
- Withdraw the appropriate volume of pertuzumab solution from the vial(s).
- Dilute into a 250 mL 0.9% sodium chloride PVC or non-PVC polyolefin infusion bag.
- Mix diluted solution by gentle inversion. Do not shake.
- Administer immediately once prepared.
- If the diluted infusion solution is not used immediately, it can be stored at 2°C to 8°C for up to 24 hours.
- Dilute with 0.9% Sodium Chloride injection only. Do not use dextrose (5%) solution.
# Overdosage
No drug overdoses have been reported with pertuzumab to date.
# Pharmacology
## Mechanism of Action
Pertuzumab targets the extracellular dimerization domain (Subdomain II) of the human epidermal growth factor receptor 2 protein (HER2) and, thereby, blocks ligand-dependent heterodimerization of HER2 with other HER family members, including EGFR, HER3, and HER4. As a result, pertuzumab inhibits ligand-initiated intracellular signaling through two major signal pathways, mitogen-activated protein (MAP) kinase, and phosphoinositide 3-kinase (PI3K). Inhibition of these signaling pathways can result in cell growth arrest and apoptosis, respectively. In addition, pertuzumab mediates antibody-dependent cell-mediated cytotoxicity (ADCC).
While pertuzumab alone inhibited the proliferation of human tumor cells, the combination of pertuzumab and trastuzumab augmented anti-tumor activity in HER2-overexpressing xenograft models.
## Structure
There is limited information regarding Pertuzumab Structure in the drug label.
## Pharmacodynamics
### Cardiac Electrophysiology
The effect of pertuzumab with an initial dose of 840 mg followed by a maintenance dose of 420 mg every three weeks on QTc interval was evaluated in a subgroup of 20 patients with HER2-positive breast cancer in Study 1. No large changes in the mean QT interval (i.e., greater than 20 ms) from placebo based on Fridericia correction method were detected in the trial. A small increase in the mean QTc interval (i.e., less than 10 ms) cannot be excluded because of the limitations of the trial design.
## Pharmacokinetics
Pertuzumab demonstrated linear pharmacokinetics at a dose range of 2 – 25 mg/kg. Based on a population PK analysis that included 481 patients, the median clearance (CL) of pertuzumab was 0.24 L/day and the median half-life was 18 days. With an initial dose of 840 mg followed by a maintenance dose of 420 mg every three weeks thereafter, the steady-state concentration of pertuzumab was reached after the first maintenance dose.
The population PK analysis suggested no PK differences based on age, gender, ethnicity (Japanese vs. non-Japanese), or disease status (neoadjuvant versus metastatic setting). Baseline serum albumin level and lean body weight as covariates only exerted a minor influence on PK parameters. Therefore, no dose adjustments based on body weight or baseline albumin level are needed.
No drug-drug interactions were observed between pertuzumab and trastuzumab, or between pertuzumab and docetaxel in a sub-study of 37 patients in Study 1.
No dedicated renal impairment trial for pertuzumab has been conducted. Based on the results of the population pharmacokinetic analysis, pertuzumab exposure in patients with mild (CLcr 60 to 90 mL/min, n=200) and moderate renal impairment (CLcr 30 to 60 mL/min, n=71) were similar to those in patients with normal renal function (CLcr greater than 90 mL/min, n=200). No relationship between CLcr and pertuzumab exposure was observed over the range of observed CLcr (27 to 244 mL/min).
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term studies in animals have not been performed to evaluate the carcinogenic potential of pertuzumab.
Studies have not been performed to evaluate the mutagenic potential of pertuzumab.
No specific fertility studies in animals have been performed to evaluate the effect of pertuzumab. No adverse effects on male and female reproductive organs were observed in repeat-dose toxicity studies of up to six months duration in cynomolgus monkeys.
# Clinical Studies
### Metastatic Breast Cancer
Study 1 was a multicenter, double-blind, placebo-controlled trial of 808 patients with HER2-positive metastatic breast cancer. HER2 overexpression was defined as a score of 3+ IHC or FISH amplification ratio of 2.0 or greater as determined by a central laboratory. Patients were randomly allocated 1:1 to receive placebo plus trastuzumab and docetaxel or pertuzumab plus trastuzumab and docetaxel. Randomization was stratified by prior treatment (prior or no prior adjuvant/neoadjuvant anti-HER2 therapy or chemotherapy) and geographic region (Europe, North America, South America, and Asia). Patients with prior adjuvant or neoadjuvant therapy were required to have a disease-free interval of greater than 12 months before trial enrollment.
Pertuzumab was given intravenously at an initial dose of 840 mg, followed by 420 mg every 3 weeks thereafter. Trastuzumab was given intravenously at an initial dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks thereafter. Patients were treated with pertuzumab and trastuzumab until progression of disease, withdrawal of consent, or unacceptable toxicity. Docetaxel was given as an initial dose of 75 mg/m2 by intravenous infusion every 3 weeks for at least 6 cycles. The docetaxel dose could be escalated to 100 mg/m2 at the investigator's discretion if the initial dose was well tolerated. At the time of the primary analysis, the mean number of cycles of study treatment administered was 16.2 in the placebo-treated group and 19.9 in the pertuzumab-treated group.
The primary endpoint of Study 1 was progression-free survival (PFS) as assessed by an independent review facility (IRF). PFS was defined as the time from the date of randomization to the date of disease progression or death (from any cause) if the death occurred within 18 weeks of the last tumor assessment. Additional endpoints included overall survival (OS), PFS (investigator-assessed), objective response rate (ORR), and duration of response.
Patient demographic and baseline characteristics were balanced between the treatment arms. The median age was 54 (range 22 to 89 years), 59% were White, 32% were Asian, and 4% were Black. All were women with the exception of 2 patients. Seventeen percent of patients were enrolled in North America, 14% in South America, 38% in Europe, and 31% in Asia. Tumor prognostic characteristics, including hormone receptor status (positive 48%, negative 50%), presence of visceral disease (78%) and non-visceral disease only (22%) were similar in the study arms. Approximately half of the patients received prior adjuvant or neoadjuvant anti-HER2 therapy or chemotherapy (placebo 47%, pertuzumab 46%). Among patients with hormone receptor positive tumors, 45% received prior adjuvant hormonal therapy and 11% received hormonal therapy for metastatic disease. Eleven percent of patients received prior adjuvant or neoadjuvant trastuzumab.
Study 1 demonstrated a statistically significant improvement in IRF-assessed PFS in the pertuzumab-treated group compared with the placebo-treated group and an increase in median PFS of 6.1 months (median PFS of 18.5 months in the pertuzumab-treated group vs. 12.4 months in the placebo-treated group) (see FIGURE 1). The results for investigator-assessed PFS were comparable to those observed for IRF-assessed PFS.
Consistent results were observed across several patient subgroups including age (< 65 or ≥ 65 years), race, geographic region, prior adjuvant/neoadjuvant anti-HER2 therapy or chemotherapy (yes or no), and prior adjuvant/neoadjuvant trastuzumab (yes or no). In the subgroup of patients with hormone receptor-negative disease (n=408), the hazard ratio was 0.55 (95% CI: 0.42, 0.72). In the subgroup of patients with hormone receptor-positive disease (n=388), the hazard ratio was 0.72 (95% CI: 0.55, 0.95). In the subgroup of patients with disease limited to non-visceral metastasis (n=178), the hazard ratio was 0.96 (95% CI: 0.61, 1.52).
At the time of the final PFS analysis, 165 patients had died, and more deaths had occurred in the placebo-treated group (23.6%) compared with the pertuzumab-treated group (17.2%); OS was not mature and interim OS analysis results did not meet the pre-specified stopping boundary for statistical significance. A second interim analysis of OS, conducted after an additional year of follow-up, demonstrated a statistically significant improvement in OS . See TABLE 4 and FIGURE 2. OS results in patient subgroups were consistent with those observed for IRF-assessed PFS with the exception of the subgroup of patients with disease limited to non-visceral metastasis .
Neoadjuvant Treatment of Breast Cancer
Study 2
- Study 2 was a multicenter, randomized trial conducted in 417 patients with operable, locally advanced, or inflammatory HER2-positive breast cancer (T2-4d) who were scheduled for neoadjuvant therapy. HER2 overexpression was defined as a score of 3+ IHC or FISH amplification ratio of 2.0 or greater as determined by a central laboratory. Patients were randomly allocated to receive 1 of 4 neoadjuvant regimens prior to surgery as follows: trastuzumab plus docetaxel, pertuzumab plus trastuzumab and docetaxel, pertuzumab plus trastuzumab, or pertuzumab plus docetaxel. Randomization was stratified by breast cancer type (operable, locally advanced, or inflammatory) and estrogen receptor (ER) or progesterone receptor (PgR) positivity.
- pertuzumab was given intravenously at an initial dose of 840 mg, followed by 420 mg every 3 weeks for 4 cycles. Trastuzumab was given intravenously at an initial dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks for 4 cycles. Docetaxel was given as an initial dose of 75 mg/m2 by intravenous infusion every 3 weeks for 4 cycles. The docetaxel dose could be escalated to 100 mg/m2 at the investigator's discretion if the initial dose was well tolerated. Following surgery all patients received 3 cycles of 5-fluorouracil (600 mg/m2), epirubicin (90 mg/m2), and cyclophosphamide (600 mg/m2) (FEC) given intravenously every 3 weeks and trastuzumab administered intravenously every 3 weeks to complete 1 year of therapy. After surgery, patients in the pertuzumab plus trastuzumab arm received docetaxel every 3 weeks for 4 cycles prior to FEC.
- The primary endpoint of the study was pathological complete response (pCR) rate in the breast (ypT0/is). The FDA-preferred definition of pCR is the absence of invasive cancer in the breast and lymph nodes (ypT0/is ypN0).
- Demographics were well balanced (median age was 49 – 50 years old, the majority were Caucasian (71%) and all were female. Overall, 7% of patients had inflammatory cancer, 32% had locally advanced cancer, and 61% had operable cancer. Approximately half the patients in each treatment group had hormone receptor-positive disease (defined as ER-positive and/or PgR-positive).
- The efficacy results are summarized in TABLE 5. Statistically significant improvements in pCR rates by both the study and FDA-preferred definitions were observed in patients receiving pertuzumab plus trastuzumab and docetaxel compared to patients receiving trastuzumab plus docetaxel. The pCR rates and magnitude of improvement with pertuzumab were lower in the subgroup of patients with hormone receptor-positive tumors compared to patients with hormone receptor-negative tumors.
Study 3
- An additional phase 2 neoadjuvant study was conducted in 225 patients with HER2-positive locally advanced, operable, or inflammatory (T2-4d) breast cancer designed primarily to assess cardiac safety in which all arms included pertuzumab. HER2 overexpression was defined as a score of 3+ IHC or FISH amplification ratio of 2.0 or greater as determined by a central laboratory.
- Patients were randomly allocated to receive 1 of 3 neoadjuvant regimens prior to surgery as follows: 3 cycles of FEC followed by 3 cycles of docetaxel all in combination with pertuzumab and trastuzumab, 3 cycles of FEC alone followed by 3 cycles of docetaxel and trastuzumab in combination with pertuzumab, or 6 cycles of docetaxel, carboplatin, and trastuzumab (TCH) in combination with pertuzumab. Randomization was stratified by breast cancer type (operable, locally advanced, or inflammatory) and ER and/or PgR positivity.
- pertuzumab was given by intravenous infusion at an initial dose of 840 mg, followed by 420 mg every 3 weeks. Trastuzumab was given by intravenous infusion at an initial dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks. 5-Fluorouracil (500 mg/m2), epirubicin (100 mg/m2), and cyclophosphamide (600 mg/m2) were given intravenously every 3 weeks for 3 cycles. In the pertuzumab plus trastuzumab, docetaxel, and FEC arms, docetaxel was given as an initial dose of 75 mg/m2 by intravenous infusion every 3 weeks for 3 cycles with the option to escalate to 100 mg/m2 at the investigator's discretion if the initial dose was well tolerated. However, in the pertuzumab plus TCH arm, docetaxel was given intravenously at 75 mg/m2 (no escalation was permitted) and carboplatin (AUC 6) was given intravenously every 3 weeks for 6 cycles. Following surgery all patients received trastuzumab to complete 1 year of therapy, which was administered intravenously every 3 weeks.
- Demographics were well balanced (median age was 49-50 years old, the majority were Caucasian (76%)) and all were female. Overall 6% of patients had inflammatory cancer, 25% had locally advanced cancer and 69% had operable cancer, with approximately half the patients in each treatment group having ER-positive and/or PgR-positive disease.
- The pCR (ypT0/is ypN0) rates were 56.2% (95% CI: 44.1%, 67.8%), 54.7% (95% CI: 42.7%, 66.2%), and 63.6% (95% CI: 51.9%, 74.3%) for patients treated with pertuzumab plus trastuzumab and FEC followed by pertuzumab plus trastuzumab and docetaxel, pertuzumab plus trastuzumab and docetaxel following FEC, or pertuzumab plus TCH, respectively. The pCR rates were lower in the subgroups of patients with hormone receptor-positive tumors: 41.0% (95% CI: 25.6%, 57.9%), 45.7% (95% CI: 28.8%, 63.4%), and 47.5% (95% CI: 31.5%, 63.9%) than with hormone receptor-negative tumors: 73.5% (95% CI: 55.6%, 87.1%), 62.5% (95% CI: 45.8%, 77.3%), and 81.1% (95% CI: 64.8%, 92.0%), respectively.
# How Supplied
- Pertuzumab is supplied as:
- 420 mg/14 mL (30 mg/mL) single-use vial containing preservative-free solution.
- NDC 50242-145-01.
## Storage
- Store vials in a refrigerator at 2°C to 8°C (36°F to 46°F) until time of use.
- Keep vial in the outer carton in order to protect from light.
- DO NOT FREEZE. DO NOT SHAKE.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise pregnant women and females of reproductive potential that pertuzumab exposure can result in fetal harm, including embryo-fetal death or birth defects.
- Advise females of reproductive potential to use effective contraception while receiving pertuzumab and for 6 months following the last dose of pertuzumab.
- Advise nursing mothers treated with pertuzumab to discontinue nursing or discontinue pertuzumab, taking into account the importance of the drug to the mother.
- Encourage women who are exposed to pertuzumab during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720.
# Precautions with Alcohol
Alcohol-Pertuzumab interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Perjeta
# Look-Alike Drug Names
There is limited information regarding Pertuzumab Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Pertuzumab
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Stefano Giannoni [2];Aparna Vuppala, M.B.B.S. [3]
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# Black Box Warning
# Overview
Pertuzumab is a monoclonal antibody that is FDA approved for the treatment of metastatic breast cancer and as a neoadjuvant treatment of breast cancer. There is a Black Box Warning for this drug as shown here. Common adverse reactions include diarrhea, alopecia, neutropenia, nausea, vomiting, fatigue, rash, and peripheral neuropathy in combination with trastuzumab and docetaxel.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Metastatic Breast Cancer
- Indicated for use in combination with trastuzumab and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease.
- Recommended initial dose of docetaxel is 75 mg/m2 administered as an intravenous infusion.
- The dose may be escalated to 100 mg/m2 administered every 3 weeks if the initial dose is well tolerated
### Neoadjuvant Treatment of Breast Cancer
- Pertuzumab is indicated for use in combination with trastuzumab and docetaxel for the neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer (either greater than 2 cm in diameter or node positive) as part of a complete treatment regimen for early breast cancer. This indication is based on demonstration of an improvement in pathological complete response rate. No data are available demonstrating improvement in event-free survival or overall survival.
- Pertuzumab should be administered every 3 weeks for 3 to 6 cycles as part of one of the following treatment regimens for early breast cancer:
- Four preoperative cycles of pertuzumab in combination with trastuzumab and docetaxel followed by 3 postoperative cycles of fluorouracil, epirubicin, and cyclophosphamide (FEC) as given in Study 2
- Three preoperative cycles of FEC alone followed by 3 preoperative cycles of pertuzumab in combination with docetaxel and trastuzumab as given in Study 3
- Six preoperative cycles of pertuzumab in combination with docetaxel, carboplatin, and trastuzumab (TCH) (escalation of docetaxel above 75 mg/m2 is not recommended) as given in Study 3
- Following surgery, patients should continue to receive trastuzumab to complete 1 year of treatment. There is insufficient evidence to recommend continued use of pertuzumab for greater than 6 cycles for early breast cancer. There is insufficient evidence to recommend concomitant administration of an anthracycline with pertuzumab, and there are no safety data to support sequential use of doxorubicin with pertuzumab.
### Recommended Doses and Schedules
- The initial dose of pertuzumab is 840 mg administered as a 60-minute intravenous infusion, followed every 3 weeks by a dose of 420 mg administered as an intravenous infusion over 30 to 60 minutes.
- When administered with pertuzumab, the recommended initial dose of trastuzumab is 8 mg/kg administered as a 90-minute intravenous infusion, followed every 3 weeks by a dose of 6 mg/kg administered as an intravenous infusion over 30 to 90 minutes.
- Pertuzumab, trastuzumab, and docetaxel should be administered sequentially. Pertuzumab and trastuzumab can be given in any order. Docetaxel should be administered after pertuzumab and trastuzumab. An observation period of 30 to 60 minutes is recommended after each pertuzumab infusion and before commencement of any subsequent infusion of trastuzumab or docetaxel.
### Dose Modification
- For delayed or missed doses, if the time between two sequential infusions is less than 6 weeks, the 420 mg dose of pertuzumab should be administered. Do not wait until the next planned dose. If the time between two sequential infusions is 6 weeks or more, the initial dose of 840 mg pertuzumab should be re-administered as a 60-minute intravenous infusion followed every 3 weeks thereafter by a dose of 420 mg administered as an intravenous infusion over 30 to 60 minutes.
- Pertuzumab should be discontinued if trastuzumab treatment is discontinued.
- Dose reductions are not recommended for pertuzumab.
- For docetaxel dose modifications, see relevant prescribing information.
Left Ventricular Ejection Fraction (LVEF):
- Withhold pertuzumab and trastuzumab dosing for at least 3 weeks for either:
- A drop in LVEF to less than 45% or
- LVEF of 45% to 49% with a 10% or greater absolute decrease below pretreatment values.
- Pertuzumab may be resumed if the LVEF has recovered to greater than 49% or to 45% to 49% associated with less than a 10% absolute decrease below pretreatment values.
- If after a repeat assessment within approximately 3 weeks, the LVEF has not improved, or has declined further, pertuzumab and trastuzumab should be discontinued, unless the benefits for the individual patient are deemed to outweigh the risks.
Infusion-Related Reactions
- The infusion rate of pertuzumab may be slowed or interrupted if the patient develops an infusion-related reaction.
Hypersensitivity Reactions/Anaphylaxis
- The infusion should be discontinued immediately if the patient experiences a serious hypersensitivity reaction
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pertuzumab in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Pertuzumab in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Pertuzumab FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pertuzumab in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Pertuzumab in pediatric patients.
# Contraindications
- Pertuzumab is contraindicated in patients with known hypersensitivity to pertuzumab or to any of its excipients.
# Warnings
### Embryo-Fetal Toxicity
- Pertuzumab can cause fetal harm when administered to a pregnant woman.
- Treatment of pregnant cynomolgus monkeys with pertuzumab resulted in oligohydramnios, delayed fetal kidney development, and embryo-fetal death.
- If pertuzumab is administered during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to a fetus.
- Verify pregnancy status prior to the initiation of pertuzumab.
- Advise patients of the risks of embryo-fetal death and birth defects and the need for contraception during and after treatment.
- Advise patients to contact their healthcare provider immediately if they suspect they may be pregnant.
- Monitor patients who become pregnant during pertuzumab therapy for oligohydramnios. If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and consistent with community standards of care.
- The efficacy of intravenous hydration in the management of oligohydramnios due to pertuzumab exposure is not known.
### Left Ventricular Dysfunction
- Decreases in LVEF have been reported with drugs that block HER2 activity, including pertuzumab.
- In Study 1, for patients with MBC, pertuzumab in combination with trastuzumab and docetaxel was not associated with increases in the incidence of symptomatic left ventricular systolic dysfunction (LVSD) or decreases in LVEF compared with placebo in combination with trastuzumab and docetaxel. Left ventricular dysfunction occurred in 4.4% of patients in the pertuzumab-treated group and 8.3% of patients in the placebo-treated group. Symptomatic left ventricular systolic dysfunction (congestive heart failure) occurred in 1.0% of patients in the pertuzumab-treated group and 1.8% of patients in the placebo-treated group.
- Patients who have received prior anthracyclines or prior radiotherapy to the chest area may be at higher risk of decreased LVEF.
- In patients receiving neoadjuvant treatment in Study 2, the incidence of LVSD was higher in the pertuzumab-treated groups compared to the trastuzumab- and docetaxel-treated group.
- An increased incidence of LVEF declines was observed in patients treated with pertuzumab in combination with trastuzumab and docetaxel. In the overall treatment period, LVEF decline > 10% and a drop to less than 50% occurred in 1.9% of patients treated with neoadjuvant trastuzumab and docetaxel as compared to 8.4% of patients treated with neoadjuvant pertuzumab in combination with trastuzumab and docetaxel.
- Symptomatic LVSD occurred in 0.9% of patients treated with neoadjuvant pertuzumab in combination with trastuzumab and no patients in the other 3 arms. LVEF recovered to ≥ 50% in all patients.
- In patients receiving neoadjuvant pertuzumab in Study 3, in the overall treatment period, LVEF decline > 10% and a drop to less than 50% occurred in 6.9% of patients treated with pertuzumab plus trastuzumab and FEC followed by pertuzumab plus trastuzumab and docetaxel, 16.0% of patients treated with pertuzumab plus trastuzumab and docetaxel following FEC, and 10.5% of patients treated with pertuzumab in combination with TCH.
- Symptomatic LVSD occurred in 4.0% of patients treated with pertuzumab plus trastuzumab and docetaxel following FEC, 1.3% of patients treated with pertuzumab in combination with TCH, and none of the patients treated with pertuzumab plus trastuzumab and FEC followed by pertuzumab plus trastuzumab and docetaxel.
- LVEF recovered to ≥ 50% in all but one patient.
- Pertuzumab has not been studied in patients with a pretreatment LVEF value of ≤ 50%, a prior history of CHF, decreases in LVEF to < 50% during prior trastuzumab therapy, or conditions that could impair left ventricular function such as uncontrolled hypertension, recent myocardial infarction, serious cardiac arrhythmia requiring treatment or a cumulative prior anthracycline exposure to > 360 mg/m2 of doxorubicin or its equivalent.
- Assess LVEF prior to initiation of pertuzumab and at regular intervals (e.g., every three months in the metastatic setting and every six weeks in the neoadjuvant setting) during treatment to ensure that LVEF is within the institution's normal limits. If LVEF is < 45%, or is 45% to 49% with a 10% or greater absolute decrease below the pretreatment value, withhold pertuzumab and trastuzumab and repeat LVEF assessment within approximately 3 weeks.
- Discontinue pertuzumab and trastuzumab if the LVEF has not improved or has declined further, unless the benefits for the individual patient outweigh the risks.
### Infusion-Related Reactions
- Pertuzumab has been associated with infusion reactions.
- An infusion reactions was defined in Study 1 as any event described as hypersensitivity, anaphylactic reaction, acute infusion reaction, or cytokine release syndrome occurring during an infusion or on the same day as the infusion.
- The initial dose of pertuzumab was given the day before trastuzumab and docetaxel to allow for the examination of pertuzumab-associated reactions.
- On the first day, when only pertuzumab was administered, the overall frequency of infusion reactions was 13.0% in the pertuzumab-treated group and 9.8% in the placebo-treated group. Less than 1% were Grade 3 or 4. The most common infusion reactions (≥ 1.0%) were pyrexia, chills, fatigue, headache, asthenia, hypersensitivity, and vomiting.
- During the second cycle when all drugs were administered on the same day, the most common infusion reactions in the pertuzumab-treated group (≥ 1.0%) were fatigue, dysgeusia, hypersensitivity, myalgia, and vomiting.
- In Study 2 and Study 3, pertuzumab was administered on the same day as the other study treatment drugs.
- Infusion reactions were consistent with those observed in Study 1, with a majority of reactions being National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI - CTCAE v3.0) Grade 1 – 2.
- Observe patients closely for 60 minutes after the first infusion and for 30 minutes after subsequent infusions of pertuzumab.
- If a significant infusion-related reaction occurs, slow or interrupt the infusion, and administer appropriate medical therapies.
- Monitor patients carefully until complete resolution of signs and symptoms.
- Consider permanent discontinuation in patients with severe infusion reactions.
### Hypersensitivity Reactions/Anaphylaxis
- In Study 1, the overall frequency of hypersensitivity/anaphylaxis reactions was 10.8% in the pertuzumab-treated group and 9.1% in the placebo-treated group. The incidence of Grade 3 – 4 hypersensitivity/anaphylaxis reactions was 2.0% in the pertuzumab-treated group and 2.5% in the placebo-treated group according to NCI - CTCAE v3.0.
- Overall, 4 patients in pertuzumab-treated group and 2 patients in the placebo-treated group experienced anaphylaxis.
- In Study 2 and Study 3, hypersensitivity/anaphylaxis events were consistent with those observed in Study 1. In Study 2, two patients in the pertuzumab- and docetaxel-treated group experienced anaphylaxis. In Study 3, the overall frequency of hypersensitivity/anaphylaxis was highest in the pertuzumab plus TCH treated group (13.2%), of which 2.6% were NCI-CTCAE (version 3) Grade 3 – 4.
- Patients should be observed closely for hypersensitivity reactions. Severe hypersensitivity, including anaphylaxis, has been observed in clinical trials with treatment of pertuzumab. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use.
- Pertuzumab is contraindicated in patients with known hypersensitivity to pertuzumab or to any of its excipients.
### HER2 Testing
- Detection of HER2 protein overexpression is necessary for selection of patients appropriate for pertuzumab therapy because these are the only patients studied and for whom benefit has been shown.
- Patients with breast cancer were required to have evidence of HER2 overexpression defined as 3+ IHC or FISH amplification ratio ≥ 2.0 in the clinical studies.
- Only limited data were available for patients whose breast cancer was positive by FISH, but did not demonstrate protein overexpression by IHC.
- Assessment of HER2 status should be performed by laboratories using FDA-approved tests with demonstrated proficiency in the specific technology being utilized.
- Improper assay performance, including use of sub-optimally fixed tissue, failure to utilize specified reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results.
# Adverse Reactions
## Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
### Metastatic Breast Cancer (MBC)
The adverse reactions described in TABLE 1 were identified in 804 patients with HER2-positive metastatic breast cancer treated in Study 1. Patients were randomized to receive either pertuzumab in combination with trastuzumab and docetaxel or placebo in combination with trastuzumab and docetaxel.
- The median duration of study treatment was 18.1 months for patients in the pertuzumab-treated group and 11.8 months for patients in the placebo-treated group. No dose adjustment was permitted for pertuzumab or trastuzumab. The rates of adverse events resulting in permanent discontinuation of all study therapy were 6.1% for patients in the pertuzumab-treated group and 5.3% for patients in the placebo-treated group. Adverse events led to discontinuation of docetaxel alone in 23.6% of patients in the pertuzumab-treated group and 23.2% of patients in the placebo-treated group. TABLE 1 reports the adverse reactions that occurred in at least 10% of patients in the pertuzumab-treated group. The safety profile of pertuzumab remained unchanged with an additional year of follow-up (median total follow-up of 30 months) in Study 1.
The most common adverse reactions (> 30%) seen with pertuzumab in combination with trastuzumab and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy.
- The most common NCI - CTCAE v3.0 Grade 3 – 4 adverse reactions (> 2%) were neutropenia, febrile neutropenia, leukopenia, diarrhea, peripheral neuropathy, anemia, asthenia, and fatigue.
- An increased incidence of febrile neutropenia was observed for Asian patients in both treatment arms compared with patients of other races and from other geographic regions.
- Among Asian patients, the incidence of febrile neutropenia was higher in the pertuzumab-treated group (26%) compared with the placebo-treated group (12%).
The following clinically relevant adverse reactions were reported in < 10% of patients in the pertuzumab-treated group in Study 1:
Skin and subcutaneous tissue disorders: Paronychia (7.1% in the pertuzumab-treated group vs. 3.5% in the placebo-treated group)
Respiratory, thoracic and mediastinal disorders: Pleural effusion (5.2% in the pertuzumab-treated group vs. 5.8% in the placebo-treated group)
Cardiac disorders: Left ventricular dysfunction (4.4% in the pertuzumab-treated group vs. 8.3% in the placebo-treated group) including symptomatic left ventricular systolic dysfunction (CHF) (1.0% in the pertuzumab-treated group vs. 1.8% in the placebo-treated group)
Immune system disorders: Hypersensitivity (10.1% in the pertuzumab-treated group vs. 8.6% in placebo-treated group)
Adverse Reactions Reported in Patients Receiving pertuzumab and Trastuzumab after Discontinuation of Docetaxel
In Study 1, adverse reactions were reported less frequently after discontinuation of docetaxel treatment. All adverse reactions in the pertuzumab and trastuzumab treatment group occurred in < 10% of patients with the exception of diarrhea (19.1%), upper respiratory tract infection (12.8%), rash (11.7%), headache (11.4%), and fatigue (11.1%).
Neoadjuvant Treatment of Breast Cancer (Study 2)
In Study 2, the most common adverse reactions seen with pertuzumab in combination with trastuzumab and docetaxel administered for 4 cycles were similar to those seen in the pertuzumab-treated group in Study 1.
- The most common adverse reactions (> 30%) were alopecia, neutropenia, diarrhea, and nausea.
- The most common NCI – CTCAE v3.0 Grade 3 – 4 adverse reactions (> 2%) were neutropenia, febrile neutropenia, leukopenia, and diarrhea.
- In this group, one patient permanently discontinued neoadjuvant treatment due to an adverse event.
- TABLE 2 reports the adverse reactions that occurred in patients who received neoadjuvant treatment with pertuzumab for breast cancer in Study 2.
- The following adverse reactions were reported in < 10% of patients receiving neoadjuvant treatment and occurred more frequently in pertuzumab-treated groups in Study 2: (Ptz=pertuzumab; T=trastuzumab; D=docetaxel)
Blood and lymphatic system disorders:
- Anemia (6.5% in the T+D arm, 2.8% in the Ptz+T+D arm, 4.6% in the Ptz+T arm and 8.5% in the Ptz+D arm)
- Febrile neutropenia (6.5% in the T+D arm, 8.4% in the Ptz+T+D arm, 0.0% in the Ptz+T arm and 7.4% in the Ptz+D arm)
Immune system disorders:
- Hypersensitivity (1.9% in the T+D arm, 5.6% in the Ptz+T+D arm, 5.6% in the Ptz+T arm and 5.3% in the Ptz+D arm)
Nervous system disorders:
- Dizziness (3.7% in the T+D arm, 2.8% in the Ptz+T+D arm, 5.6% in the Ptz+T arm and 3.2% in the Ptz+D arm)
Infections and infestations:
- Upper respiratory tract infection (2.8% in the T+D arm, 4.7% in the Ptz+T+D arm, 1.9% in the Ptz+T arm and 7.4% in the Ptz+D arm)
Respiratory, thoracic and mediastinal disorders:
- Dyspnea (3.7% in the T+D arm, 4.7% in the Ptz+T+D arm, 2.8% in the Ptz+T arm and 2.1% in the Ptz+D arm)
Cardiac disorders:
- Left ventricular dysfunction (0.9% in the T+D arm, 2.8% in the Ptz+T+D arm, 0.0% in the Ptz+T arm, and 1.1% in the Ptz+D arm) including symptomatic left ventricular dysfunction (CHF) (0.9% in the Ptz+T arm and 0.0% in the T+D arm, Ptz+T+D arm, and Ptz+D arm)
Eye disorders:
- Lacrimation increased (1.9% in the T+D arm, 3.7% in the Ptz+T+D arm, 0.9% in the Ptz+T arm, and 4.3% in the Ptz+D arm)
Neoadjuvant Treatment of Breast Cancer (Study 3)
- In Study 3, when pertuzumab was administered in combination with trastuzumab and docetaxel for 3 cycles following 3 cycles of FEC, the most common adverse reactions (> 30%) were diarrhea, nausea, alopecia, neutropenia, vomiting, and fatigue.
- The most common NCI-CTCAE (version 3) Grade 3 – 4 adverse reactions (> 2%) were neutropenia, leukopenia, febrile neutropenia, diarrhea, left ventricular dysfunction, anemia, dyspnea, nausea, and vomiting.
Similarly, when pertuzumab was administered in combination with docetaxel, carboplatin, and trastuzumab (TCH) for 6 cycles, the most common adverse reactions (> 30%) were diarrhea, alopecia, neutropenia, nausea, fatigue, vomiting, anemia, and thrombocytopenia.
- The most common NCI-CTCAE (version 3) Grade 3 – 4 adverse reactions (> 2%) were neutropenia, febrile neutropenia, anemia, leukopenia, diarrhea, thrombocytopenia, vomiting, fatigue, ALT increased, hypokalemia, and hypersensitivity.
- The rates of adverse events resulting in permanent discontinuation of any component of neoadjuvant treatment were 6.7% for patients receiving pertuzumab in combination with trastuzumab and docetaxel following FEC and 7.9% for patients receiving pertuzumab in combination with TCH.
- TABLE 3 reports the adverse reactions that occurred in patients who received neoadjuvant treatment with pertuzumab for breast cancer in Study 3.
The following selected adverse reactions were reported in < 10% of patients receiving neoadjuvant treatment in Study 3: (Ptz=pertuzumab; T=trastuzumab; D=docetaxel; FEC= fluorouracil, epirubicin, and cyclophosphamide; TCH=docetaxel, carboplatin, and trastuzumab)
Skin and subcutaneous tissue disorders: Nail disorder (9.7% in the Ptz+T+FEC/Ptz+T+D arm, 6.7% in the FEC/Ptz+T+D arm, and 9.2% in the Ptz+TCH arm), Paronychia (0% in the Ptz+T+FEC/Ptz+T+D and 1.3% in both the FEC/Ptz+T+D and Ptz+TCH arms), Pruritis (2.8% in the Ptz+T+FEC/Ptz+T+D arm, 4.0% in the FEC/Ptz+T+D arm, and 3.9% in the Ptz+TCH arm)
Infections and infestations:
- Upper respiratory tract infection (8.3% in the Ptz+T+FEC/Ptz+T+D arm, 4.0% in the FEC/Ptz+T+D arm, and 2.6% in the Ptz+TCH arm), Nasopharyngitis (6.9% in the Ptz+T+FEC/Ptz+T+D arm, 6.7% in the FEC/Ptz+T+D arm, and 7.9% in the Ptz+TCH arm)
Respiratory, thoracic, and mediastinal disorders:
- Pleural effusion (1.4% in the Ptz+T+FEC/Ptz+T+D arm and 0% in the FEC/Ptz+T+D and Ptz+TCH arm)
Cardiac disorders:
- Left ventricular dysfunction (5.6% in the Ptz+T+FEC/PTZ+T+D arm, 4.0% in the FEC/Ptz+T+D arm, and 2.6% in the Ptz+TCH arm) including symptomatic left ventricular systolic dysfunction (CHF) (2.7% in the FEC/Ptz+T+D arm and 0% in the Ptz+T+FEC/Ptz+T+D and Ptz+TCH arms)
### Immunogenicity
- As with all therapeutic proteins, there is the potential for an immune response to pertuzumab.
- Patients in Study 1 were tested at multiple time-points for antibodies to pertuzumab.
- Approximately 2.8% (11/386) of patients in the pertuzumab-treated group and 6.2% (23/372) of patients in the placebo-treated group tested positive for anti-pertuzumab antibodies.
- Of these 34 patients, none experienced anaphylactic/hypersensitivity reactions that were clearly related to the anti-therapeutic antibodies (ATA).
- The presence of pertuzumab in patient serum at the levels expected at the time of ATA sampling can interfere with the ability of this assay to detect anti-pertuzumab antibodies.
- In addition, the assay may be detecting antibodies to trastuzumab.
- As a result, data may not accurately reflect the true incidence of anti-pertuzumab antibody development.
- Immunogenicity data are highly dependent on the sensitivity and specificity of the test methods used.
- Additionally, the observed incidence of a positive result in a test method may be influenced by several factors, including sample handling, timing of sample collection, drug interference, concomitant medication, and the underlying disease. For these reasons, comparison of the incidence of antibodies to pertuzumab with the incidence of antibodies to other products may be misleading.
## Postmarketing Experience
There is limited information regarding Pertuzumab Postmarketing Experience in the drug label.
# Drug Interactions
No drug-drug interactions were observed between pertuzumab and trastuzumab, or between pertuzumab and docetaxel.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
- There are no adequate and well-controlled studies of pertuzumab in pregnant women. Based on findings in animal studies, pertuzumab can cause fetal harm when administered to a pregnant woman. The effects of pertuzumab are likely to be present during all trimesters of pregnancy. Pertuzumab administered to pregnant cynomolgus monkeys resulted in oligohydramnios, delayed fetal kidney development, and embryo-fetal deaths at clinically relevant exposures of 2.5 to 20-fold greater than the recommended human dose, based on Cmax. If pertuzumab is administered during pregnancy, or if a patient becomes pregnant while receiving pertuzumab, the patient should be apprised of the potential hazard to the fetus.
### Animal Data
- Reproductive toxicology studies have been conducted in cynomolgus monkeys. Pregnant monkeys were treated on Gestational Day (GD)19 with loading doses of 30 to 150 mg/kg pertuzumab, followed by bi-weekly doses of 10 to 100 mg/kg. These dose levels resulted in clinically relevant exposures of 2.5 to 20-fold greater than the recommended human dose, based on Cmax. Intravenous administration of pertuzumab from GD19 through GD50 (period of organogenesis) was embryotoxic, with dose-dependent increases in embryo-fetal death between GD25 to GD70. The incidences of embryo-fetal loss were 33, 50, and 85% for dams treated with bi-weekly pertuzumab doses of 10, 30, and 100 mg/kg, respectively (2.5 to 20-fold greater than the recommended human dose, based on Cmax). At Caesarean section on GD100, oligohydramnios, decreased relative lung and kidney weights, and microscopic evidence of renal hypoplasia consistent with delayed renal development were identified in all pertuzumab dose groups. Pertuzumab exposure was reported in offspring from all treated groups, at levels of 29% to 40% of maternal serum levels at GD100.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Pertuzumab in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Pertuzumab during labor and delivery.
### Nursing Mothers
- It is not known whether pertuzumab is excreted in human milk, but human IgG is excreted in human milk. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from pertuzumab, a decision should be made whether to discontinue nursing, or discontinue drug, taking into account the elimination half-life of pertuzumab and the importance of the drug to the mother
### Pediatric Use
- The safety and effectiveness of pertuzumab have not been established in pediatric patients.
### Geriatic Use
- Of 402 patients who received pertuzumab in Study 1, 60 patients (15%) were ≥ 65 years of age and 5 patients (1%) were ≥ 75 years of age. No overall differences in efficacy and safety of pertuzumab were observed between these patients and younger patients.
Based on a population pharmacokinetic analysis, no significant difference was observed in the pharmacokinetics of pertuzumab between patients < 65 years (n=306) and patients ≥ 65 years (n=175).
### Gender
There is no FDA guidance on the use of Pertuzumab with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Pertuzumab with respect to specific racial populations.
### Renal Impairment
Dose adjustments of pertuzumab are not needed in patients with mild (creatinine clearance [[[CLcr]]] 60 to 90 mL/min) or moderate (CLcr 30 to 60 mL/min) renal impairment. No dose adjustment can be recommended for patients with severe renal impairment (CLcr less than 30 mL/min) because of the limited pharmacokinetic data available
### Hepatic Impairment
- No clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of pertuzumab.
### Females of Reproductive Potential and Males
- Pertuzumab can cause embryo-fetal harm when administered during pregnancy. Counsel patients regarding pregnancy prevention and planning. *Advise females of reproductive potential to use effective contraception while receiving pertuzumab and for 6 months following the last dose of pertuzumab.
### Immunocompromised Patients
There is no FDA guidance one the use of Pertuzumab in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous infusion
### Monitoring
- Infusion-Related Reactions: Monitor for signs and symptoms. If a significant infusion-associated reaction occurs, slow or interrupt the infusion and administer appropriate medical therapies.
- Hypersensitivity Reactions/Anaphylaxis: Monitor for signs and symptoms
- Monitor patients who become pregnant during pertuzumab therapy for oligohydramnios.
# IV Compatibility
### Preparation for Administration
Administer as an intravenous infusion only. Do not administer as an intravenous push or bolus. Do not mix pertuzumab with other drugs.
### Preparation
Prepare the solution for infusion, using aseptic technique, as follows:
- Parenteral drug products should be inspected visually for particulates and discoloration prior to administration.
- Withdraw the appropriate volume of pertuzumab solution from the vial(s).
- Dilute into a 250 mL 0.9% sodium chloride PVC or non-PVC polyolefin infusion bag.
- Mix diluted solution by gentle inversion. Do not shake.
- Administer immediately once prepared.
- If the diluted infusion solution is not used immediately, it can be stored at 2°C to 8°C for up to 24 hours.
- Dilute with 0.9% Sodium Chloride injection only. Do not use dextrose (5%) solution.
# Overdosage
No drug overdoses have been reported with pertuzumab to date.
# Pharmacology
## Mechanism of Action
Pertuzumab targets the extracellular dimerization domain (Subdomain II) of the human epidermal growth factor receptor 2 protein (HER2) and, thereby, blocks ligand-dependent heterodimerization of HER2 with other HER family members, including EGFR, HER3, and HER4. As a result, pertuzumab inhibits ligand-initiated intracellular signaling through two major signal pathways, mitogen-activated protein (MAP) kinase, and phosphoinositide 3-kinase (PI3K). Inhibition of these signaling pathways can result in cell growth arrest and apoptosis, respectively. In addition, pertuzumab mediates antibody-dependent cell-mediated cytotoxicity (ADCC).
While pertuzumab alone inhibited the proliferation of human tumor cells, the combination of pertuzumab and trastuzumab augmented anti-tumor activity in HER2-overexpressing xenograft models.
## Structure
There is limited information regarding Pertuzumab Structure in the drug label.
## Pharmacodynamics
### Cardiac Electrophysiology
The effect of pertuzumab with an initial dose of 840 mg followed by a maintenance dose of 420 mg every three weeks on QTc interval was evaluated in a subgroup of 20 patients with HER2-positive breast cancer in Study 1. No large changes in the mean QT interval (i.e., greater than 20 ms) from placebo based on Fridericia correction method were detected in the trial. A small increase in the mean QTc interval (i.e., less than 10 ms) cannot be excluded because of the limitations of the trial design.
## Pharmacokinetics
Pertuzumab demonstrated linear pharmacokinetics at a dose range of 2 – 25 mg/kg. Based on a population PK analysis that included 481 patients, the median clearance (CL) of pertuzumab was 0.24 L/day and the median half-life was 18 days. With an initial dose of 840 mg followed by a maintenance dose of 420 mg every three weeks thereafter, the steady-state concentration of pertuzumab was reached after the first maintenance dose.
The population PK analysis suggested no PK differences based on age, gender, ethnicity (Japanese vs. non-Japanese), or disease status (neoadjuvant versus metastatic setting). Baseline serum albumin level and lean body weight as covariates only exerted a minor influence on PK parameters. Therefore, no dose adjustments based on body weight or baseline albumin level are needed.
No drug-drug interactions were observed between pertuzumab and trastuzumab, or between pertuzumab and docetaxel in a sub-study of 37 patients in Study 1.
No dedicated renal impairment trial for pertuzumab has been conducted. Based on the results of the population pharmacokinetic analysis, pertuzumab exposure in patients with mild (CLcr 60 to 90 mL/min, n=200) and moderate renal impairment (CLcr 30 to 60 mL/min, n=71) were similar to those in patients with normal renal function (CLcr greater than 90 mL/min, n=200). No relationship between CLcr and pertuzumab exposure was observed over the range of observed CLcr (27 to 244 mL/min).
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term studies in animals have not been performed to evaluate the carcinogenic potential of pertuzumab.
Studies have not been performed to evaluate the mutagenic potential of pertuzumab.
No specific fertility studies in animals have been performed to evaluate the effect of pertuzumab. No adverse effects on male and female reproductive organs were observed in repeat-dose toxicity studies of up to six months duration in cynomolgus monkeys.
# Clinical Studies
### Metastatic Breast Cancer
Study 1 was a multicenter, double-blind, placebo-controlled trial of 808 patients with HER2-positive metastatic breast cancer. HER2 overexpression was defined as a score of 3+ IHC or FISH amplification ratio of 2.0 or greater as determined by a central laboratory. Patients were randomly allocated 1:1 to receive placebo plus trastuzumab and docetaxel or pertuzumab plus trastuzumab and docetaxel. Randomization was stratified by prior treatment (prior or no prior adjuvant/neoadjuvant anti-HER2 therapy or chemotherapy) and geographic region (Europe, North America, South America, and Asia). Patients with prior adjuvant or neoadjuvant therapy were required to have a disease-free interval of greater than 12 months before trial enrollment.
Pertuzumab was given intravenously at an initial dose of 840 mg, followed by 420 mg every 3 weeks thereafter. Trastuzumab was given intravenously at an initial dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks thereafter. Patients were treated with pertuzumab and trastuzumab until progression of disease, withdrawal of consent, or unacceptable toxicity. Docetaxel was given as an initial dose of 75 mg/m2 by intravenous infusion every 3 weeks for at least 6 cycles. The docetaxel dose could be escalated to 100 mg/m2 at the investigator's discretion if the initial dose was well tolerated. At the time of the primary analysis, the mean number of cycles of study treatment administered was 16.2 in the placebo-treated group and 19.9 in the pertuzumab-treated group.
The primary endpoint of Study 1 was progression-free survival (PFS) as assessed by an independent review facility (IRF). PFS was defined as the time from the date of randomization to the date of disease progression or death (from any cause) if the death occurred within 18 weeks of the last tumor assessment. Additional endpoints included overall survival (OS), PFS (investigator-assessed), objective response rate (ORR), and duration of response.
Patient demographic and baseline characteristics were balanced between the treatment arms. The median age was 54 (range 22 to 89 years), 59% were White, 32% were Asian, and 4% were Black. All were women with the exception of 2 patients. Seventeen percent of patients were enrolled in North America, 14% in South America, 38% in Europe, and 31% in Asia. Tumor prognostic characteristics, including hormone receptor status (positive 48%, negative 50%), presence of visceral disease (78%) and non-visceral disease only (22%) were similar in the study arms. Approximately half of the patients received prior adjuvant or neoadjuvant anti-HER2 therapy or chemotherapy (placebo 47%, pertuzumab 46%). Among patients with hormone receptor positive tumors, 45% received prior adjuvant hormonal therapy and 11% received hormonal therapy for metastatic disease. Eleven percent of patients received prior adjuvant or neoadjuvant trastuzumab.
Study 1 demonstrated a statistically significant improvement in IRF-assessed PFS in the pertuzumab-treated group compared with the placebo-treated group [hazard ratio (HR)=0.62 (95% CI: 0.51, 0.75), p < 0.0001] and an increase in median PFS of 6.1 months (median PFS of 18.5 months in the pertuzumab-treated group vs. 12.4 months in the placebo-treated group) (see FIGURE 1). The results for investigator-assessed PFS were comparable to those observed for IRF-assessed PFS.
Consistent results were observed across several patient subgroups including age (< 65 or ≥ 65 years), race, geographic region, prior adjuvant/neoadjuvant anti-HER2 therapy or chemotherapy (yes or no), and prior adjuvant/neoadjuvant trastuzumab (yes or no). In the subgroup of patients with hormone receptor-negative disease (n=408), the hazard ratio was 0.55 (95% CI: 0.42, 0.72). In the subgroup of patients with hormone receptor-positive disease (n=388), the hazard ratio was 0.72 (95% CI: 0.55, 0.95). In the subgroup of patients with disease limited to non-visceral metastasis (n=178), the hazard ratio was 0.96 (95% CI: 0.61, 1.52).
At the time of the final PFS analysis, 165 patients had died, and more deaths had occurred in the placebo-treated group (23.6%) compared with the pertuzumab-treated group (17.2%); OS was not mature and interim OS analysis results did not meet the pre-specified stopping boundary for statistical significance. A second interim analysis of OS, conducted after an additional year of follow-up, demonstrated a statistically significant improvement in OS [HR=0.66 (95% CI: 0.52, 0.84), p=0.0008]. See TABLE 4 and FIGURE 2. OS results in patient subgroups were consistent with those observed for IRF-assessed PFS with the exception of the subgroup of patients with disease limited to non-visceral metastasis [HR=1.42 (95% CI: 0.71, 2.84)].
Neoadjuvant Treatment of Breast Cancer
Study 2
- Study 2 was a multicenter, randomized trial conducted in 417 patients with operable, locally advanced, or inflammatory HER2-positive breast cancer (T2-4d) who were scheduled for neoadjuvant therapy. HER2 overexpression was defined as a score of 3+ IHC or FISH amplification ratio of 2.0 or greater as determined by a central laboratory. Patients were randomly allocated to receive 1 of 4 neoadjuvant regimens prior to surgery as follows: trastuzumab plus docetaxel, pertuzumab plus trastuzumab and docetaxel, pertuzumab plus trastuzumab, or pertuzumab plus docetaxel. Randomization was stratified by breast cancer type (operable, locally advanced, or inflammatory) and estrogen receptor (ER) or progesterone receptor (PgR) positivity.
- pertuzumab was given intravenously at an initial dose of 840 mg, followed by 420 mg every 3 weeks for 4 cycles. Trastuzumab was given intravenously at an initial dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks for 4 cycles. Docetaxel was given as an initial dose of 75 mg/m2 by intravenous infusion every 3 weeks for 4 cycles. The docetaxel dose could be escalated to 100 mg/m2 at the investigator's discretion if the initial dose was well tolerated. Following surgery all patients received 3 cycles of 5-fluorouracil (600 mg/m2), epirubicin (90 mg/m2), and cyclophosphamide (600 mg/m2) (FEC) given intravenously every 3 weeks and trastuzumab administered intravenously every 3 weeks to complete 1 year of therapy. After surgery, patients in the pertuzumab plus trastuzumab arm received docetaxel every 3 weeks for 4 cycles prior to FEC.
- The primary endpoint of the study was pathological complete response (pCR) rate in the breast (ypT0/is). The FDA-preferred definition of pCR is the absence of invasive cancer in the breast and lymph nodes (ypT0/is ypN0).
- Demographics were well balanced (median age was 49 – 50 years old, the majority were Caucasian (71%) and all were female. Overall, 7% of patients had inflammatory cancer, 32% had locally advanced cancer, and 61% had operable cancer. Approximately half the patients in each treatment group had hormone receptor-positive disease (defined as ER-positive and/or PgR-positive).
- The efficacy results are summarized in TABLE 5. Statistically significant improvements in pCR rates by both the study and FDA-preferred definitions were observed in patients receiving pertuzumab plus trastuzumab and docetaxel compared to patients receiving trastuzumab plus docetaxel. The pCR rates and magnitude of improvement with pertuzumab were lower in the subgroup of patients with hormone receptor-positive tumors compared to patients with hormone receptor-negative tumors.
Study 3
- An additional phase 2 neoadjuvant study was conducted in 225 patients with HER2-positive locally advanced, operable, or inflammatory (T2-4d) breast cancer designed primarily to assess cardiac safety in which all arms included pertuzumab. HER2 overexpression was defined as a score of 3+ IHC or FISH amplification ratio of 2.0 or greater as determined by a central laboratory.
- Patients were randomly allocated to receive 1 of 3 neoadjuvant regimens prior to surgery as follows: 3 cycles of FEC followed by 3 cycles of docetaxel all in combination with pertuzumab and trastuzumab, 3 cycles of FEC alone followed by 3 cycles of docetaxel and trastuzumab in combination with pertuzumab, or 6 cycles of docetaxel, carboplatin, and trastuzumab (TCH) in combination with pertuzumab. Randomization was stratified by breast cancer type (operable, locally advanced, or inflammatory) and ER and/or PgR positivity.
- pertuzumab was given by intravenous infusion at an initial dose of 840 mg, followed by 420 mg every 3 weeks. Trastuzumab was given by intravenous infusion at an initial dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks. 5-Fluorouracil (500 mg/m2), epirubicin (100 mg/m2), and cyclophosphamide (600 mg/m2) were given intravenously every 3 weeks for 3 cycles. In the pertuzumab plus trastuzumab, docetaxel, and FEC arms, docetaxel was given as an initial dose of 75 mg/m2 by intravenous infusion every 3 weeks for 3 cycles with the option to escalate to 100 mg/m2 at the investigator's discretion if the initial dose was well tolerated. However, in the pertuzumab plus TCH arm, docetaxel was given intravenously at 75 mg/m2 (no escalation was permitted) and carboplatin (AUC 6) was given intravenously every 3 weeks for 6 cycles. Following surgery all patients received trastuzumab to complete 1 year of therapy, which was administered intravenously every 3 weeks.
- Demographics were well balanced (median age was 49-50 years old, the majority were Caucasian (76%)) and all were female. Overall 6% of patients had inflammatory cancer, 25% had locally advanced cancer and 69% had operable cancer, with approximately half the patients in each treatment group having ER-positive and/or PgR-positive disease.
- The pCR (ypT0/is ypN0) rates were 56.2% (95% CI: 44.1%, 67.8%), 54.7% (95% CI: 42.7%, 66.2%), and 63.6% (95% CI: 51.9%, 74.3%) for patients treated with pertuzumab plus trastuzumab and FEC followed by pertuzumab plus trastuzumab and docetaxel, pertuzumab plus trastuzumab and docetaxel following FEC, or pertuzumab plus TCH, respectively. The pCR rates were lower in the subgroups of patients with hormone receptor-positive tumors: 41.0% (95% CI: 25.6%, 57.9%), 45.7% (95% CI: 28.8%, 63.4%), and 47.5% (95% CI: 31.5%, 63.9%) than with hormone receptor-negative tumors: 73.5% (95% CI: 55.6%, 87.1%), 62.5% (95% CI: 45.8%, 77.3%), and 81.1% (95% CI: 64.8%, 92.0%), respectively.
# How Supplied
- Pertuzumab is supplied as:
- 420 mg/14 mL (30 mg/mL) single-use vial containing preservative-free solution.
- NDC 50242-145-01.
## Storage
- Store vials in a refrigerator at 2°C to 8°C (36°F to 46°F) until time of use.
- Keep vial in the outer carton in order to protect from light.
- DO NOT FREEZE. DO NOT SHAKE.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise pregnant women and females of reproductive potential that pertuzumab exposure can result in fetal harm, including embryo-fetal death or birth defects.
- Advise females of reproductive potential to use effective contraception while receiving pertuzumab and for 6 months following the last dose of pertuzumab.
- Advise nursing mothers treated with pertuzumab to discontinue nursing or discontinue pertuzumab, taking into account the importance of the drug to the mother.
- Encourage women who are exposed to pertuzumab during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720.
# Precautions with Alcohol
Alcohol-Pertuzumab interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Perjeta[1]
# Look-Alike Drug Names
There is limited information regarding Pertuzumab Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Perjeta | |
cb5a93a433fc98c8680ba9c7d974cc2af9fa31ef | wikidoc | Permethrin | Permethrin
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Permethrin is a dermatological agent that is FDA approved for the treatment of scabies, pediculosis capitis. Common adverse reactions include pruritus, erythema, numbness, tingling, rash, headache, fever, dizziness, abdominal pain, diarrhea, nausea and vomiting.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
# Indications
- Permethrin 5% Cream is indicated for the treatment of scabies caused by Sarcoptes scabiei
# Dosage
- Thoroughly massage Permethrin 5% Cream into the skin from the head to the soles of the feet. Scabies rarely infests the scalp of adults, although the hairline, neck, temple, and forehead may be infested in infants and geriatric patients. Usually 30 grams is sufficient for an average adult. The cream should be removed by washing (shower or bath) after 8 to 14 hours. Infants should be treated on the scalp, temple, and forehead. ONE APPLICATION IS GENERALLY CURATIVE.
- Patients may experience persistent pruritus after treatment. This is rarely a sign of treatment failure and is not an indication for retreatment. Demonstrable living mites after 14 days indicate that retreatment is necessary.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Permethrin in adult patients.
### Non–Guideline-Supported Use
# Indications and Dosing
- Pediculosis capitis: apply to damp hair that has just been shampooed with a non conditioning shampoo; saturate hair and scalp beginning behind the ears and at back of neck; leave on 10 minutes; rinse with warm water; remove nits with nit comb; repeat application if live lice present 7 days after initial treatment.
- Scabies: apply a generous amount of cream from head to feet, leave on for 8 to 14 hours, wash with soap/water, repeat application if living mites present 14 days after initial treatment.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
# Indications
- Permethrin 5% Cream is indicated for the treatment of scabies caused by Sarcoptes scabiei.
# Dosing
- Safety and efficacy have not been established in pediatric patients 2 months or younger.
- Thoroughly massage Permethrin 5% Cream into the skin from the head to the soles of the feet. Scabies rarely infests the scalp of adults, although the hairline, neck, temple, and forehead may be infested in infants patients. The cream should be removed by washing (shower or bath) after 8 to 14 hours. Infants should be treated on the scalp, temple, and forehead. ONE APPLICATION IS GENERALLY CURATIVE.
- Patients may experience persistent pruritus after treatment. This is rarely a sign of treatment failure and is not an indication for retreatment. Demonstrable living mites after 14 days indicate that retreatment is necessary.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Permethrin in pediatric patients.
### Non–Guideline-Supported Use
# Indications and Dosage
- Safety and efficacy have not been established in pediatric patients 2 months or younger.
- Pediculosis capitis: apply to damp hair that has just been shampooed with a non conditioning shampoo; saturate hair and scalp beginning behind the ears and at back of neck; leave on 10 minutes; rinse with warm water; remove nits with nit comb; repeat application if live lice present 7 days after initial treatment.
- Scabies: apply a generous amount of cream from head to feet, leave on for 8 to 14 hours, wash with soap/water, repeat application if living mites present 14 days after initial treatment.
# Contraindications
- Permethrin 5% Cream is contraindicated in patients with known hypersensitivity to any of its components, to any synthetic pyrethroid or pyrethrin.
# Warnings
There is limited information regarding Warnings of Permethrin in patients.
# Adverse Reactions
## Clinical Trials Experience
- In clinical trials, generally mild and transient burning and stinging followed application with permethrin 5% Cream in 10% of patients and was associated with the severity of infestation. Pruritus was reported in 7% of patients at various times post-application. Erythema, numbness, tingling, and rash were reported in 1 to 2% or less of patients.
## Postmarketing Experience
- Other adverse events reported since marketing Permethrin 5% Cream include: headache, fever, dizziness, abdominal pain, diarrhea and nausea and/or vomiting. Although extremely uncommon and not expected when used as directed , rare occurrences of seizure have been reported. None have been medically confirmed as associated with Permethrin™ treatment.
# Drug Interactions
There is limited information regarding Drug Interactions of Permethrin in patients.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
There is no FDA guidance on usage of Permethrin in women who are pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Permethrin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Permethrin during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Permethrin in women who are nursing.
### Pediatric Use
There is no FDA guidance on the use of Permethrin in pediatric settings.
### Geriatic Use
There is no FDA guidance on the use of Permethrin in geriatric settings.
### Gender
There is no FDA guidance on the use of Permethrin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Permethrin with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Permethrin in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Permethrin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Permethrin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Permethrin in patients who are immunocompromised.
### Others
# Administration and Monitoring
### Administration
Topical
- Shake bottle well prior to use.
- Do not use near eyes, inside the nose, mouth, or vagina; protect eyes with a washcloth or towel during application.
- (Permethrin 1%) apply to damp hair that has just been shampooed with a nonconditioning shampoo; saturate hair and scalp beginning behind the ears and at back of neck; leave on 10 minutes; rinse with warm water; remove nits with nit comb;
- Repeat application if live lice present 7 days after initial treatment.
- (Permethrin 1%) do not rewash hair for 1 to 2 days after treatment.
- (Permethrin 5% cream) apply a generous amount of cream from head to feet, leave on for 8 to 14 hours, wash with soap/water, repeat application if living mites present 14 days after initial treatment.
### Monitoring
- Presence of lice
# IV Compatibility
There is limited information regarding the compatibility of Permethrin and IV administrations.
# Overdosage
- No instance of accidental ingestion of Permethrin™ (permethrin) 5% Cream has been reported. If ingested, gastric lavage and general supportive measures should be employed. Excessive topical use may result in increased irritation and erythema.
# Pharmacology
## Mechanism of Action
- It acts on the nerve cell membrane to disrupt the sodium channel current by which the polarization of the membrane is regulated. Delayed repolarization and paralysis of the pests are the consequences of this disturbance.
- Permethrin is rapidly metabolized by ester hydrolysis to inactive metabolites which are excreted primarily in the urine. Although the amount of permethrin absorbed after a single application of the 5% cream has not been determined precisely, data from studies with 14C-labeled permethrin and absorption studies of the cream applied to patients with moderate to severe scabies indicate it is 2% or less of the amount applied.
## Structure
- Permethrin™ (permethrin) 5% Cream is a topical scabicidal agent for the treatment of infestation with Sarcoptesscabiei (scabies). It is available in an off-white, vanishing cream base. Permethrin™ (permethrin) 5% Cream is for topical use only.
Chemical Name - The permethrin used is an approximate 1:3 mixture of the cis and trans isomers of the pyrethroid 3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylic acid, (3-phenoxyphenyl) methyl ester. Permethrin has a molecular formula of C21H20Cl2O3 and a molecular weight of 391.29. It is a yellow to light orange-brown, low melting solid or viscous liquid.
Active Ingredient - Each gram contains permethrin 50 mg (5%).
Inactive Ingredients - Butylated hydroxytoluene, carbomer homopolymer type B, fractionated coconut oil, glycerin, glyceryl monostearate, isopropyl myristate, lanolin alcohols, mineral oil, polyoxyethylene cetyl ethers, purified water, and sodium hydroxide. Formaldehyde 1 mg (0.1%) is added as a preservative.
## Pharmacodynamics
There is limited information regarding Permethrin Pharmacodynamics in the drug label.
## Pharmacokinetics
Absorption
Topical: 2% or less absorbed.
Excretion
Topical: Renal.
## Nonclinical Toxicology
There is limited information regarding Permethrin Nonclinical Toxicology in the drug label.
# Clinical Studies
There is limited information regarding Permethrin Clinical Studies in the drug label.
# How Supplied
Permethrin™ 5% Cream is available as follows:
60 g tube (NDC 40076-115-60)
## Storage
- Store at 20-25°C (68-77°F) .
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Permethrin Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Permethrin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
Permethrin™
# Look-Alike Drug Names
There is limited information regarding Permethrin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
Drug Shortage
# Price | Permethrin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Permethrin is a dermatological agent that is FDA approved for the treatment of scabies, pediculosis capitis. Common adverse reactions include pruritus, erythema, numbness, tingling, rash, headache, fever, dizziness, abdominal pain, diarrhea, nausea and vomiting.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
# Indications
- Permethrin 5% Cream is indicated for the treatment of scabies caused by Sarcoptes scabiei
# Dosage
- Thoroughly massage Permethrin 5% Cream into the skin from the head to the soles of the feet. Scabies rarely infests the scalp of adults, although the hairline, neck, temple, and forehead may be infested in infants and geriatric patients. Usually 30 grams is sufficient for an average adult. The cream should be removed by washing (shower or bath) after 8 to 14 hours. Infants should be treated on the scalp, temple, and forehead. ONE APPLICATION IS GENERALLY CURATIVE.
- Patients may experience persistent pruritus after treatment. This is rarely a sign of treatment failure and is not an indication for retreatment. Demonstrable living mites after 14 days indicate that retreatment is necessary.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Permethrin in adult patients.
### Non–Guideline-Supported Use
# Indications and Dosing
- Pediculosis capitis: apply to damp hair that has just been shampooed with a non conditioning shampoo; saturate hair and scalp beginning behind the ears and at back of neck; leave on 10 minutes; rinse with warm water; remove nits with nit comb; repeat application if live lice present 7 days after initial treatment.
- Scabies: apply a generous amount of cream from head to feet, leave on for 8 to 14 hours, wash with soap/water, repeat application if living mites present 14 days after initial treatment.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
# Indications
- Permethrin 5% Cream is indicated for the treatment of scabies caused by Sarcoptes scabiei.
# Dosing
- Safety and efficacy have not been established in pediatric patients 2 months or younger.
- Thoroughly massage Permethrin 5% Cream into the skin from the head to the soles of the feet. Scabies rarely infests the scalp of adults, although the hairline, neck, temple, and forehead may be infested in infants patients. The cream should be removed by washing (shower or bath) after 8 to 14 hours. Infants should be treated on the scalp, temple, and forehead. ONE APPLICATION IS GENERALLY CURATIVE.
- Patients may experience persistent pruritus after treatment. This is rarely a sign of treatment failure and is not an indication for retreatment. Demonstrable living mites after 14 days indicate that retreatment is necessary.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Permethrin in pediatric patients.
### Non–Guideline-Supported Use
# Indications and Dosage
- Safety and efficacy have not been established in pediatric patients 2 months or younger.
- Pediculosis capitis: apply to damp hair that has just been shampooed with a non conditioning shampoo; saturate hair and scalp beginning behind the ears and at back of neck; leave on 10 minutes; rinse with warm water; remove nits with nit comb; repeat application if live lice present 7 days after initial treatment.
- Scabies: apply a generous amount of cream from head to feet, leave on for 8 to 14 hours, wash with soap/water, repeat application if living mites present 14 days after initial treatment.
# Contraindications
- Permethrin 5% Cream is contraindicated in patients with known hypersensitivity to any of its components, to any synthetic pyrethroid or pyrethrin.
# Warnings
There is limited information regarding Warnings of Permethrin in patients.
# Adverse Reactions
## Clinical Trials Experience
- In clinical trials, generally mild and transient burning and stinging followed application with permethrin 5% Cream in 10% of patients and was associated with the severity of infestation. Pruritus was reported in 7% of patients at various times post-application. Erythema, numbness, tingling, and rash were reported in 1 to 2% or less of patients.
## Postmarketing Experience
- Other adverse events reported since marketing Permethrin 5% Cream include: headache, fever, dizziness, abdominal pain, diarrhea and nausea and/or vomiting. Although extremely uncommon and not expected when used as directed , rare occurrences of seizure have been reported. None have been medically confirmed as associated with Permethrin™ treatment.
# Drug Interactions
There is limited information regarding Drug Interactions of Permethrin in patients.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
There is no FDA guidance on usage of Permethrin in women who are pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Permethrin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Permethrin during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Permethrin in women who are nursing.
### Pediatric Use
There is no FDA guidance on the use of Permethrin in pediatric settings.
### Geriatic Use
There is no FDA guidance on the use of Permethrin in geriatric settings.
### Gender
There is no FDA guidance on the use of Permethrin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Permethrin with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Permethrin in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Permethrin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Permethrin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Permethrin in patients who are immunocompromised.
### Others
# Administration and Monitoring
### Administration
Topical
- Shake bottle well prior to use.
- Do not use near eyes, inside the nose, mouth, or vagina; protect eyes with a washcloth or towel during application.
- (Permethrin 1%) apply to damp hair that has just been shampooed with a nonconditioning shampoo; saturate hair and scalp beginning behind the ears and at back of neck; leave on 10 minutes; rinse with warm water; remove nits with nit comb;
- Repeat application if live lice present 7 days after initial treatment.
- (Permethrin 1%) do not rewash hair for 1 to 2 days after treatment.
- (Permethrin 5% cream) apply a generous amount of cream from head to feet, leave on for 8 to 14 hours, wash with soap/water, repeat application if living mites present 14 days after initial treatment.
### Monitoring
- Presence of lice
# IV Compatibility
There is limited information regarding the compatibility of Permethrin and IV administrations.
# Overdosage
- No instance of accidental ingestion of Permethrin™ (permethrin) 5% Cream has been reported. If ingested, gastric lavage and general supportive measures should be employed. Excessive topical use may result in increased irritation and erythema.
# Pharmacology
## Mechanism of Action
- It acts on the nerve cell membrane to disrupt the sodium channel current by which the polarization of the membrane is regulated. Delayed repolarization and paralysis of the pests are the consequences of this disturbance.
- Permethrin is rapidly metabolized by ester hydrolysis to inactive metabolites which are excreted primarily in the urine. Although the amount of permethrin absorbed after a single application of the 5% cream has not been determined precisely, data from studies with 14C-labeled permethrin and absorption studies of the cream applied to patients with moderate to severe scabies indicate it is 2% or less of the amount applied.
## Structure
- Permethrin™ (permethrin) 5% Cream is a topical scabicidal agent for the treatment of infestation with Sarcoptesscabiei (scabies). It is available in an off-white, vanishing cream base. Permethrin™ (permethrin) 5% Cream is for topical use only.
Chemical Name - The permethrin used is an approximate 1:3 mixture of the cis and trans isomers of the pyrethroid 3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylic acid, (3-phenoxyphenyl) methyl ester. Permethrin has a molecular formula of C21H20Cl2O3 and a molecular weight of 391.29. It is a yellow to light orange-brown, low melting solid or viscous liquid.
Active Ingredient - Each gram contains permethrin 50 mg (5%).
Inactive Ingredients - Butylated hydroxytoluene, carbomer homopolymer type B, fractionated coconut oil, glycerin, glyceryl monostearate, isopropyl myristate, lanolin alcohols, mineral oil, polyoxyethylene cetyl ethers, purified water, and sodium hydroxide. Formaldehyde 1 mg (0.1%) is added as a preservative.
## Pharmacodynamics
There is limited information regarding Permethrin Pharmacodynamics in the drug label.
## Pharmacokinetics
Absorption
Topical: 2% or less absorbed.
Excretion
Topical: Renal.
## Nonclinical Toxicology
There is limited information regarding Permethrin Nonclinical Toxicology in the drug label.
# Clinical Studies
There is limited information regarding Permethrin Clinical Studies in the drug label.
# How Supplied
Permethrin™ 5% Cream is available as follows:
60 g tube (NDC 40076-115-60)
## Storage
- Store at 20-25°C (68-77°F) [see USP Controlled Room Temperature].
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Permethrin Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Permethrin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
Permethrin™
# Look-Alike Drug Names
There is limited information regarding Permethrin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
Drug Shortage
# Price | https://www.wikidoc.org/index.php/Permethrin | |
cc8e91c196eb08a57ac26afb4a37877c7df4b956 | wikidoc | Peroxidase | Peroxidase
Peroxidases (EC number 1.11.1.x) are a large family of enzymes. A majority of peroxidase protein sequences can be found in the PeroxiBase database. Peroxidases typically catalyze a reaction of the form:
For many of these enzymes the optimal substrate is hydrogen peroxide, but others are more active with organic hydroperoxides such as lipid peroxides. Peroxidases can contain a heme cofactor in their active sites, or redox-active cysteine or selenocysteine residues.
The nature of the electron donor is very dependent on the structure of the enzyme.
- For example, horseradish peroxidase can use a variety of organic compounds as electron donors and acceptors. Horseradish peroxidase has an accessible active site and many compounds can reach the site of the reaction.
- For an enzyme such as cytochrome c peroxidase, the compounds that donate electrons are very specific, because there is a very closed active site.
While the exact mechanisms have yet to be elucidated, peroxidases are known to play a part in increasing a plant's defenses against pathogens.
Peroxidases are sometimes used as histological marker. Cytochrome c peroxidase is used as a soluble, easily purified model for cytochrome c oxidase.
Glutathione peroxidase is a peroxidase found in humans, which contains selenocysteine. It uses glutathione as an electron donor and is active with both hydrogen peroxide and organic hydroperoxide substrates.
Amyloid beta, when bound to heme has been shown to have peroxidase activity. | Peroxidase
Peroxidases (EC number 1.11.1.x) are a large family of enzymes. A majority of peroxidase protein sequences can be found in the PeroxiBase database. Peroxidases typically catalyze a reaction of the form:
For many of these enzymes the optimal substrate is hydrogen peroxide, but others are more active with organic hydroperoxides such as lipid peroxides. Peroxidases can contain a heme cofactor in their active sites, or redox-active cysteine or selenocysteine residues.
The nature of the electron donor is very dependent on the structure of the enzyme.
- For example, horseradish peroxidase can use a variety of organic compounds as electron donors and acceptors. Horseradish peroxidase has an accessible active site and many compounds can reach the site of the reaction.
- For an enzyme such as cytochrome c peroxidase, the compounds that donate electrons are very specific, because there is a very closed active site.
While the exact mechanisms have yet to be elucidated, peroxidases are known to play a part in increasing a plant's defenses against pathogens.[1]
Peroxidases are sometimes used as histological marker. Cytochrome c peroxidase is used as a soluble, easily purified model for cytochrome c oxidase.
Glutathione peroxidase is a peroxidase found in humans, which contains selenocysteine. It uses glutathione as an electron donor and is active with both hydrogen peroxide and organic hydroperoxide substrates.
Amyloid beta, when bound to heme has been shown to have peroxidase activity.[2] | https://www.wikidoc.org/index.php/Peroxidase | |
0a9ef5f43f0f66b9665f52b59521859b97bb7a6c | wikidoc | Psychalgia | Psychalgia
Synonyms and keywords: Persistent somatoform pain disorder; phrenalgia
# Overview
Psychalgia is psychological or emotional pain or distress that accompanies a mental effort, especially in clinical depression. It is also called phrenalgia. Psychalgia may also describe physical pain that is possibly of psychological origin.
# Definition
Within the ICD-10 classification, psychalgia is another term for persistent somatoform pain disorder (F45.4).
# Diagnosis
## History and Symptoms
The principal symptom is of persistent and distressing pain that cannot be accounted for by a physical complaint or physiological disorder. It occurs in relation to psychosocial issues or emotional stress in such a way as to suggest they are causative factors.
Psychogenic pain, and pain associated with an episode of depression or schizophrenia is excluded from this diagnosis. | Psychalgia
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Synonyms and keywords: Persistent somatoform pain disorder; phrenalgia
# Overview
Psychalgia is psychological or emotional pain or distress that accompanies a mental effort, especially in clinical depression. It is also called phrenalgia. Psychalgia may also describe physical pain that is possibly of psychological origin.
# Definition
Within the ICD-10 classification, psychalgia is another term for persistent somatoform pain disorder (F45.4).
# Diagnosis
## History and Symptoms
The principal symptom is of persistent and distressing pain that cannot be accounted for by a physical complaint or physiological disorder. It occurs in relation to psychosocial issues or emotional stress in such a way as to suggest they are causative factors.
Psychogenic pain, and pain associated with an episode of depression or schizophrenia is excluded from this diagnosis. | https://www.wikidoc.org/index.php/Persistent_Somatoform_Pain_Disorder | |
2f4edd68f5967023362f1a5d9e9d1f84b06bcc30 | wikidoc | Pestilence | Pestilence
A pestilence is any virulent and highly infectious disease that can cause an epidemic or even a pandemic. The word can also be used about parasites causing large scale sickness and death, such as Guinea worm.
Originally the word referred to the disease plague, which is called pestis in Latin.
The 14th-century English poet Geoffrey Chaucer spoke of "pestilence" in "The Pardoner's Tale", referring to the Black Death: | Pestilence
A pestilence is any virulent and highly infectious disease that can cause an epidemic or even a pandemic. The word can also be used about parasites causing large scale sickness and death, such as Guinea worm.
Originally the word referred to the disease plague, which is called pestis in Latin.
The 14th-century English poet Geoffrey Chaucer spoke of "pestilence" in "The Pardoner's Tale", referring to the Black Death: | https://www.wikidoc.org/index.php/Pestilence | |
556f27ade3314c3641cb7a03e45c689345b92c89 | wikidoc | Pestivirus | Pestivirus
Pestivirus is a genus of viruses that belong to the family Flaviviridae. Viruses in the genus Pestivirus infect mammals, including members of the family Bovidae (which includes, but is not limited to, cattle, sheep, and goats) and the family Suidae (which includes various species of swine).
# Pathogenesis
Pestiviruses account for important diseases in animals such as Classical swine fever (CSF) and Bovine viral diarrhoea / Mucosal disease (BVD/MD). According to the current O.I.E. list CSF and BVD/MD are notifiable diseases and eradication programms are administered in many countries worldwide. One hallmark of pestiviruses is their unique strategy to establish persistent infection during pregnancy. Persistent infection with pestiviruses often goes unnoticed.
# Virus Genetics and Structure
Pestivirus viruses have a single strand of positive-sense RNA (i.e. RNA which can be directly translated into viral proteins) which is around 12.5 kilobases (kb) long (equal to the length of 12,500 nucleotides). Sometimes virions (individual virus particles) contain sections of an animal's genome which have been duplicated, though this is not normally the case. There is no Poly-A on the 3' end of the genome. (This means that these viruses have no post-transcriptional modifications, and have simple RNA genomes.) The genome contains RNA to encode both structural and non-structural proteins.
The molecular biology of pestiviruses shares many similarities and peculiarities with the human hepaciviruses. Genome organisation and translation strategy are highly similar for the members of both genera. For BVDV frequently nonhomologous RNA recombination events lead to the appearance of genetically distinct viruses that are lethal to the host.
Each virion is approximately 40-60 nanometers (nm) in diameter, and consists of a nucleocapsid enveloped with the cytoplasm of infected cells.
# Transmission and Prevention
Pestivirus is widespread in Australia, mainly in cattle. Some adult cattle are immune to the disease, while others are life-long carriers. If a foetus becomes infected within the first three to four months of gestation then it will fail to develop antibodies towards the virus. In these cases the animals often die before birth or shortly after.
Symptoms of Pestivirus infection include diarrhoea, respiratory problems and bleeding disorders.
Pestivirus vaccines exist and the correct vaccine strain should be given, depending on the herd's location and the endemic strain in that region. This vaccination must be given regularly to maintain immunity. | Pestivirus
Pestivirus is a genus of viruses that belong to the family Flaviviridae. Viruses in the genus Pestivirus infect mammals, including members of the family Bovidae (which includes, but is not limited to, cattle, sheep, and goats) and the family Suidae (which includes various species of swine).
# Pathogenesis
Pestiviruses account for important diseases in animals such as Classical swine fever (CSF) and Bovine viral diarrhoea / Mucosal disease (BVD/MD). According to the current O.I.E. list CSF and BVD/MD are notifiable diseases and eradication programms are administered in many countries worldwide. One hallmark of pestiviruses is their unique strategy to establish persistent infection during pregnancy. Persistent infection with pestiviruses often goes unnoticed.[1]
# Virus Genetics and Structure
Pestivirus viruses have a single strand of positive-sense RNA (i.e. RNA which can be directly translated into viral proteins) which is around 12.5 kilobases (kb) long (equal to the length of 12,500 nucleotides). Sometimes virions (individual virus particles) contain sections of an animal's genome which have been duplicated, though this is not normally the case. There is no Poly-A on the 3' end of the genome. (This means that these viruses have no post-transcriptional modifications, and have simple RNA genomes.) The genome contains RNA to encode both structural and non-structural proteins.
The molecular biology of pestiviruses shares many similarities and peculiarities with the human hepaciviruses. Genome organisation and translation strategy are highly similar for the members of both genera. For BVDV frequently nonhomologous RNA recombination events lead to the appearance of genetically distinct viruses that are lethal to the host.[1]
Each virion is approximately 40-60 nanometers (nm) in diameter, and consists of a nucleocapsid enveloped with the cytoplasm of infected cells.
# Transmission and Prevention
Pestivirus is widespread in Australia, mainly in cattle. Some adult cattle are immune to the disease, while others are life-long carriers. If a foetus becomes infected within the first three to four months of gestation then it will fail to develop antibodies towards the virus. In these cases the animals often die before birth or shortly after.
Symptoms of Pestivirus infection include diarrhoea, respiratory problems and bleeding disorders.
Pestivirus vaccines exist and the correct vaccine strain should be given, depending on the herd's location and the endemic strain in that region. This vaccination must be given regularly to maintain immunity. | https://www.wikidoc.org/index.php/Pestivirus | |
5e9c106229c921968eeea5b7756cc1c470df695a | wikidoc | Phenacetin | Phenacetin
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
# Overview
Phenacetin, introduced in 1887, was used principally as an analgesic, and was the first NSAID and fever reducer to go on the market. Typical doses of 300mg to 500mg a day result in an analgesic effect. Its analgesic effects are due to its actions on the sensory tracts of the spinal cord. In addition, phenacetin has a depressant action of the heart, where it acts as a negative inotrope. It is an antipyretic, acting on the brain to decrease the temperature set point. It is also used to treat rheumatoid arthritis (subacute type), intercostal neuralgia, and some forms of ataxia.
Phenacetin, and products containing phenacetin have been shown in an animal model to be carcinogenic. In humans, many case reports have implicated products containing phenacetin in urothelial neoplasms, especially transitional cell carcinoma of the renal pelvis. In one prospective series, phenacetin was associated with an increased risk of death due to urologic or renal diseases, death due to cancers, and death due to cardiovascular diseases.
In addition, people with glucose-6-phosphate dehydrogenase deficiency may experience acute hemolysis while taking this drug. Acute hemolysis is possible in the case of patients who develop an IgM response to Phenacetin leading to immune complexes that bind to erythrocytes in blood. The erythrocytes are then lysed when the complexes activate the complement cascade.
Synthesis (Northern Kentucky University)
ETHER SYNTHESIS: CONVERSION OF ACETAMINOPHEN INTO PHENACETIN
Required Pre-lab readings: Ege, 5th Ed., sect 13.4, pp 498-501; Morhig, Chapter 19.
Techniques you must be prepared to use: reflux; extraction; rotary evaporation;
recrystallization.
In the reaction today you will be converting 4-acetamidophenol (Acetaminophen) into ethyl 4-
acetamidophenyl ether (Phenacetin). Both compounds are ingredients in many over-the-counter
analgesics. This reaction is an example of the Williamson ether synthesis. For most ether
syntheses strong bases such as amide ion are necessary to generate the nucleophile.
In a 50 mL round-bottomed flask place 12 mmol of liquid ethyl iodide, 15 mL of methyl ethyl
ketone (2-butanone; MEK) as solvent, Acetaminophen (1.5 g; ?? mmol.), and powered anhydrous
K2CO3 (2.5 g; ?? mmol). Mechanically stir this mixture and reflux for 1 hour. After the reflux is complete cool the flask in an ice/water bath and gravity filter the contents into a separatory funnel.
Use small amounts of ether to insure that you have quantitatively transferred all the organic
material from the flask to the funnel. Wash the organic phase with 5% aq. NaOH (what is the
purpose of this step?), then dry it (Na2SO4) and decant into a flask and remove the solvents by
rotary evaporation. The product is purified by recrystallization from water. Allow the purified
product to air dry.
Phenacetin was widely used until the third quarter of the twentieth century, but was then largely replaced by non-carcinogenic drugs. Some branded phenacetin-based preparations continued to be sold, but with the phenacetin replaced by safer alternatives. A popular brand of phenacetin was Roche's Saridon, which was reformulated in 1983 to contain propyphenazone, paracetamol and caffeine. Paracetamol is a metabolite of phenacetin with similar analgesic and antipyretic effects, but the new formulation has not been found to have phenacetin's carcinogenicity.
# Connection between chronic phenacetin use and renal papillary necrosis
Chronic use of phenacetin is known to lead to renal papillary necrosis. This is a condition which results in destruction of some or all of the renal papillae in the kidneys.
# Use as a filler for illegal cocaine
Phenacetin is now being widely used as a cutting agent to adulterate illegally supplied cocaine due to the similar physical features of the two drugs.
# Notes and references
- ↑ Dubach U, Rosner B, Stürmer T (1991). "An epidemiologic study of abuse of analgesic drugs. Effects of phenacetin and salicylate on mortality and cardiovascular morbidity (1968 to 1987)". N Engl J Med. 324 (3): 155–60. PMID 1984193.CS1 maint: Multiple names: authors list (link) .mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ Cochran A, Lawson D, Linton A (1967). "Renal papillary necrosis following phenacetin excess". Scott Med J. 12 (7): 246–50. PMID 6036245.CS1 maint: Multiple names: authors list (link)
- ↑ Tan G, Rabbino M, Hopper J (1964). "Is Phenacetin a Nephrotoxin? A Report on Twenty-three Users of the Drug". Calif Med. 101: 73–7. PMID 14180501.CS1 maint: Multiple names: authors list (link)
- ↑ Brix A. "Renal papillary necrosis". Toxicol Pathol. 30 (6): 672–4. PMID 12512867.
- ↑ "Cancer chemical in street cocaine". BBC News. 23 November 2006.
- Carcinogen report from the NIH
- Safety (MSDS) data for phenacetin | Phenacetin
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [1] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
# Overview
Phenacetin, introduced in 1887, was used principally as an analgesic, and was the first NSAID and fever reducer to go on the market. Typical doses of 300mg to 500mg a day result in an analgesic effect. Its analgesic effects are due to its actions on the sensory tracts of the spinal cord. In addition, phenacetin has a depressant action of the heart, where it acts as a negative inotrope. It is an antipyretic, acting on the brain to decrease the temperature set point. It is also used to treat rheumatoid arthritis (subacute type), intercostal neuralgia, and some forms of ataxia.
Phenacetin, and products containing phenacetin have been shown in an animal model to be carcinogenic. In humans, many case reports have implicated products containing phenacetin in urothelial neoplasms, especially transitional cell carcinoma of the renal pelvis. In one prospective series, phenacetin was associated with an increased risk of death due to urologic or renal diseases, death due to cancers, and death due to cardiovascular diseases.[1]
In addition, people with glucose-6-phosphate dehydrogenase deficiency may experience acute hemolysis while taking this drug. Acute hemolysis is possible in the case of patients who develop an IgM response to Phenacetin leading to immune complexes that bind to erythrocytes in blood. The erythrocytes are then lysed when the complexes activate the complement cascade.
Synthesis (Northern Kentucky University)
ETHER SYNTHESIS: CONVERSION OF ACETAMINOPHEN INTO PHENACETIN
Required Pre-lab readings: Ege, 5th Ed., sect 13.4, pp 498-501; Morhig, Chapter 19.
Techniques you must be prepared to use: reflux; extraction; rotary evaporation;
recrystallization.
In the reaction today you will be converting 4-acetamidophenol (Acetaminophen) into ethyl 4-
acetamidophenyl ether (Phenacetin). Both compounds are ingredients in many over-the-counter
analgesics. This reaction is an example of the Williamson ether synthesis. For most ether
syntheses strong bases such as amide ion are necessary to generate the nucleophile.
In a 50 mL round-bottomed flask place 12 mmol of liquid ethyl iodide, 15 mL of methyl ethyl
ketone (2-butanone; MEK) as solvent, Acetaminophen (1.5 g; ?? mmol.), and powered anhydrous
K2CO3 (2.5 g; ?? mmol). Mechanically stir this mixture and reflux for 1 hour. After the reflux is complete cool the flask in an ice/water bath and gravity filter the contents into a separatory funnel.
Use small amounts of ether to insure that you have quantitatively transferred all the organic
material from the flask to the funnel. Wash the organic phase with 5% aq. NaOH (what is the
purpose of this step?), then dry it (Na2SO4) and decant into a flask and remove the solvents by
rotary evaporation. The product is purified by recrystallization from water. Allow the purified
product to air dry.
Phenacetin was widely used until the third quarter of the twentieth century, but was then largely replaced by non-carcinogenic drugs. Some branded phenacetin-based preparations continued to be sold, but with the phenacetin replaced by safer alternatives. A popular brand of phenacetin was Roche's Saridon, which was reformulated in 1983 to contain propyphenazone, paracetamol and caffeine. Paracetamol is a metabolite of phenacetin with similar analgesic and antipyretic effects, but the new formulation has not been found to have phenacetin's carcinogenicity.
# Connection between chronic phenacetin use and renal papillary necrosis
Chronic use of phenacetin is known to lead to renal papillary necrosis.[2][3][4] This is a condition which results in destruction of some or all of the renal papillae in the kidneys.
# Use as a filler for illegal cocaine
Phenacetin is now being widely used as a cutting agent to adulterate illegally supplied cocaine due to the similar physical features of the two drugs. [5]
# Notes and references
- ↑ Dubach U, Rosner B, Stürmer T (1991). "An epidemiologic study of abuse of analgesic drugs. Effects of phenacetin and salicylate on mortality and cardiovascular morbidity (1968 to 1987)". N Engl J Med. 324 (3): 155–60. PMID 1984193.CS1 maint: Multiple names: authors list (link) .mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ Cochran A, Lawson D, Linton A (1967). "Renal papillary necrosis following phenacetin excess". Scott Med J. 12 (7): 246–50. PMID 6036245.CS1 maint: Multiple names: authors list (link)
- ↑ Tan G, Rabbino M, Hopper J (1964). "Is Phenacetin a Nephrotoxin? A Report on Twenty-three Users of the Drug". Calif Med. 101: 73–7. PMID 14180501.CS1 maint: Multiple names: authors list (link)
- ↑ Brix A. "Renal papillary necrosis". Toxicol Pathol. 30 (6): 672–4. PMID 12512867.
- ↑ "Cancer chemical in street cocaine". BBC News. 23 November 2006.
- Carcinogen report from the NIH
- Safety (MSDS) data for phenacetin
Template:Jb1
Template:SIB
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Phenacetin | |
49a81bc80e940fbe585f8521f1aed09b7d99eb71 | wikidoc | Phenazepam | Phenazepam
Phenazepam is a benzodiazepine drug, which was developed in Soviet Union and now produced in Russia and some CIS countries. Phenazepam is used in the treatment of neurological disorders such as epilepsy, alcohol withdrawal and insomnia. It can be used as a premedication before surgery as it augments the effects of anesthetics and reduces anxiety.
# Dosage
An average phenazepam dosage is 0.5 mg 2-3 times daily. The maximum daily dosage must not exceed 10 mg.
# Side effects
Side effects include dizziness, loss of coordination, drowsiness. As with other sedatives, in case of abrupt discontinuation following prolonged use, severe withdrawal symptoms may occur.
# Legal Status
Phenazepam does not appear in the list of Controlled Substances in the Laws of either the USA or the UK, where in each country, benzodiazepines are generally Class C, Schedule IV substances. Like all benzodiazepines, it is legally classified as a C-IV substance in accordance with the analogue act in the U.S. (Flunitrazepam, aka "rohypnol", is dually scheduled.)
According to the official investigation report, effects of phenazepam on pilot Pavel Gruzin may have contributed to errors that caused the crash of Crossair Flight 498. | Phenazepam
Phenazepam is a benzodiazepine drug, which was developed in Soviet Union and now produced in Russia and some CIS countries. Phenazepam is used in the treatment of neurological disorders such as epilepsy, alcohol withdrawal and insomnia. It can be used as a premedication before surgery as it augments the effects of anesthetics and reduces anxiety.
# Dosage
An average phenazepam dosage is 0.5 mg 2-3 times daily. The maximum daily dosage must not exceed 10 mg.
# Side effects
Side effects include dizziness, loss of coordination, drowsiness. As with other sedatives, in case of abrupt discontinuation following prolonged use, severe withdrawal symptoms may occur.
# Legal Status
Phenazepam does not appear in the list of Controlled Substances in the Laws of either the USA or the UK, where in each country, benzodiazepines are generally Class C, Schedule IV substances. Like all benzodiazepines, it is legally classified as a C-IV substance in accordance with the analogue act in the U.S. (Flunitrazepam, aka "rohypnol", is dually scheduled.)
According to the official investigation report, effects of phenazepam on pilot Pavel Gruzin may have contributed to errors that caused the crash of Crossair Flight 498.[1] | https://www.wikidoc.org/index.php/Phenazepam | |
179d7b18eae6c35b4828dbf22c5fc85f80e44a07 | wikidoc | Phenformin | Phenformin
# Overview
Phenformin is an antidiabetic drug from the biguanide class. It was marketed as DBI by Ciba-Geigy, but was withdrawn from most markets in the late 1970s due to a high risk of lactic acidosis, which was fatal in 50% of cases.
Phenformin was discovered in 1957 by Ungar, Freedman and Seymour Shapiro, working for the US Vitamin Corporation. Clinical trials begun in 1958 showed it to be effective, but with gastrointestinal side effects.
# Toxicity
Phenformin sales began to decline in the US from 1973 due to negative trial studies and reports of lactic acidosis. By October 1976, the FDA Endocrinology and Metabolism Advisory Committee recommended phenformin be removed from the market. The FDA began formal proceedings in May 1977, leading to its eventual withdrawal on November 15, 1978.
In 1977, 385,000 patients with early-stage diabetes were taking phenformin in the US. Ralph Nader's Health Research Group put the US government under pressure to ban the drug. Ciba-Geigy Corp resisted, claiming there was no satisfactory alternative for many patients. However, in July the FDA declared the drug an "imminent hazard to the public health" and gave doctors 90 days to switch to an alternative treatment (such as insulin, dietary restrictions or other drugs). As of 2008, phenformin was still legally available in Italy, Brazil, Uruguay, China, Poland, Greece and Portugal. Cases of phenformin-induced lactic acidosis continue to be reported worldwide. In Hong Kong, where phenformin is banned, cases of phenformin-induced lactic acidosis have occurred after taking Chinese proprietary medicines, claiming to be herbal, which were adulterated with phenformin. In the US, the FDA has recalled Chinese "herbal products" containing phenformin.
The related drug metformin is considerably safer than phenformin, with three cases of lactic acidosis per 100,000 patient-years compared to 64 cases per 100,000 patient-years, and those are mostly confined to patients with impaired renal function.
Cimetidine may reduce renal clearance of phenformin and increase lactic acidosis risk. There is also increased risk of lactic acidosis with alcohol, nephrotoxic drugs.
# Chemistry and pharmacokinetics
Phenformin hydrochloride is a white crystalline powder, with a melting point of 175 to 178 °C; it is soluble at 1 in 8 parts of water and 1 in 15 of ethanol, and practically insoluble in chloroform and ether. Its dissociation constant (pKa) is 2.7, 11.8 (at 32 °C), and partition coefficient (log P in octanol/water) = –0.8. Phenformin is well absorbed after oral administration. The major metabolic reaction is aromatic hydroxylation to form 4–hydroxyphenformin, which is then conjugated with glucuronic acid. Up to about 50% of a dose is excreted in the urine in 24 h, about two–thirds in the form of unchanged drug and one–third as the hydroxy metabolite. Following a single oral dose of 50 mg to eight subjects, peak plasma concentrations of 0.08 to 0.18 mg/l (mean 0.13) were attained in about 3 h; plasma concentrations were higher in four subjects who were poor metabolisers of debrisoquine in comparison with the four extensive metabolisers. Following daily oral doses of 50 mg three times a day to 8 subjects, plasma concentrations of 0.10 to 0.24 mg/l (mean 0.18) were reported 2 h after a dose. Plasma half–life of phenformin is 10 to 15 h. Phenformin protein-binding in plasma is about 12 to 20%.
# Dosage
When given orally for type 2 diabetes mellitus, the dosage is 200–400 mg, twice daily, for adults.
# Anticancer properties
Phenformin, along with buformin and metformin, inhibits the growth and development of cancer. Respective studies were initiated by Vladimir Dilman (see f.e. The anticancer property of these drugs may be due to their ability to disrupt the Warburg effect and revert the cytosolic glycolysis characteristic of cancer cells to normal oxidation of pyruvate by the mitochondria. Metformin reduces liver glucose production in diabetics and disrupts the Warburg effect in cancer by AMPK activation and inhibition of the mTor pathway. | Phenformin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Phenformin is an antidiabetic drug from the biguanide class. It was marketed as DBI by Ciba-Geigy, but was withdrawn from most markets in the late 1970s due to a high risk of lactic acidosis, which was fatal in 50% of cases.
Phenformin was discovered in 1957 by Ungar, Freedman and Seymour Shapiro, working for the US Vitamin Corporation. Clinical trials begun in 1958 showed it to be effective, but with gastrointestinal side effects.[1]
# Toxicity
Phenformin sales began to decline in the US from 1973 due to negative trial studies and reports of lactic acidosis. By October 1976, the FDA Endocrinology and Metabolism Advisory Committee recommended phenformin be removed from the market. The FDA began formal proceedings in May 1977, leading to its eventual withdrawal on November 15, 1978.[2]
In 1977, 385,000 patients with early-stage diabetes were taking phenformin in the US. Ralph Nader's Health Research Group put the US government under pressure to ban the drug. Ciba-Geigy Corp resisted, claiming there was no satisfactory alternative for many patients. However, in July the FDA declared the drug an "imminent hazard to the public health" and gave doctors 90 days to switch to an alternative treatment (such as insulin, dietary restrictions or other drugs).[3] As of 2008, phenformin was still legally available in Italy, Brazil, Uruguay, China, Poland, Greece and Portugal. Cases of phenformin-induced lactic acidosis continue to be reported worldwide.[4] In Hong Kong, where phenformin is banned, cases of phenformin-induced lactic acidosis have occurred after taking Chinese proprietary medicines, claiming to be herbal, which were adulterated with phenformin.[5] In the US, the FDA has recalled Chinese "herbal products" containing phenformin.[6]
The related drug metformin is considerably safer than phenformin, with three cases of lactic acidosis per 100,000 patient-years compared to 64 cases per 100,000 patient-years, and those are mostly confined to patients with impaired renal function.[7]
Cimetidine may reduce renal clearance of phenformin and increase lactic acidosis risk. There is also increased risk of lactic acidosis with alcohol, nephrotoxic drugs.
# Chemistry and pharmacokinetics
Phenformin hydrochloride is a white crystalline powder, with a melting point of 175 to 178 °C; it is soluble at 1 in 8 parts of water and 1 in 15 of ethanol, and practically insoluble in chloroform and ether. Its dissociation constant (pKa) is 2.7, 11.8 (at 32 °C), and partition coefficient (log P in octanol/water) = –0.8. Phenformin is well absorbed after oral administration. The major metabolic reaction is aromatic hydroxylation to form 4–hydroxyphenformin, which is then conjugated with glucuronic acid. Up to about 50% of a dose is excreted in the urine in 24 h, about two–thirds in the form of unchanged drug and one–third as the hydroxy metabolite. Following a single oral dose of 50 mg to eight subjects, peak plasma concentrations of 0.08 to 0.18 mg/l (mean 0.13) were attained in about 3 h; plasma concentrations were higher in four subjects who were poor metabolisers of debrisoquine in comparison with the four extensive metabolisers. Following daily oral doses of 50 mg three times a day to 8 subjects, plasma concentrations of 0.10 to 0.24 mg/l (mean 0.18) were reported 2 h after a dose. Plasma half–life of phenformin is 10 to 15 h. Phenformin protein-binding in plasma is about 12 to 20%.[8]
# Dosage
When given orally for type 2 diabetes mellitus, the dosage is 200–400 mg, twice daily, for adults.
# Anticancer properties
Phenformin, along with buformin and metformin, inhibits the growth and development of cancer. Respective studies were initiated by Vladimir Dilman (see f.e.[9][10][11][12][13][14] The anticancer property of these drugs may be due to their ability to disrupt the Warburg effect and revert the cytosolic glycolysis characteristic of cancer cells to normal oxidation of pyruvate by the mitochondria.[15] Metformin reduces liver glucose production in diabetics and disrupts the Warburg effect in cancer by AMPK activation and inhibition of the mTor pathway.[16] | https://www.wikidoc.org/index.php/Phenformin | |
c3268847581aa08a5036d456e3a8fc76aa95ebad | wikidoc | Phenol red | Phenol red
# Overview
Phenol red (also known as phenolsulfonphthalein or PSP) is a pH indicator frequently used in cell biology laboratories.
# Chemical structure and properties
Phenol red exists as a red crystal that is stable in air. Its solubility is 0.77 grams per liter (g/l) in water and 2.9 g/l in ethanol. It is a weak acid with pKa = 8.00 at 20 °C (68 °F).
A solution of phenol red is used as a pH indicator: its color exhibits a gradual transition from yellow to red over the pH range 6.8 to 8.2. Above pH 8.2, phenol red turns a bright pink (fuchsia) color.
In crystalline form, and in solution under very acidic conditions (low pH), the compound exists as a zwitterion as in the structure shown above, with the sulfate group negatively charged, and the ketone group carrying an additional proton. This form is sometimes symbolically written as H2+PS− and is orange-red. If the pH is increased (pKa = 1.2), the proton from the ketone group is lost, resulting in the yellow, negatively charged ion denoted as HPS−. At still higher pH (pKa = 7.7), the phenol's hydroxide group loses its proton, resulting in the red ion denoted as PS2−.
In several sources, the structure of phenol red is shown with the sulfur atom being part of a cyclic group, similar to the structure of phenolphthalein. However, this cyclic structure could not be confirmed by X-ray crystallography.
Several indicators share a similar structure to phenol red, including bromothymol blue, thymol blue, bromocresol purple, thymolphthalein, and phenolphthalein. (A table of other common chemical indicators is available in the article on pH indicators.)
# Phenolsulfonphthalein test
Phenol red was used in the phenolsulfonphthalein test to estimate the overall blood flow through the kidney and is now obsolete.
The test is based on the fact that phenol red is excreted almost entirely in the urine. Phenol red solution is administered intravenously, the urine produced is collected. By measuring the amount of phenol red excreted colorimetrically, kidney function can be determined.
# Indicator for cell cultures
Most living tissues prosper at a near-neutral pH; that is, a pH close to 7. The pH of blood ranges from 7.35 to 7.45, for instance. When cells are grown in tissue culture, the medium in which they grow is held close to this physiological pH. A small amount of phenol red added to this growth medium will have a pink-red color under normal conditions. Typically, 15 mg /l are used for cell culture.
In the event of problems, waste products produced by dying cells or overgrowth of contaminants will cause a change in pH, leading to a change in indicator color. For example, a culture of relatively slowly dividing mammalian cells can be quickly overgrown by bacterial contamination. This usually results in an acidification of the medium, turning it yellow. Many biologists find this a convenient way to rapidly check on the health of tissue cultures. In addition, the waste products produced by the mammalian cells themselves will slowly decrease the pH, gradually turning the solution orange and then yellow. This color change is an indication that even in the absence of contamination, the medium needs to be replaced (generally, this should be done before the medium has turned completely orange).
Since the color of phenol red can interfere with some spectrophotometric and fluorescent assays, many types of tissue culture media are also available without phenol red.
# Estrogen mimic
Phenol red is a weak estrogen mimic, and in cell cultures can enhance the growth of cells that express the estrogen receptor.
An important breakthrough in biotechnology was reported; using phenol red as a differentiation factor, scientists produced human oocytes (eggs) from cells scraped from the surface of adult ovaries. These cells on the outer ovarian surface are known as ovarian surface epithelial cells. Such cells had been taken from five women aged 39 to 52 and were cultured in the presence of phenol red, inducing oogenesis.
Previously, human eggs had only been produced in vitro from totipotent, blastomeric embryonic stem cells. This experiment demonstrated viable human egg cells can easily be produced from an adult cell that already has some degree of specialization. Furthermore, it lessens the implications associated with the fact that women are born with all of the egg cells they will ever have throughout their lives. While this breakthrough was not without controversy, it provides hope for infertile women wishing to undergo in vitro fertilization, and hints at the possibility of new options for postmenopausal women, as well. It also suggests the future of stem cell research may not have to rely as heavily on human embryos as a source of unspecialized, totipotent cells for research.
# Use in swimming pool test kits
Phenol red, sometimes labelled with a different name, such as "Guardex Solution #2", is used as a pH indicator in home swimming pool test kits.
Chlorine can result in the bleaching of the dye in the absence of thiosulfate to inhibit the oxidizing chlorine. High levels of bromine can convert phenol red to bromophenol red (dibromophenolsulfonephthalein, whose lowered pKa results in an indicator with a range shifted in the acidic direction - water at pH 6.8 will appear to test at 7.5). Even higher levels of bromine (>20 ppm) can result in the secondary conversion of bromophenol red to bromophenol blue with an even lower pKa, erroneously giving the impression that the water has an extremely high pH despite being dangerously low. | Phenol red
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Phenol red (also known as phenolsulfonphthalein or PSP) is a pH indicator frequently used in cell biology laboratories.
# Chemical structure and properties
Phenol red exists as a red crystal that is stable in air. Its solubility is 0.77 grams per liter (g/l) in water and 2.9 g/l in ethanol.[1] It is a weak acid with pKa = 8.00 at 20 °C (68 °F).
A solution of phenol red is used as a pH indicator: its color exhibits a gradual transition from yellow to red over the pH range 6.8 to 8.2. Above pH 8.2, phenol red turns a bright pink (fuchsia) color.[2][3]
Template:PH indicator templateThis solution contains a pH indicator which helps in monitoring of the pH changes in the cell culture. It will change from red to yellow when the pH value decreases.
In crystalline form, and in solution under very acidic conditions (low pH), the compound exists as a zwitterion as in the structure shown above, with the sulfate group negatively charged, and the ketone group carrying an additional proton. This form is sometimes symbolically written as H2+PS− and is orange-red. If the pH is increased (pKa = 1.2), the proton from the ketone group is lost, resulting in the yellow, negatively charged ion denoted as HPS−. At still higher pH (pKa = 7.7), the phenol's hydroxide group loses its proton, resulting in the red ion denoted as PS2−.[4]
In several sources, the structure of phenol red is shown with the sulfur atom being part of a cyclic group, similar to the structure of phenolphthalein.[1][5] However, this cyclic structure could not be confirmed by X-ray crystallography.[6]
Several indicators share a similar structure to phenol red, including bromothymol blue, thymol blue, bromocresol purple, thymolphthalein, and phenolphthalein. (A table of other common chemical indicators is available in the article on pH indicators.)
# Phenolsulfonphthalein test
Phenol red was used in the phenolsulfonphthalein test to estimate the overall blood flow through the kidney and is now obsolete.
The test is based on the fact that phenol red is excreted almost entirely in the urine. Phenol red solution is administered intravenously, the urine produced is collected. By measuring the amount of phenol red excreted colorimetrically, kidney function can be determined.[7]
# Indicator for cell cultures
Most living tissues prosper at a near-neutral pH; that is, a pH close to 7. The pH of blood ranges from 7.35 to 7.45, for instance. When cells are grown in tissue culture, the medium in which they grow is held close to this physiological pH. A small amount of phenol red added to this growth medium will have a pink-red color under normal conditions. Typically, 15 mg /l are used for cell culture.
In the event of problems, waste products produced by dying cells or overgrowth of contaminants will cause a change in pH, leading to a change in indicator color. For example, a culture of relatively slowly dividing mammalian cells can be quickly overgrown by bacterial contamination. This usually results in an acidification of the medium, turning it yellow. Many biologists find this a convenient way to rapidly check on the health of tissue cultures. In addition, the waste products produced by the mammalian cells themselves will slowly decrease the pH, gradually turning the solution orange and then yellow. This color change is an indication that even in the absence of contamination, the medium needs to be replaced (generally, this should be done before the medium has turned completely orange).
Since the color of phenol red can interfere with some spectrophotometric and fluorescent assays, many types of tissue culture media are also available without phenol red.
# Estrogen mimic
Phenol red is a weak estrogen mimic, and in cell cultures can enhance the growth of cells that express the estrogen receptor.[8]
An important breakthrough in biotechnology was reported; using phenol red as a differentiation factor, scientists produced human oocytes (eggs) from cells scraped from the surface of adult ovaries. These cells on the outer ovarian surface are known as ovarian surface epithelial cells. Such cells had been taken from five women aged 39 to 52 and were cultured in the presence of phenol red, inducing oogenesis.[9]
Previously, human eggs had only been produced in vitro from totipotent, blastomeric embryonic stem cells. This experiment demonstrated viable human egg cells can easily be produced from an adult cell that already has some degree of specialization. Furthermore, it lessens the implications associated with the fact that women are born with all of the egg cells they will ever have throughout their lives. While this breakthrough was not without controversy, it provides hope for infertile women wishing to undergo in vitro fertilization, and hints at the possibility of new options for postmenopausal women, as well. It also suggests the future of stem cell research may not have to rely as heavily on human embryos as a source of unspecialized, totipotent cells for research.[citation needed]
# Use in swimming pool test kits
Phenol red, sometimes labelled with a different name, such as "Guardex Solution #2", is used as a pH indicator in home swimming pool test kits.[10]
Chlorine can result in the bleaching of the dye in the absence of thiosulfate to inhibit the oxidizing chlorine. High levels of bromine can convert phenol red to bromophenol red (dibromophenolsulfonephthalein, whose lowered pKa results in an indicator with a range shifted in the acidic direction - water at pH 6.8 will appear to test at 7.5). Even higher levels of bromine (>20 ppm) can result in the secondary conversion of bromophenol red to bromophenol blue with an even lower pKa, erroneously giving the impression that the water has an extremely high pH despite being dangerously low.[11] | https://www.wikidoc.org/index.php/Phenol_red | |
44340cc419094b8f31f002a9d561d128cfea1363 | wikidoc | Phenothrin | Phenothrin
# Overview
Phenothrin, also called sumithrin, is a synthetic pyrethroid that kills adult fleas and ticks. It has also been used to kill head lice in humans.
Phenothrin is often used with methoprene, an insect growth regulator that interrupts the insect's biological life cycle by killing the eggs.
In 2005, the EPA required Hartz Mountain Corporation to cancel uses of several flea and tick products containing phenothrin that may be associated with a range of adverse reactions, including hair loss, salivation, tremors, and numerous deaths in cats and kittens. In the short term, the agreement calls for new warning labels on the products. | Phenothrin
Template:Chembox new
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Phenothrin, also called sumithrin, is a synthetic pyrethroid that kills adult fleas and ticks. It has also been used to kill head lice in humans.
Phenothrin is often used with methoprene, an insect growth regulator that interrupts the insect's biological life cycle by killing the eggs.
In 2005, the EPA required Hartz Mountain Corporation to cancel uses of several flea and tick products containing phenothrin that may be associated with a range of adverse reactions, including hair loss, salivation, tremors, and numerous deaths in cats and kittens. In the short term, the agreement calls for new warning labels on the products. | https://www.wikidoc.org/index.php/Phenothrin | |
2e10951a42c963ab87fb0b6b80ddf9e745a20473 | wikidoc | Phocomelia | Phocomelia
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
# Overview
Phocomelia (from Greek φoko = "seal" plus μέλος (plural μέλεα) = "limb") is a congenital disorder involving the limbs (dysmelia). An individual exhibiting phocomelia may be referred to as a phocomelus.
# Presentation
It presents at birth very short or absent long bones and flipper-like appearance of hands and sometimes feet. Amphibian deformities often take the form of phocomelia, in which the limbs are shortened due to lack or malformation of long bones, as opposed to other forms of dysmelia such as amelia, which is characterized by the complete lack of a limb, or polymelia, the presence of extra limbs, which are often fused together.
# Causes
The condition may be inherited or occurs sporadically. It is also connected with prenatal exposure to the anti-nausea drug thalidomide.
# Notable cases
Famous phocomelic people include Stanley Berent, also known as "Sealo The Seal Boy" (who made his living from performing / being exhibited in "freak shows") and, more currently, actor Mat Fraser, opera singer Thomas Quasthoff, guitarist Rick Renstrom and artist Alison Lapper. Marc Quinn's 15-foot-high nude sculpture of Alison Lapper Pregnant is shown on the formerly-vacant fourth plinth in Trafalgar Square. Hee Ah Lee is a renowned pianist with only two fingers on each hand. | Phocomelia
Template:DiseaseDisorder infobox
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [1] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
# Overview
Phocomelia (from Greek φoko = "seal" plus μέλος (plural μέλεα) = "limb") is a congenital disorder involving the limbs (dysmelia). An individual exhibiting phocomelia may be referred to as a phocomelus.
# Presentation
It presents at birth very short or absent long bones and flipper-like appearance of hands and sometimes feet. Amphibian deformities often take the form of phocomelia, in which the limbs are shortened due to lack or malformation of long bones, as opposed to other forms of dysmelia such as amelia, which is characterized by the complete lack of a limb, or polymelia, the presence of extra limbs, which are often fused together.
# Causes
The condition may be inherited or occurs sporadically. It is also connected with prenatal exposure to the anti-nausea drug thalidomide.
# Notable cases
Famous phocomelic people include Stanley Berent, also known as "Sealo The Seal Boy" (who made his living from performing / being exhibited in "freak shows") and, more currently, actor Mat Fraser, opera singer Thomas Quasthoff, guitarist Rick Renstrom and artist Alison Lapper. Marc Quinn's 15-foot-high nude sculpture of Alison Lapper Pregnant is shown on the formerly-vacant fourth plinth in Trafalgar Square. Hee Ah Lee is a renowned pianist with only two fingers on each hand.
# External links
- Template:GPnotebook
Template:SIB
de:Phocomelie
it:Focomelia
nl:Focomelie
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Phocomelia | |
732565e959dd9dc1014b99ef65aa4cf09abb41de | wikidoc | Pholcodine | Pholcodine
Pholcodine is a drug which is an opioid cough suppressant (antitussive). It helps suppress unproductive coughs and also has a mild sedative effect, but has little or no analgesic effects. It is also known as morpholinylethylmorphine and homocodeine.
Pholcodine is found in certain cough lozenges. However, in the UK, the preparation is almost exclusively an oral solution, typically 5 mg / 5 ml. Adult dosage is 5-10ml up to 3-4 times daily. Pholcodine now largely replaces the previously more common codeine linctus, as it has a much lower potential for dependence.
Pholcodine is not prescribed in the United States where it is a Schedule I drug. It is a class B substance in the United Kingdom but can be purchased over-the-counter in most UK pharmacies.
# Mechanism of action
Pholcodine is readily absorbed from the gastrointestinal tract and freely crosses the blood–brain barrier. It acts primarily on the central nervous system (CNS), causing depression of the cough reflex, partly by a direct effect on the cough centre in the medulla. It is metabolized in the liver and its action may be prolonged in individuals with hepatic insufficiency (i.e. liver problems). Its use is therefore contraindicated in patients with liver disease, while care is advised in patients with hepatic impairment.
# Metabolism and excretion
Pholcodine is slowly biotransformed in the body via oxidation and conjugation to a series of metabolites that are eliminated primarily in the urine. With an average half-life of approximately 2.3 days, steady-state in someone taking the drug chronically would not be reached for nearly 2 weeks. Nearly one-half of a single dose is eventually excreted as free or conjugated parent drug. The most important urinary metabolite is conjugated morphine, which may be detectable for days or weeks after the last dose. This could trigger a positive result for opiates in a urine drug testing program.
# Side Effects
Side effects are rare and may include dizziness and gastrointestinal disturbances such as nausea or vomiting. Adverse effects such as constipation, drowsiness, excitation, ataxia and respiratory depression have been reported occasionally or after large doses. The primary safety concerns with pholcodine revolve around death during general anaesthesia.
# Anaphylaxis During General Anaesthesia
Administration of pholcodine causes production of antibodies linked with fatalities during surgery, when essential neuromuscular blocking agents (NMBAs) are administered to prevent patient movement under general anaesthesia. These antibody levels gradually fall to low levels several years after last dose of pholcodine. However, the presence of these antibodies causes a 300-fold increase in risk of anaphylaxis during anaesthesia.
The link was suspected when neighbouring Norway and Sweden were found to have tenfold differences of surgical anaphylaxis deaths. Sweden had no products approved containing pholcodine, whereas 40% of the population in Norway had consumed the single approved pholcodine product. Norway withdrew pholcodine from the market in 2007, and the prevalence of anti-suxamethonium antibodies fell by over 80% in two years. A corresponding fall in anaesthesia deaths followed.
A similar disparity exists between NMBA anaphylaxis rates in Australia, where pholcodine consumption is high and the US, where pholcodine is banned. In the US, anaphylaxis rates are so low that some anaesthetists question the existence of such reactions to NMBAs. Conversely, Australian anaesthetists have requested a ban on pholcodine due to the high anaphylaxis rate in the country. However, the Therapeutic Goods Administration declined the request in January 2015, pending further reviews to follow. | Pholcodine
Pholcodine is a drug which is an opioid cough suppressant (antitussive). It helps suppress unproductive coughs and also has a mild sedative effect, but has little or no analgesic effects. It is also known as morpholinylethylmorphine and homocodeine.
Pholcodine is found in certain cough lozenges.[1] However, in the UK, the preparation is almost exclusively an oral solution, typically 5 mg / 5 ml. Adult dosage is 5-10ml up to 3-4 times daily.[2] Pholcodine now largely replaces the previously more common codeine linctus, as it has a much lower potential for dependence.
Pholcodine is not prescribed in the United States where it is a Schedule I drug.[3] It is a class B substance in the United Kingdom but can be purchased over-the-counter in most UK pharmacies[citation needed].
# Mechanism of action
Pholcodine is readily absorbed from the gastrointestinal tract and freely crosses the blood–brain barrier. It acts primarily on the central nervous system (CNS), causing depression of the cough reflex, partly by a direct effect on the cough centre in the medulla. It is metabolized in the liver and its action may be prolonged in individuals with hepatic insufficiency (i.e. liver problems). Its use is therefore contraindicated in patients with liver disease, while care is advised in patients with hepatic impairment.
# Metabolism and excretion
Pholcodine is slowly biotransformed in the body via oxidation and conjugation to a series of metabolites that are eliminated primarily in the urine. With an average half-life of approximately 2.3 days, steady-state in someone taking the drug chronically would not be reached for nearly 2 weeks. Nearly one-half of a single dose is eventually excreted as free or conjugated parent drug. The most important urinary metabolite is conjugated morphine, which may be detectable for days or weeks after the last dose. This could trigger a positive result for opiates in a urine drug testing program.[4][5]
# Side Effects
Side effects are rare and may include dizziness and gastrointestinal disturbances such as nausea or vomiting. Adverse effects such as constipation, drowsiness, excitation, ataxia and respiratory depression have been reported occasionally or after large doses. The primary safety concerns with pholcodine revolve around death during general anaesthesia.
# Anaphylaxis During General Anaesthesia
Administration of pholcodine causes production of antibodies linked with fatalities during surgery, when essential neuromuscular blocking agents (NMBAs) are administered to prevent patient movement under general anaesthesia.[6] These antibody levels gradually fall to low levels several years after last dose of pholcodine. However, the presence of these antibodies causes a 300-fold increase in risk of anaphylaxis during anaesthesia.[7]
The link was suspected when neighbouring Norway and Sweden were found to have tenfold differences of surgical anaphylaxis deaths. Sweden had no products approved containing pholcodine, whereas 40% of the population in Norway had consumed the single approved pholcodine product.[7] Norway withdrew pholcodine from the market in 2007, and the prevalence of anti-suxamethonium antibodies fell by over 80% in two years.[8] A corresponding fall in anaesthesia deaths followed.[7]
A similar disparity exists between NMBA anaphylaxis rates in Australia, where pholcodine consumption is high and the US, where pholcodine is banned.[9] In the US, anaphylaxis rates are so low that some anaesthetists question the existence of such reactions to NMBAs.[10] Conversely, Australian anaesthetists have requested a ban on pholcodine[11] due to the high anaphylaxis rate in the country.[12] However, the Therapeutic Goods Administration declined the request in January 2015,[13] pending further reviews to follow. | https://www.wikidoc.org/index.php/Pholcodeine | |
42d6a7378189d2936da5ed94a79294632c4f3ec8 | wikidoc | Scramblase | Scramblase
Scramblase is a hypothetical protein thought to be responsible for transportation of phospholipids between the lipid bilayer of a cell membrane. The inner leaflet facing the inside of the cell contains negatively charged amino-phospholipids and phosphatidylcholine. The outer leaflet, facing the outside environment, contains phosphatidylcholine and sphingomyelin. Scramblase acts as an enzyme, present in the cell membrane, that is able to transport (to scramble) the negatively charged phospholipids from the inner leaflet to the outer leaflet and vice versa.
# Biochemical properties
The enzymatic activity of scramblase depends on the calcium concentration present inside the cell. The calcium concentration inside cells is under normal conditions very low. An increase in calcium concentration activates the phospholipid transportation activity resulting in a symmetric distribution of negatively charged phospholipids between both leaflets of the lipid bilayer. The transportation activity of scramblase does not require energy meaning that there is no contribution of adenosine triphosphate in the process.
# Enzyme activation
Scramblase is inactive in healthy cells however activation occurs when cells are exposed to a variety of stress conditions.
## Scramblase activity in platelets
Collagen is a protein found in the connective tissue and this protein is normally not in contact with flowing blood.
Contact between collagen and flowing blood occurs when blood vessels are damaged by for example physical insults. The exposure of collagen to flowing blood starts a series of processes which end in the formation of a blood clot:
- Adhesion of circulating blood platelets to collagen.
- Activation of dormant platelets via protein receptors that interact with the exposed collagen.
- Several biochemical and morphological processes occur which are started by activated platelets.
Activation of platelets lead for example to a change in morphology, to the membrane expression of P-selectin and to the activation of scramblase. (consult for further information the article about platelets)
Activation of scramblase causes the transport of negatively charged phospholipids to the platelet membrane surface. The negatively charged phospholipids form a catalytic surface for several inactive coagulation factors present in blood such as prothrombin, factor Va and factor Xa. (consult for further information the article about the prothrombinase complex)
## Scramblase activity during apoptosis
Scramblase is also thought to be involved in the transportation of negatively charged phospholipids to the cell membrane surface of cells which have become apoptotic. Apoptosis is a cellular process which occurs under stress conditions such as exposure to ultra violet radiation (in sun rays) or toxic chemicals. The negatively charged phospholipids on the cell surface function as a recognition marker for white blood cells. The white blood cells respond to this marker by phagocytosis of the apoptotic cell. | Scramblase
Scramblase is a hypothetical protein thought to be responsible for transportation of phospholipids between the lipid bilayer of a cell membrane[1]. The inner leaflet facing the inside of the cell contains negatively charged amino-phospholipids and phosphatidylcholine. The outer leaflet, facing the outside environment, contains phosphatidylcholine and sphingomyelin. Scramblase acts as an enzyme, present in the cell membrane, that is able to transport (to scramble) the negatively charged phospholipids from the inner leaflet to the outer leaflet and vice versa.
# Biochemical properties
The enzymatic activity of scramblase depends on the calcium concentration present inside the cell. The calcium concentration inside cells is under normal conditions very low. An increase in calcium concentration activates the phospholipid transportation activity resulting in a symmetric distribution of negatively charged phospholipids between both leaflets of the lipid bilayer. The transportation activity of scramblase does not require energy meaning that there is no contribution of adenosine triphosphate in the process.
# Enzyme activation
Scramblase is inactive in healthy cells however activation occurs when cells are exposed to a variety of stress conditions.
## Scramblase activity in platelets
Collagen is a protein found in the connective tissue and this protein is normally not in contact with flowing blood.
Contact between collagen and flowing blood occurs when blood vessels are damaged by for example physical insults. The exposure of collagen to flowing blood starts a series of processes which end in the formation of a blood clot:
- Adhesion of circulating blood platelets to collagen.
- Activation of dormant platelets via protein receptors that interact with the exposed collagen.
- Several biochemical and morphological processes occur which are started by activated platelets.
Activation of platelets lead for example to a change in morphology, to the membrane expression of P-selectin and to the activation of scramblase. (consult for further information the article about platelets)
Activation of scramblase causes the transport of negatively charged phospholipids to the platelet membrane surface. The negatively charged phospholipids form a catalytic surface for several inactive coagulation factors present in blood such as prothrombin, factor Va and factor Xa. (consult for further information the article about the prothrombinase complex)
## Scramblase activity during apoptosis
Scramblase is also thought to be involved in the transportation of negatively charged phospholipids to the cell membrane surface of cells which have become apoptotic. Apoptosis is a cellular process which occurs under stress conditions such as exposure to ultra violet radiation (in sun rays) or toxic chemicals. The negatively charged phospholipids on the cell surface function as a recognition marker for white blood cells. The white blood cells respond to this marker by phagocytosis of the apoptotic cell.
# External links
- ↑ Zwaal RF, Comfurius P, Bevers EM (2005). "Surface exposure of phosphatidylserine in pathological cells". Cellular and Molecular Life Sciences. 62 (9): 971-988.CS1 maint: Multiple names: authors list (link) .mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- Scripps Institute
- Phospholipid+Scramblase at the US National Library of Medicine Medical Subject Headings (MeSH)
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Phospholipid_transfer_proteins | |
23a103dba72279558ac0e59a818151cd26e62c8b | wikidoc | Phosphorus | Phosphorus
# Overview
Phosphorus, (Template:IPAEng, Template:Lang-el meaning "light", and phoros meaning "bearer"), is the chemical element that has the symbol P and atomic number 15. A multivalent nonmetal of the nitrogen group, phosphorus is commonly found in inorganic phosphate rocks.
Due to its high reactivity, phosphorus is never found as a free element in nature. One form of phosphorus (white phosphorus) emits a faint glow upon exposure to oxygen (hence its Greek derivation and the Latin 'light-bearer', meaning the planet Venus as Hesperus or "Morning Star").
Phosphorus is a component of DNA and RNA and an essential element for all living cells. The most important commercial use of phosphorus-based chemicals is the production of fertilisers.
Phosphorus compounds are also widely used in explosives, nerve agents, friction matches, fireworks, pesticides, toothpaste, and detergents.
# Characteristics
## Allotropes
Elemental phosphorus can exist in several allotropes, most commonly white, red and black.
White phosphorus (P4) exists as individual molecules made up of four atoms in a tetrahedral arrangement, resulting in very high ring strain and instability. It contains 6 single bonds.
White phosphorus is a yellow, waxy transparent solid. For this reason it is also called yellow phosphorus. It glows greenish in the dark (when exposed to oxygen), is highly flammable and pyrophoric (self-igniting) upon contact with air as well as toxic (causing severe liver damage on ingestion). The odour of combustion of this form has a characteristic garlic smell, and samples are commonly coated with white "(di)phosphorus pentoxide", which consists of P4O10 tetrahedra with oxygen inserted between the phosphorus atoms and at their vertices. White phosphorus is insoluble in water but soluble in carbon disulfide.
The white allotrope can be produced using several different methods. In one process, calcium phosphate, which is derived from phosphate rock, is heated in an electric or fuel-fired furnace in the presence of carbon and silica. Elemental phosphorus is then liberated as a vapour and can be collected under phosphoric acid. This process is similar to the first synthesis of phosphorus from calcium phosphate in urine.
Red phosphorus may be formed by heating white phosphorus to 250°C (482°F) or by exposing white phosphorus to sunlight. Phosphorus after this treatment exists as an amorphous network of atoms which reduces strain and gives greater stability; further heating results in the red phosphorus becoming crystalline. Red phosphorus does not catch fire in air at temperatures below 240°C, whereas white phosphorus ignites at about 30°C.
In 1865 Hittorf discovered that when phosphorus was recrystallized from molten lead, a red/purple form is obtained. This purple form is sometimes known as "Hittorf's phosphorus." In addition, a fibrous form exists with similar phosphorus cages. Below is shown a chain of phosphorus atoms which exhibits both the purple and fibrous forms.
One of the forms of red/black phosphorus is a cubic solid.
Black phosphorus has an orthorhombic structure (Cmca) and is the least reactive allotrope, it consists of many six-membered rings which are interlinked. Each atom is bonded to three other atoms. A recent synthesis of black phosphorus using metal salts as catalysts has been reported.
The diphosphorus allotrope (P2) can be obtained normally only under extreme conditions (for example, from P4 at 1100 kelvin). Nevertheless, some advancements were obtained in generating the diatomic molecule in homogenous solution, under normal condtitions with the use by some transitional metal complexes (based on for example tungsten and niobium).
## Glow
The glow from phosphorus was the attraction of its discovery around 1669, but the mechanism for that glow was not fully described until 1974. It was known from early times that the glow would persist for a time in a stoppered jar but then cease. Robert Boyle in the 1680s ascribed it to "debilitation" of the air; in fact it is oxygen being consumed. By the 18th century it was known that in pure oxygen phosphorus does not glow at all, there is only a range of partial pressure where it does. Heat can be applied to drive the reaction at higher pressures.
In 1974 the glow was explained by R. J. van Zee and A. U. Khan. A reaction with oxygen takes place at the surface of the solid (or liquid) phosphorus, forming the short-lived molecules HPO and P2O2 that both emit visible light. The reaction is slow and only very little of the intermediates is required to produce the luminescence, hence the extended time the glow continues in a stoppered jar.
Although the term phosphorescence is derived from phosphorus, the reaction which gives phosphorus its glow is properly called luminescence (glowing by its own reaction, in this case chemoluminescence), not phosphorescence (re-emitting light that previously fell on it).
# Applications
Concentrated phosphoric acids, which can consist of 70% to 75% P2O5 are very important to agriculture and farm production in the form of fertilisers. Global demand for fertilizers led to large increases in phosphate (PO43-) production in the second half of the 20th century. Other uses;
- Phosphates are utilized in the making of special glasses that are used for sodium lamps.
- Bone-ash, calcium phosphate, is used in the production of fine china.
- Sodium tripolyphosphate made from phosphoric acid is used in laundry detergents in several countries, and banned for this use in others.
- Phosphoric acid made from elemental phosphorus is used in food applications such as soda beverages. The acid is also a starting point to make food grade phosphates. These include mono-calcium phosphate which is employed in baking powder and sodium tripolyphosphate and other sodium phosphates. Among other uses these are used to improve the characteristics of processed meat and cheese. Others are used in toothpaste. Trisodium phosphate is used in cleaning agents to soften water and for preventing pipe/boiler tube corrosion.
- Phosphorus is widely used to make organophosphorus compounds, through the intermediates phosphorus chlorides and the two phosphorus sulfides: phosphorus pentasulfide, and phosphorus sesquisulfide. Organophosphorus compounds have many applications, including in plasticizers, flame retardants, pesticides, extraction agents, and water treatment.
- Phosphorus is also an important component in steel production, in the making of phosphor bronze, and in many other related products.
- White phosphorus is used in military applications as incendiary bombs, for smoke-screening as smoke pots and smoke bombs, and in tracer ammunition.
- Red phosphorus is essential for manufacturing matchbook strikers, flares, safety matches, pharmaceutical grade and street methamphetamine, and is used in cap gun caps.
- Phosphorus sesquisulfide is used in heads of strike-anywhere matches.
- In trace amounts, phosphorus is used as a dopant for N-type semiconductors.
- 32P and 33P are used as radioactive tracers in biochemical laboratories (see Isotopes).
# Biological role
Phosphorus is a key element in all known forms of life. Inorganic phosphorus in the form of the phosphate PO43- plays a major role in biological molecules such as DNA and RNA where it forms part of the structural framework of these molecules. Living cells also use phosphate to transport cellular energy via adenosine triphosphate (ATP). Nearly every cellular process that uses energy obtains it in the form of ATP. ATP is also important for phosphorylation, a key regulatory event in cells. Phospholipids are the main structural components of all cellular membranes. Calcium phosphate salts assist in stiffening bones.
An average adult human contains a little less than 1 kg of phosphorus, about 85% of which is present in bones and teeth in the form of apatite, and the remainder inside cells in soft tissues. A well-fed adult in the industrialized world consumes and excretes about 1-3 g of phosphorus per day in the form of phosphate. Only about 0.1% of body phosphate circulates in the blood, but this amount reflects the amount of phosphate available to soft tissue cells.
In medicine, low phosphate syndromes are caused by malnutrition, by failure to absorb phosphate, and by metabolic syndromes which draw phosphate from the blood or pass too much of it into the urine. All are characterized by hypophosphatemia (see article for medical details). Symptoms of low phosphate include muscle and neurological dysfunction, and disruption of muscle and blood cells due to lack of ATP.
Phosphorus is an essential macromineral for plants, which is studied extensively in soil conservation in order to understand plant uptake from soil systems. In ecological terms, phosphorus is often a limiting nutrient in many environments; i.e. the availability of phosphorus governs the rate of growth of many organisms. In ecosystems an excess of phosphorus can be problematic, especially in aquatic systems, see eutrophication and algal blooms.
# History
Phosphorus (Greek phosphoros was the ancient name for the planet Venus, but in Greek mythology, Hesperus and Eosphorus could be confused with Phosphorus) was discovered by German alchemist Hennig Brand in 1669 through a preparation from urine, which contains considerable quantities of dissolved phosphates from normal metabolism. Working in Hamburg, Brand attempted to distill some salts by evaporating urine, and in the process produced a white material that glowed in the dark and burned brilliantly. Since that time, phosphorescence has been used to describe substances that shine in the dark without burning.
Phosphorus was first made commercially, for the match industry, in the 19th century, by distilling off phosphorus vapor from precipitated phosphates heated in a retort. The precipitated phosphates were made from ground-up bones that had been de-greased and treated with strong acids. This process became obsolete in the late 1890s when the electric arc furnace was adapted to reduce phosphate rock.
Early matches used white phosphorus in their composition, which was dangerous due to its toxicity. Murders, suicides and accidental poisonings resulted from its use. (An apocryphal tale tells of a woman attempting to murder her husband with white phosphorus in his food, which was detected by the stew giving off luminous steam). In addition, exposure to the vapours gave match workers a necrosis of the bones of the jaw, the infamous "phossy jaw." When a safe process for manufacturing red phosphorus was discovered, with its far lower flammability and toxicity, laws were enacted, under a Berne Convention, requiring its adoption as a safer alternative for match manufacture.
The electric furnace method allowed production to increase to the point where phosphorus could be used in weapons of war. In World War I it was used in incendiaries, smoke screens and tracer bullets. A special incendiary bullet was developed to shoot at hydrogen-filled Zeppelins over Britain (hydrogen being highly inflammable if it can be ignited). During World War II, Molotov cocktails of benzene and phosphorus were distributed in Britain to specially selected civilians within the British resistance operation, for defence; and phosphorus incendiary bombs were used in war on a large scale. Burning phosphorus is difficult to extinguish and if it splashes onto human skin it has horrific effects (see precautions below). People covered in it have been known to commit suicide due to the torment.
Today phosphorus production is larger than ever. It is used as a precursor for various chemicals, in particular the herbicide glyphosate sold under the brand name Roundup. Production of white phosphorus takes place at large facilities and it is transported heated in liquid form. Some major accidents have occurred during transportation, train derailments at Brownston, Nebraska and Miamisburg, Ohio led to large fires. The worst accident in recent times was an environmental one in 1968 when phosphorus spilled into the sea from a plant at Placentia Bay, Newfoundland.
# Occurrence
Due to its reactivity with air and many other oxygen-containing substances, phosphorus is not found free in nature but it is widely distributed in many different minerals.
Phosphate rock, which is partially made of apatite (an impure tri-calcium phosphate mineral), is an important commercial source of this element. Large deposits of apatite are located in China, Russia, Morocco, Florida, Idaho, Tennessee, Utah, and elsewhere. Albright and Wilson in the United Kingdom and their Niagara Falls plant, for instance, were using phosphate rock in the 1890s and 1900s from Connetable, Tennessee and Florida; by 1950 they were using phosphate rock mainly from Tennessee and North Africa. In the early 1990s Albright and Wilson's purified wet phosphoric acid business was being affected by phosphate rock sales by China and the entry of their long standing Moroccan phosphate suppliers into the purified wet phosphoric acid business.
At today's rate of consumption, the supply of phosphorous is estimated to run out in 345 years.
# Precautions
Organic compounds of phosphorus form a wide class of materials, some of which are extremely toxic. Fluorophosphate esters are among the most potent neurotoxins known. A wide range of organophosphorus compounds are used for their toxicity to certain organisms as pesticides (herbicides, insecticides, fungicides, etc.) and weaponized as nerve agents. Most inorganic phosphates are relatively nontoxic and essential nutrients. For environmentally adverse effects of phosphates see eutrophication and algal blooms.
The white phosphorus allotrope should be kept under water at all times as it presents a significant fire hazard due to its extreme reactivity with atmospheric oxygen, and it should only be manipulated with forceps since contact with skin can cause severe burns. Chronic white phosphorus poisoning leads to necrosis of the jaw called "phossy jaw". Ingestion of white phosphorus may cause a medical condition known as "Smoking Stool Syndrome".
When the white form is exposed to sunlight or when it is heated in its own vapour to 250°C, it is transmuted to the red form, which does not phosphoresce in air. The red allotrope does not spontaneously ignite in air and is not as dangerous as the white form. Nevertheless, it should be handled with care because it reverts to white phosphorus in some temperature ranges and it also emits highly toxic fumes that consist of phosphorus oxides when it is heated.
Upon exposure to elemental phosphorus, in the past it was suggested to wash the affected area with 2% copper sulfate solution to form harmless compounds that can be washed away. According to the recent US Navy's Treatment of Chemical Agent Casualties and Conventional Military Chemical Injuries: FM8-285: Part 2 Conventional Military Chemical Injuries, "Cupric (copper(II)) sulfate has been used by U.S. personnel in the past and is still being used by some nations. However, copper sulfate is toxic and its use will be discontinued. Copper sulfate may produce kidney and cerebral toxicity as well as intravascular hemolysis."
The manual suggests instead "a bicarbonate solution to neutralize phosphoric acid, which will then allow removal of visible WP. Particles often can be located by their emission of smoke when air strikes them, or by their phosphorescence in the dark. In dark surroundings, fragments are seen as luminescent spots." Then, "Promptly debride the burn if the patient's condition will permit removal of bits of WP which might be absorbed later and possibly produce systemic poisoning. DO NOT apply oily-based ointments until it is certain that all WP has been removed. Following complete removal of the particles, treat the lesions as thermal burns." As white phosphorus readily mixes with oils, any oily substances or ointments are not recommended until the area is thoroughly cleaned and all white phosphorus removed.
Further warnings of toxic effects and recommendations for treatment can be found in the Emergency War Surgery NATO Handbook: Part I: Types of Wounds and Injuries: Chapter III: Burn Injury: Chemical Burns And White Phosphorus injury.
## DEA List I status
Phosphorus can reduce elemental iodine to hydroiodic acid, which is a reagent effective for reducing ephedrine or pseudoephedrine to methamphetamine. For this reason, two allotropes of elemental phosphorus—red phosphorus and white phosphorus—were designated by the United States Drug Enforcement Administration as List I precursor chemicals under 21 CFR 1310.02 effective November 17, 2001. As a result, in the United States, handlers of red phosphorus or white phosphorus are subject to stringent regulatory controls pursuant to the Controlled Substances Act in order to reduce diversion of these substances for use in clandestine production of controlled substances.
# As an exception to the octet rule
The simple Lewis structure for the trigonal bipyramidal PCl5 molecule contains five covalent bonds, implying a hypervalent molecule with ten valence electrons contrary to the octet rule.
An alternate description of the bonding, however, respects the octet rule by using 3-center-4-electron (3c-4e) bonds. In this model the octet on the P atom corresponds to six electrons which form three Lewis (2c-2e) bonds to the three equatorial Cl atoms, plus the two electrons in the 3-centre Cl-P-Cl bonding molecular orbital for the two axial Cl electrons. The two electrons in the corresponding nonbonding molecular orbital are not included because this orbital is localized on the two Cl atoms and does not contribute to the electron density on P.
# Isotopes
Radioactive isotopes of phosphorus include
- 32P; a beta-emitter (1.71 MeV) with a half-life of 14.3 days which is used routinely in life-science laboratories, primarily to produce radiolabeled DNA and RNA probes, e.g. for use in Northern blots or Southern blots. Because the high energy beta particles produced penetrate skin and corneas, and because any 32P ingested, inhaled, or absorbed is readily incorporated into bone and nucleic acids, Occupational Safety and Health Administration requires that a lab coat, disposable gloves, and safety glasses or goggles be worn when working with 32P, and that working directly over an open container be avoided in order to protect the eyes. Monitoring personal, clothing, and surface contamination is also required. In addition, due to the high energy of the beta particles, shielding this radiation with the normally used dense materials (e.g. lead), gives rise to secondary emission of X-rays via a process known as Bremsstrahlung, meaning braking radiation. Therefore shielding must be accomplished with low density materials, e.g. Plexiglas, Lucite, plastic, wood, or water.
- 33P; a beta-emitter (0.25 MeV) with a half-life of 25.4 days. It is used in life-science laboratories in applications in which lower energy beta emissions are advantageous such as DNA sequencing.
# Spelling
According to the Oxford English Dictionary the correct spelling of the element is phosphorus. The word phosphorous is the adjectival form for the P3+ valency: so, just as sulfur forms sulfurous and sulfuric compounds, phosphorus forms phosphorous and phosphoric compounds.
# Compounds
- Hydride: PH3
- Halides: PBr5, PBr3, PCl3, PI3
- Oxides:P4O6, P4O10
- Sulfides: P2S5, P4S3
- Phosphorus oxoacids: H3PO2, H3PO4
- Phosphates: (NH4)3PO4, Ca3(PO4)2), FePO4, Fe3(PO4)2, Na3PO4, Ca(H2PO4)2, KH2PO4
- Phosphides: Ca3P2, GaP, Zn3P2
- Organophosphorus and organophosphates: Lawesson's reagent, Parathion, Sarin, Soman, Tabun, Triphenyl phosphine, VX nerve gas
See also Phosphorus compounds | Phosphorus
Editor-In-Chief: Henry A. Hoff
Template:Infobox phosphorus
# Overview
Phosphorus, (Template:IPAEng, Template:Lang-el meaning "light", and phoros meaning "bearer"), is the chemical element that has the symbol P and atomic number 15. A multivalent nonmetal of the nitrogen group, phosphorus is commonly found in inorganic phosphate rocks.
Due to its high reactivity, phosphorus is never found as a free element in nature. One form of phosphorus (white phosphorus) emits a faint glow upon exposure to oxygen (hence its Greek derivation and the Latin 'light-bearer', meaning the planet Venus as Hesperus or "Morning Star").
Phosphorus is a component of DNA and RNA and an essential element for all living cells. The most important commercial use of phosphorus-based chemicals is the production of fertilisers.
Phosphorus compounds are also widely used in explosives, nerve agents, friction matches, fireworks, pesticides, toothpaste, and detergents.
# Characteristics
## Allotropes
Elemental phosphorus can exist in several allotropes, most commonly white, red and black.
White phosphorus (P4) exists as individual molecules made up of four atoms in a tetrahedral arrangement, resulting in very high ring strain and instability. It contains 6 single bonds.
White phosphorus is a yellow, waxy transparent solid. For this reason it is also called yellow phosphorus. It glows greenish in the dark (when exposed to oxygen), is highly flammable and pyrophoric (self-igniting) upon contact with air as well as toxic (causing severe liver damage on ingestion). The odour of combustion of this form has a characteristic garlic smell, and samples are commonly coated with white "(di)phosphorus pentoxide", which consists of P4O10 tetrahedra with oxygen inserted between the phosphorus atoms and at their vertices. White phosphorus is insoluble in water but soluble in carbon disulfide.
The white allotrope can be produced using several different methods. In one process, calcium phosphate, which is derived from phosphate rock, is heated in an electric or fuel-fired furnace in the presence of carbon and silica[1]. Elemental phosphorus is then liberated as a vapour and can be collected under phosphoric acid. This process is similar to the first synthesis of phosphorus from calcium phosphate in urine.
Red phosphorus may be formed by heating white phosphorus to 250°C (482°F) or by exposing white phosphorus to sunlight. Phosphorus after this treatment exists as an amorphous network of atoms which reduces strain and gives greater stability; further heating results in the red phosphorus becoming crystalline. Red phosphorus does not catch fire in air at temperatures below 240°C, whereas white phosphorus ignites at about 30°C.
In 1865 Hittorf discovered that when phosphorus was recrystallized from molten lead, a red/purple form is obtained. This purple form is sometimes known as "Hittorf's phosphorus." In addition, a fibrous form exists with similar phosphorus cages. Below is shown a chain of phosphorus atoms which exhibits both the purple and fibrous forms.
One of the forms of red/black phosphorus is a cubic solid.[2]
Black phosphorus has an orthorhombic structure (Cmca) and is the least reactive allotrope, it consists of many six-membered rings which are interlinked. Each atom is bonded to three other atoms.[3][4] A recent synthesis of black phosphorus using metal salts as catalysts has been reported.[5]
The diphosphorus allotrope (P2) can be obtained normally only under extreme conditions (for example, from P4 at 1100 kelvin). Nevertheless, some advancements were obtained in generating the diatomic molecule in homogenous solution, under normal condtitions with the use by some transitional metal complexes (based on for example tungsten and niobium).[6]
## Glow
The glow from phosphorus was the attraction of its discovery around 1669, but the mechanism for that glow was not fully described until 1974.[7] It was known from early times that the glow would persist for a time in a stoppered jar but then cease. Robert Boyle in the 1680s ascribed it to "debilitation" of the air; in fact it is oxygen being consumed. By the 18th century it was known that in pure oxygen phosphorus does not glow at all,[8] there is only a range of partial pressure where it does. Heat can be applied to drive the reaction at higher pressures.[9]
In 1974 the glow was explained by R. J. van Zee and A. U. Khan.[7] A reaction with oxygen takes place at the surface of the solid (or liquid) phosphorus, forming the short-lived molecules HPO and P2O2 that both emit visible light. The reaction is slow and only very little of the intermediates is required to produce the luminescence, hence the extended time the glow continues in a stoppered jar.
Although the term phosphorescence is derived from phosphorus, the reaction which gives phosphorus its glow is properly called luminescence (glowing by its own reaction, in this case chemoluminescence), not phosphorescence (re-emitting light that previously fell on it).
# Applications
Concentrated phosphoric acids, which can consist of 70% to 75% P2O5 are very important to agriculture and farm production in the form of fertilisers. Global demand for fertilizers led to large increases in phosphate (PO43-) production in the second half of the 20th century. Other uses;
- Phosphates are utilized in the making of special glasses that are used for sodium lamps.
- Bone-ash, calcium phosphate, is used in the production of fine china.
- Sodium tripolyphosphate made from phosphoric acid is used in laundry detergents in several countries, and banned for this use in others.
- Phosphoric acid made from elemental phosphorus is used in food applications such as soda beverages. The acid is also a starting point to make food grade phosphates.[1] These include mono-calcium phosphate which is employed in baking powder and sodium tripolyphosphate and other sodium phosphates[1]. Among other uses these are used to improve the characteristics of processed meat and cheese. Others are used in toothpaste.[1] Trisodium phosphate is used in cleaning agents to soften water and for preventing pipe/boiler tube corrosion.
- Phosphorus is widely used to make organophosphorus compounds, through the intermediates phosphorus chlorides and the two phosphorus sulfides: phosphorus pentasulfide, and phosphorus sesquisulfide.[1] Organophosphorus compounds have many applications, including in plasticizers, flame retardants, pesticides, extraction agents, and water treatment.
- Phosphorus is also an important component in steel production, in the making of phosphor bronze, and in many other related products.
- White phosphorus is used in military applications as incendiary bombs, for smoke-screening as smoke pots and smoke bombs, and in tracer ammunition.
- Red phosphorus is essential for manufacturing matchbook strikers, flares,[1] safety matches, pharmaceutical grade and street methamphetamine, and is used in cap gun caps.
- Phosphorus sesquisulfide is used in heads of strike-anywhere matches.[1]
- In trace amounts, phosphorus is used as a dopant for N-type semiconductors.
- 32P and 33P are used as radioactive tracers in biochemical laboratories (see Isotopes).
# Biological role
Phosphorus is a key element in all known forms of life. Inorganic phosphorus in the form of the phosphate PO43- plays a major role in biological molecules such as DNA and RNA where it forms part of the structural framework of these molecules. Living cells also use phosphate to transport cellular energy via adenosine triphosphate (ATP). Nearly every cellular process that uses energy obtains it in the form of ATP. ATP is also important for phosphorylation, a key regulatory event in cells. Phospholipids are the main structural components of all cellular membranes. Calcium phosphate salts assist in stiffening bones.
An average adult human contains a little less than 1 kg of phosphorus, about 85% of which is present in bones and teeth in the form of apatite, and the remainder inside cells in soft tissues. A well-fed adult in the industrialized world consumes and excretes about 1-3 g of phosphorus per day in the form of phosphate. Only about 0.1% of body phosphate circulates in the blood, but this amount reflects the amount of phosphate available to soft tissue cells.
In medicine, low phosphate syndromes are caused by malnutrition, by failure to absorb phosphate, and by metabolic syndromes which draw phosphate from the blood or pass too much of it into the urine. All are characterized by hypophosphatemia (see article for medical details). Symptoms of low phosphate include muscle and neurological dysfunction, and disruption of muscle and blood cells due to lack of ATP.
Phosphorus is an essential macromineral for plants, which is studied extensively in soil conservation in order to understand plant uptake from soil systems. In ecological terms, phosphorus is often a limiting nutrient in many environments; i.e. the availability of phosphorus governs the rate of growth of many organisms. In ecosystems an excess of phosphorus can be problematic, especially in aquatic systems, see eutrophication and algal blooms.
# History
Phosphorus (Greek phosphoros was the ancient name for the planet Venus, but in Greek mythology, Hesperus and Eosphorus could be confused with Phosphorus) was discovered by German alchemist Hennig Brand in 1669 through a preparation from urine, which contains considerable quantities of dissolved phosphates from normal metabolism. Working in Hamburg, Brand attempted to distill some salts by evaporating urine, and in the process produced a white material that glowed in the dark and burned brilliantly. Since that time, phosphorescence has been used to describe substances that shine in the dark without burning.
Phosphorus was first made commercially, for the match industry, in the 19th century, by distilling off phosphorus vapor from precipitated phosphates heated in a retort.[1] The precipitated phosphates were made from ground-up bones that had been de-greased and treated with strong acids.[1] This process became obsolete in the late 1890s when the electric arc furnace was adapted to reduce phosphate rock.[1]
Early matches used white phosphorus in their composition, which was dangerous due to its toxicity. Murders, suicides and accidental poisonings resulted from its use. (An apocryphal tale tells of a woman attempting to murder her husband with white phosphorus in his food, which was detected by the stew giving off luminous steam).[7] In addition, exposure to the vapours gave match workers a necrosis of the bones of the jaw, the infamous "phossy jaw." When a safe process for manufacturing red phosphorus was discovered, with its far lower flammability and toxicity, laws were enacted, under a Berne Convention, requiring its adoption as a safer alternative for match manufacture.
The electric furnace method allowed production to increase to the point where phosphorus could be used in weapons of war.[7][1] In World War I it was used in incendiaries, smoke screens and tracer bullets.[1] A special incendiary bullet was developed to shoot at hydrogen-filled Zeppelins over Britain (hydrogen being highly inflammable if it can be ignited).[1] During World War II, Molotov cocktails of benzene and phosphorus were distributed in Britain to specially selected civilians within the British resistance operation, for defence; and phosphorus incendiary bombs were used in war on a large scale. Burning phosphorus is difficult to extinguish and if it splashes onto human skin it has horrific effects (see precautions below). People covered in it have been known to commit suicide due to the torment.
Today phosphorus production is larger than ever. It is used as a precursor for various chemicals,[10] in particular the herbicide glyphosate sold under the brand name Roundup. Production of white phosphorus takes place at large facilities and it is transported heated in liquid form. Some major accidents have occurred during transportation, train derailments at Brownston, Nebraska and Miamisburg, Ohio led to large fires. The worst accident in recent times was an environmental one in 1968 when phosphorus spilled into the sea from a plant at Placentia Bay, Newfoundland.
# Occurrence
Due to its reactivity with air and many other oxygen-containing substances, phosphorus is not found free in nature but it is widely distributed in many different minerals.
Phosphate rock, which is partially made of apatite (an impure tri-calcium phosphate mineral), is an important commercial source of this element. Large deposits of apatite are located in China, Russia, Morocco, Florida, Idaho, Tennessee, Utah, and elsewhere. Albright and Wilson in the United Kingdom and their Niagara Falls plant, for instance, were using phosphate rock in the 1890s and 1900s from Connetable, Tennessee and Florida; by 1950 they were using phosphate rock mainly from Tennessee and North Africa[1]. In the early 1990s Albright and Wilson's purified wet phosphoric acid business was being affected by phosphate rock sales by China and the entry of their long standing Moroccan phosphate suppliers into the purified wet phosphoric acid business.[11]
At today's rate of consumption, the supply of phosphorous is estimated to run out in 345 years.[12]
# Precautions
Organic compounds of phosphorus form a wide class of materials, some of which are extremely toxic. Fluorophosphate esters are among the most potent neurotoxins known. A wide range of organophosphorus compounds are used for their toxicity to certain organisms as pesticides (herbicides, insecticides, fungicides, etc.) and weaponized as nerve agents. Most inorganic phosphates are relatively nontoxic and essential nutrients. For environmentally adverse effects of phosphates see eutrophication and algal blooms.
The white phosphorus allotrope should be kept under water at all times as it presents a significant fire hazard due to its extreme reactivity with atmospheric oxygen, and it should only be manipulated with forceps since contact with skin can cause severe burns. Chronic white phosphorus poisoning leads to necrosis of the jaw called "phossy jaw". Ingestion of white phosphorus may cause a medical condition known as "Smoking Stool Syndrome". [13]
When the white form is exposed to sunlight or when it is heated in its own vapour to 250°C, it is transmuted to the red form, which does not phosphoresce in air. The red allotrope does not spontaneously ignite in air and is not as dangerous as the white form. Nevertheless, it should be handled with care because it reverts to white phosphorus in some temperature ranges and it also emits highly toxic fumes that consist of phosphorus oxides when it is heated.
Upon exposure to elemental phosphorus, in the past it was suggested to wash the affected area with 2% copper sulfate solution to form harmless compounds that can be washed away. According to the recent US Navy's Treatment of Chemical Agent Casualties and Conventional Military Chemical Injuries: FM8-285: Part 2 Conventional Military Chemical Injuries, "Cupric (copper(II)) sulfate has been used by U.S. personnel in the past and is still being used by some nations. However, copper sulfate is toxic and its use will be discontinued. Copper sulfate may produce kidney and cerebral toxicity as well as intravascular hemolysis."[14]
The manual suggests instead "a bicarbonate solution to neutralize phosphoric acid, which will then allow removal of visible WP. Particles often can be located by their emission of smoke when air strikes them, or by their phosphorescence in the dark. In dark surroundings, fragments are seen as luminescent spots." Then, "Promptly debride the burn if the patient's condition will permit removal of bits of WP which might be absorbed later and possibly produce systemic poisoning. DO NOT apply oily-based ointments until it is certain that all WP has been removed. Following complete removal of the particles, treat the lesions as thermal burns." As white phosphorus readily mixes with oils, any oily substances or ointments are not recommended until the area is thoroughly cleaned and all white phosphorus removed.
Further warnings of toxic effects and recommendations for treatment can be found in the Emergency War Surgery NATO Handbook: Part I: Types of Wounds and Injuries: Chapter III: Burn Injury: Chemical Burns And White Phosphorus injury.[15]
## DEA List I status
Phosphorus can reduce elemental iodine to hydroiodic acid, which is a reagent effective for reducing ephedrine or pseudoephedrine to methamphetamine.[16] For this reason, two allotropes of elemental phosphorus—red phosphorus and white phosphorus—were designated by the United States Drug Enforcement Administration as List I precursor chemicals under 21 CFR 1310.02 effective November 17, 2001.[17] As a result, in the United States, handlers of red phosphorus or white phosphorus are subject to stringent regulatory controls pursuant to the Controlled Substances Act in order to reduce diversion of these substances for use in clandestine production of controlled substances.[17][18][19]
# As an exception to the octet rule
The simple Lewis structure for the trigonal bipyramidal PCl5 molecule contains five covalent bonds, implying a hypervalent molecule with ten valence electrons contrary to the octet rule.
An alternate description of the bonding, however, respects the octet rule by using 3-center-4-electron (3c-4e) bonds. In this model the octet on the P atom corresponds to six electrons which form three Lewis (2c-2e) bonds to the three equatorial Cl atoms, plus the two electrons in the 3-centre Cl-P-Cl bonding molecular orbital for the two axial Cl electrons. The two electrons in the corresponding nonbonding molecular orbital are not included because this orbital is localized on the two Cl atoms and does not contribute to the electron density on P.
# Isotopes
Radioactive isotopes of phosphorus include
- 32P; a beta-emitter (1.71 MeV) with a half-life of 14.3 days which is used routinely in life-science laboratories, primarily to produce radiolabeled DNA and RNA probes, e.g. for use in Northern blots or Southern blots. Because the high energy beta particles produced penetrate skin and corneas, and because any 32P ingested, inhaled, or absorbed is readily incorporated into bone and nucleic acids, Occupational Safety and Health Administration requires that a lab coat, disposable gloves, and safety glasses or goggles be worn when working with 32P, and that working directly over an open container be avoided in order to protect the eyes. Monitoring personal, clothing, and surface contamination is also required. In addition, due to the high energy of the beta particles, shielding this radiation with the normally used dense materials (e.g. lead), gives rise to secondary emission of X-rays via a process known as Bremsstrahlung, meaning braking radiation. Therefore shielding must be accomplished with low density materials, e.g. Plexiglas, Lucite, plastic, wood, or water.[20]
- 33P; a beta-emitter (0.25 MeV) with a half-life of 25.4 days. It is used in life-science laboratories in applications in which lower energy beta emissions are advantageous such as DNA sequencing.
# Spelling
According to the Oxford English Dictionary the correct spelling of the element is phosphorus. The word phosphorous is the adjectival form for the P3+ valency: so, just as sulfur forms sulfurous and sulfuric compounds, phosphorus forms phosphorous and phosphoric compounds.
# Compounds
- Hydride: PH3
- Halides: PBr5, PBr3, PCl3, PI3
- Oxides:P4O6, P4O10
- Sulfides: P2S5, P4S3
- Phosphorus oxoacids: H3PO2, H3PO4
- Phosphates: (NH4)3PO4, Ca3(PO4)2), FePO4, Fe3(PO4)2, Na3PO4, Ca(H2PO4)2, KH2PO4
- Phosphides: Ca3P2, GaP, Zn3P2
- Organophosphorus and organophosphates: Lawesson's reagent, Parathion, Sarin, Soman, Tabun, Triphenyl phosphine, VX nerve gas
See also Phosphorus compounds
# External links
- Los Alamos National Laboratory – Phosphorus
- WebElements.com: Phosphorus
- Entrez PubMed: Acute Yellow Phosphorus Poisoning
- eMedicine.com: Article on White Phophorus as used as weapon
- Website of the Technische Universität Darmstadt and the CEEP about Phosphorus Recovery | https://www.wikidoc.org/index.php/Phosphorus | |
ee7844708cf17683deb9cb1e1f90932e8d8e7992 | wikidoc | Phossy jaw | Phossy jaw
Phossy jaw is a deadly occupational hazard for those who work with white phosphorus in an environment without proper safeguards. It was most commonly seen in workers in the match industry in the 19th and early 20th century. Modern industrial hygiene practices have eliminated the conditions which lead to this affliction.
Chronic exposure to white phosphorus vapour, the active ingredient of most matches from the 1840s to the 1910s, caused a deposition of phosphorus in the jaw bones. It also caused serious brain damage. Workers afflicted would begin suffering painful toothaches and swelling of the gums. Over time, the jaw bone would begin to abscess, a process which was both extremely painful and disfiguring to the patient, and repellent to others, since drainage from the dying bone tissue was exceedingly foul-smelling. The jawbones would gradually rot away and would actually glow a greenish-white color in the dark. Surgical removal of the afflicted jaw bones might save the sufferers' life at this point—otherwise, death from organ failure would invariably follow.
Public revulsion eventually caused changes in match manufacturing which eliminated the disease. In some nations, legislative action was required to force these changes on a reluctant industry.
A related condition, osteonecrosis of the jaw, has been described as a side-effect of bisphosphonates, a class of phosphorus-based drugs that inhibit bone resorption, and are used widely for treating osteoporosis, bone disease in cancer and some other situations. | Phossy jaw
Phossy jaw is a deadly occupational hazard for those who work with white phosphorus in an environment without proper safeguards. It was most commonly seen in workers in the match industry in the 19th and early 20th century. Modern industrial hygiene practices have eliminated the conditions which lead to this affliction.
Chronic exposure to white phosphorus vapour, the active ingredient of most matches from the 1840s to the 1910s, caused a deposition of phosphorus in the jaw bones. It also caused serious brain damage. Workers afflicted would begin suffering painful toothaches and swelling of the gums. Over time, the jaw bone would begin to abscess, a process which was both extremely painful and disfiguring to the patient, and repellent to others, since drainage from the dying bone tissue was exceedingly foul-smelling. The jawbones would gradually rot away and would actually glow a greenish-white color in the dark. Surgical removal of the afflicted jaw bones might save the sufferers' life at this point—otherwise, death from organ failure would invariably follow.
Public revulsion eventually caused changes in match manufacturing which eliminated the disease. In some nations, legislative action was required to force these changes on a reluctant industry.[1]
A related condition, osteonecrosis of the jaw, has been described as a side-effect of bisphosphonates, a class of phosphorus-based drugs that inhibit bone resorption, and are used widely for treating osteoporosis, bone disease in cancer and some other situations.[2] | https://www.wikidoc.org/index.php/Phossy_jaw | |
b79ca0bb7468882bfb706f5890bc40a2e4b609c8 | wikidoc | Phragmites | Phragmites
Phragmites australis, the Common Reed (see Reed (plant) for other species also called 'reed'), is a large perennial grass native to wetland sites throughout temperate and tropical regions of the world. It is generally regarded as the sole species of the genus Phragmites, though some botanists divide the genus into three or four species.
It commonly forms extensive stands, up to a square kilometre or more (known as reedbeds); where conditions are suitable, it can spread at up to 5 m or more per year by horizontal 'runner' stems, which put down roots at regular intervals. The erect stems grow to 2–6 m tall, with the taller plants growing in areas with hot summers and fertile growing conditions. The leaves are broad for a grass, 20–50 cm long and 2–3 cm broad. The flowers are produced in a dense, dark purple panicle 20–50 cm long.
The Common Reed is a very important plant for wildlife and conservation, particularly in Europe and Asia, where several species of birds are strongly tied to large Phragmites stands, notably:-
- Bearded Tit Panurus biarmicus
- Reed Warbler Acrocephalus scirpaceus
- Great Bittern Botaurus stellaris
In North America, the species' status was misunderstood. It was commonly considered to be an exotic species, not native but introduced from Europe; however, there is clear evidence of the existence of Phragmites native in North America long before European colonisation of the continent. It is now known that the North American native forms of Phragmites are markedly less vigorous than European forms; the recent marked increase in Phragmites in North America may be due to a vigorous, but otherwise almost indistinguishable European form of the species, best detectable by genetic analysis. This is causing serious problems for many other North American wetland plants, including the local form of the species.
Recent studies have characterised morphological variation among the introduced and native stands of Phragmites in North America. The Eurasian genotype can be distinguished from the North American genotype by its shorter ligules (up to 0.9 mm vs. over 1.0 mm), shorter glumes (under 3.2 mm vs. over 3.2 mm, although there is some overlap in this character), and culm characteristics. Recently, the North American genotype has been described as a distinct subspecies, Phragmites australis subsp. americanus Saltonstall, Peterson, and Soreng; the Eurasian genotype is referred to as Phragmites australis subsp. australis. Rhizomes of the plant are rich in N,N-DMT alkaloids (Wassel et al. 1985).
Synonyms include Arundo phragmites L. (the basionym), Phragmites altissimus, P. berlandieri, P. communis, P. dioicus, P. maximus, P. vulgaris.
# In literature
One reference to reeds in European literature is Frenchman Blaise Pascal's saying that Man is but a 'thinking reed' (roseau pensant). In La Fontaine's famous fable (Le chêne et le roseau), the reed tells the proud oak: "I bend, and break not" ("Je plie, et ne romps pas"), before the tree's fall.
Moses was "drawn out of the water where his mother had placed him in a reed basket to save him from the death that had been decreed by the Pharaoh against the firstborn of all of the children of Israel in Egypt (Exodus 2:10)." | Phragmites
Phragmites australis, the Common Reed (see Reed (plant) for other species also called 'reed'), is a large perennial grass native to wetland sites throughout temperate and tropical regions of the world. It is generally regarded as the sole species of the genus Phragmites, though some botanists divide the genus into three or four species.
It commonly forms extensive stands, up to a square kilometre or more (known as reedbeds); where conditions are suitable, it can spread at up to 5 m or more per year by horizontal 'runner' stems, which put down roots at regular intervals. The erect stems grow to 2–6 m tall, with the taller plants growing in areas with hot summers and fertile growing conditions. The leaves are broad for a grass, 20–50 cm long and 2–3 cm broad. The flowers are produced in a dense, dark purple panicle 20–50 cm long.
The Common Reed is a very important plant for wildlife and conservation, particularly in Europe and Asia, where several species of birds are strongly tied to large Phragmites stands, notably:-
- Bearded Tit Panurus biarmicus
- Reed Warbler Acrocephalus scirpaceus
- Great Bittern Botaurus stellaris
In North America, the species' status was misunderstood. It was commonly considered to be an exotic species, not native but introduced from Europe; however, there is clear evidence of the existence of Phragmites native in North America long before European colonisation of the continent. It is now known that the North American native forms of Phragmites are markedly less vigorous than European forms; the recent marked increase in Phragmites in North America may be due to a vigorous, but otherwise almost indistinguishable European form of the species, best detectable by genetic analysis. This is causing serious problems for many other North American wetland plants, including the local form of the species.[1]
Recent studies have characterised morphological variation among the introduced and native stands of Phragmites in North America. The Eurasian genotype can be distinguished from the North American genotype by its shorter ligules (up to 0.9 mm vs. over 1.0 mm), shorter glumes (under 3.2 mm vs. over 3.2 mm, although there is some overlap in this character), and culm characteristics. Recently, the North American genotype has been described as a distinct subspecies, Phragmites australis subsp. americanus Saltonstall, Peterson, and Soreng; the Eurasian genotype is referred to as Phragmites australis subsp. australis. Rhizomes of the plant are rich in N,N-DMT alkaloids (Wassel et al. 1985).
Synonyms include Arundo phragmites L. (the basionym), Phragmites altissimus, P. berlandieri, P. communis, P. dioicus, P. maximus, P. vulgaris.
# In literature
One reference to reeds in European literature is Frenchman Blaise Pascal's saying that Man is but a 'thinking reed' (roseau pensant). In La Fontaine's famous fable (Le chêne et le roseau), the reed tells the proud oak: "I bend, and break not" ("Je plie, et ne romps pas"), before the tree's fall.
Moses was "drawn out of the water where his mother had placed him in a reed basket to save him from the death that had been decreed by the Pharaoh against the firstborn of all of the children of Israel in Egypt (Exodus 2:10)."[2] | https://www.wikidoc.org/index.php/Phragmites | |
f8065c601c2414592ff9011e57b7a43b7c5b164d | wikidoc | Pikachurin | Pikachurin
Pikachurin, also known as AGRINL (AGRINL) and EGF-like, fibronectin type-III and laminin G-like domain-containing protein (EGFLAM), is a protein that in humans is encoded by the EGFLAM gene.
Pikachurin is a dystroglycan-interacting protein which has an essential role in the precise interactions between the photoreceptor ribbon synapse and the bipolar dendrites. The binding with dystroglycan (DG) depends on several factors (glycosylation of DG, presence of divalent cations, presence of other proteins).
A non-correct binding between pikachurin and DG is associated with muscular dystrophies that often involve eye abnormalities.
# Discovery and nomenclature
Pikachurin is an extracellular matrix-like retinal protein first described in 2008 in Japan by Shigeru Sato et al., and named after Pikachu, a species of the Pokémon franchise. The name of this "nimble" protein was inspired due to Pikachu's "lightning-fast moves and shocking electric effects".
Pikachurin was initially identified in a microarray analysis of gene expression profiles of the retinas of wild-type and Otx2 knockout mice. A RT-PCR analysis was used to confirm that Otx2 regulates the expression of pikachurin, it was known because there was an absence of expression of pikachurin in the Otx2 mice retina, so it indicates that Otx2 regulates pikachurin. The localization of pikachurin to synaptic cleft in the photoreceptor ribbon synapse was determined using fluorescent antibodies. Tissue targeting of gene disruption of pikachurin was used to determine that this protein is necessary for proper synaptic signal transmission and visual function. α-dystroglycan was shown to interact with pikachurin through immunoprecipitation.
# Pikachurin-dystroglycan interaction
Dystroglycan ligand with other proteins is essential. Glycosylation of dystroglycan is necessary for its ligand binding activity. Mutations in glycosyltransferase enzymes cause abnormal glycosylation of dystroglycan. This hypoglycosylation is associated with less binding with other proteins and causes some congenital muscular dystrophy. Pikachurin is the most recently identified dystroglycan ligand protein and is localized in the synaptic cleft in the photoreceptor ribbon synapse. The binding between dystroglycan and pikachurin requires divalent cations. Ca2+ produces strongest binding; Mn2+ produces only faint bindings and no binding with Mg2+ alone. Dystroglycan has different domains that allow multiple Ca2+ sites to form a stable pikachurin-dystroglycan connection. This shows that pikachurin can form oligomeric structures; and suggests the possibility of clustering effects can be important in modulating pikachurin-dystroglycan interactions.
Another thing to be considered is that the presence of NaCl (0.5M) strongly inhibits interaction between DG and other ligand proteins but has a modest inhibitory effect with pikachurin-DG ligand. This shows that there are differences between the binding of pikachurin-DG binding and DG binding with other proteins.
Pikachurin seems to have more domains to bind with DG than other proteins. For example, experiments in ligand competition shows that presence of pikachurin inhibits laminin-111 binding with DG, but high concentrations of laminin-111 do not inhibit pikachurin binding to DG.
# Function
The protein is colocalized with both dystrophin and dystroglycan at the ribbon synapses.
Pikachurin, along with laminin, perlecan, agrin, neurexin, binds to α-dystroglycan in the extracellular space. As such, pikachurin, as well as the other previously-mentioned proteins, is necessary for the proper functioning of dystroglycan. Pikachurin is necessary for the apposition of presynaptic and postsynaptic termini in the ribbon synapse; deletion of pikachurin causes an abnormal electroretinogram, similarly to the deletion of nestin.
## Ribbon synapse relation
Synapse formation is crucial for the mammalian CNS (central nervous system) to function correctly. Retinal photoreceptors finish at the axon terminal which forms a specialized structure, the ribbon synapse, which specifically connects photoreceptor synaptic terminals with bipolar and horizontal cell terminals in the outer plexiform layer (OPL) of the retina.
It is clear that Pikachurin, an extracellular matrix–like retinal protein, is localized to the synaptic cleft in the photoreceptor ribbon synapse. It is demonstrated that with a lack of Pikachurin, there is an improper apposition of the bipolar cell dendritic tips to the photoreceptor ribbon synapses, resulting in alterations in synaptic signal transmission and visual function. The function of Pikachurin remains unknown, but it is a fact that pikachurin is critically involved in the normal photoreceptor ribbon synapse formation and also in physiological functions of visual perception.
# Associated pathologies: muscular dystrophies
Congenital muscular dystrophies (CMD) such as muscle-eye-brain disease are caused by defective glycosylation of α-dystroglycan (α-DG) exhibit defective photoreceptor synaptic function. Pikachurin plays an essential role in CMD. Precise interactions between the photoreceptor ribbon synapse and the bipolar dendrites which are realized due to Pikachurin may advance our understanding of the molecular mechanisms underlying the retinal electrophysiological abnormalities observed in muscular dystrophy patients. The muscle-eye-brain dystrophy is caused by mutations in POMGnT1 or LARGE. These two genes mediated a post-translational modification on O-mannose, which is essential for pikachurin binding to dystroglycan, so people who suffer muscle-eye-disease have an hypoglycosylation of pikachurin-α-dystroglycan interactions.
# Therapeutic applications
Since pikachurin seems to provide better visual acuity, Sato et al. of the Osaka Bioscience Institute believe that the protein could be used to develop a treatment for retinitis pigmentosa and other eye disorders. | Pikachurin
Pikachurin, also known as AGRINL (AGRINL) and EGF-like, fibronectin type-III and laminin G-like domain-containing protein (EGFLAM), is a protein that in humans is encoded by the EGFLAM gene.[1][2][3]
Pikachurin is a dystroglycan-interacting protein which has an essential role in the precise interactions between the photoreceptor ribbon synapse and the bipolar dendrites.[2] The binding with dystroglycan (DG) depends on several factors (glycosylation of DG, presence of divalent cations, presence of other proteins).
A non-correct binding between pikachurin and DG is associated with muscular dystrophies that often involve eye abnormalities.[4]
# Discovery and nomenclature
Pikachurin is an extracellular matrix-like retinal protein first described in 2008 in Japan by Shigeru Sato et al., and named after Pikachu, a species of the Pokémon franchise.[2] The name of this "nimble" protein was inspired due to Pikachu's "lightning-fast moves and shocking electric effects".[5]
Pikachurin was initially identified in a microarray analysis of gene expression profiles of the retinas of wild-type and Otx2 knockout mice. A RT-PCR analysis was used to confirm that Otx2 regulates the expression of pikachurin, it was known because there was an absence of expression of pikachurin in the Otx2 mice retina, so it indicates that Otx2 regulates pikachurin. The localization of pikachurin to synaptic cleft in the photoreceptor ribbon synapse was determined using fluorescent antibodies. Tissue targeting of gene disruption of pikachurin was used to determine that this protein is necessary for proper synaptic signal transmission and visual function. α-dystroglycan was shown to interact with pikachurin through immunoprecipitation.[2]
# Pikachurin-dystroglycan interaction
Dystroglycan ligand with other proteins is essential. Glycosylation of dystroglycan is necessary for its ligand binding activity. Mutations in glycosyltransferase enzymes cause abnormal glycosylation of dystroglycan. This hypoglycosylation is associated with less binding with other proteins and causes some congenital muscular dystrophy. Pikachurin is the most recently identified dystroglycan ligand protein and is localized in the synaptic cleft in the photoreceptor ribbon synapse. The binding between dystroglycan and pikachurin requires divalent cations. Ca2+ produces strongest binding; Mn2+ produces only faint bindings and no binding with Mg2+ alone. Dystroglycan has different domains that allow multiple Ca2+ sites to form a stable pikachurin-dystroglycan connection. This shows that pikachurin can form oligomeric structures; and suggests the possibility of clustering effects can be important in modulating pikachurin-dystroglycan interactions.
Another thing to be considered is that the presence of NaCl (0.5M) strongly inhibits interaction between DG and other ligand proteins but has a modest inhibitory effect with pikachurin-DG ligand. This shows that there are differences between the binding of pikachurin-DG binding and DG binding with other proteins.
Pikachurin seems to have more domains to bind with DG than other proteins. For example, experiments in ligand competition shows that presence of pikachurin inhibits laminin-111 binding with DG, but high concentrations of laminin-111 do not inhibit pikachurin binding to DG.[4]
# Function
The protein is colocalized with both dystrophin and dystroglycan at the ribbon synapses.
Pikachurin, along with laminin, perlecan, agrin, neurexin, binds to α-dystroglycan in the extracellular space. As such, pikachurin, as well as the other previously-mentioned proteins, is necessary for the proper functioning of dystroglycan. Pikachurin is necessary for the apposition of presynaptic and postsynaptic termini in the ribbon synapse; deletion of pikachurin causes an abnormal electroretinogram, similarly to the deletion of nestin.[6]
## Ribbon synapse relation
Synapse formation is crucial for the mammalian CNS (central nervous system) to function correctly. Retinal photoreceptors finish at the axon terminal which forms a specialized structure, the ribbon synapse, which specifically connects photoreceptor synaptic terminals with bipolar and horizontal cell terminals in the outer plexiform layer (OPL) of the retina.[2]
It is clear that Pikachurin, an extracellular matrix–like retinal protein, is localized to the synaptic cleft in the photoreceptor ribbon synapse.[7] It is demonstrated that with a lack of Pikachurin, there is an improper apposition of the bipolar cell dendritic tips to the photoreceptor ribbon synapses, resulting in alterations in synaptic signal transmission and visual function. The function of Pikachurin remains unknown, but it is a fact that pikachurin is critically involved in the normal photoreceptor ribbon synapse formation and also in physiological functions of visual perception.[8]
# Associated pathologies: muscular dystrophies
Congenital muscular dystrophies (CMD) such as muscle-eye-brain disease are caused by defective glycosylation of α-dystroglycan (α-DG) exhibit defective photoreceptor synaptic function. Pikachurin plays an essential role in CMD. Precise interactions between the photoreceptor ribbon synapse and the bipolar dendrites which are realized due to Pikachurin may advance our understanding of the molecular mechanisms underlying the retinal electrophysiological abnormalities observed in muscular dystrophy patients. The muscle-eye-brain dystrophy is caused by mutations in POMGnT1 or LARGE. These two genes mediated a post-translational modification on O-mannose, which is essential for pikachurin binding to dystroglycan, so people who suffer muscle-eye-disease have an hypoglycosylation of pikachurin-α-dystroglycan interactions.[8]
# Therapeutic applications
Since pikachurin seems to provide better visual acuity, Sato et al. of the Osaka Bioscience Institute believe that the protein could be used to develop a treatment for retinitis pigmentosa and other eye disorders.[2][9] | https://www.wikidoc.org/index.php/Pikachurin | |
d712a39aa961cfc51221e218845e413e1ac1426c | wikidoc | Pilocarpus | Pilocarpus
Pilocarpus is a genus of about 13 species of plants belonging to the family Rutaceae, native to the neotropics of South America. Various species are important pharmacologically. Many of the species have the common name Jaborandi.
'pilocarpine'. It stimulates specific receptors in lacrimal gland and cause increased secretion of tears. The medicinal properties of pilocarpine, including its ability to stimulate salivation, have been recognized for many centuries by the Tupi Indian tribe of northern Brazil, who named this indigenous shrub "jaborandi," or the "slobber-mouth plant."
indicated for 1) the treatment of symptoms of dry mouth from salivary gland hypofunction caused by radiotherapy for cancer of the head and neck; and 2) the treatment of symptoms of dry mouth in patients with Sjogren's syndrome.
The taxonomic name Pilocarpus means cap-shaped fruit.
- Pilocarpus jaborandi (Pernambuco Jaborandi)
- Pilocarpus microphyllus (Maranham Jaborandi)
- Pilocarpus racemosus (Guadeloupe Jaborandi)
- Pilocarpus pennatifolius (Paraguay Jaborandi)
- Pilocarpus spicatus (Aracati Jaborandi) | Pilocarpus
Pilocarpus is a genus of about 13 species of plants belonging to the family Rutaceae, native to the neotropics of South America. Various species are important pharmacologically. Many of the species have the common name Jaborandi.
'pilocarpine'. It stimulates specific receptors in lacrimal gland and cause increased secretion of tears. The medicinal properties of pilocarpine, including its ability to stimulate salivation, have been recognized for many centuries by the Tupi Indian tribe of northern Brazil, who named this indigenous shrub "jaborandi," or the "slobber-mouth plant."
indicated for 1) the treatment of symptoms of dry mouth from salivary gland hypofunction caused by radiotherapy for cancer of the head and neck; and 2) the treatment of symptoms of dry mouth in patients with Sjogren's syndrome.
The taxonomic name Pilocarpus means cap-shaped fruit.
- Pilocarpus jaborandi (Pernambuco Jaborandi)
- Pilocarpus microphyllus (Maranham Jaborandi)
- Pilocarpus racemosus (Guadeloupe Jaborandi)
- Pilocarpus pennatifolius (Paraguay Jaborandi)
- Pilocarpus spicatus (Aracati Jaborandi)
# External links
- Germplasm Resources Information Network: Pilocarpus | https://www.wikidoc.org/index.php/Pilocarpus | |
f9146bfa55eefdc4b84ac25771c1acb3c66af2ca | wikidoc | Pinguecula | Pinguecula
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# Overview
A pinguecula is a type of conjunctival degeneration in the eye. It is extremely common and is seen as a yellow-white deposit on the conjunctiva adjacent to the limbus (the junction between the cornea and sclera). It is to be distinguished from pterygium clinically, which is a wedge shaped area of fibrosis, that appears to grow into the cornea. It is most prevalent in tropical climates and is in direct correlation with UV exposure.
Histologically it shows degeneration of the collagen fibres of the conjunctival stroma with thinning of the overlying epithelium and occasional calcification.
They may enlarge slowly but is a benign condition requiring no treatment. If cosmesis is a concern surgical excision is sometimes done.
A pinguecula is one of the differential diagnoses for a limbal nodule. | Pinguecula
For patient information click here
Please Join in Editing This Page and Apply to be an Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [1] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
# Overview
A pinguecula is a type of conjunctival degeneration in the eye. It is extremely common and is seen as a yellow-white deposit on the conjunctiva adjacent to the limbus (the junction between the cornea and sclera). It is to be distinguished from pterygium clinically, which is a wedge shaped area of fibrosis, that appears to grow into the cornea. It is most prevalent in tropical climates and is in direct correlation with UV exposure.
Histologically it shows degeneration of the collagen fibres of the conjunctival stroma with thinning of the overlying epithelium and occasional calcification.
They may enlarge slowly but is a benign condition requiring no treatment. If cosmesis is a concern surgical excision is sometimes done.
A pinguecula is one of the differential diagnoses for a limbal nodule. | https://www.wikidoc.org/index.php/Pinguecula | |
ac73fb40365f35bdd04099fc932644c8f5f90adf | wikidoc | Pintumomab | Pintumomab
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# Overview
Pintumomab is a mouse monoclonal antibody and which it is used to treat cancer. Pintumomab has a radioisotope, technetium-99m Tc. | Pintumomab
Template:Drugbox-mab
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# Overview
Pintumomab is a mouse monoclonal antibody and which it is used to treat cancer. Pintumomab has a radioisotope, technetium-99m Tc.
Template:Mousemonoclonals
Template:SIB
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Pintumomab | |
76ebd87daa5992430bd889b9b32ae66f66794263 | wikidoc | Piped link | Piped link
# Overview
A piped link is a link within the project or to a sister project which is labeled differently from the name of the page it links to. This allows linking a word or phrase within the text of a page rather than using "see also", even if the wording does not exactly correspond with the name of the other page. With a suitable browser and depending on the preferences set, one can still see what page is linked to: when you point at the link, the name shows up in a hover box and is also shown in the status bar.
For instance:
will show: How to set up a coffee house
The term piped refers to the use of the pipe character "|" used to separate the good description from the actual link. This character is named after an alternative use of it; see Pipe (computing).
Another example would be ] rendering as station. This is useful where the word "station" is used in an article on trains; from the context, it would be clear that a train station is meant. The piped link is more convenient to the user than a link to station which is a disambiguation page.
# Using a redirect as an alternative
An alternative is simply using ] to create How to set up a coffee house (note that, unlike above, what pops up when you point at the link, if applicable for your browser, is simply the text already shown), and making How to set up a coffee house a redirect page.
This is convenient if the redirect is already there or will also be of use elsewhere; however, there are a few drawbacks:
- the popup does not show the page one will arrive at
- "Related changes" does gives the changes in the redirect page
- the redirect message on the new page slightly clutters it
On the other hand, one may prefer the link title to provide some information that is not in the name of the page one links to, such as the value of a unit in terms of other units. In that case one can make a page whose pagename is the info one wants in the link title, and which redirects to a page with a more appropriate name. See e.g. w:Template:Ft, containing ], with the page w:30.48 cm redirecting to w:Foot (unit of length).
# Automatic conversion of the wikitext
## Pipe trick
If in a piped link the part after the "|" is left empty, it is converted to an abbreviated form of the page name on the left, as follows:
- any namespace prefix (such as "Help:") or an interwiki prefix (such as "commons:") is removed
- if there is text in parentheses at the end it will be removed
- if there are no parentheses but there is a comma, the comma and everything after it is removed
For example:
- ] is converted to ], which is rendered as en:Pipe
- ] is converted to ], which is rendered as Template
- ] is converted to ], which is rendered as Boston.
Just like for the three or four tildes when signing on Talk pages and the use of subst, in a preview, the result already shows up in the preview itself, but the conversion in the edit box is not yet shown. Save and press Edit again to see the result of the conversion.
For links between language versions of Wikipedia and between language versions of Wiktionary, the pipe trick is either not applicable (if the link comes at the edge) or is limited in use because of the starting colon.
In some projects and some cases the pipe trick does not work and the piped link wikitext is not even rendered as a link.
### Examples
produces
- a
- project:a
- project:a
- project:a
- de:project:a
- project:a
- project:a
- project:a
## Inverse pipe trick
On page "A (c)", ] is automatically converted to ].
Similarly, on page "A, c", ] is automatically converted to ].
# Syntax for external links
For external links a space is used instead of a pipe character; see Help:Editing. A general term used for both is also clean link. | Piped link
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
A piped link is a link within the project or to a sister project which is labeled differently from the name of the page it links to. This allows linking a word or phrase within the text of a page rather than using "see also", even if the wording does not exactly correspond with the name of the other page. With a suitable browser and depending on the preferences set, one can still see what page is linked to: when you point at the link, the name shows up in a hover box and is also shown in the status bar.
For instance:
will show: How to set up a coffee house
The term piped refers to the use of the pipe character "|" used to separate the good description from the actual link. This character is named after an alternative use of it; see Pipe (computing).
Another example would be [[train station|station]] rendering as station. This is useful where the word "station" is used in an article on trains; from the context, it would be clear that a train station is meant. The piped link is more convenient to the user than a link to station which is a disambiguation page.
# Using a redirect as an alternative
An alternative is simply using [[How to set up a coffee house]] to create How to set up a coffee house (note that, unlike above, what pops up when you point at the link, if applicable for your browser, is simply the text already shown), and making How to set up a coffee house a redirect page.
This is convenient if the redirect is already there or will also be of use elsewhere; however, there are a few drawbacks:
- the popup does not show the page one will arrive at
- "Related changes" does gives the changes in the redirect page
- the redirect message on the new page slightly clutters it
On the other hand, one may prefer the link title to provide some information that is not in the name of the page one links to, such as the value of a unit in terms of other units. In that case one can make a page whose pagename is the info one wants in the link title, and which redirects to a page with a more appropriate name. See e.g. w:Template:Ft, containing [[30.48 cm|ft]], with the page w:30.48 cm redirecting to w:Foot (unit of length).
# Automatic conversion of the wikitext
## Pipe trick
If in a piped link the part after the "|" is left empty, it is converted to an abbreviated form of the page name on the left, as follows:
- any namespace prefix (such as "Help:") or an interwiki prefix (such as "commons:") is removed
- if there is text in parentheses at the end it will be removed
- if there are no parentheses but there is a comma, the comma and everything after it is removed
For example:
- [[w:en:Pipe (computing)|]] is converted to [[w:en:Pipe (computing)|en:Pipe]], which is rendered as en:Pipe
- [[Help:Template|]] is converted to [[Help:Template|Template]], which is rendered as Template
- [[commons:Boston, Massachusetts|]] is converted to [[commons:Boston, Massachusetts|Boston]], which is rendered as Boston.
Just like for the three or four tildes when signing on Talk pages and the use of subst, in a preview, the result already shows up in the preview itself, but the conversion in the edit box is not yet shown. Save and press Edit again to see the result of the conversion.
For links between language versions of Wikipedia and between language versions of Wiktionary, the pipe trick is either not applicable (if the link comes at the edge) or is limited in use because of the starting colon.
In some projects and some cases the pipe trick does not work and the piped link wikitext is not even rendered as a link.
### Examples
produces
- a
- project:a
- project:a
- project:a
- de:project:a
- project:a
- project:a
- project:a
## Inverse pipe trick
On page "A (c)", [[|b]] is automatically converted to [[b (c)|b]].
Similarly, on page "A, c", [[|b]] is automatically converted to [[b, c|b]].
# Syntax for external links
For external links a space is used instead of a pipe character; see Help:Editing. A general term used for both is also clean link. | https://www.wikidoc.org/index.php/Piped_link | |
a22dfb89590a3cfa51780c8c17ae3c8738e9a253 | wikidoc | Piperazine | Piperazine
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Piperazine is {{{aOrAn}}} {{{drugClass}}} that is FDA approved for the {{{indicationType}}} of {{{indication}}}. Common adverse reactions include {{{adverseReactions}}}.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
There is limited information regarding Piperazine FDA-Labeled Indications and Dosage (Adult) in the drug label.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Piperazine in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Piperazine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Piperazine FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Piperazine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Piperazine in pediatric patients.
# Contraindications
There is limited information regarding Piperazine Contraindications in the drug label.
# Warnings
There is limited information regarding Piperazine Warnings' in the drug label.
# Adverse Reactions
## Clinical Trials Experience
There is limited information regarding Piperazine Clinical Trials Experience in the drug label.
## Postmarketing Experience
There is limited information regarding Piperazine Postmarketing Experience in the drug label.
# Drug Interactions
There is limited information regarding Piperazine Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
There is no FDA guidance on usage of Piperazine in women who are pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Piperazine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Piperazine during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Piperazine in women who are nursing.
### Pediatric Use
There is no FDA guidance on the use of Piperazine in pediatric settings.
### Geriatic Use
There is no FDA guidance on the use of Piperazine in geriatric settings.
### Gender
There is no FDA guidance on the use of Piperazine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Piperazine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Piperazine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Piperazine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Piperazine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Piperazine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Piperazine Administration in the drug label.
### Monitoring
There is limited information regarding Piperazine Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Piperazine and IV administrations.
# Overdosage
There is limited information regarding Piperazine overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
There is limited information regarding Piperazine Mechanism of Action in the drug label.
## Structure
There is limited information regarding Piperazine Structure in the drug label.
## Pharmacodynamics
There is limited information regarding Piperazine Pharmacodynamics in the drug label.
## Pharmacokinetics
There is limited information regarding Piperazine Pharmacokinetics in the drug label.
## Nonclinical Toxicology
There is limited information regarding Piperazine Nonclinical Toxicology in the drug label.
# Clinical Studies
There is limited information regarding Piperazine Clinical Studies in the drug label.
# How Supplied
There is limited information regarding Piperazine How Supplied in the drug label.
## Storage
There is limited information regarding Piperazine Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Piperazine Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Piperazine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
There is limited information regarding Piperazine Brand Names in the drug label.
# Look-Alike Drug Names
There is limited information regarding Piperazine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Piperazine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Piperazine is {{{aOrAn}}} {{{drugClass}}} that is FDA approved for the {{{indicationType}}} of {{{indication}}}. Common adverse reactions include {{{adverseReactions}}}.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
There is limited information regarding Piperazine FDA-Labeled Indications and Dosage (Adult) in the drug label.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Piperazine in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Piperazine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Piperazine FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Piperazine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Piperazine in pediatric patients.
# Contraindications
There is limited information regarding Piperazine Contraindications in the drug label.
# Warnings
There is limited information regarding Piperazine Warnings' in the drug label.
# Adverse Reactions
## Clinical Trials Experience
There is limited information regarding Piperazine Clinical Trials Experience in the drug label.
## Postmarketing Experience
There is limited information regarding Piperazine Postmarketing Experience in the drug label.
# Drug Interactions
There is limited information regarding Piperazine Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
There is no FDA guidance on usage of Piperazine in women who are pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Piperazine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Piperazine during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Piperazine in women who are nursing.
### Pediatric Use
There is no FDA guidance on the use of Piperazine in pediatric settings.
### Geriatic Use
There is no FDA guidance on the use of Piperazine in geriatric settings.
### Gender
There is no FDA guidance on the use of Piperazine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Piperazine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Piperazine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Piperazine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Piperazine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Piperazine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Piperazine Administration in the drug label.
### Monitoring
There is limited information regarding Piperazine Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Piperazine and IV administrations.
# Overdosage
There is limited information regarding Piperazine overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
Template:Chembox new
## Mechanism of Action
There is limited information regarding Piperazine Mechanism of Action in the drug label.
## Structure
There is limited information regarding Piperazine Structure in the drug label.
## Pharmacodynamics
There is limited information regarding Piperazine Pharmacodynamics in the drug label.
## Pharmacokinetics
There is limited information regarding Piperazine Pharmacokinetics in the drug label.
## Nonclinical Toxicology
There is limited information regarding Piperazine Nonclinical Toxicology in the drug label.
# Clinical Studies
There is limited information regarding Piperazine Clinical Studies in the drug label.
# How Supplied
There is limited information regarding Piperazine How Supplied in the drug label.
## Storage
There is limited information regarding Piperazine Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Piperazine Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Piperazine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
There is limited information regarding Piperazine Brand Names in the drug label.
# Look-Alike Drug Names
There is limited information regarding Piperazine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Piperazine | |
15e198b1226584f51cb783d81a7ec084eba33644 | wikidoc | Pirlimycin | Pirlimycin
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
Pirlimycin hydrochloride belongs to the lincosamide class of antimicrobials. It is bacteriostatic and acts by inhibiting bacterial protein synthesis via binding with the 50S subunit of the ribosome. It is frequently used in the treatment of bovine mastitis caused by Gram-positive bacteria, specifically Staphylococcus aureus and coagulase negative species of Staphylococcus and Streptococcus. It has no activity against Gram-negative bacteria. | Pirlimycin
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [1] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
Pirlimycin hydrochloride belongs to the lincosamide class of antimicrobials. It is bacteriostatic and acts by inhibiting bacterial protein synthesis via binding with the 50S subunit of the ribosome. It is frequently used in the treatment of bovine mastitis caused by Gram-positive bacteria, specifically Staphylococcus aureus and coagulase negative species of Staphylococcus and Streptococcus. It has no activity against Gram-negative bacteria.
Template:SIB
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Pirlimycin | |
ffb9d1baa47e643173639851d19a73615a7cf3aa | wikidoc | Pithovirus | Pithovirus
# Overview
Pithovirus is a genus of giant virus known from one species, Pithovirus sibericum, which infects amoebas. It is a double-stranded DNA virus, and is member of the nucleocytoplasmic large DNA viruses clade. It was first described in 2014 after a specimen was revived from a 30,000-year-old ice core harvested from Siberia's permafrost.
# Description
A specimen of Pithovirus measures approximately 1.5 µm in length and 0.5 µm in diameter, making it the largest virus yet found. It is 50% larger than the pandoraviruses, the previous largest known viruses. The species has a thick, oval wall with an opening at one end. Internally, its structure resembles a honeycomb.
The genome of Pithovirus contains approximately 500 distinct genes, more than a typical virus but an order of magnitude less than found in Pandoravirus. Thus, its genome is far less densely packed than any other known virus. Two-thirds of its proteins are unlike those of other viruses. Despite the physical similarity with Pandoravirus, the Pithovirus genome sequence reveals that it is barely related to that virus, but more closely resembles members of Marseilleviridae, Megaviridae and Iridoviridae. These families all contain large icosahedral viruses with DNA genomes. The Pithovirus genome has 36% GC-content, similar to the Megaviridae, in contrast to greater than 61% for pandoraviruses.
## Replication
The viral genome encodes all the proteins needed to produce mRNA; these proteins are present in the purified virions. Pithovirus therefore undergoes its entire replication cycle in its host's cytoplasm, like other large DNA viruses such as poxviruses and the Megaviridae (although unlike Pandoravirus), rather than the more typical method of taking over the host's nucleus.
# Discovery
Pithovirus sibericum was discovered in a 30,000 year old sample of Siberian permafrost by Chantal Abergel and Jean-Michel Claverie of Aix-Marseille University. The virus was discovered buried 30 m (98 ft) below the surface of a late Pleistocene sediment. It was found when riverbank samples harvested in 2000 were exposed to amoebas. The amoebas started dying and when examined were found to contain giant virus specimens. The genus name Pithovirus, a reference to large storage containers of ancient Greece known as pithos, was chosen to describe the new species. The authors said they got the idea to probe permafrost samples for new viruses after reading about an experiment that revived a similar aged seed of Silene stenophylla two years earlier. The Pithovirus findings were published in the Proceedings of the National Academy of Sciences in March 2014.
Although the virus is harmless to humans, its viability after being frozen for millennia has raised concerns that global climate change and tundra drilling operations could lead to previously undiscovered and potentially deadly viruses being unearthed. | Pithovirus
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rim Halaby, M.D. [2]
# Overview
Pithovirus is a genus of giant virus known from one species, Pithovirus sibericum, which infects amoebas.[1][2] It is a double-stranded DNA virus, and is member of the nucleocytoplasmic large DNA viruses clade. It was first described in 2014 after a specimen was revived from a 30,000-year-old ice core harvested from Siberia's permafrost.
# Description
A specimen of Pithovirus measures approximately 1.5 µm in length and 0.5 µm in diameter, making it the largest virus yet found. It is 50% larger than the pandoraviruses, the previous largest known viruses.[3] The species has a thick, oval wall with an opening at one end. Internally, its structure resembles a honeycomb.[1]
The genome of Pithovirus contains approximately 500 distinct genes, more than a typical virus but an order of magnitude less than found in Pandoravirus.[3] Thus, its genome is far less densely packed than any other known virus. Two-thirds of its proteins are unlike those of other viruses. Despite the physical similarity with Pandoravirus, the Pithovirus genome sequence reveals that it is barely related to that virus, but more closely resembles members of Marseilleviridae, Megaviridae and Iridoviridae. These families all contain large icosahedral viruses with DNA genomes. The Pithovirus genome has 36% GC-content, similar to the Megaviridae, in contrast to greater than 61% for pandoraviruses.
## Replication
The viral genome encodes all the proteins needed to produce mRNA; these proteins are present in the purified virions.[4] Pithovirus therefore undergoes its entire replication cycle in its host's cytoplasm, like other large DNA viruses such as poxviruses and the Megaviridae (although unlike Pandoravirus), rather than the more typical method of taking over the host's nucleus.[1][4][5]
# Discovery
Pithovirus sibericum was discovered in a 30,000 year old sample of Siberian permafrost by Chantal Abergel and Jean-Michel Claverie of Aix-Marseille University.[1] The virus was discovered buried 30 m (98 ft) below the surface of a late Pleistocene sediment.[2][4] It was found when riverbank samples harvested in 2000 were exposed to amoebas.[6] The amoebas started dying and when examined were found to contain giant virus specimens. The genus name Pithovirus, a reference to large storage containers of ancient Greece known as pithos, was chosen to describe the new species. The authors said they got the idea to probe permafrost samples for new viruses after reading about an experiment that revived a similar aged seed of Silene stenophylla two years earlier.[1] The Pithovirus findings were published in the Proceedings of the National Academy of Sciences in March 2014.[3]
Although the virus is harmless to humans, its viability after being frozen for millennia has raised concerns that global climate change and tundra drilling operations could lead to previously undiscovered and potentially deadly viruses being unearthed.[3] | https://www.wikidoc.org/index.php/Pithovirus | |
eb0c464a1d96b20ce41ee2ebb0a01c64013b3658 | wikidoc | Pixantrone | Pixantrone
# Overview
Pixantrone (rINN; trade name Pixuvri)
is an experimental antineoplastic (anti-cancer) drug, an analogue of mitoxantrone with fewer toxic effects on cardiac tissue. It acts as a topoisomerase II poison and intercalating agent. The code name BBR 2778 refers to pixantrone dimaleate, the actual substance commonly used in clinical trials.
# History
Anthracyclines are important chemotherapy agents. However, their use is associated with irreversible and cumulative heart damage. Investigators have attempted to design related drugs that maintain the biological activity, but do not possess the cardiotoxicity of the anthracyclines. Pixantrone was developed to reduce heart damage related to treatment while retaining efficacy.
Random screening at the US National Cancer Institute of a vast number of compounds provided by the Allied Chemical Company led to the discovery of ametantrone as having significant anti-tumor activity. Further investigation regarding the rational development of analogs of ametantrone led to the synthesis of mitoxantrone, which also exhibited marked anti-tumor activity Mitoxantrone was considered as an analog of doxorubicin with less structural complexity but with a similar mode of action. In clinical studies, mitoxantrone was shown to be effective against numerous types of tumors with less toxic side effects than those resulting from doxorubicin therapy. However, mitoxantrone was not totally free of cardiotoxicity. A number of structurally modified analogs of mitoxantrone were synthesized and structure-activity relationship studies made. BBR 2778 was originally synthesized by University of Vermont researchers Miles P. Hacker and Paul A. Krapcho and initially characterized in vitro for tumor cell cytotoxicity and mechanism of action by studies at the Boehringer Mannheim Italia Research Center, Monza, and University of Vermont, Burlington. Other studies have been completed at the University of Texas M. D. Anderson Cancer Center, Houston, the Istituto Nazionale Tumori, Milan, and the University of Padua. In the search for novel heteroanalogs of anthracenediones, it was selected as the most promising compound. Toxicological studies indicated that BBR 2778 was not cardiotoxic, and US patents are held by the University of Vermont. An additional US patent application was completed in June 1995 by Boehringer Mannheim, Italy.
Novuspharma, an Italian company, was established in 1998 following the merger of Boehringer Mannheim and Hoffmann-La Roche, and BBR 2778 was developed as Novuspharma's leading anti-cancer drug, pixantrone. A patent application for the injectable preparation was filed in May 2003.
In 2003, Cell Therapeutics, a Seattle biotechnology company, acquired pixantrone through a merger with Novuspharma.
# Clinical trials
Pixantrone is a substance that is being studied in the treatment of cancer. It belongs to the family of drugs called antitumor antibiotics. phase III clinical trials of pixantrone have been completed. Pixantrone is being studied as an antineoplastic for different kinds of cancer, including solid tumors and hematological malignancies such as non-Hodgkin lymphomas.
Animal studies demonstrated that pixantrone does not worsen pre-existing heart muscle damage, suggesting that pixantrone may be useful in patients pretreated with anthracyclines. While only minimal cardiac changes are observed in mice given repeated cycles of pixantrone, 2 cycles of traditional anthracyclines doxorubicin or mitoxantrone result in marked or severe heart muscle degeneragion.
Clinical trials substituting pixantrone for doxorubicin in standard first-line treatment of patients with aggressive non-Hodgkin's lymphoma, had a reduction in severe side effects when compared to patients treated with standard doxorubicin-based therapy. Despite pixantrone patients receiving more treatment cycles, a three-fold reduction in the incidence of severe heart damage was seen as well as clinically significant reductions in infections and thrombocytopenia, and a significant reduction in febrile neutropenia. These findings could have major implications for treating patients with breast cancer, lymphoma, and leukemia, where debilitating cardiac damage from doxorubicin might be prevented. Previous treatment options for multiply relapsed aggressive non-Hodgkin lymphoma had disappointing response rates.
The completed phase II RAPID trial compared the CHOP-R regimen of Cyclophosphamide, Doxorubicin, Vincristine, Prednisone, and Rituximab to the same regimen, but substituting Doxorubicin with Pixantrone. The objective was to show that Pixantrone was not inferior to Doxorubicin and less toxic to the heart.
Pixantrone was shown to have potentially reduced cardiotoxicity and demonstrated promising clinical activity in these phase II studies in heavily pretreated non-Hodgkin lymphoma patients.
The pivotal phase III EXTEND (PIX301) randomized clinical trial studied pixantrone to see how well it works compared to other chemotherapy drugs in treating patients with relapsed non-Hodgkin's lymphoma. The complete response rate in patients treated with pixantrone has been significantly higher than in those receiving other chemotherapeutic agents for treatment of relapsed/refractory aggressive non-Hodgkin lymphoma.
# Administration
It can be administered through a peripheral vein rather than a central implanted catheter as required for other similar drugs.
# Regulatory approval
## U.S. Food and Drug Administration
The FDA granted fast track designation for pixantrone in patients who had previously been treated two or more times for relapsed or refractory aggressive NHL. Study sponsor Cell Therapeutics announced that Pixantrone achieved the primary efficacy endpoint. The minutes of the Oncologic Drugs Advisory Committee meeting of March 22, 2010 show that this had not in fact been achieved with statistical significance and this combined with major safety concerns lead to the conclusion that the trial was not sufficient to support approval. In April 2010 the FDA asked for an additional trial.
## European Medicines Agency
On May 5, 2009, Pixantrone became available in Europe on a Named-Patient Basis. A named-patient program is a compassionate use drug supply program under which physicians can legally supply investigational drugs to qualifying patients. Under a named-patient program, investigational drugs can be administered to patients who are suffering from serious illnesses prior to the drug being approved by the European Medicines Evaluation Agency. "Named-patient" distribution refers to the distribution or sale of a product to a specific healthcare professional for the treatment of an individual patient. In Europe, under the named-patient program the drug is most often purchased through the national health system.
In 2012 pixantrone received conditional marketing authorization in the European Union as Monotherapy to Treat Adult Patients with Multiply Relapsed or Refractory Aggressive Non-Hodgkin B-Cell Lymphomas.
# Research
Pixantrone is as potent as mitoxantrone in animal models of multiple sclerosis. Pixantrone has a similar mechanism of action as mitoxantrone on the effector function of lymphomonocyte B and T cells in experimental allergic encephalomyelitis but with lower cardiotoxicity. Pixantrone inhibits antigen specific and mitogen induced lymphomononuclear cell proliferation, as well as IFN-gamma production. Clinical trials are currently ongoing in Europe.
Pixantrone also reduces the severity of experimental autoimmune myasthenia gravis in Lewis rats, and in vitro cell viability experiments indicated that Pixantrone significantly reduces amyloid beta (A beta(1-42)) neurotoxicity, a mechanism implicated in Alzheimer's disease. | Pixantrone
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Pixantrone (rINN; trade name Pixuvri)
is an experimental antineoplastic (anti-cancer) drug, an analogue of mitoxantrone with fewer toxic effects on cardiac tissue.[1] It acts as a topoisomerase II poison and intercalating agent.[2][3] The code name BBR 2778 refers to pixantrone dimaleate, the actual substance commonly used in clinical trials.[4]
# History
Anthracyclines are important chemotherapy agents. However, their use is associated with irreversible and cumulative heart damage. Investigators have attempted to design related drugs that maintain the biological activity, but do not possess the cardiotoxicity of the anthracyclines.[5] Pixantrone was developed to reduce heart damage related to treatment while retaining efficacy.[1]
Random screening at the US National Cancer Institute of a vast number of compounds provided by the Allied Chemical Company led to the discovery of ametantrone as having significant anti-tumor activity. Further investigation regarding the rational development of analogs of ametantrone led to the synthesis of mitoxantrone, which also exhibited marked anti-tumor activity[5] Mitoxantrone was considered as an analog of doxorubicin with less structural complexity but with a similar mode of action. In clinical studies, mitoxantrone was shown to be effective against numerous types of tumors with less toxic side effects than those resulting from doxorubicin therapy. However, mitoxantrone was not totally free of cardiotoxicity. A number of structurally modified analogs of mitoxantrone were synthesized and structure-activity relationship studies made.[5] BBR 2778 was originally synthesized by University of Vermont researchers Miles P. Hacker and Paul A. Krapcho[5] and initially characterized in vitro for tumor cell cytotoxicity and mechanism of action by studies at the Boehringer Mannheim Italia Research Center, Monza, and University of Vermont, Burlington.[4] Other studies have been completed at the University of Texas M. D. Anderson Cancer Center, Houston, the Istituto Nazionale Tumori, Milan, and the University of Padua.[2][6][4] In the search for novel heteroanalogs of anthracenediones, it was selected as the most promising compound. Toxicological studies indicated that BBR 2778 was not cardiotoxic, and US patents are held by the University of Vermont. An additional US patent application was completed in June 1995 by Boehringer Mannheim, Italy.[5]
Novuspharma, an Italian company, was established in 1998 following the merger of Boehringer Mannheim and Hoffmann-La Roche, and BBR 2778 was developed as Novuspharma's leading anti-cancer drug, pixantrone.[7] A patent application for the injectable preparation was filed in May 2003.[8]
In 2003, Cell Therapeutics, a Seattle biotechnology company, acquired pixantrone through a merger with Novuspharma.[9]
# Clinical trials
Pixantrone is a substance that is being studied in the treatment of cancer. It belongs to the family of drugs called antitumor antibiotics.[10] phase III clinical trials of pixantrone have been completed.[11][12] Pixantrone is being studied as an antineoplastic for different kinds of cancer, including solid tumors and hematological malignancies such as non-Hodgkin lymphomas.
Animal studies demonstrated that pixantrone does not worsen pre-existing heart muscle damage, suggesting that pixantrone may be useful in patients pretreated with anthracyclines. While only minimal cardiac changes are observed in mice given repeated cycles of pixantrone, 2 cycles of traditional anthracyclines doxorubicin or mitoxantrone result in marked or severe heart muscle degeneragion.[1]
Clinical trials substituting pixantrone for doxorubicin in standard first-line treatment of patients with aggressive non-Hodgkin's lymphoma, had a reduction in severe side effects when compared to patients treated with standard doxorubicin-based therapy. Despite pixantrone patients receiving more treatment cycles, a three-fold reduction in the incidence of severe heart damage was seen as well as clinically significant reductions in infections and thrombocytopenia, and a significant reduction in febrile neutropenia. These findings could have major implications for treating patients with breast cancer, lymphoma, and leukemia, where debilitating cardiac damage from doxorubicin might be prevented.[13] Previous treatment options for multiply relapsed aggressive non-Hodgkin lymphoma had disappointing response rates.[14]
The completed phase II RAPID trial compared the CHOP-R regimen of Cyclophosphamide, Doxorubicin, Vincristine, Prednisone, and Rituximab to the same regimen, but substituting Doxorubicin with Pixantrone. The objective was to show that Pixantrone was not inferior to Doxorubicin and less toxic to the heart.[15]
Pixantrone was shown to have potentially reduced cardiotoxicity and demonstrated promising clinical activity in these phase II studies in heavily pretreated non-Hodgkin lymphoma patients.[14]
The pivotal phase III EXTEND (PIX301) randomized clinical trial studied pixantrone to see how well it works compared to other chemotherapy drugs in treating patients with relapsed non-Hodgkin's lymphoma.[16] The complete response rate in patients treated with pixantrone has been significantly higher than in those receiving other chemotherapeutic agents for treatment of relapsed/refractory aggressive non-Hodgkin lymphoma.[14]
# Administration
It can be administered through a peripheral vein rather than a central implanted catheter as required for other similar drugs.[8][14]
# Regulatory approval
## U.S. Food and Drug Administration
The FDA granted fast track designation for pixantrone in patients who had previously been treated two or more times for relapsed or refractory aggressive NHL. Study sponsor Cell Therapeutics announced that Pixantrone achieved the primary efficacy endpoint. The minutes of the Oncologic Drugs Advisory Committee meeting of March 22, 2010[17] show that this had not in fact been achieved with statistical significance and this combined with major safety concerns lead to the conclusion that the trial was not sufficient to support approval. In April 2010 the FDA asked for an additional trial.[18]
## European Medicines Agency
On May 5, 2009, Pixantrone became available in Europe on a Named-Patient Basis. A named-patient program is a compassionate use drug supply program under which physicians can legally supply investigational drugs to qualifying patients. Under a named-patient program, investigational drugs can be administered to patients who are suffering from serious illnesses prior to the drug being approved by the European Medicines Evaluation Agency. "Named-patient" distribution refers to the distribution or sale of a product to a specific healthcare professional for the treatment of an individual patient. In Europe, under the named-patient program the drug is most often purchased through the national health system.[19]
In 2012 pixantrone received conditional marketing authorization in the European Union as Monotherapy to Treat Adult Patients with Multiply Relapsed or Refractory Aggressive Non-Hodgkin B-Cell Lymphomas.
# Research
Pixantrone is as potent as mitoxantrone in animal models of multiple sclerosis.[20] Pixantrone has a similar mechanism of action as mitoxantrone on the effector function of lymphomonocyte B and T cells in experimental allergic encephalomyelitis but with lower cardiotoxicity. Pixantrone inhibits antigen specific and mitogen induced lymphomononuclear cell proliferation, as well as IFN-gamma production.[21] Clinical trials are currently ongoing in Europe.
Pixantrone also reduces the severity of experimental autoimmune myasthenia gravis in Lewis rats,[22] and in vitro cell viability experiments indicated that Pixantrone significantly reduces amyloid beta (A beta(1-42)) neurotoxicity, a mechanism implicated in Alzheimer's disease.[23] | https://www.wikidoc.org/index.php/Pixantrone | |
bb48ed4fab7342e59f448084a8d3669227c1b771 | wikidoc | Place cell | Place cell
Place cells are principal neurons in the hippocampus that fire strongly whenever an animal is in a specific location in an environment corresponding to the cell's "place field". These neurons are distinct from other neurons with spatial firing properties, such as grid cells, head direction cells, and spatial view cells. In the CA1 and CA3 hippocampal subfields, place cells are believed to be pyramidal cells, while those in the dentate gyrus are believed to be granule cells.
Place cells were first described in rats by O'Keefe and Dostrovsky. Based on this discovery, O'Keefe and Nadel hypothesized that the primary function of the rat hippocampus is to form a cognitive map of the rat's environment. Ekstrom and colleagues have found cells with similar properties in the human hippocampus, using extracellular recordings from epilepsy patients undergoing invasive monitoring of their brain activity.
# Place fields
Place cells show increased frequency of firing when an animal is in a specific area referred to as the cell's place field. The firing rate increase can be quite dramatic, from virtually zero outside the field to as much as 100 Hz (for brief periods) in the middle of the place field. When a rat forages randomly in an environment, place fields are only weakly modulated by the direction the rat faces, or not at all. However, when an animal engages in stereotyped behaviour (e.g. shuttling between goal locations), place cells tend to be active in the place field on passes in one direction only.
On initial exposure to a new environment, place fields become established within minutes. The place fields of cells tend to be stable over repeated exposures to the same environment. In a different environment, however, a cell may have a completely different place field or no place field at all. This phenomenon is referred to as "remapping". In any particular environment, roughly 40-50% of the hippocampal place cells will be active.
In an environment with few or no directional cues (for instance, a circular environment surrounded by black curtains), place fields will tend to have a fixed radial position, but the entire set of place fields may rotate around the maze as predicted by a theory that rats are slowly losing their orientation. If a polarizing cue is introduced (commonly a large white rectangle of paper), place fields will tend to have fixed positions relative to the cue. If the cue is moved while the animal can see it, place fields will tend to remain unaffected; however, if the animal is briefly removed from the environment then the cue is moved and the animal returned, the place fields will rotate so as to maintain their position relative to the cue card. Although visual cues seem to be the primary determinant of place cell firing, it is worth noting that firing persists in the dark, suggesting that proprioception or other senses contribute as well.
In an environment in which a rat is constrained to walk along a linear track, place fields will often have a directional component in addition to a place component. A place cell that fires at a particular location while the rat walks in one direction along the track will not necessarily fire as the rat visits that location from the other direction. If the rat frequently turns around at the same point, however, place fields there will often be independent of direction.
The size of place fields and their signal to noise ratio varies depending on the region of brain in consideration. In the hippocampus, place fields are smallest and sharpest at the dorsal pole, becoming larger toward the ventral pole. This may reflect the topography of projections to the hippocampus. For example, the ventral hippocampus receives much more input from the amygdala, while dorsal hippocampus is more preferentially innervated by entorhinal cortex.
Spatial modulated cells are also found in the entorhinal cortex, which feed input from neocortex into the hippocampus. Neurons in the lateral entorhinal cortex exhibit little spatial selectivity, while neurons of the medial entorhinal (MEA) cortex exhibit multiple "place fields" that are arranged in an hexagonal pattern, and are therefore called "grid cells". These fields and spacing between fields increase from the dorso-lateral MEA to the ventro-medial MEA
# Phase Precession
The hippocampus is one of many brain structures that can show a characteristic 4-12 Hz oscillation, theta rhythm, in an EEG recording. The oscillation has been observed in all mammalian species tested. In both rats and humans, it is associated with real or virtual movement through space.
When a neuron discharges, it can be said to fire in relation to the current phase of a theta cycle (0-360 degrees). When a rat enters a cell's place field, the cell will initially discharge when perisomatic inhibition is weakest. For theta recorded in the CA1 pyramidal cell layer, this approximately corresponds with the peak of the oscillation. On each following cycle as the rat progresses through the field, the cell will discharge at earlier and earlier phases, typically stopping just before the trough of the cycle (as recorded in CA1 stratum pyramidale). In other words, the place cell produces a rhythmic discharge of a slightly higher frequency than the ongoing theta oscillation.
Because place fields of different cells overlap, at any particular time the rat will be at different distances in different fields, so each place cell will fire at a different phase of theta, allowing the rat's position to be determined with good precision. This potentially provides an alternative temporal code for location. Phase precession also results in the compression of temporal sequences of place cell firing - a phenomenon believed to facilitate synaptic plasticity. There is evidence that phase precession is related to depolarisation of the neuron, such that the firing rate and firing phase of the cell are tightly coupled,. However, phase precession can also be robustly independent of firing rate in freely moving animals This caveat of phase precession, which alludes to the potential neural mechanisms underlying it, requires further investigation before arriving at a definitive answer. | Place cell
Template:Infobox neuron
Place cells are principal neurons in the hippocampus that fire strongly whenever an animal is in a specific location in an environment corresponding to the cell's "place field". These neurons are distinct from other neurons with spatial firing properties, such as grid cells, head direction cells, and spatial view cells. In the CA1 and CA3 hippocampal subfields, place cells are believed to be pyramidal cells, while those in the dentate gyrus are believed to be granule cells.
Place cells were first described in rats by O'Keefe and Dostrovsky.[1] Based on this discovery, O'Keefe and Nadel hypothesized that the primary function of the rat hippocampus is to form a cognitive map of the rat's environment.[2] Ekstrom and colleagues have found cells with similar properties in the human hippocampus, using extracellular recordings from epilepsy patients undergoing invasive monitoring of their brain activity. [3]
# Place fields
Place cells show increased frequency of firing when an animal is in a specific area referred to as the cell's place field. The firing rate increase can be quite dramatic, from virtually zero outside the field to as much as 100 Hz (for brief periods) in the middle of the place field. When a rat forages randomly in an environment, place fields are only weakly modulated by the direction the rat faces, or not at all. However, when an animal engages in stereotyped behaviour (e.g. shuttling between goal locations), place cells tend to be active in the place field on passes in one direction only[4].
On initial exposure to a new environment, place fields become established within minutes. The place fields of cells tend to be stable over repeated exposures to the same environment. In a different environment, however, a cell may have a completely different place field or no place field at all. This phenomenon is referred to as "remapping". In any particular environment, roughly 40-50% of the hippocampal place cells will be active.[5][6]
In an environment with few or no directional cues (for instance, a circular environment surrounded by black curtains), place fields will tend to have a fixed radial position, but the entire set of place fields may rotate around the maze as predicted by a theory that rats are slowly losing their orientation.[7] If a polarizing cue is introduced (commonly a large white rectangle of paper), place fields will tend to have fixed positions relative to the cue. If the cue is moved while the animal can see it, place fields will tend to remain unaffected; however, if the animal is briefly removed from the environment then the cue is moved and the animal returned, the place fields will rotate so as to maintain their position relative to the cue card. Although visual cues seem to be the primary determinant of place cell firing, it is worth noting that firing persists in the dark, suggesting that proprioception or other senses contribute as well.
In an environment in which a rat is constrained to walk along a linear track, place fields will often have a directional component in addition to a place component. A place cell that fires at a particular location while the rat walks in one direction along the track will not necessarily fire as the rat visits that location from the other direction. If the rat frequently turns around at the same point, however, place fields there will often be independent of direction.
The size of place fields and their signal to noise ratio varies depending on the region of brain in consideration. In the hippocampus, place fields are smallest and sharpest at the dorsal pole, becoming larger toward the ventral pole.[8] This may reflect the topography of projections to the hippocampus. For example, the ventral hippocampus receives much more input from the amygdala, while dorsal hippocampus is more preferentially innervated by entorhinal cortex.
Spatial modulated cells are also found in the entorhinal cortex, which feed input from neocortex into the hippocampus. Neurons in the lateral entorhinal cortex exhibit little spatial selectivity,[9] while neurons of the medial entorhinal (MEA) cortex exhibit multiple "place fields" that are arranged in an hexagonal pattern, and are therefore called "grid cells". These fields and spacing between fields increase from the dorso-lateral MEA to the ventro-medial MEA[10][11]
# Phase Precession
The hippocampus is one of many brain structures that can show a characteristic 4-12 Hz oscillation, theta rhythm, in an EEG recording. The oscillation has been observed in all mammalian species tested. In both rats and humans, it is associated with real or virtual movement through space.
When a neuron discharges, it can be said to fire in relation to the current phase of a theta cycle (0-360 degrees). When a rat enters a cell's place field, the cell will initially discharge when perisomatic inhibition is weakest. For theta recorded in the CA1 pyramidal cell layer, this approximately corresponds with the peak of the oscillation. On each following cycle as the rat progresses through the field, the cell will discharge at earlier and earlier phases,[12] typically stopping just before the trough of the cycle (as recorded in CA1 stratum pyramidale). In other words, the place cell produces a rhythmic discharge of a slightly higher frequency than the ongoing theta oscillation.
Because place fields of different cells overlap, at any particular time the rat will be at different distances in different fields, so each place cell will fire at a different phase of theta, allowing the rat's position to be determined with good precision. This potentially provides an alternative temporal code for location. Phase precession also results in the compression of temporal sequences of place cell firing - a phenomenon believed to facilitate synaptic plasticity.[13] There is evidence that phase precession is related to depolarisation of the neuron, such that the firing rate and firing phase of the cell are tightly coupled,[14].[15] However, phase precession can also be robustly independent of firing rate in freely moving animals[16] This caveat of phase precession, which alludes to the potential neural mechanisms underlying it, requires further investigation before arriving at a definitive answer. | https://www.wikidoc.org/index.php/Place_cell | |
43ab5e11577f5be4591842db066138ad892de8b5 | wikidoc | Plasticity | Plasticity
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
# Overview
Plasticity generally means ability to permanently change or deform. (It differs from "elasticity", which refers to ability to change temporarily and revert back to original form.)
More specific meanings include:
in the sciences:
- Phenotypic plasticity: Describes the degree to which an organism's phenotype is determined by its genotype.
- Neuroplasticity: Entire brain structures can change to better cope with the environment. Specifically, when an area of the brain is damaged and non-functional, another area may take over some of the function. This is known as neuroplasticity.
Synaptic plasticity: In neuroscience, plasticity is a property of a neuron or synapse to change its internal parameters in response to its history.
- Synaptic plasticity: In neuroscience, plasticity is a property of a neuron or synapse to change its internal parameters in response to its history.
- Plasticity (tissues): In body tissues, plasticity refers to the ability of differentiated cells to undergo transdifferentiation.
ur:لدونت
de:Umformbarkeit | Plasticity
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [1] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]
# Overview
Plasticity generally means ability to permanently change or deform. (It differs from "elasticity", which refers to ability to change temporarily and revert back to original form.)
More specific meanings include:
in the sciences:
- Phenotypic plasticity: Describes the degree to which an organism's phenotype is determined by its genotype.
- Neuroplasticity: Entire brain structures can change to better cope with the environment. Specifically, when an area of the brain is damaged and non-functional, another area may take over some of the function. This is known as neuroplasticity.
Synaptic plasticity: In neuroscience, plasticity is a property of a neuron or synapse to change its internal parameters in response to its history.
- Synaptic plasticity: In neuroscience, plasticity is a property of a neuron or synapse to change its internal parameters in response to its history.
- Plasticity (tissues): In body tissues, plasticity refers to the ability of differentiated cells to undergo transdifferentiation.
ur:لدونت
de:Umformbarkeit | https://www.wikidoc.org/index.php/Plasticity | |
f4e3482edab6196862efcfa3511488dfd835cbc6 | wikidoc | Platinosis | Platinosis
# Overview
Platinosis is an allergy-like reaction to exposure to soluble salts of platinum.
The symptoms of platinosis may include asthma, dermatitis, dyspnea, conjunctival vasodilatation, and rhinopharyngitis.
The symptoms are progressive, sometimes taking months to years to appear. Platinosis is usually associated with workers in industries related to platinum production.
The effects are permanent.
Halogeno-platinum compounds are among the most potent respiratory and skin sensitisers known, therefore it is vital that exposure via the skin and by breathing contaminated air is carefully controlled.
In practice, the compounds mainly responsible for platinum sensitisation are typically the soluble, ionic, platinum-chloro compounds such as ammonium hexachloroplatinate and tetrachloroplatinate, and hexachloroplatinic acid. Other ionic halogeno compounds are also sensitisers, the order of allergenicity being Cl > Br > I.
Neutral compounds such as cis-platin and ammine and nitro complexes such as Cl2, K2 and platinum nitrate are not considered to be allergenic; neither is the metal. | Platinosis
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Platinosis is an allergy-like reaction to exposure to soluble salts of platinum.
The symptoms of platinosis may include asthma, dermatitis, dyspnea, conjunctival vasodilatation, and rhinopharyngitis.
The symptoms are progressive, sometimes taking months to years to appear. Platinosis is usually associated with workers in industries related to platinum production.
The effects are permanent.
Halogeno-platinum compounds are among the most potent respiratory and skin sensitisers known, therefore it is vital that exposure via the skin and by breathing contaminated air is carefully controlled.
In practice, the compounds mainly responsible for platinum sensitisation are typically the soluble, ionic, platinum-chloro compounds such as ammonium hexachloroplatinate and tetrachloroplatinate, and hexachloroplatinic acid. Other ionic halogeno compounds are also sensitisers, the order of allergenicity being Cl > Br > I.
Neutral compounds such as cis-platin and ammine and nitro complexes such as [Pt(NH3)4]Cl2, K2[Pt(NO2)4] and platinum nitrate are not considered to be allergenic; neither is the metal. | https://www.wikidoc.org/index.php/Platinosis | |
4105a0af70042ce1536ab26b1b5317ac676021ee | wikidoc | Plazomicin | Plazomicin
# Disclaimer
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# Black Box Warning
# Overview
Plazomicin is an aminoglycoside antibacterial that is FDA approved for the treatment of patients 18 years of age or older with Complicated Urinary Tract Infections (cUTI) including Pyelonephritis. There is a Black Box Warning for this drug as shown here. Common adverse reactions include decreased renal function, diarrhea, hypertension, headache, nausea, vomiting and hypotension.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Indication
- Plazomicin is indicated in patients 18 years of age or older for the treatment of complicated urinary tract infections (cUTI), including pyelonephritis caused by the following susceptible microorganism(s): Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and Enterobacter cloacae.
- As only limited clinical safety and efficacy data for plazomicin are currently available, reserve plazomicin for use in cUTI patients who have limited or no alternative treatment options.
- To reduce the development of drug-resistant bacteria and maintain the effectiveness of plazomicin and other antibacterial drugs, plazomicin should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.
Dosage
- Administer plazomicin 15 mg/kg every 24 hours by intravenous (IV) infusion over 30 minutes to patients 18 years of age or older with creatinine clearance greater than or equal to 90 mL/min.
- Recommended duration of treatment is 4 to 7 days for cUTI, including pyelonephritis.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding plazomicin Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding plazomicin Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- The safety and effectiveness of plazomicin in patients less than 18 years of age have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding plazomicin Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding plazomicin Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
- Plazomicin is contraindicated in patients with known hypersensitivity to any aminoglycoside.
# Warnings
- Nephrotoxicity has been reported with the use of plazomicin. Most serum creatinine increases were ≤ 1 mg/dL above baseline and reversible.
- In Trial 1, the incidence of adverse reactions associated with renal function (acute kidney injury, serum creatinine increased, chronic kidney disease, creatinine clearance decreased, renal failure, renal impairment) was 3.6% (11/303) in plazomicin-treated patients compared with 1.3% (4/301) in meropenem-treated patients.
- Serum creatinine increases of 0.5 mg/dL or greater above baseline occurred in 7% (21/300) of plazomicin-treated patients compared with 4% (12/297) of meropenem-treated patients. These increases mainly occurred in patients with CLcr ≤ 90 mL/min and were associated with a plazomicin trough level (Cmin) greater than or equal to 3 mcg/mL.
- Assess CLcr in all patients prior to initiating therapy and daily during therapy with plazomicin, particularly in those at increased risk of nephrotoxicity, such as those with renal impairment, the elderly, and those receiving concomitant potentially nephrotoxic medications. In the setting of worsening renal function, the benefit of continuing plazomicin should be assessed.
- Adjust the initial dosage regimen in cUTI patients with CLcr ≥ 15 mL/min and < 60 mL/min. For subsequent doses, TDM is recommended for patients with CLcr ≥15 mL/min and < 90 mL/min.
- Ototoxicity, manifested as hearing loss, tinnitus, and/or vertigo, has been reported with plazomicin. Symptoms of aminoglycoside-associated ototoxicity may be irreversible and may not become evident until after completion of therapy.
- Regarding the incidence of adverse reactions associated with cochlear or vestibular function, in Trial 1, there was one case of reversible hypoacusis (1/303;0.3%) in plazomicin-treated patients and one case of tinnitus (1/301;0.3%) in meropenem-treated patients. In Trial 2, one case each of irreversible tinnitus and reversible vertigo was reported in plazomicin-treated patients, and one case of an abnormal audiogram occurred in a levofloxacin-treated patient.
- Aminoglycoside-associated ototoxicity has been observed primarily in patients with a family history of hearing loss (excluding age-related hearing loss), patients with renal impairment, and in patients receiving higher doses and/or for longer periods than recommended. In Trial 1 and Trial 2, patients with a history of hearing loss, with the exception of age-related hearing loss, were excluded. The benefit-risk of plazomicin therapy should be considered in these patients.
- Aminoglycosides have been associated with exacerbation of muscle weakness in patients with underlying neuromuscular disorders, or delay in recovery of neuromuscular function in patients receiving concomitant neuromuscular blocking agents.
- During therapy with plazomicin, monitor for adverse reactions associated with neuromuscular blockade, particularly in high-risk patients, such as patients with underlying neuromuscular disorders (including myasthenia gravis) or those patients concomitantly receiving neuromuscular blocking agents.
- Aminoglycosides, including plazomicin, can cause fetal harm when administered to a pregnant woman. Aminoglycosides cross the placenta, and streptomycin has been associated with several reports of total, irreversible, bilateral congenital deafness in pediatric patients exposed in utero. Patients who use plazomicin during pregnancy, or become pregnant while taking plazomicin should be apprised of the potential hazard to the fetus.
- Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving aminoglycoside antibacterial drugs. Before therapy with plazomicin is instituted, careful inquiry about previous hypersensitivity reactions to other aminoglycosides should be made. A history of hypersensitivity to other aminoglycosides is a contraindication to the use of plazomicin, because cross-sensitivity among aminoglycoside antibacterial drugs has been established. Discontinue plazomicin if an allergic reaction occurs.
- Clostridium difficile-associated diarrhea (CDAD) has been reported for nearly all systemic antibacterial drugs and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial drugs alters the normal flora of the colon and may permit overgrowth of C. difficile.
- C. difficile produces toxins A and B that contribute to the development of CDAD. Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary because CDAD has been reported to occur more than 2 months after the administration of antibacterial drugs.
- If CDAD is suspected or confirmed, antibacterial drugs not directed against C. difficile may need to be discontinued. Manage fluid and electrolyte levels as appropriate, supplement protein intake, monitor antibacterial treatment of C. difficile, and institute surgical evaluation as clinically indicated.
- Prescribing plazomicin in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be compared directly to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- Plazomicin was evaluated in two comparator-controlled clinical trials (Trial 1, NCT02486627 and Trial 2, NCT01096849) in patients with cUTI, including pyelonephritis. In both trials, patients with CLcr greater than 60 mL/min received plazomicin 15 mg/kg IV once daily as a 30-minute infusion.
- Trial 1 included 303 patients treated with plazomicin and 301 patients treated with meropenem. Patients were to receive 4 to 7 days of plazomicin (mean duration of 5.1 days). In some patients, parenteral therapy was followed by a switch to an oral antibacterial drug.
- The median age of patients treated with plazomicin in Trial 1 was 62 years (range 18 to 90 years) and 45.2% of patients were 65 years of age or older. Patients treated with plazomicin were predominantly female (56.1%) and White (99.3%). A majority of patients (68.0%) had mild or moderate renal impairment (CLcr >30 to 90 mL/min) at baseline. Patients with CLcr of 30 mL/min or less were excluded.
Adverse Reactions Leading to Treatment Discontinuations in Trial 1
- In Trial 1, treatment discontinuation from IV study drug due to an adverse reaction occurred in 2.0% of patients receiving plazomicin (6/303) and meropenem (6/301), respectively.
Common Adverse Reactions in Trial 1
- Table 3 lists adverse reactions occurring in 1% or more of patients receiving plazomicin in Trial 1.
- The adverse reactions profile for the cUTI patients in Trial 2 were similar to those observed in Trial 1.
Nephrotoxicity Reported in Trial 1
- In Trial 1, serum creatinine increases of 0.5 mg/dL or greater above baseline occurred in 7.0% (21/300) of plazomicin-treated patients compared with 4.0% (12/297) of meropenem-treated patients. Of these, the incidence during IV therapy was 3.7% (11/300) vs 3.0% (9/297) in plazomicin- and meropenem-treated patients, respectively. By the last follow-up visit (between 8 to 43 days after completion of IV therapy), the majority of plazomicin-treated patients (9/11) and all meropenem treated patients (9/9) with serum creatinine increases while on therapy had fully recovered renal function. Serum creatinine increases of 0.5 mg/dL or greater above baseline were observed following completion of IV therapy. These increases were generally ≤ 1.0 mg/dL above baseline and recovered by the next measurement.
- In cUTI patients with CLcr of greater than 30 and less than or equal to 90 mL/min, 9.7% (20/207) plazomicin-treated and 4.1% (9/217) meropenem-treated patients had serum creatinine increases of 0.5 mg/dL or greater above baseline. In cUTI patients with CLcr greater than 90 mL/min, 1.1% (1/93) plazomicin-treated and 3.8% (3/80) of meropenem-treated patients had serum creatinine increases of 0.5 mg/dL or greater above baseline.
Ototoxicity
- Pure tone audiometry was evaluated in Phase 1 trials and in Trial 2. Treatment associated ototoxicity could not be definitively excluded according to the American Speech-Language-Hearing Association criteria1 in 2.2% (4/182) of plazomicin-exposed and 2.0% (1/49) of comparator- or placebo-exposed adults.
Other Adverse Reactions Reported with plazomicin
- The following selected adverse reactions were reported in more than one plazomicin-treated patient in Trials 1 and 2 and are not described elsewhere in the labeling:
Gastrointestinal disorders: constipation, gastritis
Laboratory Investigations: alanine aminotransferase increased
Metabolism and nutrition disorders: hypokalemia
Nervous system disorders: dizziness
Renal and urinary disorders: hematuria
Respiratory, thoracic and mediastinal disorders: dyspnea
- Gastrointestinal disorders: constipation, gastritis
- Laboratory Investigations: alanine aminotransferase increased
- Metabolism and nutrition disorders: hypokalemia
- Nervous system disorders: dizziness
- Renal and urinary disorders: hematuria
- Respiratory, thoracic and mediastinal disorders: dyspnea
## Postmarketing Experience
There is limited information regarding Plazomicin Postmarketing Experience in the drug label.
# Drug Interactions
There is limited information regarding Plazomicin Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Risk Summary
- Aminoglycosides, including plazomicin, can cause fetal harm when administered to a pregnant woman. There are no available data on the use of plazomicin in pregnant women to inform a drug associated risk of adverse developmental outcomes. Published literature reports of streptomycin, an aminoglycoside, state that it can cause total, irreversible, bilateral congenital deafness in children whose mothers received streptomycin during pregnancy. No drug-related visceral or skeletal malformations were observed in pregnant rats and rabbits administered subcutaneous plazomicin during organogenesis at maternal exposures approximately 0.8-fold (rats) and 2.5-fold (rabbits) of the human AUC at the clinical dose of 15 mg/kg/day. Auditory function of offspring was not measured in animal studies. Advise pregnant women of the potential risk to a fetus.
- The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Animal Data
- In an embryo-fetal development study in rats, plazomicin doses of 0, 8, 25, or 50 mg/kg/day administered subcutaneously during organogenesis did not cause drug-related visceral or skeletal malformations, or reduce survival of fetuses. The mid and high doses caused maternal toxicity (reductions in food consumption and body weight gain; increased kidney weight). The high dose resulted in maternal exposure (AUC) approximately 0.8-fold the human AUC at the clinical dose of 15 mg/kg once daily.
- In an embryo-fetal development study in rabbits, plazomicin administered subcutaneously at doses of 0, 10, 30, or 50 mg/kg/day did not cause visceral or skeletal malformations or reduced fetal survival. At the high dose, significant maternal toxicity was observed (including renal injury and lethality) and exposure was approximately 2.5-fold the human AUC at the recommended clinical dose.
- In a pre- and postnatal development study in rats, maternal animals received subcutaneous plazomicin at 0, 3, 8, or 30 mg/kg/day from the start of organogenesis through lactation. There were no adverse effects on maternal function or pre- and postnatal survival, development, behavior, or reproductive function of the offspring at up to 30 mg/kg/day (0.32-fold human AUC at the clinical daily dose of 15 mg/kg).
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Plazomicin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Plazomicin during labor and delivery.
### Nursing Mothers
Risk Summary
- There are no data on the presence of plazomicin in human milk, the effects on the breastfed infant, or the effects on milk production. Plazomicin was detected in rat milk (see DATA). The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for plazomicin and any potential adverse effects on the breastfed infant from plazomicin or from the underlying maternal condition.
Data
- In a pre- and postnatal development study in rats, low concentrations of plazomicin in maternal milk were detected, with mean concentrations representing 2% to 4% of maternal plasma concentrations. In nursing pups, the systemic exposure (AUC) to plazomicin through lactational exposure was approximately 0.04% of maternal systemic exposure.
### Pediatric Use
- The safety and effectiveness of plazomicin in patients less than 18 years of age have not been established.
### Geriatic Use
- Of the 425 patients treated with plazomicin in Trials 1 and 2, 40% (170/425) were 65 years of age and older, including 17.2% (73/425) patients 75 years of age and older. In Trial 1, for plazomicin- treated patients ≥ 65 years old, the incidence rate of adverse reactions was 27% (37/137) versus 18.9% (27/143) in the meropenem-treated patients ≥ 65 years old. For plazomicin- treated patients < 65 years old, the incidence rate of adverse reactions was 13.3% (22/166) versus 24.1% (38/158) in the meropenem-treated patients < 65 years old.
- The rate of adverse reactions associated with renal function for the plazomicin-treated patients ≥ 65 years old was 6.6% (9/137) versus 2.8% (4/143) in the meropenem-treated patients. For plazomicin- treated patients < 65 years old, the incidence rate of adverse reactions associated with renal function was 1.2% (2/166), versus 0% (0/158) in the meropenem-treated patients.
- Plazomicin is substantially excreted by the kidneys, and the risk of adverse reactions to plazomicin may be greater in patients with renal impairment. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and renal function should be monitored. Dosage adjustment in elderly patients should take into account renal function and plazomicin concentrations as appropriate.
### Gender
There is no FDA guidance on the use of Plazomicin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Plazomicin with respect to specific racial populations.
### Renal Impairment
- Plazomicin total body clearance was significantly decreased in patients with CLcr greater than or equal to 15 to less than 60 mL/min compared to patients with CLcr greater than or equal to 60 mL/min. Monitor CLcr daily and adjust plazomicin dosage accordingly. There is insufficient information to recommend a dosage regimen in patients with CLcr less than 15 mL/min or on renal replacement therapy, including hemodialysis or continuous renal replacement therapy.
- For patients with CLcr greater than or equal to 15 mL/min and less than 90 mL/min, TDM is recommended. Monitor plazomicin trough concentrations and adjust plazomicin dosage accordingly.
### Hepatic Impairment
There is no FDA guidance on the use of Plazomicin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Plazomicin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Plazomicin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Recommended Dosage
- The recommended dosage regimen of plazomicin is 15 mg/kg administered every 24 hours by intravenous (IV) infusion over 30 minutes in patients 18 years of age or older and with creatinine clearance (CLcr) greater than or equal to 90 mL/min (Table 1). The duration of therapy should be guided by the severity of infection and the patient's clinical status for up to 7 days. During treatment, dosage adjustments may be required based on change in renal function.
Dosage in Adult Patients With Renal Impairment
- The recommended initial dosage regimen of plazomicin in adult patients with CLcr greater than or equal to 15 and less than 90 mL/min, estimated by the Cockcroft-Gault formula, is described in Table 2.
- Patients with CLcr greater than or equal to 15 and less than 90 mL/min receiving plazomicin may require subsequent dosage adjustments based on change in renal function and/or Therapeutic Drug Monitoring (TDM) as appropriate.
- There is insufficient information to recommend a dosage regimen in patients with CLcr less than 15 mL/min or on renal replacement therapy, including hemodialysis or continuous renal replacement therapy.
TDM in cUTI Patients With Renal Impairment
- For cUTI patients with CLcr greater than or equal to 15 mL/min and less than 90 mL/min, TDM is recommended to maintain plasma trough concentrations below 3 mcg/mL. Measure plazomicin plasma trough concentration within approximately 30 minutes before administration of the second dose of plazomicin. Adjustment of the plazomicin dosage regimen based on TDM involves extending plazomicin dosing interval by 1.5 fold (i.e., from every 24 hours to every 36 hours or from every 48 hours to every 72 hours) for patients with plasma trough concentrations greater than or equal to 3 mcg/mL.
Preparation of Diluted Solutions of plazomicin
- Plazomicin is supplied as a single-dose fliptop 10-mL vial that contains plazomicin sulfate equivalent to 500 mg plazomicin freebase in 10 mL Water for Injection (concentration of 50 mg/mL). The appropriate volume of plazomicin solution (50 mg/mL) for the required dose should be diluted in 0.9% Sodium Chloride Injection, USP or Lactated Ringer's Injection, USP to achieve a final volume of 50 mL for intravenous infusion. The stability of plazomicin solution in the compatible diluents is described below.
- Plazomicin does not contain preservatives. Aseptic technique must be followed in preparing the infusion solution. Discard unused portion of the plazomicin vial.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Stability of plazomicin Solution in Intravenous Fluids
- After dilution, plazomicin solution for administration is stable for 24 hours at room temperature at concentrations of 2.5 mg/mL to 45 mg/mL in the following solutions:
0.9% Sodium Chloride Injection, USP
Lactated Ringer's Injection, USP
- 0.9% Sodium Chloride Injection, USP
- Lactated Ringer's Injection, USP
Drug Compatibility
- Compatibility of plazomicin for administration with other drugs has not been established. Plazomicin should not be mixed with other drugs or physically added to solutions containing other drugs. Other medications should not be infused simultaneously with plazomicin through the same IV line.
### Monitoring
Monitoring of Renal Function
- Assess creatinine clearance in all patients prior to initiating therapy and daily during therapy with plazomicin.
# IV Compatibility
- Plazomicin is administered by intravenous infusion.
# Overdosage
- In the event of overdosage, plazomicin should be discontinued and supportive care is advised. Maintenance of glomerular filtration and careful monitoring of renal function is recommended. Hemodialysis may aid in the removal of plazomicin from the blood, especially if renal function is, or becomes, compromised. No clinical information is available on the use of hemodialysis to treat plazomicin overdosage.
# Pharmacology
## Mechanism of Action
- Plazomicin is an antibacterial drug.
## Structure
- Plazomicin contains plazomicin sulfate, a semi-synthetic aminoglycoside antibacterial derived from sisomicin.
- Plazomicin sulfate contains a theoretical 2.5 molar equivalents of sulfate relative to the freebase, based on complete protonation. The molecular weight of plazomicin sulfate is calculated based on 1:2.5 stoichiometry. The corresponding empirical formula is C25H48N6O10∙2.5 H2SO4 (plazomicin sulfate) and the molecular weight of the plazomicin sulfate salt is 837.89 g/mol and the molecular weight of the freebase is 592.69 g/mol.
## Pharmacodynamics
- The ratio of area under the plasma concentration-time curve to the minimum inhibitory concentration (AUC:MIC) for plazomicin has been shown to best correlate with efficacy in animal and in vitro models of infection against Enterobacteriaceae.
Exposure- Response Relationship for Nephrotoxicity in cUTI Patients
- Based on exposure-response analysis for nephrotoxicity, defined as serum creatinine increases greater than or equal to 0.5 mg/dL from baseline, using the data from two cUTI clinical trials (Trial 1 and Trial 2), development of nephrotoxicity was associated with estimated plazomicin exposure (i.e., the plasma trough concentration ) in patients with CLcr greater than 30 mL/min and less than or equal to 90 mL/min (N=243). The incidence of nephrotoxicity was higher in patients with plazomicin Cmin greater than or equal to 3 mcg/mL (36%, 10/28) compared to patients with plazomicin Cmin less than 3 mcg/mL (5%, 11/215).
Cardiac Electrophysiology
- The effect of plazomicin on the QTc interval was evaluated in a Phase 1 randomized, placebo and positive controlled, double-blind, single-dose, crossover thorough QTc study in 56 healthy adult subjects. At a single dose of 20 mg/kg (1.3 times the maximum recommended dose), plazomicin did not prolong the QTc interval to any clinically relevant extent.
## Pharmacokinetics
- The pharmacokinetic (PK) parameters of plazomicin are similar for single- and multiple-dose administration of plazomicin in healthy subjects. No appreciable accumulation of plazomicin was observed following multiple IV infusions of 15 mg/kg administered every 24 hours in subjects with normal renal function. The AUC, maximum plasma concentration (Cmax), and Cmin increased in proportion to the dose over the dose range of 4 to 15 mg/kg. The plazomicin AUC, Cmax, and Cmin are summarized in Table 4.
Distribution
- The mean (±SD) volume of distribution of plazomicin in healthy adults and cUTI patients is 17.9 (±4.8) and 30.8 (±12.1) L, respectively. The average binding of plazomicin to human plasma proteins is approximately 20%. The degree of protein binding was concentration-independent across the range tested in vitro (5 to 100 mcg/mL).
Elimination
- The mean (±SD) total body clearance of plazomicin in healthy adults and cUTI patients is 4.5 (±0.9) and 5.1 (±2.01) L/h, respectively. The mean (±SD) half-life of plazomicin was 3.5 h (±0.5) in healthy adults with normal renal function (n=54).
Metabolism
- Plazomicin does not appear to be metabolized to any appreciable extent.
Excretion
- Plazomicin is primarily excreted by the kidneys. Following a single 15 mg/kg IV dose of radiolabeled plazomicin in healthy subjects, 56% of the total administered radioactivity was recovered in urine within 4 hours, 89.1% was recovered within 168 hours, with less than 0.2% in feces. In total, 97.5% of the dose was recovered in the urine as unchanged plazomicin. The mean renal clearance (±SD) of plazomicin (4.6 L/h) was similar to total body clearance, suggesting that plazomicin is eliminated by the kidneys.
Specific Populations
- No clinically significant differences in the pharmacokinetics of plazomicin were observed based on age (18 to 90 years of age), sex, or race/ethnicity. The pharmacokinetics of plazomicin in patients with hepatic impairment is unknown.
Patients with Renal Impairment
- Following a single 7.5 mg/kg IV dose (0.5 times the recommended dose) of plazomicin as a 30-minute infusion, the geometric mean AUC0-inf of plazomicin in subjects with mild (CLcr 60 to <90 mL/min, n=6), moderate (CLcr 30 to <60 mL/min, n=6), and severe (CLcr 15 to <30 mL/min, n=6) renal impairment was 1.01-fold, 1.98-fold, and 4.42-fold higher, respectively, compared to subjects with normal renal function (CLcr ≥90 mL/min, n=6).
- Based on the population PK model, the recommended dosage of plazomicin was associated with a mean (±SD) Cmin of 1.0 (±1.3) and 1.7 (±1.4) mcg/mL in cUTI patients with mild (CLcr 60 to <90 mL/min, n=104) and moderate (CLcr 30 to <60 mL/min, n=89) renal impairment, respectively. The mean (±SD) area under the curve from time zero to 24 hours (AUC0-24h) was 261 (±102) and 224 (±147) mcg∙h/mL in cUTI patients with mild (CLcr 60 to <90 mL/min, n=104) and moderate (CLcr 30 to <60 mL/min, n=89) renal impairment, respectively. There were insufficient data to calculate Cmin and AUC0-24h for patients with severe renal impairment (CLcr 15 to <30 mL/min).
Geriatric Patients
- No clinically relevant trend in plazomicin exposure (Cmax and AUC0-24h) was observed with regard to age alone. Higher Cmin in elderly subjects (65 to 90 years of age) as compared to non-elderly adult subjects (18 to 64 years of age) was mainly attributable to age-related changes in renal function.
Drug Interaction Studies
Clinical Studies
- Based on the results of a clinical drug-drug interaction (DDI) study that evaluated the effect of a single dose of plazomicin (15 mg/kg) on the single dose plasma PK of metformin, plazomicin did not affect the PK of metformin, which is a substrate of OCT and MATE transporters.
In Vitro Studies
Drug-Metabolizing Enzymes
- Plazomicin does not inhibit the following cytochrome P450 isoforms: CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5. Plazomicin does not induce CYP1A2, CYP2B6, and CYP3A4.
Membrane Transporters
- Plazomicin is not a substrate of P-gp or BCRP transporters. Plazomicin does not inhibit the following hepatic and renal transporters in vitro at clinically relevant concentrations: P-gp, BCRP, BSEP, MRP2, OATP1B1, OATP1B3, OAT1, OAT3, OCT1, and OCT2. Plazomicin selectively inhibited the MATE1 and MATE2-K renal transporter in vitro with an IC50 value of 1300 and 338 mcg/mL, respectively.
## Microbiology
Mechanism of Action
- Plazomicin is an aminoglycoside that acts by binding to bacterial 30S ribosomal subunit, thereby inhibiting protein synthesis. Plazomicin has concentration-dependent bactericidal activity as measured by time kill studies. In vitro studies demonstrated a plazomicin post-antibiotic effect ranging from 0.2 to 2.6 hours at 2× MIC against Enterobacteriaceae.
Resistance
- Resistance to aminoglycosides includes production of aminoglycoside modifying enzymes (AMEs), alteration of the ribosomal target through production of 16S rRNA methyltransferases, up-regulation of efflux pumps and reduced permeability into bacterial cell due to loss of outer membrane porins.
- Plazomicin is not inhibited by most AMEs known to affect gentamicin, amikacin and tobramycin, including acetyltransferases (AACs), phosphotransferases (APHs) and nucleotidyltransferases (ANTs). Plazomicin, like other aminoglycosides, is inactive against bacterial isolates that produce 16S rRNA methyltransferases. Plazomicin may have reduced activity against Enterobacteriaceae that overexpress certain efflux pumps (e.g., acrAB-tolC) or lower expression of porins (e.g., ompF or ompK36).
- Plazomicin has no in vitro activity against streptococci (including Streptococcus pneumonia), enterococci (including Enterococcus faecalis, E. faecium), anaerobes, Stenotrophomonas maltophilia and Acinetobacter spp and variable activity against Pseudomonas aeruginosa.
- Activity of plazomicin was demonstrated in vitro against Enterobacteriaceae in the presence of certain beta-lactamases, including extended-spectrum beta-lactamases (TEM, SHV, CTX-M, AmpC), serine carbapenemases (KPC-2, KPC-3), and oxacillinase (OXA-48). Bacteria producing metallo-beta-lactamases often co-express 16S rRNA methyltransferase, conferring resistance to plazomicin.
Interaction With Other Antimicrobials
- In vitro studies have demonstrated that against Enterobacteriaceae isolates, no antagonism was observed for plazomicin in combination with clindamycin, colistin, daptomycin, fosfomycin, levofloxacin, linezolid, rifampin, tigecycline and vancomycin; few isolates showed synergy with ceftazidime, meropenem and piperacillin-tazobactam. The clinical significance of these findings is unknown.
Animal Infection Models
- Plazomicin demonstrated activity in animal models of infection (e.g., thigh infection, lung infection, and septicemia) caused by either amikacin-non-susceptible, gentamicin-non-susceptible, or beta-lactamase producing Enterobacteriaceae.
Antimicrobial Activity
- Plazomicin has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections:
- Aerobic Bacteria
- Gram-negative Bacteria
Escherichia coli
Klebsiella pneumoniae
Proteus mirabilis
Enterobacter cloacae
- Escherichia coli
- Klebsiella pneumoniae
- Proteus mirabilis
- Enterobacter cloacae
- The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for plazomicin against isolates of similar genus or organism group. However, the efficacy of plazomicin in treating clinical infections caused by these bacteria has not been established in adequate and well-controlled clinical trials.
- Aerobic Bacteria
- Gram-negative Bacteria
Citrobacter freundii
Citrobacter koseri
Enterobacter aerogenes
Klebsiella oxytoca
Morganella morganii
Proteus vulgaris
Providencia stuartii
Serratia marcescens
- Citrobacter freundii
- Citrobacter koseri
- Enterobacter aerogenes
- Klebsiella oxytoca
- Morganella morganii
- Proteus vulgaris
- Providencia stuartii
- Serratia marcescens
## Nonclinical Toxicology
Carcinogenesis
- Long term carcinogenicity studies in animals have not been conducted with plazomicin.
Mutagenesis
- Plazomicin was negative for mutagenicity in an Ames test and did not induce chromosome aberrations in cultured human peripheral blood lymphocytes. In vivo, a mouse bone marrow micronucleus assay showed no evidence of clastogenic potential.
Impairment of Fertility
- In a fertility and early embryonic development study, male and female rats received subcutaneous plazomicin at 0, 8, 25, or 50 mg/kg/day from prior to pairing through the mating and postmating period. Parental toxicity (reduced food consumption and body weight gain, and gross kidney changes) was observed at the mid and high doses. Plazomicin had no adverse effects on fertility in male rats at up to 50 mg/kg/day, resulting in an exposure (AUC) approximately 0.8-fold the human AUC at the clinical dose of 15 mg/kg once daily. In female rats, there were no effects on estrous cyclicity or reproductive performance including mating indices, fertility and fecundity indices, and copulatory intervals. At 25 and 50 mg/kg/day, female rats had fewer corpora lutea, leading to fewer uterine implantation sites and viable embryos per dam. The no observed effect level (NOEL) for fertility and reproductive performance in female rats was 8 mg/kg/day (0.1-fold human AUC).
# Clinical Studies
- A total of 609 adults hospitalized with cUTI (including pyelonephritis) were randomized in a multinational, double-blind, noninferiority trial comparing plazomicin (15 mg/kg IV once daily as a 30-minute infusion) to meropenem (1 g intravenously every 8 hours as a 30-minute infusion) (Trial 1, NCT02486627). Switch to an oral antibacterial drug, such as levofloxacin, was allowed after a minimum of 4 and maximum of 7 days of IV therapy for a total of 7 to 10 days of treatment.
- Efficacy was assessed in the microbiological modified intent-to-treat (mMITT) population, which included all patients who received study medication and had at least 1 baseline uropathogen. The mMITT population excluded patients with organisms resistant to study drugs. Patient demographic and baseline characteristics were balanced between treatment groups in the mMITT population. The mMITT population consisted of 388 patients with cUTI, including 162 (41.8%) with pyelonephritis. The median age was 64 years, 52.8% were female and 99.5% were White. The majority of the patients (99%) were from Eastern Europe; 3 patients were from the United States. Concomitant bacteremia was identified in 25 (13.1%) and 23 (11.7%) patients at baseline in the plazomicin and meropenem groups, respectively. The median treatment duration of IV study drug was 6 days in both groups.
- Plazomicin demonstrated efficacy for composite cure at Day 5 and the Test of Cure (TOC) visit (Table 5). Composite cure at Day 5 was defined as resolution or improvement of clinical cUTI symptoms and a microbiological outcome of eradication (all baseline uropathogens reduced to <104 colony-forming units /mL). Composite cure at the TOC visit (Day 17 ± 2 from the first dose of study drug) was defined as resolution of clinical cUTI symptoms and a microbiological outcome of eradication.
- Microbiological eradication rates at the TOC visit by baseline uropathogen in the mMITT population are presented in Table 6. Composite Cure at the TOC visit in individuals with concomitant bacteremia at baseline was achieved in 72.0% (18/25) of patients in the plazomicin group and 56.5% (13/23) of patients in the meropenem group.
- There were 52 baseline Enterobacteriaceae isolates in 51/189 (27%) patients in the plazomicin group that were non-susceptible (defined as intermediate or resistant) to gentamicin, or tobramycin or both. All of these isolates were susceptible to plazomicin and all but one was susceptible to amikacin (one isolate was intermediate to amikacin). The microbiological eradication rate at the TOC visit in this subset was 78.9% (41/52) in the plazomicin group. Note that certain resistance mechanisms can confer resistance to all aminoglycosides, including plazomicin.
# How Supplied
- Plazomicin injection 500 mg/10 mL (50 mg/mL) is supplied in single-dose, 10-mL vials fitted with flip-off seals with royal blue polypropylene buttons as a clear, colorless to yellow, sterile solution. Each vial contains plazomicin sulfate equivalent to 500 mg plazomicin freebase at a concentration of 50 mg/mL plazomicin in Water for Injection. Each vial contains sodium hydroxide for pH adjustment to 6.5. The solution may become yellow in color; this does not indicate a decrease in potency.
## Storage
- Store plazomicin injection 500 mg/10 mL (50 mg/mL) refrigerated at 2°C to 8°C (36°F to 46°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Nephrotoxicity
- Advise patients, their families, or caregivers that nephrotoxicity has been reported with plazomicin therapy. Counsel patients to follow their physician's directions regarding renal function laboratory tests, maintenance of adequate hydration, and avoidance of potentially nephrotoxic agents while receiving plazomicin therapy.
Ototoxicity
- Advise patients, their families, or caregivers that hearing loss, vertigo, and tinnitus have been reported with plazomicin therapy. Counsel patients to inform their physician if they experience changes in hearing or balance, or if they experience new onset or changes in preexisting buzzing or roaring in their ear(s), even if it occurs after the completion of plazomicin therapy.
Aggravation of Neuromuscular Disorders
- Advise patients, their families, or caregivers that aggravation of muscle weakness has been reported for other aminoglycosides, particularly in patients with underlying neuromuscular disease or receiving neuromuscular blocking agents. Counsel patients to inform their physician if they have an underlying neuromuscular disorder such as myasthenia gravis or are receiving neuromuscular blocking agents.
Fetal Harm
- Aminoglycosides, including plazomicin, can cause fetal harm when administered to a pregnant woman. Counsel women of childbearing potential about the potential risk of fetal harm if plazomicin is used during pregnancy. Advise pregnant women that aminoglycosides can cause irreversible congenital deafness when administered to a pregnant woman. Tell women of childbearing potential to notify their prescribing physician/ healthcare provider if they become pregnant during plazomicin treatment.
Hypersensitivity Reactions
- Advise patients, their families, or caregivers that allergic reactions, including serious allergic reactions, could occur and that serious reactions require immediate treatment. Ask them about any previous hypersensitivity reactions to plazomicin or other aminoglycosides.
Potentially Serious Diarrhea
- Advise patients, their families, or caregivers that diarrhea is a common problem caused by antibacterial drugs, including plazomicin. Sometimes, frequent watery or bloody diarrhea may occur and may be a sign of a more serious intestinal infection. If severe watery or bloody diarrhea develops, tell patient to contact his or her healthcare provider.
Antibacterial Resistance
- Counsel patients, their families, or caregivers that antibacterial drugs, including plazomicin, should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When plazomicin is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by plazomicin or other antibacterial drugs in the future.
# Precautions with Alcohol
Alcohol-Plazomicin interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
Zemdri
# Look-Alike Drug Names
There is limited information regarding Plazomicin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Plazomicin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Zach Leibowitz [2]
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# Black Box Warning
# Overview
Plazomicin is an aminoglycoside antibacterial that is FDA approved for the treatment of patients 18 years of age or older with Complicated Urinary Tract Infections (cUTI) including Pyelonephritis. There is a Black Box Warning for this drug as shown here. Common adverse reactions include decreased renal function, diarrhea, hypertension, headache, nausea, vomiting and hypotension.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Indication
- Plazomicin is indicated in patients 18 years of age or older for the treatment of complicated urinary tract infections (cUTI), including pyelonephritis caused by the following susceptible microorganism(s): Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and Enterobacter cloacae.
- As only limited clinical safety and efficacy data for plazomicin are currently available, reserve plazomicin for use in cUTI patients who have limited or no alternative treatment options.
- To reduce the development of drug-resistant bacteria and maintain the effectiveness of plazomicin and other antibacterial drugs, plazomicin should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.
Dosage
- Administer plazomicin 15 mg/kg every 24 hours by intravenous (IV) infusion over 30 minutes to patients 18 years of age or older with creatinine clearance greater than or equal to 90 mL/min.
- Recommended duration of treatment is 4 to 7 days for cUTI, including pyelonephritis.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding plazomicin Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding plazomicin Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- The safety and effectiveness of plazomicin in patients less than 18 years of age have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding plazomicin Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding plazomicin Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
- Plazomicin is contraindicated in patients with known hypersensitivity to any aminoglycoside.
# Warnings
- Nephrotoxicity has been reported with the use of plazomicin. Most serum creatinine increases were ≤ 1 mg/dL above baseline and reversible.
- In Trial 1, the incidence of adverse reactions associated with renal function (acute kidney injury, serum creatinine increased, chronic kidney disease, creatinine clearance decreased, renal failure, renal impairment) was 3.6% (11/303) in plazomicin-treated patients compared with 1.3% (4/301) in meropenem-treated patients.
- Serum creatinine increases of 0.5 mg/dL or greater above baseline occurred in 7% (21/300) of plazomicin-treated patients compared with 4% (12/297) of meropenem-treated patients. These increases mainly occurred in patients with CLcr ≤ 90 mL/min and were associated with a plazomicin trough level (Cmin) greater than or equal to 3 mcg/mL.
- Assess CLcr in all patients prior to initiating therapy and daily during therapy with plazomicin, particularly in those at increased risk of nephrotoxicity, such as those with renal impairment, the elderly, and those receiving concomitant potentially nephrotoxic medications. In the setting of worsening renal function, the benefit of continuing plazomicin should be assessed.
- Adjust the initial dosage regimen in cUTI patients with CLcr ≥ 15 mL/min and < 60 mL/min. For subsequent doses, TDM is recommended for patients with CLcr ≥15 mL/min and < 90 mL/min.
- Ototoxicity, manifested as hearing loss, tinnitus, and/or vertigo, has been reported with plazomicin. Symptoms of aminoglycoside-associated ototoxicity may be irreversible and may not become evident until after completion of therapy.
- Regarding the incidence of adverse reactions associated with cochlear or vestibular function, in Trial 1, there was one case of reversible hypoacusis (1/303;0.3%) in plazomicin-treated patients and one case of tinnitus (1/301;0.3%) in meropenem-treated patients. In Trial 2, one case each of irreversible tinnitus and reversible vertigo was reported in plazomicin-treated patients, and one case of an abnormal audiogram occurred in a levofloxacin-treated patient.
- Aminoglycoside-associated ototoxicity has been observed primarily in patients with a family history of hearing loss (excluding age-related hearing loss), patients with renal impairment, and in patients receiving higher doses and/or for longer periods than recommended. In Trial 1 and Trial 2, patients with a history of hearing loss, with the exception of age-related hearing loss, were excluded. The benefit-risk of plazomicin therapy should be considered in these patients.
- Aminoglycosides have been associated with exacerbation of muscle weakness in patients with underlying neuromuscular disorders, or delay in recovery of neuromuscular function in patients receiving concomitant neuromuscular blocking agents.
- During therapy with plazomicin, monitor for adverse reactions associated with neuromuscular blockade, particularly in high-risk patients, such as patients with underlying neuromuscular disorders (including myasthenia gravis) or those patients concomitantly receiving neuromuscular blocking agents.
- Aminoglycosides, including plazomicin, can cause fetal harm when administered to a pregnant woman. Aminoglycosides cross the placenta, and streptomycin has been associated with several reports of total, irreversible, bilateral congenital deafness in pediatric patients exposed in utero. Patients who use plazomicin during pregnancy, or become pregnant while taking plazomicin should be apprised of the potential hazard to the fetus.
- Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving aminoglycoside antibacterial drugs. Before therapy with plazomicin is instituted, careful inquiry about previous hypersensitivity reactions to other aminoglycosides should be made. A history of hypersensitivity to other aminoglycosides is a contraindication to the use of plazomicin, because cross-sensitivity among aminoglycoside antibacterial drugs has been established. Discontinue plazomicin if an allergic reaction occurs.
- Clostridium difficile-associated diarrhea (CDAD) has been reported for nearly all systemic antibacterial drugs and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial drugs alters the normal flora of the colon and may permit overgrowth of C. difficile.
- C. difficile produces toxins A and B that contribute to the development of CDAD. Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary because CDAD has been reported to occur more than 2 months after the administration of antibacterial drugs.
- If CDAD is suspected or confirmed, antibacterial drugs not directed against C. difficile may need to be discontinued. Manage fluid and electrolyte levels as appropriate, supplement protein intake, monitor antibacterial treatment of C. difficile, and institute surgical evaluation as clinically indicated.
- Prescribing plazomicin in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be compared directly to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- Plazomicin was evaluated in two comparator-controlled clinical trials (Trial 1, NCT02486627 and Trial 2, NCT01096849) in patients with cUTI, including pyelonephritis. In both trials, patients with CLcr greater than 60 mL/min received plazomicin 15 mg/kg IV once daily as a 30-minute infusion.
- Trial 1 included 303 patients treated with plazomicin and 301 patients treated with meropenem. Patients were to receive 4 to 7 days of plazomicin (mean duration of 5.1 days). In some patients, parenteral therapy was followed by a switch to an oral antibacterial drug.
- The median age of patients treated with plazomicin in Trial 1 was 62 years (range 18 to 90 years) and 45.2% of patients were 65 years of age or older. Patients treated with plazomicin were predominantly female (56.1%) and White (99.3%). A majority of patients (68.0%) had mild or moderate renal impairment (CLcr >30 to 90 mL/min) at baseline. Patients with CLcr of 30 mL/min or less were excluded.
Adverse Reactions Leading to Treatment Discontinuations in Trial 1
- In Trial 1, treatment discontinuation from IV study drug due to an adverse reaction occurred in 2.0% of patients receiving plazomicin (6/303) and meropenem (6/301), respectively.
Common Adverse Reactions in Trial 1
- Table 3 lists adverse reactions occurring in 1% or more of patients receiving plazomicin in Trial 1.
- The adverse reactions profile for the cUTI patients in Trial 2 were similar to those observed in Trial 1.
Nephrotoxicity Reported in Trial 1
- In Trial 1, serum creatinine increases of 0.5 mg/dL or greater above baseline occurred in 7.0% (21/300) of plazomicin-treated patients compared with 4.0% (12/297) of meropenem-treated patients. Of these, the incidence during IV therapy was 3.7% (11/300) vs 3.0% (9/297) in plazomicin- and meropenem-treated patients, respectively. By the last follow-up visit (between 8 to 43 days after completion of IV therapy), the majority of plazomicin-treated patients (9/11) and all meropenem treated patients (9/9) with serum creatinine increases while on therapy had fully recovered renal function. Serum creatinine increases of 0.5 mg/dL or greater above baseline were observed following completion of IV therapy. These increases were generally ≤ 1.0 mg/dL above baseline and recovered by the next measurement.
- In cUTI patients with CLcr of greater than 30 and less than or equal to 90 mL/min, 9.7% (20/207) plazomicin-treated and 4.1% (9/217) meropenem-treated patients had serum creatinine increases of 0.5 mg/dL or greater above baseline. In cUTI patients with CLcr greater than 90 mL/min, 1.1% (1/93) plazomicin-treated and 3.8% (3/80) of meropenem-treated patients had serum creatinine increases of 0.5 mg/dL or greater above baseline.
Ototoxicity
- Pure tone audiometry was evaluated in Phase 1 trials and in Trial 2. Treatment associated ototoxicity could not be definitively excluded according to the American Speech-Language-Hearing Association criteria1 in 2.2% (4/182) of plazomicin-exposed and 2.0% (1/49) of comparator- or placebo-exposed adults.
Other Adverse Reactions Reported with plazomicin
- The following selected adverse reactions were reported in more than one plazomicin-treated patient in Trials 1 and 2 and are not described elsewhere in the labeling:
Gastrointestinal disorders: constipation, gastritis
Laboratory Investigations: alanine aminotransferase increased
Metabolism and nutrition disorders: hypokalemia
Nervous system disorders: dizziness
Renal and urinary disorders: hematuria
Respiratory, thoracic and mediastinal disorders: dyspnea
- Gastrointestinal disorders: constipation, gastritis
- Laboratory Investigations: alanine aminotransferase increased
- Metabolism and nutrition disorders: hypokalemia
- Nervous system disorders: dizziness
- Renal and urinary disorders: hematuria
- Respiratory, thoracic and mediastinal disorders: dyspnea
## Postmarketing Experience
There is limited information regarding Plazomicin Postmarketing Experience in the drug label.
# Drug Interactions
There is limited information regarding Plazomicin Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Risk Summary
- Aminoglycosides, including plazomicin, can cause fetal harm when administered to a pregnant woman. There are no available data on the use of plazomicin in pregnant women to inform a drug associated risk of adverse developmental outcomes. Published literature reports of streptomycin, an aminoglycoside, state that it can cause total, irreversible, bilateral congenital deafness in children whose mothers received streptomycin during pregnancy. No drug-related visceral or skeletal malformations were observed in pregnant rats and rabbits administered subcutaneous plazomicin during organogenesis at maternal exposures approximately 0.8-fold (rats) and 2.5-fold (rabbits) of the human AUC at the clinical dose of 15 mg/kg/day. Auditory function of offspring was not measured in animal studies. Advise pregnant women of the potential risk to a fetus.
- The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Animal Data
- In an embryo-fetal development study in rats, plazomicin doses of 0, 8, 25, or 50 mg/kg/day administered subcutaneously during organogenesis did not cause drug-related visceral or skeletal malformations, or reduce survival of fetuses. The mid and high doses caused maternal toxicity (reductions in food consumption and body weight gain; increased kidney weight). The high dose resulted in maternal exposure (AUC) approximately 0.8-fold the human AUC at the clinical dose of 15 mg/kg once daily.
- In an embryo-fetal development study in rabbits, plazomicin administered subcutaneously at doses of 0, 10, 30, or 50 mg/kg/day did not cause visceral or skeletal malformations or reduced fetal survival. At the high dose, significant maternal toxicity was observed (including renal injury and lethality) and exposure was approximately 2.5-fold the human AUC at the recommended clinical dose.
- In a pre- and postnatal development study in rats, maternal animals received subcutaneous plazomicin at 0, 3, 8, or 30 mg/kg/day from the start of organogenesis through lactation. There were no adverse effects on maternal function or pre- and postnatal survival, development, behavior, or reproductive function of the offspring at up to 30 mg/kg/day (0.32-fold human AUC at the clinical daily dose of 15 mg/kg).
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Plazomicin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Plazomicin during labor and delivery.
### Nursing Mothers
Risk Summary
- There are no data on the presence of plazomicin in human milk, the effects on the breastfed infant, or the effects on milk production. Plazomicin was detected in rat milk (see DATA). The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for plazomicin and any potential adverse effects on the breastfed infant from plazomicin or from the underlying maternal condition.
Data
- In a pre- and postnatal development study in rats, low concentrations of plazomicin in maternal milk were detected, with mean concentrations representing 2% to 4% of maternal plasma concentrations. In nursing pups, the systemic exposure (AUC) to plazomicin through lactational exposure was approximately 0.04% of maternal systemic exposure.
### Pediatric Use
- The safety and effectiveness of plazomicin in patients less than 18 years of age have not been established.
### Geriatic Use
- Of the 425 patients treated with plazomicin in Trials 1 and 2, 40% (170/425) were 65 years of age and older, including 17.2% (73/425) patients 75 years of age and older. In Trial 1, for plazomicin- treated patients ≥ 65 years old, the incidence rate of adverse reactions was 27% (37/137) versus 18.9% (27/143) in the meropenem-treated patients ≥ 65 years old. For plazomicin- treated patients < 65 years old, the incidence rate of adverse reactions was 13.3% (22/166) versus 24.1% (38/158) in the meropenem-treated patients < 65 years old.
- The rate of adverse reactions associated with renal function for the plazomicin-treated patients ≥ 65 years old was 6.6% (9/137) versus 2.8% (4/143) in the meropenem-treated patients. For plazomicin- treated patients < 65 years old, the incidence rate of adverse reactions associated with renal function was 1.2% (2/166), versus 0% (0/158) in the meropenem-treated patients.
- Plazomicin is substantially excreted by the kidneys, and the risk of adverse reactions to plazomicin may be greater in patients with renal impairment. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and renal function should be monitored. Dosage adjustment in elderly patients should take into account renal function and plazomicin concentrations as appropriate.
### Gender
There is no FDA guidance on the use of Plazomicin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Plazomicin with respect to specific racial populations.
### Renal Impairment
- Plazomicin total body clearance was significantly decreased in patients with CLcr greater than or equal to 15 to less than 60 mL/min compared to patients with CLcr greater than or equal to 60 mL/min. Monitor CLcr daily and adjust plazomicin dosage accordingly. There is insufficient information to recommend a dosage regimen in patients with CLcr less than 15 mL/min or on renal replacement therapy, including hemodialysis or continuous renal replacement therapy.
- For patients with CLcr greater than or equal to 15 mL/min and less than 90 mL/min, TDM is recommended. Monitor plazomicin trough concentrations and adjust plazomicin dosage accordingly.
### Hepatic Impairment
There is no FDA guidance on the use of Plazomicin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Plazomicin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Plazomicin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Recommended Dosage
- The recommended dosage regimen of plazomicin is 15 mg/kg administered every 24 hours by intravenous (IV) infusion over 30 minutes in patients 18 years of age or older and with creatinine clearance (CLcr) greater than or equal to 90 mL/min (Table 1). The duration of therapy should be guided by the severity of infection and the patient's clinical status for up to 7 days. During treatment, dosage adjustments may be required based on change in renal function.
Dosage in Adult Patients With Renal Impairment
- The recommended initial dosage regimen of plazomicin in adult patients with CLcr greater than or equal to 15 and less than 90 mL/min, estimated by the Cockcroft-Gault formula, is described in Table 2.
- Patients with CLcr greater than or equal to 15 and less than 90 mL/min receiving plazomicin may require subsequent dosage adjustments based on change in renal function and/or Therapeutic Drug Monitoring (TDM) as appropriate.
- There is insufficient information to recommend a dosage regimen in patients with CLcr less than 15 mL/min or on renal replacement therapy, including hemodialysis or continuous renal replacement therapy.
TDM in cUTI Patients With Renal Impairment
- For cUTI patients with CLcr greater than or equal to 15 mL/min and less than 90 mL/min, TDM is recommended to maintain plasma trough concentrations below 3 mcg/mL. Measure plazomicin plasma trough concentration within approximately 30 minutes before administration of the second dose of plazomicin. Adjustment of the plazomicin dosage regimen based on TDM involves extending plazomicin dosing interval by 1.5 fold (i.e., from every 24 hours to every 36 hours or from every 48 hours to every 72 hours) for patients with plasma trough concentrations greater than or equal to 3 mcg/mL.
Preparation of Diluted Solutions of plazomicin
- Plazomicin is supplied as a single-dose fliptop 10-mL vial that contains plazomicin sulfate equivalent to 500 mg plazomicin freebase in 10 mL Water for Injection (concentration of 50 mg/mL). The appropriate volume of plazomicin solution (50 mg/mL) for the required dose should be diluted in 0.9% Sodium Chloride Injection, USP or Lactated Ringer's Injection, USP to achieve a final volume of 50 mL for intravenous infusion. The stability of plazomicin solution in the compatible diluents is described below.
- Plazomicin does not contain preservatives. Aseptic technique must be followed in preparing the infusion solution. Discard unused portion of the plazomicin vial.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Stability of plazomicin Solution in Intravenous Fluids
- After dilution, plazomicin solution for administration is stable for 24 hours at room temperature at concentrations of 2.5 mg/mL to 45 mg/mL in the following solutions:
0.9% Sodium Chloride Injection, USP
Lactated Ringer's Injection, USP
- 0.9% Sodium Chloride Injection, USP
- Lactated Ringer's Injection, USP
Drug Compatibility
- Compatibility of plazomicin for administration with other drugs has not been established. Plazomicin should not be mixed with other drugs or physically added to solutions containing other drugs. Other medications should not be infused simultaneously with plazomicin through the same IV line.
### Monitoring
Monitoring of Renal Function
- Assess creatinine clearance in all patients prior to initiating therapy and daily during therapy with plazomicin.
# IV Compatibility
- Plazomicin is administered by intravenous infusion.
# Overdosage
- In the event of overdosage, plazomicin should be discontinued and supportive care is advised. Maintenance of glomerular filtration and careful monitoring of renal function is recommended. Hemodialysis may aid in the removal of plazomicin from the blood, especially if renal function is, or becomes, compromised. No clinical information is available on the use of hemodialysis to treat plazomicin overdosage.
# Pharmacology
## Mechanism of Action
- Plazomicin is an antibacterial drug.
## Structure
- Plazomicin contains plazomicin sulfate, a semi-synthetic aminoglycoside antibacterial derived from sisomicin.
- Plazomicin sulfate contains a theoretical 2.5 molar equivalents of sulfate relative to the freebase, based on complete protonation. The molecular weight of plazomicin sulfate is calculated based on 1:2.5 stoichiometry. The corresponding empirical formula is C25H48N6O10∙2.5 H2SO4 (plazomicin sulfate) and the molecular weight of the plazomicin sulfate salt is 837.89 g/mol and the molecular weight of the freebase is 592.69 g/mol.
## Pharmacodynamics
- The ratio of area under the plasma concentration-time curve to the minimum inhibitory concentration (AUC:MIC) for plazomicin has been shown to best correlate with efficacy in animal and in vitro models of infection against Enterobacteriaceae.
Exposure- Response Relationship for Nephrotoxicity in cUTI Patients
- Based on exposure-response analysis for nephrotoxicity, defined as serum creatinine increases greater than or equal to 0.5 mg/dL from baseline, using the data from two cUTI clinical trials (Trial 1 and Trial 2), development of nephrotoxicity was associated with estimated plazomicin exposure (i.e., the plasma trough concentration [Cmin]) in patients with CLcr greater than 30 mL/min and less than or equal to 90 mL/min (N=243). The incidence of nephrotoxicity was higher in patients with plazomicin Cmin greater than or equal to 3 mcg/mL (36%, 10/28) compared to patients with plazomicin Cmin less than 3 mcg/mL (5%, 11/215).
Cardiac Electrophysiology
- The effect of plazomicin on the QTc interval was evaluated in a Phase 1 randomized, placebo and positive controlled, double-blind, single-dose, crossover thorough QTc study in 56 healthy adult subjects. At a single dose of 20 mg/kg (1.3 times the maximum recommended dose), plazomicin did not prolong the QTc interval to any clinically relevant extent.
## Pharmacokinetics
- The pharmacokinetic (PK) parameters of plazomicin are similar for single- and multiple-dose administration of plazomicin in healthy subjects. No appreciable accumulation of plazomicin was observed following multiple IV infusions of 15 mg/kg administered every 24 hours in subjects with normal renal function. The AUC, maximum plasma concentration (Cmax), and Cmin increased in proportion to the dose over the dose range of 4 to 15 mg/kg. The plazomicin AUC, Cmax, and Cmin are summarized in Table 4.
Distribution
- The mean (±SD) volume of distribution of plazomicin in healthy adults and cUTI patients is 17.9 (±4.8) and 30.8 (±12.1) L, respectively. The average binding of plazomicin to human plasma proteins is approximately 20%. The degree of protein binding was concentration-independent across the range tested in vitro (5 to 100 mcg/mL).
Elimination
- The mean (±SD) total body clearance of plazomicin in healthy adults and cUTI patients is 4.5 (±0.9) and 5.1 (±2.01) L/h, respectively. The mean (±SD) half-life of plazomicin was 3.5 h (±0.5) in healthy adults with normal renal function (n=54).
Metabolism
- Plazomicin does not appear to be metabolized to any appreciable extent.
Excretion
- Plazomicin is primarily excreted by the kidneys. Following a single 15 mg/kg IV dose of radiolabeled plazomicin in healthy subjects, 56% of the total administered radioactivity was recovered in urine within 4 hours, 89.1% was recovered within 168 hours, with less than 0.2% in feces. In total, 97.5% of the dose was recovered in the urine as unchanged plazomicin. The mean renal clearance (±SD) of plazomicin (4.6 [±1.2] L/h) was similar to total body clearance, suggesting that plazomicin is eliminated by the kidneys.
Specific Populations
- No clinically significant differences in the pharmacokinetics of plazomicin were observed based on age (18 to 90 years of age), sex, or race/ethnicity. The pharmacokinetics of plazomicin in patients with hepatic impairment is unknown.
Patients with Renal Impairment
- Following a single 7.5 mg/kg IV dose (0.5 times the recommended dose) of plazomicin as a 30-minute infusion, the geometric mean AUC0-inf of plazomicin in subjects with mild (CLcr 60 to <90 mL/min, n=6), moderate (CLcr 30 to <60 mL/min, n=6), and severe (CLcr 15 to <30 mL/min, n=6) renal impairment was 1.01-fold, 1.98-fold, and 4.42-fold higher, respectively, compared to subjects with normal renal function (CLcr ≥90 mL/min, n=6).
- Based on the population PK model, the recommended dosage of plazomicin was associated with a mean (±SD) Cmin of 1.0 (±1.3) and 1.7 (±1.4) mcg/mL in cUTI patients with mild (CLcr 60 to <90 mL/min, n=104) and moderate (CLcr 30 to <60 mL/min, n=89) renal impairment, respectively. The mean (±SD) area under the curve from time zero to 24 hours (AUC0-24h) was 261 (±102) and 224 (±147) mcg∙h/mL in cUTI patients with mild (CLcr 60 to <90 mL/min, n=104) and moderate (CLcr 30 to <60 mL/min, n=89) renal impairment, respectively. There were insufficient data to calculate Cmin and AUC0-24h for patients with severe renal impairment (CLcr 15 to <30 mL/min).
Geriatric Patients
- No clinically relevant trend in plazomicin exposure (Cmax and AUC0-24h) was observed with regard to age alone. Higher Cmin in elderly subjects (65 to 90 years of age) as compared to non-elderly adult subjects (18 to 64 years of age) was mainly attributable to age-related changes in renal function.
Drug Interaction Studies
Clinical Studies
- Based on the results of a clinical drug-drug interaction (DDI) study that evaluated the effect of a single dose of plazomicin (15 mg/kg) on the single dose plasma PK of metformin, plazomicin did not affect the PK of metformin, which is a substrate of OCT and MATE transporters.
In Vitro Studies
Drug-Metabolizing Enzymes
- Plazomicin does not inhibit the following cytochrome P450 isoforms: CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5. Plazomicin does not induce CYP1A2, CYP2B6, and CYP3A4.
Membrane Transporters
- Plazomicin is not a substrate of P-gp or BCRP transporters. Plazomicin does not inhibit the following hepatic and renal transporters in vitro at clinically relevant concentrations: P-gp, BCRP, BSEP, MRP2, OATP1B1, OATP1B3, OAT1, OAT3, OCT1, and OCT2. Plazomicin selectively inhibited the MATE1 and MATE2-K renal transporter in vitro with an IC50 value of 1300 and 338 mcg/mL, respectively.
## Microbiology
Mechanism of Action
- Plazomicin is an aminoglycoside that acts by binding to bacterial 30S ribosomal subunit, thereby inhibiting protein synthesis. Plazomicin has concentration-dependent bactericidal activity as measured by time kill studies. In vitro studies demonstrated a plazomicin post-antibiotic effect ranging from 0.2 to 2.6 hours at 2× MIC against Enterobacteriaceae.
Resistance
- Resistance to aminoglycosides includes production of aminoglycoside modifying enzymes (AMEs), alteration of the ribosomal target through production of 16S rRNA methyltransferases, up-regulation of efflux pumps and reduced permeability into bacterial cell due to loss of outer membrane porins.
- Plazomicin is not inhibited by most AMEs known to affect gentamicin, amikacin and tobramycin, including acetyltransferases (AACs), phosphotransferases (APHs) and nucleotidyltransferases (ANTs). Plazomicin, like other aminoglycosides, is inactive against bacterial isolates that produce 16S rRNA methyltransferases. Plazomicin may have reduced activity against Enterobacteriaceae that overexpress certain efflux pumps (e.g., acrAB-tolC) or lower expression of porins (e.g., ompF or ompK36).
- Plazomicin has no in vitro activity against streptococci (including Streptococcus pneumonia), enterococci (including Enterococcus faecalis, E. faecium), anaerobes, Stenotrophomonas maltophilia and Acinetobacter spp and variable activity against Pseudomonas aeruginosa.
- Activity of plazomicin was demonstrated in vitro against Enterobacteriaceae in the presence of certain beta-lactamases, including extended-spectrum beta-lactamases (TEM, SHV, CTX-M, AmpC), serine carbapenemases (KPC-2, KPC-3), and oxacillinase (OXA-48). Bacteria producing metallo-beta-lactamases often co-express 16S rRNA methyltransferase, conferring resistance to plazomicin.
Interaction With Other Antimicrobials
- In vitro studies have demonstrated that against Enterobacteriaceae isolates, no antagonism was observed for plazomicin in combination with clindamycin, colistin, daptomycin, fosfomycin, levofloxacin, linezolid, rifampin, tigecycline and vancomycin; few isolates showed synergy with ceftazidime, meropenem and piperacillin-tazobactam. The clinical significance of these findings is unknown.
Animal Infection Models
- Plazomicin demonstrated activity in animal models of infection (e.g., thigh infection, lung infection, and septicemia) caused by either amikacin-non-susceptible, gentamicin-non-susceptible, or beta-lactamase producing Enterobacteriaceae.
Antimicrobial Activity
- Plazomicin has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections:
- Aerobic Bacteria
- Gram-negative Bacteria
Escherichia coli
Klebsiella pneumoniae
Proteus mirabilis
Enterobacter cloacae
- Escherichia coli
- Klebsiella pneumoniae
- Proteus mirabilis
- Enterobacter cloacae
- The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for plazomicin against isolates of similar genus or organism group. However, the efficacy of plazomicin in treating clinical infections caused by these bacteria has not been established in adequate and well-controlled clinical trials.
- Aerobic Bacteria
- Gram-negative Bacteria
Citrobacter freundii
Citrobacter koseri
Enterobacter aerogenes
Klebsiella oxytoca
Morganella morganii
Proteus vulgaris
Providencia stuartii
Serratia marcescens
- Citrobacter freundii
- Citrobacter koseri
- Enterobacter aerogenes
- Klebsiella oxytoca
- Morganella morganii
- Proteus vulgaris
- Providencia stuartii
- Serratia marcescens
## Nonclinical Toxicology
Carcinogenesis
- Long term carcinogenicity studies in animals have not been conducted with plazomicin.
Mutagenesis
- Plazomicin was negative for mutagenicity in an Ames test and did not induce chromosome aberrations in cultured human peripheral blood lymphocytes. In vivo, a mouse bone marrow micronucleus assay showed no evidence of clastogenic potential.
Impairment of Fertility
- In a fertility and early embryonic development study, male and female rats received subcutaneous plazomicin at 0, 8, 25, or 50 mg/kg/day from prior to pairing through the mating and postmating period. Parental toxicity (reduced food consumption and body weight gain, and gross kidney changes) was observed at the mid and high doses. Plazomicin had no adverse effects on fertility in male rats at up to 50 mg/kg/day, resulting in an exposure (AUC) approximately 0.8-fold the human AUC at the clinical dose of 15 mg/kg once daily. In female rats, there were no effects on estrous cyclicity or reproductive performance including mating indices, fertility and fecundity indices, and copulatory intervals. At 25 and 50 mg/kg/day, female rats had fewer corpora lutea, leading to fewer uterine implantation sites and viable embryos per dam. The no observed effect level (NOEL) for fertility and reproductive performance in female rats was 8 mg/kg/day (0.1-fold human AUC).
# Clinical Studies
- A total of 609 adults hospitalized with cUTI (including pyelonephritis) were randomized in a multinational, double-blind, noninferiority trial comparing plazomicin (15 mg/kg IV once daily as a 30-minute infusion) to meropenem (1 g intravenously every 8 hours as a 30-minute infusion) (Trial 1, NCT02486627). Switch to an oral antibacterial drug, such as levofloxacin, was allowed after a minimum of 4 and maximum of 7 days of IV therapy for a total of 7 to 10 days of treatment.
- Efficacy was assessed in the microbiological modified intent-to-treat (mMITT) population, which included all patients who received study medication and had at least 1 baseline uropathogen. The mMITT population excluded patients with organisms resistant to study drugs. Patient demographic and baseline characteristics were balanced between treatment groups in the mMITT population. The mMITT population consisted of 388 patients with cUTI, including 162 (41.8%) with pyelonephritis. The median age was 64 years, 52.8% were female and 99.5% were White. The majority of the patients (99%) were from Eastern Europe; 3 patients were from the United States. Concomitant bacteremia was identified in 25 (13.1%) and 23 (11.7%) patients at baseline in the plazomicin and meropenem groups, respectively. The median treatment duration of IV study drug was 6 days in both groups.
- Plazomicin demonstrated efficacy for composite cure at Day 5 and the Test of Cure (TOC) visit (Table 5). Composite cure at Day 5 was defined as resolution or improvement of clinical cUTI symptoms and a microbiological outcome of eradication (all baseline uropathogens reduced to <104 colony-forming units [CFU]/mL). Composite cure at the TOC visit (Day 17 ± 2 from the first dose of study drug) was defined as resolution of clinical cUTI symptoms and a microbiological outcome of eradication.
- Microbiological eradication rates at the TOC visit by baseline uropathogen in the mMITT population are presented in Table 6. Composite Cure at the TOC visit in individuals with concomitant bacteremia at baseline was achieved in 72.0% (18/25) of patients in the plazomicin group and 56.5% (13/23) of patients in the meropenem group.
- There were 52 baseline Enterobacteriaceae isolates in 51/189 (27%) patients in the plazomicin group that were non-susceptible (defined as intermediate or resistant) to gentamicin, or tobramycin or both. All of these isolates were susceptible to plazomicin and all but one was susceptible to amikacin (one isolate was intermediate to amikacin). The microbiological eradication rate at the TOC visit in this subset was 78.9% (41/52) in the plazomicin group. Note that certain resistance mechanisms can confer resistance to all aminoglycosides, including plazomicin.
# How Supplied
- Plazomicin injection 500 mg/10 mL (50 mg/mL) is supplied in single-dose, 10-mL vials fitted with flip-off seals with royal blue polypropylene buttons as a clear, colorless to yellow, sterile solution. Each vial contains plazomicin sulfate equivalent to 500 mg plazomicin freebase at a concentration of 50 mg/mL plazomicin in Water for Injection. Each vial contains sodium hydroxide for pH adjustment to 6.5. The solution may become yellow in color; this does not indicate a decrease in potency.
## Storage
- Store plazomicin injection 500 mg/10 mL (50 mg/mL) refrigerated at 2°C to 8°C (36°F to 46°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Nephrotoxicity
- Advise patients, their families, or caregivers that nephrotoxicity has been reported with plazomicin therapy. Counsel patients to follow their physician's directions regarding renal function laboratory tests, maintenance of adequate hydration, and avoidance of potentially nephrotoxic agents while receiving plazomicin therapy.
Ototoxicity
- Advise patients, their families, or caregivers that hearing loss, vertigo, and tinnitus have been reported with plazomicin therapy. Counsel patients to inform their physician if they experience changes in hearing or balance, or if they experience new onset or changes in preexisting buzzing or roaring in their ear(s), even if it occurs after the completion of plazomicin therapy.
Aggravation of Neuromuscular Disorders
- Advise patients, their families, or caregivers that aggravation of muscle weakness has been reported for other aminoglycosides, particularly in patients with underlying neuromuscular disease or receiving neuromuscular blocking agents. Counsel patients to inform their physician if they have an underlying neuromuscular disorder such as myasthenia gravis or are receiving neuromuscular blocking agents.
Fetal Harm
- Aminoglycosides, including plazomicin, can cause fetal harm when administered to a pregnant woman. Counsel women of childbearing potential about the potential risk of fetal harm if plazomicin is used during pregnancy. Advise pregnant women that aminoglycosides can cause irreversible congenital deafness when administered to a pregnant woman. Tell women of childbearing potential to notify their prescribing physician/ healthcare provider if they become pregnant during plazomicin treatment.
Hypersensitivity Reactions
- Advise patients, their families, or caregivers that allergic reactions, including serious allergic reactions, could occur and that serious reactions require immediate treatment. Ask them about any previous hypersensitivity reactions to plazomicin or other aminoglycosides.
Potentially Serious Diarrhea
- Advise patients, their families, or caregivers that diarrhea is a common problem caused by antibacterial drugs, including plazomicin. Sometimes, frequent watery or bloody diarrhea may occur and may be a sign of a more serious intestinal infection. If severe watery or bloody diarrhea develops, tell patient to contact his or her healthcare provider.
Antibacterial Resistance
- Counsel patients, their families, or caregivers that antibacterial drugs, including plazomicin, should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When plazomicin is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by plazomicin or other antibacterial drugs in the future.
# Precautions with Alcohol
Alcohol-Plazomicin interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
Zemdri
# Look-Alike Drug Names
There is limited information regarding Plazomicin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Plazomicin | |
1609222ab7221d8e847c2fcd8fda19c9e66347f7 | wikidoc | Pleconaril | Pleconaril
# Overview
Pleconaril is an antiviral drug that was being developed by Schering-Plough for prevention of asthma exacerbations and common cold symptoms in patients exposed to picornavirus respiratory infections. Pleconaril is oral medication, which is active against viruses in the Picornaviridae family, including Enterovirus and Rhinovirus.
# History
Pleconaril was originally developed by Sanofi-Aventis, and licensed to ViroPharma in 1997. ViroPharma developed it further, and submitted a New Drug Application to the United States Food and Drug Administration (FDA) in 2001. The application was rejected, citing safety concerns; and ViroPharma re-licensed it to Schering-Plough in 2003. The Phase II clinical trial was completed in 2007. A pleconaril intranasal spray had reached phase II clinical trial for the treatment of the common cold symptoms and asthma complications. However, the results have yet to be reported.
# Mechanism of action
Pleconaril in enteroviruses, prevents the virus from exposing its RNA, and in rhinoviruses prevents the virus from attaching itself to the host cell.
Human rhinoviruses (HRVs) contain four structural proteins labeled VP1-VP4. Proteins VP1,VP2 and VP3 are eight stranded anti-parallel β-barrels. VP4 is an extended polypeptide chain on the viral capsid inner surface. Pleconaril binds to a hydrophobic pocket in the VP1 protein. Pleconaril has been shown in viral assembly to associate with viral particles. Through noncovalent, hydrophobic interactions compounds can bind to the hydrophobic pocket. Amino acids in positions Tyr152 and Val191 are a part of the VP1 drug binding pocket.
In Coxsackievirus, Pleconaril efficiency correlates to the susceptibility of CVB3 with the amino acid at position 1092 in the hydrophobic pocket. Amino acid 1092 is in close proximity to the central ring of capsid binders. The binding of pleconaril in the hydrophobic pocket creates conformational changes, which increases the rigidity of the virion and decreases the virions' ability to interact with its receptor. Drugs bind with the methylisoxazole ring close to the entrance pocket in VP1, the 3-fluromethyl oxadiazole ring at the end of the pocket and the phenyl ring in the center of the pocket.
# Clinical Trials
The results of two randomized, double blind, placebo studies found Pleconaril treatment could benefit patients suffering from colds due to picornaviruses. Participants in the studies were healthy adults from Canada and the United States, with self-diagnosed colds that had occurred within 24 hours of trial enrollment. Participants were randomly given a placebo or two 200 mg tablets to take three times daily for five days. To increase absorption it was recommended to be taken after a meal. To monitor the effectiveness of Pleconaril, participants recorded the severity of their symptoms and nasal mucosal samples were obtained at enrollment, day 3, day 6 and day 18. The two studies had a total of 2096 participates and more than 90% (1945) completed the trial. The most common reason for a participant not finishing the trial was an adverse event. Pleconaril treatment showed a reduction in nose blowing, sleep disturbance, and less cold medication used.
Another study showed over 87% of virus isolates in cell culture were inhibited by pleconaril. Virus variants were detected in 0.7% of the placebo group and 10.7% of the pleconaril group. Of the two isolates a subject from the placebo group had a resistant virus in cell culture to pleconaril. The other strain was susceptible to the drug. The pleconaril group had 21 virus strains, which remained susceptible. Resistance strains were found in 7 pleconaril patients.
# Resistance
In Human Rhinoviruses mutations in amino acids at positions 152 and 191 decrease the efficiency of pleconaril. The resistant HRV have Phenylalanine at position 152 and Leucine at position 191. In vitro studies have shown resistance to pleconaril may emerge. The wild type resistance frequency to pleconaril was about 5X10^-5. Coxsackievirus B3(CVB3) strain Nancy and other mutants carry amino acid substitutions at position 1092 of Ile1092->Leu1092 or Ile1092->Met in VP1. The Ile->Leu mutation causes complete resistance to pleconaril. The study found resistance of CVB3 to pleconaril can be overcome by substitution of the central phenyl group. Methyl and Bromine substiutions created an increase of pleconaril activity towards sensitive and resistant strains. Amino acid substitutions in the hydrophobic pocket and receptor binding region of viral capsid proteins were shown to have an effect against the sensitivity of capsid binding antivirals.
# Side Effects of Pleconaril
The U.S. Food and Drug Administration rejected pleconaril in 2002 due to the side effects. The most commonly reported side effects were mild to moderate headache, diarrhea, and nausea. Some women were having symptoms of spotting in between periods. Menstrual irregularities were reported by 3.5% of the 320 pleconaril treated women using oral contraceptives and by none of the 291 placebo treated women. In the clinical trial two women became pregnant due to the drug interfering with hormonal birth control. Other patients have described painful nasal inflammation.
Another side effect of the Pleconaril drug trials was activation of cytochrome P-450 3A enzymes. | Pleconaril
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Pleconaril is an antiviral drug that was being developed by Schering-Plough for prevention of asthma exacerbations and common cold symptoms in patients exposed to picornavirus respiratory infections.[1] Pleconaril is oral medication, which is active against viruses in the Picornaviridae family, including Enterovirus[2] and Rhinovirus.[3]
# History
Pleconaril was originally developed by Sanofi-Aventis, and licensed to ViroPharma in 1997. ViroPharma developed it further, and submitted a New Drug Application to the United States Food and Drug Administration (FDA) in 2001. The application was rejected, citing safety concerns; and ViroPharma re-licensed it to Schering-Plough in 2003. The Phase II clinical trial was completed in 2007.[1] A pleconaril intranasal spray had reached phase II clinical trial for the treatment of the common cold symptoms and asthma complications. However, the results have yet to be reported.[4]
# Mechanism of action
Pleconaril in enteroviruses, prevents the virus from exposing its RNA, and in rhinoviruses prevents the virus from attaching itself to the host cell.[5]
Human rhinoviruses (HRVs) contain four structural proteins labeled VP1-VP4. Proteins VP1,VP2 and VP3 are eight stranded anti-parallel β-barrels. VP4 is an extended polypeptide chain on the viral capsid inner surface.[6] Pleconaril binds to a hydrophobic pocket in the VP1 protein. Pleconaril has been shown in viral assembly to associate with viral particles.[7] Through noncovalent, hydrophobic interactions compounds can bind to the hydrophobic pocket.[8] Amino acids in positions Tyr152 and Val191 are a part of the VP1 drug binding pocket.[6]
In Coxsackievirus, Pleconaril efficiency correlates to the susceptibility of CVB3 with the amino acid at position 1092 in the hydrophobic pocket.[9] Amino acid 1092 is in close proximity to the central ring of capsid binders.[10] The binding of pleconaril in the hydrophobic pocket creates conformational changes, which increases the rigidity of the virion and decreases the virions' ability to interact with its receptor.[11] Drugs bind with the methylisoxazole ring close to the entrance pocket in VP1, the 3-fluromethyl oxadiazole ring at the end of the pocket and the phenyl ring in the center of the pocket.[4]
# Clinical Trials
The results of two randomized, double blind, placebo studies found Pleconaril treatment could benefit patients suffering from colds due to picornaviruses.[12] Participants in the studies were healthy adults from Canada and the United States, with self-diagnosed colds that had occurred within 24 hours of trial enrollment. Participants were randomly given a placebo or two 200 mg tablets to take three times daily for five days. To increase absorption it was recommended to be taken after a meal.[12] To monitor the effectiveness of Pleconaril, participants recorded the severity of their symptoms and nasal mucosal samples were obtained at enrollment, day 3, day 6 and day 18. The two studies had a total of 2096 participates and more than 90% (1945) completed the trial. The most common reason for a participant not finishing the trial was an adverse event. Pleconaril treatment showed a reduction in nose blowing, sleep disturbance, and less cold medication used.[12]
Another study showed over 87% of virus isolates in cell culture were inhibited by pleconaril.[7] Virus variants were detected in 0.7% of the placebo group and 10.7% of the pleconaril group. Of the two isolates a subject from the placebo group had a resistant virus in cell culture to pleconaril. The other strain was susceptible to the drug. The pleconaril group had 21 virus strains, which remained susceptible. Resistance strains were found in 7 pleconaril patients.[7]
# Resistance
In Human Rhinoviruses mutations in amino acids at positions 152 and 191 decrease the efficiency of pleconaril. The resistant HRV have Phenylalanine at position 152 and Leucine at position 191. In vitro studies have shown resistance to pleconaril may emerge. The wild type resistance frequency to pleconaril was about 5X10^-5. Coxsackievirus B3(CVB3) strain Nancy and other mutants carry amino acid substitutions at position 1092 of Ile1092->Leu1092 or Ile1092->Met in VP1. The Ile->Leu mutation causes complete resistance to pleconaril. The study found resistance of CVB3 to pleconaril can be overcome by substitution of the central phenyl group. Methyl and Bromine substiutions created an increase of pleconaril activity towards sensitive and resistant strains. Amino acid substitutions in the hydrophobic pocket and receptor binding region of viral capsid proteins were shown to have an effect against the sensitivity of capsid binding antivirals.[4]
# Side Effects of Pleconaril
The U.S. Food and Drug Administration rejected pleconaril in 2002 due to the side effects. The most commonly reported side effects were mild to moderate headache, diarrhea, and nausea.[12] Some women were having symptoms of spotting in between periods. Menstrual irregularities were reported by 3.5% of the 320 pleconaril treated women using oral contraceptives and by none of the 291 placebo treated women.[12] In the clinical trial two women became pregnant due to the drug interfering with hormonal birth control. Other patients have described painful nasal inflammation.[13]
Another side effect of the Pleconaril drug trials was activation of cytochrome P-450 3A enzymes. | https://www.wikidoc.org/index.php/Pleconaril | |
f89995c5f4a22cfca10bb11c9f0aa7d0dbdc0103 | wikidoc | Pleximeter | Pleximeter
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
A Pleximeter is a device used in percussion to absorb the energy generated by the strike from the plexor.
It can be made of wood, ivory, or other substances.
Alternatively, a practitioner's finger can function as the pleximeter. | Pleximeter
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [1] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
A Pleximeter is a device used in percussion to absorb the energy generated by the strike from the plexor.
It can be made of wood, ivory, or other substances.[1]
Alternatively, a practitioner's finger can function as the pleximeter. [2] | https://www.wikidoc.org/index.php/Pleximeter | |
8395348e43ed5ca7ec843b84316b4ff9dd2f280a | wikidoc | Plicamycin | Plicamycin
# Overview
Plicamycin (INN, also known as mithramycin; trade name Mithracin) is an antineoplastic antibiotic produced by Streptomyces plicatus. It is an RNA synthesis inhibitor. The manufacturer discontinued production in 2000. Several different structures are currently reported in different places all with the same chromomycin core, but with different stereochemistry in the glycoside chain, a 1999 study has re-investigated the compound and proposed a revised structure.
# Uses
Plicamycin has been used in the treatment of testicular cancer, Paget's disease of bone, and, rarely, the management of hypercalcemia.
Plicamycin has been tested in chronic myeloid leukemia.
Plicamycin is currently used in multiple areas of research, including cancer cell apoptosis and as a metastasis inhibitor.
One elucidated pathway shows it interacts by cross-binding chromatin GC-rich promoter motifs, thereby inhibiting gene transcription. | Plicamycin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Plicamycin (INN, also known as mithramycin; trade name Mithracin) is an antineoplastic antibiotic produced by Streptomyces plicatus. It is an RNA synthesis inhibitor.[1] The manufacturer discontinued production in 2000. Several different structures are currently reported in different places all with the same chromomycin core, but with different stereochemistry in the glycoside chain, a 1999 study has re-investigated the compound and proposed a revised structure. [2]
# Uses
Plicamycin has been used in the treatment of testicular cancer,[3][4] Paget's disease of bone,[5][6] and, rarely, the management of hypercalcemia.
Plicamycin has been tested in chronic myeloid leukemia.[7]
Plicamycin is currently used in multiple areas of research, including cancer cell apoptosis[8] and as a metastasis inhibitor.[9]
One elucidated pathway shows it interacts by cross-binding chromatin GC-rich promoter motifs, thereby inhibiting gene transcription.[10] | https://www.wikidoc.org/index.php/Plicamycin | |
84e176ecfe3504e75898e095d9be2cac6140d6d1 | wikidoc | Poi (food) | Poi (food)
Poi is a Hawaiian word for the primary Polynesian staple food made from the corm of the kalo plant (known widely as taro). Poi is produced by mashing the cooked corm (baked or steamed) to a highly viscous fluid. Water is added during mashing and again just before eating, to achieve a desired consistency, which can range from liquid to dough-like (poi can be known as two-finger or three-finger, alluding to how many fingers you would have to use to eat it, depending on its consistency).
Poi should not be confused with Tahitian po'e, which is a sweet, pudding-like dish made with bananas, papaya, or mangoes cooked with manioc and coconut cream.
# History and culture
The bowl of poi was considered so important and a sacred part of daily Hawaiian life that whenever a bowl of poi was uncovered at the family dinner table, it was believed that the spirit of Hāloa, the ancestor of the Hawaiian people, was present. This is because Hawaiians believed that the taro plant, or kalo, was the original ancestor of the Hawaiian people. Because of that, all conflict among family members had to come to an immediate halt.
Shortages in taro production in recent years due to pests and labor shortages have also resulted in shortages and higher prices for poi in Hawai‘i. At the same time, innovations in poi production have resulted in poi that stays fresh longer and tastes sweeter, but such products generally sell at a premium price and require refrigeration.
# Food
Most first-time tasters describe poi as resembling library paste—more an allusion to the texture than the fruit, which is delicate.
The flavor changes distinctly once the poi has been made. Fresh poi is sweet and edible all by itself. Each day thereafter the poi loses sweetness and turns slightly sour. Because of this, some people find poi more palatable when it is mixed with milk and/or sugar, although purists frown on this. The speed of this fermentation process depends upon the bacteria level in the poi. The bacteria are harmless, and some would even say beneficial. To slow the souring process, poi should be stored in a cool, dark location (such as a kitchen cupboard). Poi stored in the refrigerator should be squeezed out of the bag into a bowl, and a thin layer of water drizzled over the top to keep a crust from forming.
Sour poi is still quite edible with salted fish or lomi salmon on the side. Some would reasonably argue that poi is inedible beyond five days. Sourness is prevented by freezing or dehydrating, although the resulting poi tends to be bland in comparison with the fresh product. For best thawing results place in a microwave with a layer of tap water over the surface of the frozen poi. Sour poi is also used as a cooking ingredient, usually in breads and rolls. It has a smooth, creamy mouthfeel.
# Other uses
Poi has been used as a milk substitute for babies born with an allergy to dairy products because of its nutritional value. It is also used as a baby food for babies with severe food allergies. | Poi (food)
Poi is a Hawaiian word for the primary Polynesian staple food made from the corm of the kalo plant (known widely as taro). Poi is produced by mashing the cooked corm (baked or steamed) to a highly viscous fluid. Water is added during mashing and again just before eating, to achieve a desired consistency, which can range from liquid to dough-like (poi can be known as two-finger or three-finger, alluding to how many fingers you would have to use to eat it, depending on its consistency).
Poi should not be confused with Tahitian po'e, which is a sweet, pudding-like dish made with bananas, papaya, or mangoes cooked with manioc and coconut cream.
# History and culture
The bowl of poi was considered so important and a sacred part of daily Hawaiian life that whenever a bowl of poi was uncovered at the family dinner table, it was believed that the spirit of Hāloa, the ancestor of the Hawaiian people, was present. This is because Hawaiians believed that the taro plant, or kalo, was the original ancestor of the Hawaiian people.[1] Because of that, all conflict among family members had to come to an immediate halt.[2]
Shortages in taro production in recent years due to pests and labor shortages have also resulted in shortages and higher prices for poi in Hawai‘i. At the same time, innovations in poi production have resulted in poi that stays fresh longer and tastes sweeter, but such products generally sell at a premium price and require refrigeration.
# Food
Most first-time tasters describe poi as resembling library paste—more an allusion to the texture than the fruit, which is delicate.
The flavor changes distinctly once the poi has been made. Fresh poi is sweet and edible all by itself. Each day thereafter the poi loses sweetness and turns slightly sour. Because of this, some people find poi more palatable when it is mixed with milk and/or sugar, although purists frown on this. The speed of this fermentation process depends upon the bacteria level in the poi. The bacteria are harmless, and some would even say beneficial. To slow the souring process, poi should be stored in a cool, dark location (such as a kitchen cupboard). Poi stored in the refrigerator should be squeezed out of the bag into a bowl, and a thin layer of water drizzled over the top to keep a crust from forming.
Sour poi is still quite edible with salted fish or lomi salmon on the side. Some would reasonably argue that poi is inedible beyond five days. Sourness is prevented by freezing or dehydrating, although the resulting poi tends to be bland in comparison with the fresh product. For best thawing results place in a microwave with a layer of tap water over the surface of the frozen poi. Sour poi is also used as a cooking ingredient, usually in breads and rolls. It has a smooth, creamy mouthfeel.
# Other uses
Poi has been used as a milk substitute for babies born with an allergy to dairy products because of its nutritional value. It is also used as a baby food for babies with severe food allergies. | https://www.wikidoc.org/index.php/Poi_(food) | |
12e6d4cc68b4b3f207bc471e1c6c70496710d03e | wikidoc | Poison ivy | Poison ivy
Toxicodendron radicans (syn. Rhus toxicodendron, Rhus radicans; Poison ivy) is a plant in the family Anacardiaceae. The name is sometimes spelled "Poison-ivy" in an attempt to indicate that the plant is not a true Ivy (Hedera). It is a woody vine that is well known for its ability to produce urushiol, a skin irritant that causes an itching rash for most people, technically known as urushiol-induced contact dermatitis.
# Taxonomy
Poison-ivy is subject to frequent taxonomic reclassification and confusion; it is currently divided into eastern and western species in the genus Toxicodendron. At least six distinct subspecies of Toxicodendron radicans are recognized. Complicating identification and taxonomy are the fact that the species (even a particular subspecies) can be highly variable in growth habit and leaf appearance
# Habitat and range
It grows throughout much of North America, including all Canadian provinces except Newfoundland (but not the Territories) and all U.S. states except Alaska, Hawai‘i, and California, and is normally found in wooded areas, especially along edge areas. It also grows in exposed rocky areas and in open fields and disturbed areas. It also grows as a forest understory plant, although it is only somewhat shade tolerant. The plant is extremely common in suburban and exurban areas of New England, the Middle Atlantic and Southeastern United States. It rarely grows at altitudes above 1,500 meters (5,000 ft), although the altitude limit varies in different locations. The plants can grow as a shrub up to about 1.2 meters (4 ft) tall, as a groundcover 10–25 centimeters (4–10 in) high, or as a climbing vine on various supports. Older vines on substantial supports send out lateral branches that may at first be mistaken for tree limbs.
It is not particularly sensitive to soil moisture, although it does not grow in desert or arid conditions. It grows in a wide variety of soil types, and soil pH from 6.0 (acidic) to 7.9 (moderately alkaline). It can grow in areas subject to seasonal flooding or brackish water.
It is more common now than when Europeans first entered North America. Real estate development adjacent to wild, undeveloped land has engendered "edge effects," enabling poison ivy to form vast, lush colonies in such places. It is listed as a noxious weed in the U.S. states of Minnesota and Michigan.
# Characteristic appearance
The leaves are ternate with three almond-shaped leaflets. The berries (actually drupes) are a grayish-white color and are a favorite winter food of some birds. Hence the mnemonic,
"Leaves of three, let it be; berries white, danger in sight."
Another version is:
"Leaves of three let it be; hairy vine, no friend of mine."
The color ranges from light green (usually the younger leaves) to dark green (mature leaves), turning bright red in fall. The leaflets of mature leaves are somewhat shiny.The leaflets are 3-12 cm long, rarely up to 30 cm. Each leaflet has a few or no teeth along its edge, and the leaf surface is smooth.
Leaflet clusters are alternate on the vine, and the plant has no thorns. These three characteristics: (a) clusters of three leaflets, (b) alternate, and (c) lack of thorns, are sufficient to positively identify the plant. If it is growing up the trunk of a tree, the presence of copious root-hairs will identify it, leading to the "hairy vine, no friend of mine" warning.
Poison ivy spreads both vegetatively and sexually. The vines put down adventitious roots, or the plant can spread from rhizomes or root crowns. The plant flowers in May to July and produces mature fruits by August to November. Seeds are spread mainly by animals, and are viable after passing through the digestive tract of birds.
# Effects on the body
The reaction caused by poison-ivy, urushiol-induced contact dermatitis, is an allergic reaction. Around 15% to 30% of people have no allergic response, but most if not all will become sensitized over time with repeated or more concentrated exposure to urushiol. Note that reactions that worsen over time may progress to anaphylaxis and can therefore be dangerous, even life-threatening.
For those who are affected by urushiol, it causes a very irritating rash. In extreme cases, corticosteroids can be needed to treat rashes and severe itching. The first symptom of contact is a severe itching of the skin that develops into reddish colored inflammation or non-colored bumps, and then blistering of the skin occurs. In severe cases, clear fluids ooze from open blistered sores. Once the urushiol poison has had contact with the skin, it is quickly bound to the skin.
The oozing fluids released by itching blisters do not spread the poison. The appearance of a spreading rash indicates that some areas received more of the poison and reacted sooner than other areas. The blisters and oozing result from blood vessels that develop gaps and leak fluid through the skin; if the skin is cooled, the vessels constrict and leak less. If poison ivy is burned and the smoke then inhaled, this rash will appear on the lining of the lungs, causing extreme pain and possibly fatal respiratory difficulty. If poison ivy is eaten, the digestive tract, airway, kidneys or other organs can be damaged.
Understanding why new lesions may develop for two weeks (studied on forearm) after one exposure was made clear by a University of Miami scientist: larger amounts have earliest onset and largest reaction, smallest produce a delayed reaction. The overall severity 'progresses' with the combined active lesions. Therefore, the last new lesion should occur at two weeks after last exposure, the total rash (untreated) may go on for 3-4 weeks.
Urushiol oil can remain active for several years, so handling dead leaves or vines can cause a reaction. In addition, oil transferred from the plant to other objects (such as pet fur) can cause the rash if it comes into contact with the skin.
People who are sensitive to poison-ivy can also experience a similar rash from mangoes. Mangoes are in the same family (Anacardiaceae) as poison ivy; the sap of the mango tree and skin of mangoes has a chemical compound similar to urushiol.
Similar reactions have been reported occasionally from contact with the related aromatic sumac or Japanese lacquer tree.
# Confusion with other plants
- Boxelder Maple (Acer negundo) saplings can look almost indistinguishable from poison ivy. While Boxelder Maples often have five or seven leaflets, three leaflets are also common. The two can be differentiated by the fact that Poison-ivy has alternate leaves, while the maple has opposite leaves; in other words, by observing where the leaf stalk (the "branch" the three leaflets are attached to) meets the main branch. Another leaf stalk directly on the opposite side is characteristic of Boxelder Maple. If the three-leaflet leaves alternate along the main branch, it may be Poison-ivy.
- Virginia creeper (Parthenocissus quinquefolia) vines can look like Poison-ivy. The younger leaves can consist of three leaflets but have a few more serrations along the leaf edge, and the leaf surface is somewhat wrinkled. Most Virginia creeper leaves have five leaflets, however. Virginia creeper and poison ivy very often grow together, even on the same tree.
- Western Poison-oak (Toxicodendron diversilobum) leaflets also come in threes on the end of a stem, but each leaflet is shaped somewhat like an oak leaf. Western Poison-oak only grows in the western United States and Canada, although many people will refer to poison ivy as poison-oak. This is because poison ivy will grow in either the ivy-like form or the brushy oak-like form depending on the moisture and brightness of its environment. The ivy form likes shady areas with only a little sun, tends to climb the trunks of trees, and can spread rapidly along the ground.
- Poison Sumac (Toxicodendron vernix) has compound leaves with 7–15 leaflets. Poison sumac never has only three leaflets.
- Kudzu (Pueraria lobata) is a non-toxic edible vine that scrambles extensively over lower vegetation or grows high into trees. Kudzu is an invasive species in the southern United States. Like poison ivy it has three leaflets, but the leaflets are bigger than those of poison ivy and are pubescent underneath with hairy margins.
- Blackberry and raspberry vines bear a passing resemblance to poison ivy, with which may share territory. The chief difference between blackberry vines and poison ivy is that blackberry vines have spines on them, whereas poison ivy is smooth. Also, the three-leaflet pattern of blackberry vine leaves changes as the plant grows: the two bottom leaves both split into two leaves, for a total of five in a cluster. They have many teeth along the leaf edge, and the top surface of their leaves is very wrinkled where the veins are, and the bottom of the leaves is light minty - greenish white, while poison ivy is all green. The stem and vine of poison ivy are brown and woody, while blackberry stems are green with thorns.
- The thick vines of grape, with no rootlets visible, differ from the vines of poison ivy, which have so many rootlets that the stem going up a tree looks furry.
# Treatment | Poison ivy
Toxicodendron radicans (syn. Rhus toxicodendron, Rhus radicans; Poison ivy[1]) is a plant in the family Anacardiaceae. The name is sometimes spelled "Poison-ivy" in an attempt to indicate that the plant is not a true Ivy (Hedera). It is a woody vine that is well known for its ability to produce urushiol, a skin irritant that causes an itching rash for most people, technically known as urushiol-induced contact dermatitis.
# Taxonomy
Poison-ivy is subject to frequent taxonomic reclassification and confusion; it is currently divided into eastern and western species in the genus Toxicodendron. At least six distinct subspecies of Toxicodendron radicans are recognized. Complicating identification and taxonomy are the fact that the species (even a particular subspecies) can be highly variable in growth habit and leaf appearance
# Habitat and range
It grows throughout much of North America, including all Canadian provinces except Newfoundland (but not the Territories) and all U.S. states except Alaska, Hawai‘i, and California, and is normally found in wooded areas, especially along edge areas. It also grows in exposed rocky areas and in open fields and disturbed areas. It also grows as a forest understory plant, although it is only somewhat shade tolerant[1]. The plant is extremely common in suburban and exurban areas of New England, the Middle Atlantic and Southeastern United States. It rarely grows at altitudes above 1,500 meters (5,000 ft), although the altitude limit varies in different locations[1]. The plants can grow as a shrub up to about 1.2 meters (4 ft) tall, as a groundcover 10–25 centimeters (4–10 in) high, or as a climbing vine on various supports. Older vines on substantial supports send out lateral branches that may at first be mistaken for tree limbs.
It is not particularly sensitive to soil moisture, although it does not grow in desert or arid conditions. It grows in a wide variety of soil types, and soil pH from 6.0 (acidic) to 7.9 (moderately alkaline). It can grow in areas subject to seasonal flooding or brackish water.[1]
It is more common now than when Europeans first entered North America. Real estate development adjacent to wild, undeveloped land has engendered "edge effects," enabling poison ivy to form vast, lush colonies in such places. It is listed as a noxious weed in the U.S. states of Minnesota and Michigan.
# Characteristic appearance
The leaves are ternate with three almond-shaped leaflets. The berries (actually drupes) are a grayish-white color and are a favorite winter food of some birds. Hence the mnemonic,
"Leaves of three, let it be; berries white, danger in sight."
Another version is:
"Leaves of three let it be; hairy vine, no friend of mine."[2]
The color ranges from light green (usually the younger leaves) to dark green (mature leaves), turning bright red in fall. The leaflets of mature leaves are somewhat shiny.The leaflets are 3-12 cm long, rarely up to 30 cm. Each leaflet has a few or no teeth along its edge, and the leaf surface is smooth.
Leaflet clusters are alternate on the vine, and the plant has no thorns. These three characteristics: (a) clusters of three leaflets, (b) alternate, and (c) lack of thorns, are sufficient to positively identify the plant. If it is growing up the trunk of a tree, the presence of copious root-hairs will identify it,[3] leading to the "hairy vine, no friend of mine" warning.
Poison ivy spreads both vegetatively and sexually. The vines put down adventitious roots, or the plant can spread from rhizomes or root crowns. The plant flowers in May to July and produces mature fruits by August to November. Seeds are spread mainly by animals, and are viable after passing through the digestive tract of birds.[1]
# Effects on the body
The reaction caused by poison-ivy, urushiol-induced contact dermatitis, is an allergic reaction. Around 15%[4] to 30%[5] of people have no allergic response, but most if not all will become sensitized over time with repeated or more concentrated exposure to urushiol. Note that reactions that worsen over time may progress to anaphylaxis and can therefore be dangerous, even life-threatening.
For those who are affected by urushiol, it causes a very irritating rash. In extreme cases, corticosteroids can be needed to treat rashes and severe itching. The first symptom of contact is a severe itching of the skin that develops into reddish colored inflammation or non-colored bumps, and then blistering of the skin occurs. In severe cases, clear fluids ooze from open blistered sores. Once the urushiol poison has had contact with the skin, it is quickly bound to the skin.
The oozing fluids released by itching blisters do not spread the poison. The appearance of a spreading rash indicates that some areas received more of the poison and reacted sooner than other areas. The blisters and oozing result from blood vessels that develop gaps and leak fluid through the skin; if the skin is cooled, the vessels constrict and leak less. If poison ivy is burned and the smoke then inhaled, this rash will appear on the lining of the lungs, causing extreme pain and possibly fatal respiratory difficulty. If poison ivy is eaten, the digestive tract, airway, kidneys or other organs can be damaged.
Understanding why new lesions may develop for two weeks (studied on forearm) after one exposure was made clear by a University of Miami scientist: larger amounts have earliest onset and largest reaction, smallest produce a delayed reaction. The overall severity 'progresses' with the combined active lesions. Therefore, the last new lesion should occur at two weeks after last exposure, the total rash (untreated) may go on for 3-4 weeks.
Urushiol oil can remain active for several years, so handling dead leaves or vines can cause a reaction. In addition, oil transferred from the plant to other objects (such as pet fur) can cause the rash if it comes into contact with the skin.[6]
People who are sensitive to poison-ivy can also experience a similar rash from mangoes. Mangoes are in the same family (Anacardiaceae) as poison ivy; the sap of the mango tree and skin of mangoes has a chemical compound similar to urushiol. [7]
Similar reactions have been reported occasionally from contact with the related aromatic sumac or Japanese lacquer tree.
# Confusion with other plants
- Boxelder Maple (Acer negundo) saplings can look almost indistinguishable from poison ivy. While Boxelder Maples often have five or seven leaflets, three leaflets are also common. The two can be differentiated by the fact that Poison-ivy has alternate leaves, while the maple has opposite leaves; in other words, by observing where the leaf stalk (the "branch" the three leaflets are attached to) meets the main branch. Another leaf stalk directly on the opposite side is characteristic of Boxelder Maple. If the three-leaflet leaves alternate along the main branch, it may be Poison-ivy.
- Virginia creeper (Parthenocissus quinquefolia) vines can look like Poison-ivy. The younger leaves can consist of three leaflets but have a few more serrations along the leaf edge, and the leaf surface is somewhat wrinkled. Most Virginia creeper leaves have five leaflets, however. Virginia creeper and poison ivy very often grow together, even on the same tree.
- Western Poison-oak (Toxicodendron diversilobum) leaflets also come in threes on the end of a stem, but each leaflet is shaped somewhat like an oak leaf. Western Poison-oak only grows in the western United States and Canada, although many people will refer to poison ivy as poison-oak. This is because poison ivy will grow in either the ivy-like form or the brushy oak-like form depending on the moisture and brightness of its environment. The ivy form likes shady areas with only a little sun, tends to climb the trunks of trees, and can spread rapidly along the ground.
- Poison Sumac (Toxicodendron vernix) has compound leaves with 7–15 leaflets. Poison sumac never has only three leaflets.
- Kudzu (Pueraria lobata) is a non-toxic edible vine that scrambles extensively over lower vegetation or grows high into trees. Kudzu is an invasive species in the southern United States. Like poison ivy it has three leaflets, but the leaflets are bigger than those of poison ivy and are pubescent underneath with hairy margins.
- Blackberry and raspberry vines bear a passing resemblance to poison ivy, with which may share territory. The chief difference between blackberry vines and poison ivy is that blackberry vines have spines on them, whereas poison ivy is smooth. Also, the three-leaflet pattern of blackberry vine leaves changes as the plant grows: the two bottom leaves both split into two leaves, for a total of five in a cluster. They have many teeth along the leaf edge, and the top surface of their leaves is very wrinkled where the veins are, and the bottom of the leaves is light minty - greenish white, while poison ivy is all green. The stem and vine of poison ivy are brown and woody, while blackberry stems are green with thorns.
- The thick vines of grape, with no rootlets visible, differ from the vines of poison ivy, which have so many rootlets that the stem going up a tree looks furry.
# Treatment | https://www.wikidoc.org/index.php/Poison-ivy_(plant) | |
b738cbc092c7663fc4e56138d40b526a796c6cbb | wikidoc | Polyiodide | Polyiodide
The polyiodides are a class of polyatomic halide anions composed entirely of iodine atoms.
The triiodide ion, I3-, is the simplest polyiodide. Larger polyiodides are known, with single or multiple negative charges.
The basic 'building blocks' of polyiodides can be considered as I2, I-, and I3-. The more complex polyiodides can be made by addition of I2 to solutions containing I- and I3-, with the condition of presence of large cations to stabilise them. With cations much smaller than NMe4+, it is either not possible to precipitate the salt (for example with Na+ or K+ cations), or the crystal structure will show asymmetric iodide anions, like in caesium triiodide, CsI3.
The shapes of the polyiodides depend on their associated cations quite strongly, however some of the more simple ions have roughly constant shapes:
- I5- normally adopts a V-shaped structure and can be regarded as two I2 molecules attached to an I- ion. Bonding in this species suggests p-orbital interactions, and the bond lengths of approximately 2.8Å for the terminal bonds and 3.17Å for the centre bonds supports the I2 and I-bonding model.
- I42- is notionally composed of either two I2 species, or is almost equally bonded, depending on environment of the ion. Both models are linear.
# Footnotes
- ↑ W.W. Porterfield, "Inorganic Chemistry", Addison Wesley, Reading, Mass, USA (1984), pp 223-224
- ↑ P.W. Atkins, D.W. Shriver, "Inorganic Chemistry", 3rd Edn., OUP, Oxford, UK (2001) | Polyiodide
The polyiodides are a class of polyatomic halide anions composed entirely of iodine atoms.
The triiodide ion, I3-, is the simplest polyiodide. Larger polyiodides are known, with single or multiple negative charges.
The basic 'building blocks' of polyiodides can be considered as I2, I-, and I3-. The more complex polyiodides can be made by addition of I2 to solutions containing I- and I3-, with the condition of presence of large cations to stabilise them. With cations much smaller than NMe4+, it is either not possible to precipitate the salt (for example with Na+ or K+ cations), or the crystal structure will show asymmetric iodide anions, like in caesium triiodide, CsI3.
The shapes of the polyiodides depend on their associated cations quite strongly, however some of the more simple ions have roughly constant shapes:
- I5- normally adopts a V-shaped structure and can be regarded as two I2 molecules attached to an I- ion. Bonding in this species suggests p-orbital interactions[1], and the bond lengths of approximately 2.8Å for the terminal bonds and 3.17Å for the centre bonds[2] supports the I2 and I-bonding model.
- I42- is notionally composed of either two I2 species, or is almost equally bonded, depending on environment of the ion. Both models are linear.
# Footnotes
- ↑ W.W. Porterfield, "Inorganic Chemistry", Addison Wesley, Reading, Mass, USA (1984), pp 223-224
- ↑ P.W. Atkins, D.W. Shriver, "Inorganic Chemistry", 3rd Edn., OUP, Oxford, UK (2001) | https://www.wikidoc.org/index.php/Polyiodide | |
aa882ee5acc08af830aa13b2390071a6cd33ab8c | wikidoc | Polyketide | Polyketide
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
Polyketides are secondary metabolites from bacteria, fungi, plants, and animals. Secondary metabolites seem to be unnecessary for an organism’s ontogeny, but appear to have applications such as defence and intercellular communication. Polyketides are derived from the polymerization of acetyl and propionyl subunits in a similar process to fatty acid synthesis. They also serve as building blocks for a broad range of natural products or are derivatized.
Polyketides are structurally a very diverse family of natural products with an extremely broad range of biological activities and pharmacological properties. Polyketide antibiotics, antifungals, cytostatics, anticholesterolemics, antiparasitics, coccidiostatics, animal growth promotants and natural insecticides are in commercial use.
# Examples
- Macrolides
Picromycin, the first isolated macrolide (1950)
The antibiotics erythromycin A, clarithromycin, and azithromycin
The immunosuppressant tacrolimus (FK506)
- Picromycin, the first isolated macrolide (1950)
- The antibiotics erythromycin A, clarithromycin, and azithromycin
- The immunosuppressant tacrolimus (FK506)
- Polyene antibiotics
Amphotericin
- Amphotericin
- Tetracyclines
The tetracycline family of antibiotics
- The tetracycline family of antibiotics
- Others
Discodermolide
- Discodermolide
# Biosynthesis
Polyketides are synthesized by one or more specialized polyketide synthase (PKS) enzymes. | Polyketide
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [1] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
Polyketides are secondary metabolites from bacteria, fungi, plants, and animals. Secondary metabolites seem to be unnecessary for an organism’s ontogeny, but appear to have applications such as defence and intercellular communication. Polyketides are derived from the polymerization of acetyl and propionyl subunits in a similar process to fatty acid synthesis. They also serve as building blocks for a broad range of natural products or are derivatized.
Polyketides are structurally a very diverse family of natural products with an extremely broad range of biological activities and pharmacological properties. Polyketide antibiotics, antifungals, cytostatics, anticholesterolemics, antiparasitics, coccidiostatics, animal growth promotants and natural insecticides are in commercial use.
# Examples
- Macrolides
Picromycin, the first isolated macrolide (1950)
The antibiotics erythromycin A, clarithromycin, and azithromycin
The immunosuppressant tacrolimus (FK506)
- Picromycin, the first isolated macrolide (1950)
- The antibiotics erythromycin A, clarithromycin, and azithromycin
- The immunosuppressant tacrolimus (FK506)
- Polyene antibiotics
Amphotericin
- Amphotericin
- Tetracyclines
The tetracycline family of antibiotics
- The tetracycline family of antibiotics
- Others
Discodermolide
- Discodermolide
# Biosynthesis
Polyketides are synthesized by one or more specialized polyketide synthase (PKS) enzymes. | https://www.wikidoc.org/index.php/Polyketide | |
1794b1a874ef4d785f872d51d69604ec7baf47ca | wikidoc | Polyphenol | Polyphenol
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
# Overview
Polyphenols are a group of chemical substances found in plants, characterized by the presence of more than one phenol group per molecule. Polyphenols are generally further subdivided into hydrolyzable tannins, which are gallic acid esters of glucose and other sugars; and phenylpropanoids, such as lignins, flavonoids, and condensed tannins.
# Chemistry
## Classification and Nomenclature
The subdivision of polyphenols into tannins, lignins, and flavonoids is derived from the variety of simple polyphenolic units derived from secondary plant metabolism of the shikimate pathway as well as classical divisions based upon the relative importance of each base component to different fields of study. Tannin chemistry originated in the importance of the eponymously named tannic acid to the tanning industry; lignins to the chemistry of soil and plant structure; and flavonoids to the chemistry of plant secondary metabolites for plant defense, and flower color (e.g. from anthocyanins).
Polyphenols are also grouped and classified by the type and number of phenolic subcomponents present. More than one subcomponent can be present on a given polyphenol.
The phenolic unit can often be esterified or methylated. It can also be found dimerized or further polymerized, creating a new class of polyphenol. For example, ellagic acid is a dimer of gallic acid and forms the class of ellagitannins, or a catechin and a gallocatechin can combine to form the red compound theaflavin, a process which also results in the large class of brown thearubigins in tea.
# In Foods
Notable sources of polyphenols include berries, tea, beer, grapes/wine, olive oil, chocolate/cocoa, walnuts, peanuts, pomegranates, yerba mate, and other fruits and vegetables.
High levels of polyphenols can generally be found in the fruit skins.
# Health benefits
Polyphenols were once briefly known as Vitamin P. However they were quickly found out to be non-essential and reclassified. The health benefits of specific polyphenols such as quercetin are well-established, there are less well-established claims of health benefits from all types of polyphenols.
Research indicates that polyphenols may have antioxidant characteristics with potential health benefits. They may reduce the risk of cardiovascular disease and cancer.
Polyphenols have also been investigated as a source of additional health benefit in organic produce, but no conclusion was made.
Polyphenols bind with nonheme iron (e.g. from plant sources) in vitro in model systems.
This may decrease its absorption by the body. | Polyphenol
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [1] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
# Overview
Polyphenols are a group of chemical substances found in plants, characterized by the presence of more than one phenol group per molecule. Polyphenols are generally further subdivided into hydrolyzable tannins, which are gallic acid esters of glucose and other sugars; and phenylpropanoids, such as lignins, flavonoids, and condensed tannins.
# Chemistry
## Classification and Nomenclature
The subdivision of polyphenols into tannins, lignins, and flavonoids is derived from the variety of simple polyphenolic units derived from secondary plant metabolism of the shikimate pathway[1] as well as classical divisions based upon the relative importance of each base component to different fields of study. Tannin chemistry originated in the importance of the eponymously named tannic acid to the tanning industry; lignins to the chemistry of soil and plant structure; and flavonoids to the chemistry of plant secondary metabolites for plant defense, and flower color (e.g. from anthocyanins).
Polyphenols are also grouped and classified by the type and number of phenolic subcomponents present. More than one subcomponent can be present on a given polyphenol.
The phenolic unit can often be esterified or methylated. It can also be found dimerized or further polymerized, creating a new class of polyphenol. For example, ellagic acid is a dimer of gallic acid and forms the class of ellagitannins, or a catechin and a gallocatechin can combine to form the red compound theaflavin, a process which also results in the large class of brown thearubigins in tea.
# In Foods
Notable sources of polyphenols include berries, tea, beer, grapes/wine, olive oil, chocolate/cocoa, walnuts, peanuts, pomegranates, yerba mate, and other fruits and vegetables.
High levels of polyphenols can generally be found in the fruit skins.
# Health benefits
Polyphenols were once briefly known as Vitamin P. However they were quickly found out to be non-essential and reclassified. The health benefits of specific polyphenols such as quercetin are well-established, there are less well-established claims of health benefits from all types of polyphenols.
Research indicates that polyphenols may have antioxidant characteristics with potential health benefits. They may reduce the risk of cardiovascular disease and cancer.
[2]
Polyphenols have also been investigated as a source of additional health benefit in organic produce, but no conclusion was made.
[3]
Polyphenols bind with nonheme iron (e.g. from plant sources) in vitro in model systems.
[4]
This may decrease its absorption by the body. | https://www.wikidoc.org/index.php/Polyphenol | |
97f4a9841a788efbb5de0ce806371cae1be24fa1 | wikidoc | Polyphenon | Polyphenon
Polyphenon is a high grade green tea polyphenol extract. It is derived through a water based extraction method from green tea, purifying the polyphenol catechin molecules which are the bioactive molecule thought to be responsible for the health benefits of green tea. It has been adopted as a functional ingredient by supplements and food manufacturers for a variety of consumer products.
Polyphenon E is the form used in clinical cancer trials funded through the National Cancer Institute (NCI) and other academic institutions, to further investigate the benefits of tea catechins to humans.
Tea catechins found in Polyphenon have been reported to assist in many other areas of human health, including:
- Antiviral properties
- Antibacterial & probiotic benefits
- Managing LDL cholesterol levels
- Weight management
- Antioxidative protection against free radicals
- Maintenance of healthy blood pressure levels
- Maintenance of healthy blood sugar levels
- Anti-allergy regulation
- Chemoprevention | Polyphenon
Polyphenon is a high grade green tea polyphenol extract. It is derived through a water based extraction method from green tea, purifying the polyphenol catechin molecules which are the bioactive molecule thought to be responsible for the health benefits of green tea. It has been adopted as a functional ingredient by supplements and food manufacturers for a variety of consumer products.
Polyphenon E is the form used in clinical cancer trials funded through the National Cancer Institute (NCI) [1] and other academic institutions, to further investigate the benefits of tea catechins to humans.
Tea catechins found in Polyphenon have been reported to assist in many other areas of human health, including:
- Antiviral properties
- Antibacterial & probiotic benefits
- Managing LDL cholesterol levels
- Weight management
- Antioxidative protection against free radicals
- Maintenance of healthy blood pressure levels
- Maintenance of healthy blood sugar levels
- Anti-allergy regulation
- Chemoprevention | https://www.wikidoc.org/index.php/Polyphenon | |
be6a465596f520d7fd75968e8c8e4d48f225cfa3 | wikidoc | Polyspermy | Polyspermy
In biology, polyspermy describes an egg that has been fertilized by more than one sperm. Diploid organisms normally contain two copies of each chromosome, one from each parent. The cell resulting from polyspermy, on the other hand, contains three or more copies of each chromosome -- one from the egg and one each from multiple sperm. Usually, the result is an inviable zygote. This may occur because sperm have become too efficient at reaching and fertilizing eggs due to the selective pressures of sperm competition. This is often deleterious to the female, in other words the male-male competition among sperm spills over to create sexual conflict.
# Evolved defenses against polyspermy
The eggs of sexually reproducing organisms are adapted to avoid this situation. The defenses are particularly well characterized in the sea urchin, which responds to the acceptance of one sperm by inhibiting the successful penetration of the egg by subsequent sperm. Similar defenses exist in other eukaryotes.
The prevention of polyspermy in sea urchins depends on a change in the electrical charge across the surface of the egg, which is caused by the fusion of the first sperm with the egg. Unfertilized sea urchin eggs have a negative charge inside, but the charge becomes positive upon fertilization. When sea urchin sperm encounter an egg with a positive charge, sperm-egg fusion is blocked. Thus, after the first sperm contacts the egg and causes the change, subsequent sperm are prevented from fusing. This "electrical polyspermy block" is thought to result because a positively charged molecule in the sperm surface membrane is repelled by the positive charge at the egg surface.
Electrical polyspermy blocks operate in many animal species, including frogs, clams, and marine worms, but not in the several mammals that have been studied (hamster, rabbit, mouse). In species without an electrical block, polyspermy is usually prevented by secretion of materials that establish a mechanical barrier to polyspermy. Animals such as a sea urchins have a two-step polyspermy prevention strategy, with the fast, but transient, electrical block superseded after the first minute or so by a more slowly developing permanent mechanical block. It is thought that electrical blocks evolved in those species where a very fast block to polyspermy is needed, due to the presence of many sperm arriving simultaneously at the egg surface, as occurs in animals such as sea urchins. In sea urchins, fertilization occurs externally in the ocean, such that hundreds of sperm can encounter the egg within several seconds.
In mammals, in which fertilization occurs internally, fewer sperm reach the fertilization site in the oviduct. This may be the result of the female genital tract being adapted to minimize the number of sperm reaching the egg. Nevertheless, polyspermy preventing mechanisms are essential in mammals; a secretion reaction, the "cortical reaction" modifies the extracellular coat of the egg (the zona pellucida), and additional mechanisms that are not well understood modify the egg's plasma membrane.
Female defenses select for ever more aggressive male sperm however, leading to an evolutionary arms race. On the one hand, polyspermy creates inviable zygotes and lowers female fitness, but on the other, defenses may prevent fertilization altogether. This leads to a delicate compromise between the two, and has been suggested as one possible cause for the relatively high infertility rates seen in mammalian species. | Polyspermy
In biology, polyspermy describes an egg that has been fertilized by more than one sperm. Diploid organisms normally contain two copies of each chromosome, one from each parent. The cell resulting from polyspermy, on the other hand, contains three or more copies of each chromosome -- one from the egg and one each from multiple sperm. Usually, the result is an inviable zygote. This may occur because sperm have become too efficient at reaching and fertilizing eggs due to the selective pressures of sperm competition. This is often deleterious to the female, in other words the male-male competition among sperm spills over to create sexual conflict.[1]
# Evolved defenses against polyspermy
The eggs of sexually reproducing organisms are adapted to avoid this situation.[2] The defenses are particularly well characterized in the sea urchin, which responds to the acceptance of one sperm by inhibiting the successful penetration of the egg by subsequent sperm. Similar defenses exist in other eukaryotes.
The prevention of polyspermy in sea urchins depends on a change in the electrical charge across the surface of the egg, which is caused by the fusion of the first sperm with the egg. [3] Unfertilized sea urchin eggs have a negative charge inside, but the charge becomes positive upon fertilization. When sea urchin sperm encounter an egg with a positive charge, sperm-egg fusion is blocked. Thus, after the first sperm contacts the egg and causes the change, subsequent sperm are prevented from fusing. This "electrical polyspermy block" is thought to result because a positively charged molecule in the sperm surface membrane is repelled by the positive charge at the egg surface.[4]
Electrical polyspermy blocks operate in many animal species, including frogs, clams, and marine worms, but not in the several mammals that have been studied (hamster, rabbit, mouse). [5] In species without an electrical block, polyspermy is usually prevented by secretion of materials that establish a mechanical barrier to polyspermy. Animals such as a sea urchins have a two-step polyspermy prevention strategy, with the fast, but transient, electrical block superseded after the first minute or so by a more slowly developing permanent mechanical block. It is thought that electrical blocks evolved in those species where a very fast block to polyspermy is needed, due to the presence of many sperm arriving simultaneously at the egg surface, as occurs in animals such as sea urchins. In sea urchins, fertilization occurs externally in the ocean, such that hundreds of sperm can encounter the egg within several seconds.
In mammals, in which fertilization occurs internally, fewer sperm reach the fertilization site in the oviduct. This may be the result of the female genital tract being adapted to minimize the number of sperm reaching the egg. [6] Nevertheless, polyspermy preventing mechanisms are essential in mammals; a secretion reaction, the "cortical reaction" modifies the extracellular coat of the egg (the zona pellucida), and additional mechanisms that are not well understood modify the egg's plasma membrane. [7]
Female defenses select for ever more aggressive male sperm however, leading to an evolutionary arms race. On the one hand, polyspermy creates inviable zygotes and lowers female fitness, but on the other, defenses may prevent fertilization altogether. This leads to a delicate compromise between the two, and has been suggested as one possible cause for the relatively high infertility rates seen in mammalian species.[8] | https://www.wikidoc.org/index.php/Polyspermy | |
6bc3e6bbd1a4b171177c891dcf0bb2b0ef122a9e | wikidoc | Population | Population
In sociology and biology a population is the collection of people or organisms of a particular species living in a given geographic area or mortality, and migration, though the field encompasses many dimensions of population change including the family (marriage and divorce), public health, work and the labor force, and family planning. Various aspects of human behavior in populations are also studied in sociology, economics, and geography. Study of populations is almost always governed by the laws of probability, and the conclusions of the studies may thus not always be applicable to some individuals. This odd factor may be reduced by statistical means, but such a generalization may be too vague to imply anything. Demography is used extensively in marketing, which relates to economic units, such as retailers, to potential customers. For example, a coffee shop that wants to sell to a younger audience looks at the demographics of an area to be able to appeal to this younger audience.
# World population
According to estimates published by the United States Census Bureau, the world population hit 6.5 billion (6,500,000,000) on February 25 2006. It is estimated that by 2012, the Earth will be home to 7 billion. The United Nations Population Fund designated October 12 1999 as the approximate day on which world population reached 6 billion. This was about 12 years after world population reached 5 billion, in 1987. However, the population of some countries, such as Nigeria, is not even known to the nearest million, so there is a considerable margin of error in such estimates.
In 2007 the United Nations Population Division projected that the world's population will likely surpass 9 billion in 2050. The last 50 years have seen a rapid increase in population due to medical advances and substantial increase in agricultural productivity, particularly in the period 1960 to 1995 made by the Green Revolution.
# Population decline
Population decline is a decrease in a region's population. It can be caused by sub-replacement fertility, heavy emigration, or more dramatically disease, famine, or war. In the past, population decline was mostly caused by disease. The Black Death in Europe and the arrival of Old World diseases to the Americas all caused massive population declines.
In biology, population decline of a species is usually described as a result of gradually worsening environmental factors, such as prolonged drought or loss of inhabitable areas for the studied species. These, or other factors, may lead to a small population, in which case genetic factors may become dominant in the survival, or extinction of a population.
Under-population is recognized when there are more resources in an area (for example, food, energy and minerals) than can be used by the people living there. Hence, the maximum human potential of that area is not realized as the resources are not fully exploited. Countries like Canada and Australia can export the surplus of food, energy, and mineral resources, have high incomes, good living conditions and level of technology and immigration.
Some rural areas close to major cities in advanced countries such as the UK are under-populated due to outward migration. In the UK, the Southwest Wales and the highlands of Scotland are less densely populated compared to the rest of the country. This has also happened in older declining industrial areas and the outward movement or migration has been due to lower wages and unemployment. This phenomenon results in a decline in a population. With fewer people, there is a decrease in demands for services. The lower level of services therefore sometimes encourages further outward migration.
However, when making comparisons on a global scale, there does not seem to be any direct correlation between population density and over- or under-population. For example, Brazil is 'over-populated' with two people per square kilometer, whereas portions of California may have further carrying capacity with over 500 people per square kilometer. Therefore, this is related to the amount of available resources. Similarly, population density is not necessarily related to the GDP per capita. The Netherlands and Germany, for example, both have a high GDP per capita and a high population density whereas Canada and Australia have a high GDP per capita and a low population density, while Bangladesh has low GDP per capita and a high population density, etc.
The balance of population and resources within a country may be uneven. For example, a country may have a population, which is too great for one resource such as energy, yet too small to use fully a second such as food supply.
Various attempts to address population decline have been made:
- Improving communication networks and transport facilities makes remote places more accessible. This strategy was used in developing countries like Nigeria and Tanzania where modern railway networks were established, but these attempts were not very successful.
- Establishment of new capital cities, new towns, or development growth points. For example, Brazil has a population imbalance between the coastal parts from east and south and the rest of the country. Brasilia, the new capital was created in the 1960s in the country's geographical center to attract people into the North and Center-West regions, but this had limited effect, as most of these unpopulated areas are occupied by large forests and swamps.
- Regional development programs. In Brazil, the interior improvement of transport networks and development of secondary growth points and rural development have all been enhanced to attract more people and discourage out-migration. The standard of living in such regions is expected to gradually improve due to improved resource utilization.
- Pronatalist policies providing tax incentives, paid maternity leaves, daycare, or other benefits to families to bear more children. Such policies have been tried, with mixed success, in Western Europe in recent years.
# Population control
Population control is the practice of curtailing population increase, usually by reducing the birth rate. Surviving records from Ancient Greece document the first known examples of population control. These include the colonization movement, which saw Greek outposts being built across the Mediterranean and Black Sea basins to accommodate the excess population of individual states. An important example of mandated population control is China's one-child policy, in which having more than one child is made extremely unattractive. This has led to allegations that practices like infanticide, forced abortions, and forced sterilization are used as a result of the policy.
It is helpful to distinguish between fertility control as individual decision-making and population control as a governmental or state-level policy of regulating population growth. Fertility control may occur when individuals or couples or families take steps to decrease or to regulate the timing of their own child-bearing. In Ansley Coale's oft-cited formulation, three preconditions for a sustained decline in fertility are: (1) acceptance of calculated choice (as opposed to fate or chance or divine will) as a valid element in fertility, (2) perceived advantages from reduced fertility, and (3) knowledge and mastery of effective techniques of control. In contrast to a society with natural fertility, a society that desires to limit fertility and has the means to do so may use those means to delay childbearing, space childbearing, or stop childbearing. Delaying sexual intercourse (or marriage), or the adoption of natural or artificial means of contraception are most often an individual or family decision, not a matter of a state policy or societal-wide sanctions. On the other hand, individuals who assume some sense of control over their own fertility can also accelerate the frequency or success of child-bearing through planning.
At the societal level, declining fertility is almost an inevitable result of growing secular education of women . However, the exercise of moderate to high levels of fertility control does not necessarily imply low fertility rates. Even among societies that exercise substantial fertility control, societies with an equal ability to exercise fertility control (to determine how many children to have and when to bear them) may display widely different levels of fertility (numbers of children borne) associated with individual and cultural preferences for the number of children or size of families.
In contrast to fertility control, which is mainly an individual-level decision, governments may attempt to exercise population control by increasing access to means of contraception or by other population policies and programs. The idea of "population control" as a governmental or societal-level regulation of population growth does not require "fertility control" in the sense that it has been defined above, since a state can affect the growth of a society's population even if that society practices little fertility control. It's also important to embrace policies favoring population increase as an aspect of population control, and not to assume that states want to control population only by limiting its growth. To stimulate population growth, governments may support not only immigration but also pronatalist policies such as tax benefits, financial awards, paid work leaves, and childcare to encourage the bearing of additional children. Such policies have been pursued in recent years in France and Sweden, for example. With the same goal of increasing population growth, on occasion governments have sought to limit the use of abortion or modern means of birth control. An example was Romania's 1966 ban on access to contraception and abortion on demand.
In ecology, population control is on occasions considered to be done solely by predators, diseases, parasites, and environmental factors. At many times human effects on animal and plant populations are also considered. See also . Migrations of animals may be seen as a natural way of population control, for the food on land is more abundant on some seasons. The area of the migrations' start is left to reproduce the food supply for large mass of animals next time around. See also immigration. | Population
In sociology and biology a population is the collection of people or organisms of a particular species living in a given geographic area or mortality, and migration, though the field encompasses many dimensions of population change including the family (marriage and divorce), public health, work and the labor force, and family planning. Various aspects of human behavior in populations are also studied in sociology, economics, and geography. Study of populations is almost always governed by the laws of probability, and the conclusions of the studies may thus not always be applicable to some individuals. This odd factor may be reduced by statistical means, but such a generalization may be too vague to imply anything. Demography is used extensively in marketing, which relates to economic units, such as retailers, to potential customers. For example, a coffee shop that wants to sell to a younger audience looks at the demographics of an area to be able to appeal to this younger audience.
# World population
According to estimates published by the United States Census Bureau, the world population hit 6.5 billion (6,500,000,000) on February 25 2006. It is estimated that by 2012, the Earth will be home to 7 billion.[citation needed] The United Nations Population Fund designated October 12 1999 as the approximate day on which world population reached 6 billion. This was about 12 years after world population reached 5 billion, in 1987. However, the population of some countries, such as Nigeria, is not even known to the nearest million,[citation needed] so there is a considerable margin of error in such estimates.
In 2007 the United Nations Population Division projected that the world's population will likely surpass 9 billion in 2050.[1] The last 50 years have seen a rapid increase in population due to medical advances and substantial increase in agricultural productivity, particularly in the period 1960 to 1995[2] made by the Green Revolution.[3]
# Population decline
Population decline is a decrease in a region's population. It can be caused by sub-replacement fertility, heavy emigration, or more dramatically disease, famine, or war. In the past, population decline was mostly caused by disease. The Black Death in Europe and the arrival of Old World diseases to the Americas all caused massive population declines.
In biology, population decline of a species is usually described as a result of gradually worsening environmental factors, such as prolonged drought or loss of inhabitable areas for the studied species. These, or other factors, may lead to a small population, in which case genetic factors may become dominant in the survival, or extinction of a population.
Under-population is recognized when there are more resources in an area (for example, food, energy and minerals) than can be used by the people living there. Hence, the maximum human potential of that area is not realized as the resources are not fully exploited. Countries like Canada and Australia can export the surplus of food, energy, and mineral resources, have high incomes, good living conditions and level of technology and immigration.
Some rural areas close to major cities in advanced countries such as the UK are under-populated due to outward migration. In the UK, the Southwest Wales and the highlands of Scotland are less densely populated compared to the rest of the country. This has also happened in older declining industrial areas and the outward movement or migration has been due to lower wages and unemployment. This phenomenon results in a decline in a population. With fewer people, there is a decrease in demands for services. The lower level of services therefore sometimes encourages further outward migration.
However, when making comparisons on a global scale, there does not seem to be any direct correlation between population density and over- or under-population. For example, Brazil is 'over-populated' with two people per square kilometer, whereas portions of California may have further carrying capacity with over 500 people per square kilometer. Therefore, this is related to the amount of available resources. Similarly, population density is not necessarily related to the GDP per capita. The Netherlands and Germany, for example, both have a high GDP per capita and a high population density whereas Canada and Australia have a high GDP per capita and a low population density, while Bangladesh has low GDP per capita and a high population density, etc.
The balance of population and resources within a country may be uneven. For example, a country may have a population, which is too great for one resource such as energy, yet too small to use fully a second such as food supply.
Various attempts to address population decline have been made:
- Improving communication networks and transport facilities makes remote places more accessible. This strategy was used in developing countries like Nigeria and Tanzania where modern railway networks were established, but these attempts were not very successful.
- Establishment of new capital cities, new towns, or development growth points. For example, Brazil has a population imbalance between the coastal parts from east and south and the rest of the country. Brasilia, the new capital was created in the 1960s in the country's geographical center to attract people into the North and Center-West regions, but this had limited effect, as most of these unpopulated areas are occupied by large forests and swamps.
- Regional development programs. In Brazil, the interior improvement of transport networks and development of secondary growth points and rural development have all been enhanced to attract more people and discourage out-migration. The standard of living in such regions is expected to gradually improve due to improved resource utilization.
- Pronatalist policies providing tax incentives, paid maternity leaves, daycare, or other benefits to families to bear more children. Such policies have been tried, with mixed success, in Western Europe in recent years.
# Population control
Population control is the practice of curtailing population increase, usually by reducing the birth rate. Surviving records from Ancient Greece document the first known examples of population control. These include the colonization movement, which saw Greek outposts being built across the Mediterranean and Black Sea basins to accommodate the excess population of individual states. An important example of mandated population control is China's one-child policy, in which having more than one child is made extremely unattractive. This has led to allegations that practices like infanticide, forced abortions, and forced sterilization are used as a result of the policy.
It is helpful to distinguish between fertility control as individual decision-making and population control as a governmental or state-level policy of regulating population growth. Fertility control may occur when individuals or couples or families take steps to decrease or to regulate the timing of their own child-bearing. In Ansley Coale's oft-cited formulation, three preconditions for a sustained decline in fertility are: (1) acceptance of calculated choice (as opposed to fate or chance or divine will) as a valid element in fertility, (2) perceived advantages from reduced fertility, and (3) knowledge and mastery of effective techniques of control.[4] In contrast to a society with natural fertility, a society that desires to limit fertility and has the means to do so may use those means to delay childbearing, space childbearing, or stop childbearing. Delaying sexual intercourse (or marriage), or the adoption of natural or artificial means of contraception are most often an individual or family decision, not a matter of a state policy or societal-wide sanctions. On the other hand, individuals who assume some sense of control over their own fertility can also accelerate the frequency or success of child-bearing through planning.
At the societal level, declining fertility is almost an inevitable result of growing secular education of women . However, the exercise of moderate to high levels of fertility control does not necessarily imply low fertility rates. Even among societies that exercise substantial fertility control, societies with an equal ability to exercise fertility control (to determine how many children to have and when to bear them) may display widely different levels of fertility (numbers of children borne) associated with individual and cultural preferences for the number of children or size of families.[5]
In contrast to fertility control, which is mainly an individual-level decision, governments may attempt to exercise population control by increasing access to means of contraception or by other population policies and programs.[6] The idea of "population control" as a governmental or societal-level regulation of population growth does not require "fertility control" in the sense that it has been defined above, since a state can affect the growth of a society's population even if that society practices little fertility control. It's also important to embrace policies favoring population increase as an aspect of population control, and not to assume that states want to control population only by limiting its growth. To stimulate population growth, governments may support not only immigration but also pronatalist policies such as tax benefits, financial awards, paid work leaves, and childcare to encourage the bearing of additional children.[7] Such policies have been pursued in recent years in France and Sweden, for example. With the same goal of increasing population growth, on occasion governments have sought to limit the use of abortion or modern means of birth control. An example was Romania's 1966 ban on access to contraception and abortion on demand.
In ecology, population control is on occasions considered to be done solely by predators, diseases, parasites, and environmental factors. At many times human effects on animal and plant populations are also considered. See also [5]. Migrations of animals may be seen as a natural way of population control, for the food on land is more abundant on some seasons. The area of the migrations' start is left to reproduce the food supply for large mass of animals next time around. See also immigration. | https://www.wikidoc.org/index.php/Population | |
e05eede861a69ba1d94e62144f725be855f38efc | wikidoc | Poxviridae | Poxviridae
This page is about microbiologic aspects of the organism(s). For clinical aspects of the disease, see Molluscum contagiosum or Smallpox.
# Overview
Poxviruses (members of the family Poxviridae) can infect as a family both vertebrate and invertebrate animals. Poxviridae viral particles (virions) are generally enveloped (external enveloped virion- EEV), though the intracellular mature virion (IMV) form of the virus, which contains different envelope, is also infectious. They vary in their shape depending upon the species but are generally shaped like a brick or as an oval form similar to a rounded brick. The virion size is around 200 nm in diameter and 300 nm in length and carries its genome in a single, linear, double-stranded segment of DNA. By comparison, Rhinovirus is 1/10th as large as a typical Poxviridae virion. Electron micrographs of Orthopoxvirus and Parapoxvirus Genera, including the smallpox virus, have been collected by the International Committee on Taxonomy of Viruses in their Poxviridae picture gallery.
The prototype of poxvirus family is vaccinia virus, which has been used as a successful vaccine to eradicate smallpox virus. Vaccinia virus is also used as an effective tool for foreign protein expression to elicite strong host immune response. Vaccinia virus enters cells mainly by cell fusion, although currently the receptor is not known. Virus contains three classes of genes, early, intermediate and late, that are transcribed by viral RNA polymerase and associated transcription factors. Vaccinia virus replicates its genome in cytoplasm of the infected cells and after late gene expression virion morphogenesis produces IMV that contains envelope, although the origin of the envelope membrane is still unknown. IMV is transported to Golgi to be wrapped additional two membrane to become intracellular enveloped virus (IEV). IEV transports along microtubules to reach cell periphery and fuse with plasma membrane to become cell-associated enveloped virus (CEV) that triggers actin tails on cell surfaces or is releared as EEV.
The name of the family, Poxviridae, is a legacy of the original grouping of viruses associated with diseases that produced poxs in the skin. Modern viral classification is based on the shape and molecular features of viruses, and the smallpox virus remains as the most notable member of the family.
The only other poxvirus known to specifically infect humans is the molluscum contagiosum virus (MCV).
# Taxonomy
The following genera are currently included here:
- Subfamily Chordopoxvirinae
Genus Orthopoxvirus; type species: Vaccinia virus; diseases: cowpox, vaccinia, smallpox
Genus Parapoxvirus; type species: Orf virus
Genus Avipoxvirus; type species: Fowlpox virus
Genus Capripoxvirus; type species: Sheeppox virus
Genus Leporipoxvirus; type species: Myxoma virus
Genus Suipoxvirus; type species: Swinepox virus
Genus Molluscipoxvirus; type species: Molluscum contagiosum virus
Genus Yatapoxvirus; type species: Yaba monkey tumor virus
- Genus Orthopoxvirus; type species: Vaccinia virus; diseases: cowpox, vaccinia, smallpox
- Genus Parapoxvirus; type species: Orf virus
- Genus Avipoxvirus; type species: Fowlpox virus
- Genus Capripoxvirus; type species: Sheeppox virus
- Genus Leporipoxvirus; type species: Myxoma virus
- Genus Suipoxvirus; type species: Swinepox virus
- Genus Molluscipoxvirus; type species: Molluscum contagiosum virus
- Genus Yatapoxvirus; type species: Yaba monkey tumor virus
- Subfamily Entomopoxvirinae
Genus Entomopoxvirus A; type species: Melolontha melolontha entomopoxvirus
Genus Entomopoxvirus B; type species: Amsacta moorei entomopoxvirus
Genus Entomopoxvirus C; type species: Chironomus luridus entomopoxvirus
- Genus Entomopoxvirus A; type species: Melolontha melolontha entomopoxvirus
- Genus Entomopoxvirus B; type species: Amsacta moorei entomopoxvirus
- Genus Entomopoxvirus C; type species: Chironomus luridus entomopoxvirus
# Replication
Replication of the poxvirus involves several stages. The first thing the virus does is to bind to a receptor on the host cell surface; the receptors for the poxvirus are currently unknown. After binding to the receptor, the virus enters the cell where it uncoats. Uncoating of the virus is a two step process. Firstly the outer membrane is removed as the particle enters the cell; secondly the virus particle (without the outer membrane) is uncoated further to release the core into the cytoplasm. The pox viral genes are expressed in two phases. The early genes are expressed first. These genes encode the non-structural protein, including proteins necessary for replication of the viral genome, and are expressed before the genome is replicated. The late genes are expressed after the genome has been replicated and encode the structural proteins to make the virus particle. The assembly of the virus particle occurs in the cytoskeleton of the cell and is a complex process that is poorly understood but is currently being researched. Considering the fact that this virus is large and complex replication is relatively quick taking only 12 hours approximately. The replication of this virus is unusual for a virus with double stranded DNA genome because it encodes its own machinery for genome replication and therefore the replication occurs in the cytoplasm. Most viruses with a double stranded DNA genome replicate in the nucleus and use the host cells genome replication machinery.
# History
Viruses, especially smallpox have been known about for centuries. One of the earliest documented evidence is of the Egyptian pharaoh Ramses V who is known to have died from smallpox nearly 2000 years BC. Smallpox was thought to have been transferred to Europe around the early 700s and then to the Americas in the early 1500s. It is widely accepted that the main defeat of the Aztecs was due to a smallpox epidemic and within two years over 3.2 million Aztecs died. This can attributed to lack of sensitization to the virus as a child and therefore the Aztecs had no immunity. After Edward Jenner showed that you could use the less potent cow pox to effectively vaccinate against the more deadly smallpox, a worldwide effort to vaccinate everyone against smallpox was started (a century later) with the final goal to rid the world of what had become a plague like epidemic. The World Health Organization (WHO) declared the virus officially eradicated in 1977, with samples retained at laboratories within the two then global superpowers, United States and the Soviet Union. Post September 11 2001 the American and UK governments have had increased concern over the use of smallpox or small pox like disease, in bio-terrorism. | Poxviridae
This page is about microbiologic aspects of the organism(s). For clinical aspects of the disease, see Molluscum contagiosum or Smallpox.
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Poxviruses (members of the family Poxviridae) can infect as a family both vertebrate and invertebrate animals. Poxviridae viral particles (virions) are generally enveloped (external enveloped virion- EEV), though the intracellular mature virion (IMV) form of the virus, which contains different envelope, is also infectious. They vary in their shape depending upon the species but are generally shaped like a brick or as an oval form similar to a rounded brick. The virion size is around 200 nm in diameter and 300 nm in length and carries its genome in a single, linear, double-stranded segment of DNA.[1] By comparison, Rhinovirus is 1/10th as large as a typical Poxviridae virion.[2] Electron micrographs of Orthopoxvirus and Parapoxvirus Genera, including the smallpox virus, have been collected by the International Committee on Taxonomy of Viruses in their Poxviridae picture gallery.
The prototype of poxvirus family is vaccinia virus, which has been used as a successful vaccine to eradicate smallpox virus. Vaccinia virus is also used as an effective tool for foreign protein expression to elicite strong host immune response. Vaccinia virus enters cells mainly by cell fusion, although currently the receptor is not known. Virus contains three classes of genes, early, intermediate and late, that are transcribed by viral RNA polymerase and associated transcription factors. Vaccinia virus replicates its genome in cytoplasm of the infected cells and after late gene expression virion morphogenesis produces IMV that contains envelope, although the origin of the envelope membrane is still unknown. IMV is transported to Golgi to be wrapped additional two membrane to become intracellular enveloped virus (IEV). IEV transports along microtubules to reach cell periphery and fuse with plasma membrane to become cell-associated enveloped virus (CEV) that triggers actin tails on cell surfaces or is releared as EEV.
The name of the family, Poxviridae, is a legacy of the original grouping of viruses associated with diseases that produced poxs in the skin. Modern viral classification is based on the shape and molecular features of viruses, and the smallpox virus remains as the most notable member of the family.
The only other poxvirus known to specifically infect humans is the molluscum contagiosum virus (MCV).[3]
# Taxonomy
The following genera are currently included here:
- Subfamily Chordopoxvirinae
Genus Orthopoxvirus; type species: Vaccinia virus; diseases: cowpox, vaccinia, smallpox
Genus Parapoxvirus; type species: Orf virus
Genus Avipoxvirus; type species: Fowlpox virus
Genus Capripoxvirus; type species: Sheeppox virus
Genus Leporipoxvirus; type species: Myxoma virus
Genus Suipoxvirus; type species: Swinepox virus
Genus Molluscipoxvirus; type species: Molluscum contagiosum virus
Genus Yatapoxvirus; type species: Yaba monkey tumor virus
- Genus Orthopoxvirus; type species: Vaccinia virus; diseases: cowpox, vaccinia, smallpox
- Genus Parapoxvirus; type species: Orf virus
- Genus Avipoxvirus; type species: Fowlpox virus
- Genus Capripoxvirus; type species: Sheeppox virus
- Genus Leporipoxvirus; type species: Myxoma virus
- Genus Suipoxvirus; type species: Swinepox virus
- Genus Molluscipoxvirus; type species: Molluscum contagiosum virus
- Genus Yatapoxvirus; type species: Yaba monkey tumor virus
- Subfamily Entomopoxvirinae
Genus Entomopoxvirus A; type species: Melolontha melolontha entomopoxvirus
Genus Entomopoxvirus B; type species: Amsacta moorei entomopoxvirus
Genus Entomopoxvirus C; type species: Chironomus luridus entomopoxvirus
- Genus Entomopoxvirus A; type species: Melolontha melolontha entomopoxvirus
- Genus Entomopoxvirus B; type species: Amsacta moorei entomopoxvirus
- Genus Entomopoxvirus C; type species: Chironomus luridus entomopoxvirus
# Replication
Replication of the poxvirus involves several stages. The first thing the virus does is to bind to a receptor on the host cell surface; the receptors for the poxvirus are currently unknown. After binding to the receptor, the virus enters the cell where it uncoats. Uncoating of the virus is a two step process. Firstly the outer membrane is removed as the particle enters the cell; secondly the virus particle (without the outer membrane) is uncoated further to release the core into the cytoplasm. The pox viral genes are expressed in two phases. The early genes are expressed first. These genes encode the non-structural protein, including proteins necessary for replication of the viral genome, and are expressed before the genome is replicated. The late genes are expressed after the genome has been replicated and encode the structural proteins to make the virus particle. The assembly of the virus particle occurs in the cytoskeleton of the cell and is a complex process that is poorly understood but is currently being researched. Considering the fact that this virus is large and complex replication is relatively quick taking only 12 hours approximately. The replication of this virus is unusual for a virus with double stranded DNA genome because it encodes its own machinery for genome replication and therefore the replication occurs in the cytoplasm. Most viruses with a double stranded DNA genome replicate in the nucleus and use the host cells genome replication machinery.
# History
Viruses, especially smallpox have been known about for centuries. One of the earliest documented evidence is of the Egyptian pharaoh Ramses V who is known to have died from smallpox nearly 2000 years BC. Smallpox was thought to have been transferred to Europe around the early 700s and then to the Americas in the early 1500s. It is widely accepted that the main defeat of the Aztecs was due to a smallpox epidemic and within two years over 3.2 million Aztecs died. This can attributed to lack of sensitization to the virus as a child and therefore the Aztecs had no immunity. After Edward Jenner showed that you could use the less potent cow pox to effectively vaccinate against the more deadly smallpox, a worldwide effort to vaccinate everyone against smallpox was started (a century later) with the final goal to rid the world of what had become a plague like epidemic. The World Health Organization (WHO) declared the virus officially eradicated in 1977, with samples retained at laboratories within the two then global superpowers, United States and the Soviet Union. Post September 11 2001 the American and UK governments have had increased concern over the use of smallpox or small pox like disease, in bio-terrorism. | https://www.wikidoc.org/index.php/Pox_virus | |
5f6ea793a0c0002668cab2769a7bbc12cf26457d | wikidoc | Prajmaline | Prajmaline
# Overview
Prajmaline (Neo-gilurythmal) is a class Ia antiarrhythmic agent which has been available since the 1970s. Class Ia drugs increase the time one action potential lasts in the heart. Prajmaline is a semi-synthetic propyl derivative of ajmaline, with a higher bioavailability than its predecessor. It acts to stop arrhythmias of the heart through a frequency-dependent block of cardiac sodium channels.
# Mechanism
Prajmaline causes a resting block in the heart. A resting block is the depression of a person's Vmax after a resting period. This effect is seen more in the atrium than the ventricle. The effects of some Class I antiarrhythmics are only seen in a patient who has a normal heart rate (~1 Hz). This is due to the effect of a phenomenon called reverse use dependence. The higher the heart rate, the less effect Prajmaline will have.
# Uses
The drug Prajmaline has been used to treat a number of cardiac disorders. These include: coronary artery disease, angina, paroxysmal tachycardia and Wolff–Parkinson–White syndrome. Prajmaline has been indicated in the treatment of certain disorders where other antiarrhythmic drugs were not effective.
# Administration
Prajmaline can be administered orally, parenterally or intravenously. Three days after the last dose, a limited effect has been observed. Therefore it has been suggested that treatment of arrhythmias with Prajmaline must be continuous to see acceptable results.
# Pharmacokinetics
The main metabolites of Prajmaline are: 21-carboxyprajmaline and hydroxyprajmaline. Twenty percent of the drug is excreted in the urine unchanged.
Daily therapeutic dose is 40–80 mg.
Distribution half-life is 10 minutes.
Plasma protein binding is 60%.
Oral bioavailability is 80%.
Elimination half-life is 6 hours.
Volume of distribution is 4-5 L/kg.
# Side Effects
There are no significant adverse side-effects of Prajmaline when taken alone and with a proper dosage. Patients who are taking other treatments for their symptoms (e.g. beta blockers and nifedipine) have developed minor transient conduction defects when given Prajmaline.
# Overdose
An overdose of Prajmaline is possible. The range of symptoms seen during a Prajmaline overdose include: no symptoms, nausea/vomiting, bradycardia, tachycardia, hypotension, and death.
# Other Potential Uses
Due to Prajmaline's sodium channel-blocking properties, it has been shown to protect rat white matter from anoxia (82 +/- 15%). The concentration used causes little suppression of the preanoxic response. | Prajmaline
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Prajmaline (Neo-gilurythmal)[1] is a class Ia antiarrhythmic agent[2] which has been available since the 1970s.[3] Class Ia drugs increase the time one action potential lasts in the heart.[4] Prajmaline is a semi-synthetic propyl derivative of ajmaline, with a higher bioavailability than its predecessor.[5] It acts to stop arrhythmias of the heart through a frequency-dependent block of cardiac sodium channels.[2]
# Mechanism
Prajmaline causes a resting block in the heart.[6] A resting block is the depression of a person's Vmax after a resting period. This effect is seen more in the atrium than the ventricle.[6] The effects of some Class I antiarrhythmics are only seen in a patient who has a normal heart rate (~1 Hz).[7] This is due to the effect of a phenomenon called reverse use dependence.[7] The higher the heart rate, the less effect Prajmaline will have.
# Uses
The drug Prajmaline has been used to treat a number of cardiac disorders. These include: coronary artery disease,[8][9] angina,[8][9] paroxysmal tachycardia and Wolff–Parkinson–White syndrome.[1] Prajmaline has been indicated in the treatment of certain disorders where other antiarrhythmic drugs were not effective.[1]
# Administration
Prajmaline can be administered orally,[9] parenterally[8] or intravenously.[8] Three days after the last dose, a limited effect has been observed. Therefore it has been suggested that treatment of arrhythmias with Prajmaline must be continuous to see acceptable results.[1]
# Pharmacokinetics
The main metabolites of Prajmaline are: 21-carboxyprajmaline and hydroxyprajmaline. Twenty percent of the drug is excreted in the urine unchanged.
Daily therapeutic dose is 40–80 mg.
Distribution half-life is 10 minutes.
Plasma protein binding is 60%.
Oral bioavailability is 80%.
Elimination half-life is 6 hours.
Volume of distribution is 4-5 L/kg.
[3]
# Side Effects
There are no significant adverse side-effects of Prajmaline when taken alone and with a proper dosage.[1][8][9] Patients who are taking other treatments for their symptoms (e.g. beta blockers and nifedipine) have developed minor transient conduction defects when given Prajmaline.[8]
# Overdose
An overdose of Prajmaline is possible. The range of symptoms seen during a Prajmaline overdose include: no symptoms, nausea/vomiting, bradycardia, tachycardia, hypotension, and death.[3]
# Other Potential Uses
Due to Prajmaline's sodium channel-blocking properties, it has been shown to protect rat white matter from anoxia (82 +/- 15%).[10][11] The concentration used causes little suppression of the preanoxic response.[10][11] | https://www.wikidoc.org/index.php/Prajmaline | |
0eefba7250d8c9849ee5a9bad75c1ba75d018cd1 | wikidoc | Pramocaine | Pramocaine
# Overview
Pramocaine (INN and BAN, also known as pramoxine or pramoxine HCI) is a topical anesthetic discovered at Abbott Laboratories in 1953 and used as an antipruritic. Chemically, it is p-n butoxyphenyl gammamorpholinopropyl ether hydrochloride. During research and development, pramoxine hydrochloride stood out among a series of alkoxy aryl alkamine ethers as an especially good topical local anesthetic agent. Pharmacologic study revealed it to be potent and of low acute and subacute toxicity, well tolerated by most mucous membranes and of a low sensitizing index in man. Like other local anesthetics, paramoxine decreases the permeability of neuronal membranes to sodium ions, blocking both initiation and conduction of nerve impulses. Depolarization and repolarization of excitable neural membranes is thus inhibited, leading to numbness.
The popular itch creams Gold Bond and Calamine Lotion use pramocaine hydrochloride to numb sensitive skin, as does the pain relief variant of Neosporin and some formulations of Sarna. The hydrochloride salt form of pramocaine is water-soluble.
# Usage
Topical anesthetics are used to relieve pain and itching caused by conditions such as sunburn or other minor burns, insect bites or stings, poison ivy, poison oak, poison sumac, and minor cuts and scratches. Pramocaine and dibucaine are also common ingredients in over the counter hemorrhoid preparations.
# Synthesis | Pramocaine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Pramocaine (INN and BAN, also known as pramoxine or pramoxine HCI) is a topical anesthetic discovered at Abbott Laboratories in 1953[1] and used as an antipruritic. Chemically, it is p-n butoxyphenyl gammamorpholinopropyl ether hydrochloride. During research and development, pramoxine hydrochloride stood out among a series of alkoxy aryl alkamine ethers as an especially good topical local anesthetic agent.[1] Pharmacologic study revealed it to be potent and of low acute and subacute toxicity, well tolerated by most mucous membranes and of a low sensitizing index in man.[1] Like other local anesthetics, paramoxine decreases the permeability of neuronal membranes to sodium ions, blocking both initiation and conduction of nerve impulses. Depolarization and repolarization of excitable neural membranes is thus inhibited, leading to numbness.
The popular itch creams Gold Bond and Calamine Lotion use pramocaine hydrochloride to numb sensitive skin, as does the pain relief variant of Neosporin and some formulations of Sarna. The hydrochloride salt form of pramocaine is water-soluble.
# Usage
Topical anesthetics are used to relieve pain and itching caused by conditions such as sunburn or other minor burns, insect bites or stings, poison ivy, poison oak, poison sumac, and minor cuts and scratches.[2] Pramocaine and dibucaine are also common ingredients in over the counter hemorrhoid preparations.
# Synthesis | https://www.wikidoc.org/index.php/Pramocaine | |
477febe2400df2ff4b0ee0e9b9f497e065af6a77 | wikidoc | Pranlukast | Pranlukast
# Overview
Pranlukast is a cysteinyl leukotriene receptor-1 antagonist. This drug works similarly to Merck & Co.'s Singulair (montelukast).
Medications of this class, which go under a variety of names according to whether one looks at the American, British or European system of nomenclature, have as their primary function the antagonism of bronchospasm caused, principally in asthmatics, by an allergic reaction to accidentally or inadvertently encountered allergens.
Medications of this group are normally used as an adjunct to the standard therapy of inhaled steroids with inhaled long- and/or short-acting beta-agonists. There are several similar medications in the group; all appear to be equally effective. | Pranlukast
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Pranlukast is a cysteinyl leukotriene receptor-1 antagonist. This drug works similarly to Merck & Co.'s Singulair (montelukast).
Medications of this class, which go under a variety of names according to whether one looks at the American, British or European system of nomenclature, have as their primary function the antagonism of bronchospasm caused, principally in asthmatics, by an allergic reaction to accidentally or inadvertently encountered allergens.
Medications of this group are normally used as an adjunct to the standard therapy of inhaled steroids with inhaled long- and/or short-acting beta-agonists. There are several similar medications in the group; all appear to be equally effective. | https://www.wikidoc.org/index.php/Pranlukast | |
76e4b6e73ea01ca32c5ae32863dfef4e1f515c47 | wikidoc | Prasterone | Prasterone
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
NOTE: Most over the counter (OTC) are not reviewed and approved by the FDA. However, they may be marketed if they comply with applicable regulations and policies. FDA has not evaluated whether this product complies.
# Overview
Prasterone is a androgen that is FDA approved for the treatment of symptoms related to adrenal glands such as fatigue and low energy.. Common adverse reactions include hirsutism, acne, heart rhythm problems, liver problems, hair loss (from the scalp), and oily skin.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- For temporary relief of symptoms related to adrenal glands such as fatigue and low energy.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Prasterone in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Prasterone in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Prasterone in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Prasterone in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Prasterone in pediatric patients.
# Contraindications
NONE
# Warnings
- Keep out of reach of children. In case of overdose, contact a physician or Poison Control Center right away.
- If pregnant or breast-feeding, ask a health professional before use.
- Tamper seal: "Sealed for Your Protection."
- Do not use if seal is broken or missing.
### Precautions
- Keep out of reach of children. In case of overdose, contact a physician or Poison Control Center right away.
# Adverse Reactions
## Clinical Trials Experience
There is limited information regarding Clinical Trial Experience of Prasterone in the drug label.
## Postmarketing Experience
DHEA is a steroid hormone. High doses may cause aggressiveness, irritability, trouble sleeping, and the growth of body or facial hair on women. It also may stop menstruation and lower the levels of HDL, or "good," cholesterol, which could raise the risk of heart disease. Other reported side effects include acne, heart rhythm problems, liver problems, hair loss (from the scalp), and oily skin. It may also alter the body's regulation of blood sugar.
# Drug Interactions
There is limited information regarding Prasterone Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- If pregnant or breast-feeding, ask a health professional before use.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Prasterone in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Prasterone during labor and delivery.
### Nursing Mothers
- If pregnant or breast-feeding, ask a health professional before use.
### Pediatric Use
There is no FDA guidance on the use of Prasterone with respect to pediatric patients.
### Geriatic Use
There is no FDA guidance on the use of Prasterone with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Prasterone with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Prasterone with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Prasterone in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Prasterone in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Prasterone in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Prasterone in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Sublingual
### Monitoring
There is limited information regarding Monitoring of Prasterone in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Prasterone in the drug label.
# Overdosage
There is limited information regarding Chronic Overdose of Prasterone in the drug label.
# Pharmacology
## Mechanism of Action
There is limited information regarding Prasterone Mechanism of Action in the drug label.
## Structure
There is limited information regarding Prasterone Structure in the drug label.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Prasterone in the drug label.
## Pharmacokinetics
There is limited information regarding Pharmacokinetics of Prasterone in the drug label.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Prasterone in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Prasterone in the drug label.
# How Supplied
There is limited information regarding Prasterone How Supplied in the drug label.
## Storage
There is limited information regarding Prasterone Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Prasterone in the drug label.
# Precautions with Alcohol
- Alcohol-Prasterone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
There is limited information regarding Prasterone Brand Names in the drug label.
# Look-Alike Drug Names
There is limited information regarding Prasterone Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Prasterone
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aparna Vuppala, M.B.B.S. [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
NOTE: Most over the counter (OTC) are not reviewed and approved by the FDA. However, they may be marketed if they comply with applicable regulations and policies. FDA has not evaluated whether this product complies.
# Overview
Prasterone is a androgen that is FDA approved for the treatment of symptoms related to adrenal glands such as fatigue and low energy.. Common adverse reactions include hirsutism, acne, heart rhythm problems, liver problems, hair loss (from the scalp), and oily skin.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- For temporary relief of symptoms related to adrenal glands such as fatigue and low energy.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Prasterone in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Prasterone in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Prasterone in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Prasterone in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Prasterone in pediatric patients.
# Contraindications
NONE
# Warnings
- Keep out of reach of children. In case of overdose, contact a physician or Poison Control Center right away.
- If pregnant or breast-feeding, ask a health professional before use.
- Tamper seal: "Sealed for Your Protection."
- Do not use if seal is broken or missing.
### Precautions
- Keep out of reach of children. In case of overdose, contact a physician or Poison Control Center right away.
# Adverse Reactions
## Clinical Trials Experience
There is limited information regarding Clinical Trial Experience of Prasterone in the drug label.
## Postmarketing Experience
DHEA is a steroid hormone. High doses may cause aggressiveness, irritability, trouble sleeping, and the growth of body or facial hair on women. It also may stop menstruation and lower the levels of HDL, or "good," cholesterol, which could raise the risk of heart disease. Other reported side effects include acne, heart rhythm problems, liver problems, hair loss (from the scalp), and oily skin. It may also alter the body's regulation of blood sugar.[1]
# Drug Interactions
There is limited information regarding Prasterone Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- If pregnant or breast-feeding, ask a health professional before use.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Prasterone in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Prasterone during labor and delivery.
### Nursing Mothers
- If pregnant or breast-feeding, ask a health professional before use.
### Pediatric Use
There is no FDA guidance on the use of Prasterone with respect to pediatric patients.
### Geriatic Use
There is no FDA guidance on the use of Prasterone with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Prasterone with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Prasterone with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Prasterone in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Prasterone in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Prasterone in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Prasterone in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Sublingual
### Monitoring
There is limited information regarding Monitoring of Prasterone in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Prasterone in the drug label.
# Overdosage
There is limited information regarding Chronic Overdose of Prasterone in the drug label.
# Pharmacology
## Mechanism of Action
There is limited information regarding Prasterone Mechanism of Action in the drug label.
## Structure
There is limited information regarding Prasterone Structure in the drug label.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Prasterone in the drug label.
## Pharmacokinetics
There is limited information regarding Pharmacokinetics of Prasterone in the drug label.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Prasterone in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Prasterone in the drug label.
# How Supplied
There is limited information regarding Prasterone How Supplied in the drug label.
## Storage
There is limited information regarding Prasterone Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Prasterone in the drug label.
# Precautions with Alcohol
- Alcohol-Prasterone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
There is limited information regarding Prasterone Brand Names in the drug label.
# Look-Alike Drug Names
There is limited information regarding Prasterone Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Prasterone | |
78e83e23daf6ac20bfe015c2635147144d72a359 | wikidoc | Precession | Precession
Precession refers to a change in the direction of the axis of a rotating object. In physics, there are two types of precession, torque-free and torque-induced, the latter being discussed here in more detail. In certain contexts, "precession" may refer to the precession that the Earth experiences, the effects of this type of precession on astronomical observation, or to the precession of orbital objects.
# Torque-free
Torque-free precession occurs when the axis of rotation differs slightly from an axis about which the object can rotate stably. Poinsot's construction is an elegant geometrical method for visualizing the torque-free motion of a rotating rigid body. For example, when a plate is thrown, the plate may have some rotation around an axis that is not its axis of symmetry. When an object is not perfectly solid, internal vortices will tend to damp torque-free precession.
# Torque-induced
Torque-induced precession (gyroscopic precession) is the phenomenon in which the axis of a spinning object (e.g. a part of a gyroscope) "wobbles" when a torque is applied to it. The phenomenon is commonly seen in a spinning toy top, but all rotating objects can undergo precession. If the speed of the rotation and the magnitude of the torque are constant the axis will describe a cone, its movement at any instant being at right angles to the direction of the torque. In the case of a toy top, if the axis is not perfectly vertical the torque is applied by the force of gravity tending to tip it over.
The device depicted on the right here is gimbal mounted. From inside to outside there are three axes of rotation: the hub of the wheel, the gimbal axis and the vertical pivot.
To distinguish between the two horizontal axes, rotation around the wheel hub will be called 'rolling', and rotation around the gimbal axis will be called 'pitching.' Rotation around the pivot axis is called 'spinning'.
First, imagine that the device is spinning around the pivot axis. Then some rotation around the wheelhub is added. Imagine the gimbal axis to be locked, so that the wheel cannot pitch. The gimbal axis has sensors, that measure whether there is a torque around the gimbal axis.
In the picture, a section of the wheel has been named 'dm1'. When the rolling starts, section dm1 is at the perimeter of the spinning motion. Section dm1 has a lot of velocity and as it is forced closer to the center of rotation, it tends to move in the direction of the top-left arrow in the diagram (shown at 45o in the direction of rolling). Section dm2 of the wheel starts out at the center of rotation, and thus initially has zero velocity before the wheel is rolled. A force would be required to increase section dm2's velocity to the velocity at the perimeter of the pivot axis' plane. If that force is not provided then section dm2's inertia will make it move in the direction of the top-right arrow. Note that both arrows point in the same direction.
The same reasoning applies for the bottom half of the wheel, but there the arrows point in the opposite direction to that of the top arrows. Combined over the entire wheel, there is a torque around the gimbal axis when some rolling is added to rotation around a vertical axis.
It is important to note that the torque around the gimbal axis arises without any delay; the response is instantaneous.
In the discussion above, the setup was kept unchanging by preventing rotation around the gimbal axis. In the case of a spinning top, when the spinning top is tilting, gravity exerts a torque. Instead of rolling over, the spinning top pitches. The pitching motion reorients the spinning top with respect to the torque that is being exerted. The result is that the torque exerted by gravity elicits gyroscopic precession rather than causing the spinning top to fall to its side.
Precession or gyroscopic considerations have an effect on bicycle performance at high speed. Precession is also the mechanism behind gyrocompasses.
Gyroscopic precession also plays a large role in the flight controls on helicopters. Since the driving force behind helicopters is the rotor disk (which rotates), gyroscopic precession comes into play. If the rotor disk is to be tilted forward (to gain forward velocity), its rotation requires that the downward net force on the blade be applied roughly 90 degrees (depending on blade configuration) before, or when the blade is to one side of the pilot and rotating forward.
To ensure the pilot's inputs are correct, the aircraft has corrective linkages which vary the blade pitch in advance of the blade's position relative to the swashplate. Although the swashplate moves in the intuitively correct direction, the blade pitch links are arranged to transmit the pitch in advance of the blade's position.
# Physics
## Classical (Newtonian)
Precession is the result of the angular velocity of rotation and the angular velocity produced by the torque. It is an angular velocity about a line which makes an angle with the permanent rotation axis, and this angle lies in a plane at right angles to the plane of the couple producing the torque. The permanent axis must turn towards this line, since the body cannot continue to rotate about any line which is not a principal axis of maximum moment of inertia; that is, the permanent axis turns in a direction at right angles to that in which the torque might be expected to turn it. If the rotating body is symmetrical and its motion unconstrained, and if the torque on the spin axis is at right angles to that axis, the axis of precession will be perpendicular to both the spin axis and torque axis.
Under these circumstances the angular velocity of precession is given by:
\boldsymbol\omega_p = \frac{Q}{I_s\boldsymbol\omega_s}
In which Is is the moment of inertia, \boldsymbol\omega_s is the angular velocity of spin about the spin axis, and Q is the torque. Using \boldsymbol\omega = \frac{2\pi}{T}, we find that the period of precession is given by:
T_p = \frac{4\pi^2I_s}{QT_s}
In which Is is the moment of inertia, Ts is the period of spin about the spin axis, and Q is the torque. In general the problem is more complicated than this, however.
An informal explanation of Precession:
In a classic beginning physics demonstration, the instructor stands on a swiveling platform and holds a spinning bicycle wheel at arm's length. The wheel is vertical and the instructor is standing still. The instructor then tilts the wheel toward horizontal. This causes the instructor to start spinning slowly on the platform. Bringing the wheel back to vertical and tilting it the other way makes the instructor spin the other way. Why?
Imagine the wheel as a collection of small particles. Particles want to move in a straight line. In order for them to move in a circle there must be a force accelerating the particles toward the center of the circle (acceleration is a change in speed or direction or both — in this case just direction). This force is ultimately provided by bonds between the atoms in the wheel and spokes.
What happens when the instructor turns the spinning wheel from vertical to horizontal? Consider a particle somewhere on the wheel. If the wheel weren't being tilted, it would be accelerated around the circle as always. But since the wheel is tilting, it now has to follow a new path. A change in path is an acceleration, which in turn requires force (from the instructor's hands, transmitted through the spokes to the rim). Now consider the particle opposite the first particle on the wheel. It also has to change path, but in the opposite direction. Since the forces on opposite sides are in opposite directions, the result is torque. Each pair of opposite particles on the wheel contributes to the torque that causes the instructor to turn on the platform.
Tilting the wheel the other direction produces torque in the opposite direction, slowing the instructor's spin and eventually reversing it.
## Relativistic
The special and general theories of relativity give three types of corrections to the Newtonian precession, of a gyroscope near a large mass such as the earth, described above. They are:
- Thomas precession a special relativistic correction accounting for the observer being in a rotating non-inertial frame.
- de Sitter precession a general relativistic correction accounting for the schwarzschild metric of curved space near a large non-rotating mass.
- Lense-Thirring precession a general relativistic correction accounting for the frame dragging by the Kerr metric of curved space near a large rotating mass.
# Of the Earth's axis
The Earth goes through one complete precession cycle in a period of approximately 25,800 years, during which the positions of stars as measured in the equatorial coordinate system will slowly change; the change is actually due to the change of the coordinates. Over this cycle the Earth's north axial pole moves from where it is now, within 1° of Polaris, in a circle around the ecliptic pole, with an angular radius of about 23.5 degrees (or approximately 23 degrees 27 arcminutes ). The shift is 1 degree in 180 years, where the angle is taken from the observer, not from the center of the circle.
Discovery of the precession of the equinoxes is generally attributed to the ancient Greek astronomer Hipparchus (ca. 150 B.C.), though the difference between the sidereal and tropical years was known to Aristarchus of Samos much earlier (ca. 280 B.C.). It was later explained by Newtonian physics. The Earth has a nonspherical shape, being oblate spheroid, bulging outward at the equator. The gravitational tidal forces of the Moon and Sun apply torque as they attempt to pull the equatorial bulge into the plane of the ecliptic. The portion of the precession due to the combined action of the Sun and the Moon is called lunisolar precession.
Revolution of a planet in its orbit around the Sun is also a form of rotary motion. (In this case, the combined system of Earth and Sun is rotating.) So the axis of a planet's orbital plane will also precess over time.
The major axis of each planet's elliptical orbit also precesses within its orbital plane, partly in response to perturbations in the form of the changing gravitational forces exerted by other planets. This is called perihelion precession or apsidal precession (see apsis). Discrepancies between the observed perihelion precession rate of the planet Mercury and that predicted by classical mechanics were prominent among the forms of experimental evidence leading to the acceptance of Einstein's Theory of Relativity, which predicted the anomalies accurately.
These periodic changes of Earth's orbital parameters, combined with the precession of the equinoxes and of the inclination of the Earth's axis on its orbit, are an important part of the astronomical theory of ice ages. For precession of the lunar orbit see lunar precession.
A phenomenon analogous to apsidal precession is nodal precession (see orbital node), which affects the orientation of the orbital plane. | Precession
Precession refers to a change in the direction of the axis of a rotating object. In physics, there are two types of precession, torque-free and torque-induced, the latter being discussed here in more detail. In certain contexts, "precession" may refer to the precession that the Earth experiences, the effects of this type of precession on astronomical observation, or to the precession of orbital objects.
# Torque-free
Torque-free precession occurs when the axis of rotation differs slightly from an axis about which the object can rotate stably. Poinsot's construction is an elegant geometrical method for visualizing the torque-free motion of a rotating rigid body. For example, when a plate is thrown, the plate may have some rotation around an axis that is not its axis of symmetry. When an object is not perfectly solid, internal vortices will tend to damp torque-free precession.
# Torque-induced
Torque-induced precession (gyroscopic precession) is the phenomenon in which the axis of a spinning object (e.g. a part of a gyroscope) "wobbles" when a torque is applied to it. The phenomenon is commonly seen in a spinning toy top, but all rotating objects can undergo precession. If the speed of the rotation and the magnitude of the torque are constant the axis will describe a cone, its movement at any instant being at right angles to the direction of the torque. In the case of a toy top, if the axis is not perfectly vertical the torque is applied by the force of gravity tending to tip it over.
The device depicted on the right here is gimbal mounted. From inside to outside there are three axes of rotation: the hub of the wheel, the gimbal axis and the vertical pivot.
To distinguish between the two horizontal axes, rotation around the wheel hub will be called 'rolling', and rotation around the gimbal axis will be called 'pitching.' Rotation around the pivot axis is called 'spinning'.
First, imagine that the device is spinning around the pivot axis. Then some rotation around the wheelhub is added. Imagine the gimbal axis to be locked, so that the wheel cannot pitch. The gimbal axis has sensors, that measure whether there is a torque around the gimbal axis.
In the picture, a section of the wheel has been named 'dm1'. When the rolling starts, section dm1 is at the perimeter of the spinning motion. Section dm1 has a lot of velocity and as it is forced closer to the center of rotation, it tends to move in the direction of the top-left arrow in the diagram (shown at 45o in the direction of rolling). Section dm2 of the wheel starts out at the center of rotation, and thus initially has zero velocity before the wheel is rolled. A force would be required to increase section dm2's velocity to the velocity at the perimeter of the pivot axis' plane. If that force is not provided then section dm2's inertia will make it move in the direction of the top-right arrow. Note that both arrows point in the same direction.
The same reasoning applies for the bottom half of the wheel, but there the arrows point in the opposite direction to that of the top arrows. Combined over the entire wheel, there is a torque around the gimbal axis when some rolling is added to rotation around a vertical axis.
It is important to note that the torque around the gimbal axis arises without any delay; the response is instantaneous.
In the discussion above, the setup was kept unchanging by preventing rotation around the gimbal axis. In the case of a spinning top, when the spinning top is tilting, gravity exerts a torque. Instead of rolling over, the spinning top pitches. The pitching motion reorients the spinning top with respect to the torque that is being exerted. The result is that the torque exerted by gravity elicits gyroscopic precession rather than causing the spinning top to fall to its side.
Precession or gyroscopic considerations have an effect on bicycle performance at high speed. Precession is also the mechanism behind gyrocompasses.
Gyroscopic precession also plays a large role in the flight controls on helicopters. Since the driving force behind helicopters is the rotor disk (which rotates), gyroscopic precession comes into play. If the rotor disk is to be tilted forward (to gain forward velocity), its rotation requires that the downward net force on the blade be applied roughly 90 degrees (depending on blade configuration) before, or when the blade is to one side of the pilot and rotating forward.
To ensure the pilot's inputs are correct, the aircraft has corrective linkages which vary the blade pitch in advance of the blade's position relative to the swashplate. Although the swashplate moves in the intuitively correct direction, the blade pitch links are arranged to transmit the pitch in advance of the blade's position.
# Physics
## Classical (Newtonian)
Precession is the result of the angular velocity of rotation and the angular velocity produced by the torque. It is an angular velocity about a line which makes an angle with the permanent rotation axis, and this angle lies in a plane at right angles to the plane of the couple producing the torque. The permanent axis must turn towards this line, since the body cannot continue to rotate about any line which is not a principal axis of maximum moment of inertia; that is, the permanent axis turns in a direction at right angles to that in which the torque might be expected to turn it. If the rotating body is symmetrical and its motion unconstrained, and if the torque on the spin axis is at right angles to that axis, the axis of precession will be perpendicular to both the spin axis and torque axis.
Under these circumstances the angular velocity of precession is given by:
\boldsymbol\omega_p = \frac{Q}{I_s\boldsymbol\omega_s}
</math>
In which Is is the moment of inertia, <math>\boldsymbol\omega_s</math> is the angular velocity of spin about the spin axis, and Q is the torque. Using <math>\boldsymbol\omega</math> = <math>\frac{2\pi}{T}</math>, we find that the period of precession is given by:
T_p = \frac{4\pi^2I_s}{QT_s}
</math>
In which Is is the moment of inertia, Ts is the period of spin about the spin axis, and Q is the torque. In general the problem is more complicated than this, however.
An informal explanation of Precession:
In a classic beginning physics demonstration, the instructor stands on a swiveling platform and holds a spinning bicycle wheel at arm's length. The wheel is vertical and the instructor is standing still. The instructor then tilts the wheel toward horizontal. This causes the instructor to start spinning slowly on the platform. Bringing the wheel back to vertical and tilting it the other way makes the instructor spin the other way. Why?
Imagine the wheel as a collection of small particles. Particles want to move in a straight line. In order for them to move in a circle there must be a force accelerating the particles toward the center of the circle (acceleration is a change in speed or direction or both — in this case just direction). This force is ultimately provided by bonds between the atoms in the wheel and spokes.
What happens when the instructor turns the spinning wheel from vertical to horizontal? Consider a particle somewhere on the wheel. If the wheel weren't being tilted, it would be accelerated around the circle as always. But since the wheel is tilting, it now has to follow a new path. A change in path is an acceleration, which in turn requires force (from the instructor's hands, transmitted through the spokes to the rim). Now consider the particle opposite the first particle on the wheel. It also has to change path, but in the opposite direction. Since the forces on opposite sides are in opposite directions, the result is torque. Each pair of opposite particles on the wheel contributes to the torque that causes the instructor to turn on the platform.
Tilting the wheel the other direction produces torque in the opposite direction, slowing the instructor's spin and eventually reversing it.
## Relativistic
The special and general theories of relativity give three types of corrections to the Newtonian precession, of a gyroscope near a large mass such as the earth, described above. They are:
- Thomas precession a special relativistic correction accounting for the observer being in a rotating non-inertial frame.
- de Sitter precession a general relativistic correction accounting for the schwarzschild metric of curved space near a large non-rotating mass.
- Lense-Thirring precession a general relativistic correction accounting for the frame dragging by the Kerr metric of curved space near a large rotating mass.
# Of the Earth's axis
The Earth goes through one complete precession cycle in a period of approximately 25,800 years, during which the positions of stars as measured in the equatorial coordinate system will slowly change; the change is actually due to the change of the coordinates. Over this cycle the Earth's north axial pole moves from where it is now, within 1° of Polaris, in a circle around the ecliptic pole, with an angular radius of about 23.5 degrees (or approximately 23 degrees 27 arcminutes [1]). The shift is 1 degree in 180 years, where the angle is taken from the observer, not from the center of the circle.
Discovery of the precession of the equinoxes is generally attributed to the ancient Greek astronomer Hipparchus (ca. 150 B.C.), though the difference between the sidereal and tropical years was known to Aristarchus of Samos much earlier (ca. 280 B.C.). It was later explained by Newtonian physics. The Earth has a nonspherical shape, being oblate spheroid, bulging outward at the equator. The gravitational tidal forces of the Moon and Sun apply torque as they attempt to pull the equatorial bulge into the plane of the ecliptic. The portion of the precession due to the combined action of the Sun and the Moon is called lunisolar precession.
Revolution of a planet in its orbit around the Sun is also a form of rotary motion. (In this case, the combined system of Earth and Sun is rotating.) So the axis of a planet's orbital plane will also precess over time.
The major axis of each planet's elliptical orbit also precesses within its orbital plane, partly in response to perturbations in the form of the changing gravitational forces exerted by other planets. This is called perihelion precession or apsidal precession (see apsis). Discrepancies between the observed perihelion precession rate of the planet Mercury and that predicted by classical mechanics were prominent among the forms of experimental evidence leading to the acceptance of Einstein's Theory of Relativity, which predicted the anomalies accurately.[2][3]
These periodic changes of Earth's orbital parameters, combined with the precession of the equinoxes and of the inclination of the Earth's axis on its orbit, are an important part of the astronomical theory of ice ages. For precession of the lunar orbit see lunar precession.
A phenomenon analogous to apsidal precession is nodal precession (see orbital node), which affects the orientation of the orbital plane. | https://www.wikidoc.org/index.php/Precession | |
b1a2546ddb1cfb8df9f1a1a835ace8f490585f90 | wikidoc | Prediction | Prediction
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
A prediction is a statement or claim that a particular event will occur in the future in more certain terms than a forecast. The etymology of this word is Latin (from præ- "before" plus dicere "to say"). Niels Bohr stated "Prediction is very difficult, especially if it's about the future."
# Informal prediction from hypothesis
Outside the rigorous context of science, prediction is often confused with informed guess or opinion.
A prediction of this kind might be valid and useful if the predictor is a knowledgeable person in the field and is employing sound reasoning and accurate data. Large corporations invest heavily in this kind of activity to help focus attention on possible events, risks and business opportunities, using futurists. Such work brings together all available past and current data, as a basis on which to develop reasonable expectations about the future.
# Opinion Polls
In politics it is common to attempt to predict the outcome of elections (or assess the popularity of politicians) through the use of opinion polls. Prediction games have been used by many corporations and governments to learn about the most likely outcome of future events with amazing accuracy.
# Supernatural (prophecy)
Predictions have often been made, from antiquity until the present, by resorting to paranormal or supernatural means, such as prophecy or by observing omens. Disciplines including water divining, astrology, numerology, and fortune telling, along with many other forms of divination, have been used for centuries or even millennia to predict or attempt to predict the future. So far none of these means of prediction have been proven under controlled conditions and are heavily criticised by scientists and skeptics.
# Anticipatory science forecasts
In a scientific context, a prediction is a rigorous, (often quantitative), statement forecasting what will happen under specific conditions, typically expressed in the form If A is true, then B will also be true. The scientific method is built on testing assertions which are logical consequences of scientific theories. This is done through repeatable experiments or observational studies.
A scientific theory whose assertions are not in accordance with observations and evidence will probably be rejected. Theories that make no testable predictions remain protosciences until testable predictions become known to the community.
Additionally, if new theories generate many new predictions, they are often highly valued, for they can be quickly and easily confirmed or falsified (see predictive power). In many scientific fields, desirable theories are those which predict a large number of events from relatively few underlying principles.
Quantum physics is an unusual field of science because it enables scientists to make predictions on the basis of probability.
Mathematical models and computer models are frequently used to both describe the behaviour of something, and predict its future behaviour.
In microprocessors, branch prediction permits to avoid pipeline emptying at branch instructions. Engineering is a field that involves predicting failure and avoiding it through component or system redundancy.
Some fields of science are notorious for the difficulty of accurate prediction and forecasting, such as software reliability, natural disasters, pandemics, demography, population dynamics and meteorology.
## Example of scientific hypothesis and prediction
In the 1840s the renowned Hungarian physician Ignaz Semmelweis noticed that women giving birth in the Vienna lying-in hospital were dying in one building, but surviving in another.
Upon considering the cause, he found that the surviving women were attended by midwives and not by student physicians. Thus he proposed the hypothesis that the physicians were a factor in the deaths. This proposition impelled Semmelweis to refine the factor. What was the difference between the midwives and the doctors? After more thought, Semmelweis decided that the cadavers which the student doctors were touching must be part of the factor.
What could the doctors do to avoid the factor? Semmelweis predicted that, if the doctors were to wash their hands, then the cadaver factor would be avoided. Semmelweis therefore instructed the student doctors to wash their hands, and the women who were attended by the doctors survived. Thus his prediction was successful, and his hypothesis was validated. (Semmelweis, 1861. The Etiology, Understanding, and Prophylaxis of Childbed Fever)
Other examples abound in the history of science, ranging from expected predictions which did not occur (such as the Michelson-Morley experiment) to new and radical predictions which shockingly confirmed one theory over another (such as the bending of light around the sun seen in the 1919 eclipse, a prediction of Albert Einstein's theory of General relativity).
# Finance
Mathematical models of stock market behaviour are also unreliable in predicting future behaviour. Consequently, stock investors may anticipate or predict a stock market boom, or fail to anticipate or predict a stock market crash.
Some correlation has been seen between actual stock market movements and prediction data from large groups in surveys and prediction games
An actuary uses actuarial science to assess and predict future business risk, such that the risk(s) can be mitigated.
For example, in insurance an actuary would use a life table to predict life expectancy.
# Vision and prophecy
In literature, vision and prophecy are literary devices used to present a possible timeline of future events. They can be distinguished by vision referring to what an individual sees happen. The New Testament book of Revelation (Bible) thus uses vision as a literary device in this regard. It is also prophecy or prophetic literature when it is related by an individual in a sermon or other public forum.
Charles Dickens' A Christmas Carol also makes use of vision as a literary device. After Scrooge confronts the visions given to him by the Ghosts of Christmas Past, Present, and Yet to Come, he asks whether the future he has seen can be changed. In other words, he wants to know whether he change the outcome of the ghosts' prophecies. This question has also been addressed in many science fiction works, particularly those dealing with time travel.
# Prediction in fiction
Fiction (especially fantasy, forecasting and science fiction) often features instances of prediction achieved by unconventional means.
- In fantasy literature, predictions are often obtained through magic or prophecy, sometimes referring back to old traditions. For example, in J. R. R. Tolkien's The Lord of the Rings, many of the characters possess an awareness of events extending into the future, sometimes as prophecies, sometimes as more-or-less vague 'feelings'. The character Galadriel, in addition, employs a water "mirror" to show images, sometimes of possible future events.
- In some of Philip K. Dick's stories, mutant humans called precogs can foresee the future (ranging from days to years). In the story called The Golden Man, an exceptional mutant can predict the future to an indefinite range (presumably up to his death), and thus becomes completely non-human, an animal that follows the predicted paths automatically.
- In the Foundation series by Isaac Asimov, a mathematician finds out that historical events (up to some detail) can be theoretically modelled using equations, and then spends years trying to put the theory in practice. The new science of psychohistory founded upon his success can simulate history and extrapolate the present into the future.
- In Frank Herbert's sequels to Dune, his characters are dealing with the repercussions of being able to see the possible futures and select amongst them. Herbert sees this as a trap of stagnation, and his characters follow a Golden Path out of the trap.
- In Ursula K. Le Guin's The Left Hand of Darkness, the humanoid inhabitants of planet Gethen have mastered the art of prophecy and routinely produce data on past, present or future events on request. In this story, this was a minor plot device. | Prediction
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [1] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
Template:Tfd
A prediction is a statement or claim that a particular event will occur in the future in more certain terms than a forecast. The etymology of this word is Latin (from præ- "before" plus dicere "to say"). Niels Bohr stated "Prediction is very difficult, especially if it's about the future."
# Informal prediction from hypothesis
Outside the rigorous context of science, prediction is often confused with informed guess or opinion.
A prediction of this kind might be valid and useful if the predictor is a knowledgeable person in the field and is employing sound reasoning and accurate data. Large corporations invest heavily in this kind of activity to help focus attention on possible events, risks and business opportunities, using futurists. Such work brings together all available past and current data, as a basis on which to develop reasonable expectations about the future.
# Opinion Polls
In politics it is common to attempt to predict the outcome of elections (or assess the popularity of politicians) through the use of opinion polls. Prediction games have been used by many corporations and governments to learn about the most likely outcome of future events with amazing accuracy.
# Supernatural (prophecy)
Predictions have often been made, from antiquity until the present, by resorting to paranormal or supernatural means, such as prophecy or by observing omens. Disciplines including water divining, astrology, numerology, and fortune telling, along with many other forms of divination, have been used for centuries or even millennia to predict or attempt to predict the future. So far none of these means of prediction have been proven under controlled conditions and are heavily criticised by scientists and skeptics.
# Anticipatory science forecasts
In a scientific context, a prediction is a rigorous, (often quantitative), statement forecasting what will happen under specific conditions, typically expressed in the form If A is true, then B will also be true. The scientific method is built on testing assertions which are logical consequences of scientific theories. This is done through repeatable experiments or observational studies.
A scientific theory whose assertions are not in accordance with observations and evidence will probably be rejected. Theories that make no testable predictions remain protosciences until testable predictions become known to the community.
Additionally, if new theories generate many new predictions, they are often highly valued, for they can be quickly and easily confirmed or falsified (see predictive power). In many scientific fields, desirable theories are those which predict a large number of events from relatively few underlying principles.
Quantum physics is an unusual field of science because it enables scientists to make predictions on the basis of probability.
Mathematical models and computer models are frequently used to both describe the behaviour of something, and predict its future behaviour.
In microprocessors, branch prediction permits to avoid pipeline emptying at branch instructions. Engineering is a field that involves predicting failure and avoiding it through component or system redundancy.
Some fields of science are notorious for the difficulty of accurate prediction and forecasting, such as software reliability, natural disasters, pandemics, demography, population dynamics and meteorology.
## Example of scientific hypothesis and prediction
In the 1840s the renowned Hungarian physician Ignaz Semmelweis noticed that women giving birth in the Vienna lying-in hospital were dying in one building, but surviving in another.
Upon considering the cause, he found that the surviving women were attended by midwives and not by student physicians. Thus he proposed the hypothesis that the physicians were a factor in the deaths. This proposition impelled Semmelweis to refine the factor. What was the difference between the midwives and the doctors? After more thought, Semmelweis decided that the cadavers which the student doctors were touching must be part of the factor.
What could the doctors do to avoid the factor? Semmelweis predicted that, if the doctors were to wash their hands, then the cadaver factor would be avoided. Semmelweis therefore instructed the student doctors to wash their hands, and the women who were attended by the doctors survived. Thus his prediction was successful, and his hypothesis was validated. (Semmelweis, 1861. The Etiology, Understanding, and Prophylaxis of Childbed Fever)
Other examples abound in the history of science, ranging from expected predictions which did not occur (such as the Michelson-Morley experiment) to new and radical predictions which shockingly confirmed one theory over another (such as the bending of light around the sun seen in the 1919 eclipse, a prediction of Albert Einstein's theory of General relativity).
# Finance
Mathematical models of stock market behaviour are also unreliable in predicting future behaviour. Consequently, stock investors may anticipate or predict a stock market boom, or fail to anticipate or predict a stock market crash.
Some correlation has been seen between actual stock market movements and prediction data from large groups in surveys and prediction games
An actuary uses actuarial science to assess and predict future business risk, such that the risk(s) can be mitigated.
For example, in insurance an actuary would use a life table to predict life expectancy.
# Vision and prophecy
In literature, vision and prophecy are literary devices used to present a possible timeline of future events. They can be distinguished by vision referring to what an individual sees happen. The New Testament book of Revelation (Bible) thus uses vision as a literary device in this regard. It is also prophecy or prophetic literature when it is related by an individual in a sermon or other public forum.
Charles Dickens' A Christmas Carol also makes use of vision as a literary device. After Scrooge confronts the visions given to him by the Ghosts of Christmas Past, Present, and Yet to Come, he asks whether the future he has seen can be changed.[1] In other words, he wants to know whether he change the outcome of the ghosts' prophecies. This question has also been addressed in many science fiction works, particularly those dealing with time travel.
# Prediction in fiction
Fiction (especially fantasy, forecasting and science fiction) often features instances of prediction achieved by unconventional means.
- In fantasy literature, predictions are often obtained through magic or prophecy, sometimes referring back to old traditions. For example, in J. R. R. Tolkien's The Lord of the Rings, many of the characters possess an awareness of events extending into the future, sometimes as prophecies, sometimes as more-or-less vague 'feelings'. The character Galadriel, in addition, employs a water "mirror" to show images, sometimes of possible future events.
- In some of Philip K. Dick's stories, mutant humans called precogs can foresee the future (ranging from days to years). In the story called The Golden Man, an exceptional mutant can predict the future to an indefinite range (presumably up to his death), and thus becomes completely non-human, an animal that follows the predicted paths automatically.
- In the Foundation series by Isaac Asimov, a mathematician finds out that historical events (up to some detail) can be theoretically modelled using equations, and then spends years trying to put the theory in practice. The new science of psychohistory founded upon his success can simulate history and extrapolate the present into the future.
- In Frank Herbert's sequels to Dune, his characters are dealing with the repercussions of being able to see the possible futures and select amongst them. Herbert sees this as a trap of stagnation, and his characters follow a Golden Path out of the trap.
- In Ursula K. Le Guin's The Left Hand of Darkness, the humanoid inhabitants of planet Gethen have mastered the art of prophecy and routinely produce data on past, present or future events on request. In this story, this was a minor plot device. | https://www.wikidoc.org/index.php/Prediction | |
9e3bbaf9a56248f17a250ac0b0001d091550979f | wikidoc | Pregabalin | Pregabalin
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# Overview
Pregabalin is a GABA analogue that is FDA approved for the treatment of neuropathic pain associated with diabetic peripheral neuropathy (DPN), postherpetic neuralgia (PHN), adjunctive therapy for adult patients with partial onset seizures ,fibromyalgia, neuropathic pain associated with spinal cord injury. Common adverse reactions include dizziness, somnolence, dry mouth, edema, blurred vision, weight gain and abnormal thinking (primarily difficulty with concentration/attention).
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- LYRICA is indicated for:
- Management of neuropathic pain associated with diabetic peripheral neuropathy
- Management of postherpetic neuralgia
- Adjunctive therapy for adult patients with partial onset seizures
- Management of fibromyalgia
- Management of neuropathic pain associated with spinal cord injury
### Dosage And Administration
- LYRICA is given orally with or without food.
- When discontinuing LYRICA, taper gradually over a minimum of 1 week.
### Neuropathic Pain Associated with Diabetic Peripheral Neuropathy
- The maximum recommended dose of LYRICA is 100 mg three times a day (300 mg/day) in patients with creatinine clearance of at least 60 mL/min. Begin dosing at 50 mg three times a day (150 mg/day). The dose may be increased to 300 mg/day within 1 week based on efficacy and tolerability. Because LYRICA is eliminated primarily by renal excretion, adjust the dose in patients with reduced renal function.
- Although LYRICA was also studied at 600 mg/day, there is no evidence that this dose confers additional significant benefit and this dose was less well tolerated. In view of the dose-dependent adverse reactions, treatment with doses above 300 mg/day is not recommended.
### Postherpetic Neuralgia
- The recommended dose of LYRICA is 75 to 150 mg two times a day, or 50 to 100 mg three times a day (150 to 300 mg/day) in patients with creatinine clearance of at least 60 mL/min. Begin dosing at 75 mg two times a day, or 50 mg three times a day (150 mg/day). The dose may be increased to 300 mg/day within 1 week based on efficacy and tolerability. Because LYRICA is eliminated primarily by renal excretion, adjust the dose in patients with reduced renal function.
- Patients who do not experience sufficient pain relief following 2 to 4 weeks of treatment with 300 mg/day, and who are able to tolerate LYRICA, may be treated with up to 300 mg two times a day, or 200 mg three times a day (600 mg/day). In view of the dose-dependent adverse reactions and the higher rate of treatment discontinuation due to adverse reactions, reserve dosing above 300 mg/day for those patients who have on-going pain and are tolerating 300 mg daily.
### Adjunctive Therapy for Adult Patients with Partial Onset Seizures
- LYRICA at doses of 150 to 600 mg/day has been shown to be effective as adjunctive therapy in the treatment of partial onset seizures in adults. Both the efficacy and adverse event profiles of LYRICA have been shown to be dose-related. Administer the total daily dose in two or three divided doses. In general, it is recommended that patients be started on a total daily dose no greater than 150 mg/day (75 mg two times a day, or 50 mg three times a day). Based on individual patient response and tolerability, the dose may be increased to a maximum dose of 600 mg/day.
- Because LYRICA is eliminated primarily by renal excretion, adjust the dose in patients with reduced renal function.
- The effect of dose escalation rate on the tolerability of LYRICA has not been formally studied.
- The efficacy of add-on LYRICA in patients taking gabapentin has not been evaluated in controlled trials. Consequently, dosing recommendations for the use of LYRICA with gabapentin cannot be offered.
### Management of Fibromyalgia
- The recommended dose of LYRICA for fibromyalgia is 300 to 450 mg/day. Begin dosing at 75 mg two times a day (150 mg/day). The dose may be increased to 150 mg two times a day (300 mg/day) within 1 week based on efficacy and tolerability. Patients who do not experience sufficient benefit with 300 mg/day may be further increased to 225 mg two times a day (450 mg/day). Although LYRICA was also studied at 600 mg/day, there is no evidence that this dose confers additional benefit and this dose was less well tolerated. In view of the dose-dependent adverse reactions, treatment with doses above 450 mg/day is not recommended. Because LYRICA is eliminated primarily by renal excretion, adjust the dose in patients with reduced renal function.
### Neuropathic Pain Associated with Spinal Cord Injury
- The recommended dose range of LYRICA for the treatment of neuropathic pain associated with spinal cord injury is 150 to 600 mg/day. The recommended starting dose is 75 mg two times a day (150 mg/day). The dose may be increased to 150 mg two times a day (300 mg/day) within 1 week based on efficacy and tolerability. Patients who do not experience sufficient pain relief after 2 to 3 weeks of treatment with 150 mg two times a day and who tolerate LYRICA may be treated with up to 300 mg two times a day. Because LYRICA is eliminated primarily by renal excretion, adjust the dose in patients with reduced renal function.
### Patients with Renal Impairment
- In view of dose-dependent adverse reactions and since LYRICA is eliminated primarily by renal excretion, adjust the dose in patients with reduced renal function. Base the dose adjustment in patients with renal impairment on creatinine clearance (CLcr), as indicated in Table 1. To use this dosing table, an estimate of the patient's CLcr in mL/min is needed. CLcr in mL/min may be estimated from serum creatinine (mg/dL) determination using the Cockcroft and Gault equation:
- Next, refer to the Dosage and Administration section to determine the recommended total daily dose based on indication, for a patient with normal renal function (CLcr ≥60 mL/min). Then refer to Table 1 to determine the corresponding renal adjusted dose.
- (For example: A patient initiating LYRICA therapy for postherpetic neuralgia with normal renal function (CLcr ≥60 mL/min), receives a total daily dose of 150 mg/day pregabalin. Therefore, a renal impaired patient with a CLcr of 50 mL/min would receive a total daily dose of 75 mg/day pregabalin administered in two or three divided doses.)
- For patients undergoing hemodialysis, adjust the pregabalin daily dose based on renal function. In addition to the daily dose adjustment, administer a supplemental dose immediately following every 4-hour hemodialysis treatment (see Table 1).
### Oral Solution Concentration and Dispensing
- The oral solution is 20 mg pregabalin per milliliter (mL) and prescriptions should be written in milligrams (mg). The pharmacist will calculate the applicable dose in mL for dispensing (e.g., 150 mg equals 7.5 mL oral solution).
### Dosage Forms And Strengths
- Capsules: 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 225 mg, and 300 mg
- Oral Solution: 20 mg/mL
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pregabalin in adult patients.
### Non–Guideline-Supported Use
- 450 mg per day
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Pregabalin in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pregabalin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Pregabalin in pediatric patients.
# Contraindications
- LYRICA is contraindicated in patients with known hypersensitivity to pregabalin or any of its components. Angioedema and hypersensitivity reactions have occurred in patients receiving pregabalin therapy.
# Warnings
### Precautions
- Angioedema
- There have been postmarketing reports of angioedema in patients during initial and chronic treatment with LYRICA. Specific symptoms included swelling of the face, mouth (tongue, lips, and gums), and neck (throat and larynx). There were reports of life-threatening angioedema with respiratory compromise requiring emergency treatment. Discontinue LYRICA immediately in patients with these symptoms.
- Exercise caution when prescribing LYRICA to patients who have had a previous episode of angioedema. In addition, patients who are taking other drugs associated with angioedema (e.g., angiotensin converting enzyme inhibitors ACE-inhibitors) may be at increased risk of developing angioedema.
- Hypersensitivity
- There have been postmarketing reports of hypersensitivity in patients shortly after initiation of treatment with LYRICA. Adverse reactions included skin redness, blisters, hives, rash, dyspnea, and wheezing. Discontinue LYRICA immediately in patients with these symptoms.
- Withdrawal of Antiepileptic Drugs (AEDs)
- As with all AEDs, withdraw LYRICA gradually to minimize the potential of increased seizure frequency in patients with seizure disorders. If LYRICA is discontinued, taper the drug gradually over a minimum of 1 week.
- Suicidal Behavior and Ideation
- Antiepileptic drugs (AEDs), including LYRICA, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Monitor patients treated with any AED for any indication for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
- Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.
- The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
- The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5–100 years) in the clinical trials analyzed.
- Table 2 shows absolute and relative risk by indication for all evaluated AEDs.
- The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.
- Anyone considering prescribing LYRICA or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
- Inform patients, their caregivers, and families that LYRICA and other AEDs increase the risk of suicidal thoughts and behavior and advise them of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Report behaviors of concern immediately to healthcare providers.
- Peripheral Edema
- LYRICA treatment may cause peripheral edema. In short-term trials of patients without clinically significant heart or peripheral vascular disease, there was no apparent association between peripheral edema and cardiovascular complications such as hypertension or congestive heart failure. Peripheral edema was not associated with laboratory changes suggestive of deterioration in renal or hepatic function.
- In controlled clinical trials the incidence of peripheral edema was 6% in the LYRICA group compared with 2% in the placebo group. In controlled clinical trials, 0.5% of LYRICA patients and 0.2% placebo patients withdrew due to peripheral edema.
- Higher frequencies of weight gain and peripheral edema were observed in patients taking both LYRICA and a thiazolidinedione antidiabetic agent compared to patients taking either drug alone. The majority of patients using thiazolidinedione antidiabetic agents in the overall safety database were participants in studies of pain associated with diabetic peripheral neuropathy. In this population, peripheral edema was reported in 3% (2/60) of patients who were using thiazolidinedione antidiabetic agents only, 8% (69/859) of patients who were treated with LYRICA only, and 19% (23/120) of patients who were on both LYRICA and thiazolidinedione antidiabetic agents. Similarly, weight gain was reported in 0% (0/60) of patients on thiazolidinediones only; 4% (35/859) of patients on LYRICA only; and 7.5% (9/120) of patients on both drugs.
- As the thiazolidinedione class of antidiabetic drugs can cause weight gain and/or fluid retention, possibly exacerbating or leading to heart failure, exercise caution when co-administering LYRICA and these agents.
- Because there are limited data on congestive heart failure patients with New York Heart Association (NYHA) Class III or IV cardiac status, exercise caution when using LYRICA in these patients.
- Dizziness and Somnolence
- LYRICA may cause dizziness and somnolence. Inform patients that LYRICA-related dizziness and somnolence may impair their ability to perform tasks such as driving or operating machinery.
- In the LYRICA controlled trials, dizziness was experienced by 30% of LYRICA-treated patients compared to 8% of placebo-treated patients; somnolence was experienced by 23% of LYRICA-treated patients compared to 8% of placebo-treated patients. Dizziness and somnolence generally began shortly after the initiation of LYRICA therapy and occurred more frequently at higher doses. Dizziness and somnolence were the adverse reactions most frequently leading to withdrawal (4% each) from controlled studies. In LYRICA-treated patients reporting these adverse reactions in short-term, controlled studies, dizziness persisted until the last dose in 30% and somnolence persisted until the last dose in 42% of patients.
- Weight Gain
- LYRICA treatment may cause weight gain. In LYRICA controlled clinical trials of up to 14 weeks, a gain of 7% or more over baseline weight was observed in 9% of LYRICA-treated patients and 2% of placebo-treated patients. Few patients treated with LYRICA (0.3%) withdrew from controlled trials due to weight gain. LYRICA associated weight gain was related to dose and duration of exposure, but did not appear to be associated with baseline BMI, gender, or age. Weight gain was not limited to patients with edema.
- Although weight gain was not associated with clinically important changes in blood pressure in short-term controlled studies, the long-term cardiovascular effects of LYRICA-associated weight gain are unknown.
- Among diabetic patients, LYRICA-treated patients gained an average of 1.6 kg (range: -16 to 16 kg), compared to an average 0.3 kg (range: -10 to 9 kg) weight gain in placebo patients. In a cohort of 333 diabetic patients who received LYRICA for at least 2 years, the average weight gain was 5.2 kg.
- While the effects of LYRICA-associated weight gain on glycemic control have not been systematically assessed, in controlled and longer-term open label clinical trials with diabetic patients, LYRICA treatment did not appear to be associated with loss of glycemic control (as measured by HbA1C).
- Abrupt or Rapid Discontinuation
- Following abrupt or rapid discontinuation of LYRICA, some patients reported symptoms including insomnia, nausea, headache, anxiety, hyperhidrosis, and diarrhea. Taper LYRICA gradually over a minimum of 1 week rather than discontinuing the drug abruptly.
- Tumorigenic Potential
- In standard preclinical in vivo lifetime carcinogenicity studies of LYRICA, an unexpectedly high incidence of hemangiosarcoma was identified in two different strains of mice. The clinical significance of this finding is unknown. Clinical experience during LYRICA's premarketing development provides no direct means to assess its potential for inducing tumors in humans.
- In clinical studies across various patient populations, comprising 6396 patient-years of exposure in patients >12 years of age, new or worsening-preexisting tumors were reported in 57 patients. Without knowledge of the background incidence and recurrence in similar populations not treated with LYRICA, it is impossible to know whether the incidence seen in these cohorts is or is not affected by treatment.
- Ophthalmological Effects
- In controlled studies, a higher proportion of patients treated with LYRICA reported blurred vision (7%) than did patients treated with placebo (2%), which resolved in a majority of cases with continued dosing. Less than 1% of patients discontinued LYRICA treatment due to vision-related events (primarily blurred vision).
- Prospectively planned ophthalmologic testing, including visual acuity testing, formal visual field testing and dilated funduscopic examination, was performed in over 3600 patients. In these patients, visual acuity was reduced in 7% of patients treated with LYRICA, and 5% of placebo-treated patients. Visual field changes were detected in 13% of LYRICA-treated, and 12% of placebo-treated patients. Funduscopic changes were observed in 2% of LYRICA-treated and 2% of placebo-treated patients.
- Although the clinical significance of the ophthalmologic findings is unknown, inform patients to notify their physician if changes in vision occur. If visual disturbance persists, consider further assessment. Consider more frequent assessment for patients who are already routinely monitored for ocular conditions.
- Creatine Kinase Elevations
- LYRICA treatment was associated with creatine kinase elevations. Mean changes in creatine kinase from baseline to the maximum value were 60 U/L for LYRICA-treated patients and 28 U/L for the placebo patients. In all controlled trials across multiple patient populations, 1.5% of patients on LYRICA and 0.7% of placebo patients had a value of creatine kinase at least three times the upper limit of normal. Three LYRICA treated subjects had events reported as rhabdomyolysis in premarketing clinical trials. The relationship between these myopathy events and LYRICA is not completely understood because the cases had documented factors that may have caused or contributed to these events. Instruct patients to promptly report unexplained muscle pain, tenderness, or weakness, particularly if these muscle symptoms are accompanied by malaise or fever. Discontinue treatment with LYRICA if myopathy is diagnosed or suspected or if markedly elevated creatine kinase levels occur.
- Decreased Platelet Count
- LYRICA treatment was associated with a decrease in platelet count. LYRICA-treated subjects experienced a mean maximal decrease in platelet count of 20 × 103/µL, compared to 11 × 103/µL in placebo patients. In the overall database of controlled trials, 2% of placebo patients and 3% of LYRICA patients experienced a potentially clinically significant decrease in platelets, defined as 20% below baseline value and <<<150 × 103/µL. A single LYRICA treated subject developed severe thrombocytopenia with a platelet count less than 20 × 103/ µL. In randomized controlled trials, LYRICA was not associated with an increase in bleeding-related adverse reactions.
- PR Interval Prolongation
- LYRICA treatment was associated with PR interval prolongation. In analyses of clinical trial ECG data, the mean PR interval increase was 3–6 msec at LYRICA doses ≥300 mg/day. This mean change difference was not associated with an increased risk of PR increase ≥25% from baseline, an increased percentage of subjects with on-treatment PR >200 msec, or an increased risk of adverse reactions of second or third degree AV block.
- Subgroup analyses did not identify an increased risk of PR prolongation in patients with baseline PR prolongation or in patients taking other PR prolonging medications. However, these analyses cannot be considered definitive because of the limited number of patients in these categories.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- In all controlled and uncontrolled trials across various patient populations during the premarketing development of LYRICA, more than 10,000 patients have received LYRICA. Approximately 5000 patients were treated for 6 months or more, over 3100 patients were treated for 1 year or longer, and over 1400 patients were treated for at least 2 years.
- Adverse Reactions Most Commonly Leading to Discontinuation in All Premarketing Controlled Clinical Studies
- In premarketing controlled trials of all populations combined, 14% of patients treated with LYRICA and 7% of patients treated with placebo discontinued prematurely due to adverse reactions. In the LYRICA treatment group, the adverse reactions most frequently leading to discontinuation were dizziness (4%) and somnolence (4%). In the placebo group, 1% of patients withdrew due to dizziness and <1% withdrew due to somnolence. Other adverse reactions that led to discontinuation from controlled trials more frequently in the LYRICA group compared to the placebo group were ataxia, confusion, asthenia, thinking abnormal, blurred vision, incoordination, and peripheral edema (1% each).
- Most Common Adverse Reactions in All Premarketing Controlled Clinical Studies
- In premarketing controlled trials of all patient populations combined, dizziness, somnolence, dry mouth, edema, blurred vision, weight gain, and "thinking abnormal" (primarily difficulty with concentration/attention) were more commonly reported by subjects treated with LYRICA than by subjects treated with placebo (≥5% and twice the rate of that seen in placebo).
- Controlled Studies with Neuropathic Pain Associated with Diabetic Peripheral Neuropathy
- Adverse Reactions Leading to Discontinuation
- In clinical trials in patients with neuropathic pain associated with diabetic peripheral neuropathy, 9% of patients treated with LYRICA and 4% of patients treated with placebo discontinued prematurely due to adverse reactions. In the LYRICA treatment group, the most common reasons for discontinuation due to adverse reactions were dizziness (3%) and somnolence (2%). In comparison, <1% of placebo patients withdrew due to dizziness and somnolence. Other reasons for discontinuation from the trials, occurring with greater frequency in the LYRICA group than in the placebo group, were asthenia, confusion, and peripheral edema. Each of these events led to withdrawal in approximately 1% of patients.
- Most Common Adverse Reactions
- Table 3 lists all adverse reactions, regardless of causality, occurring in ≥1% of patients with neuropathic pain associated with diabetic neuropathy in the combined LYRICA group for which the incidence was greater in this combined LYRICA group than in the placebo group. A majority of pregabalin-treated patients in clinical studies had adverse reactions with a maximum intensity of "mild" or "moderate".
- Controlled Studies in Postherpetic Neuralgia
- Adverse Reactions Leading to Discontinuation
- In clinical trials in patients with postherpetic neuralgia, 14% of patients treated with LYRICA and 7% of patients treated with placebo discontinued prematurely due to adverse reactions. In the LYRICA treatment group, the most common reasons for discontinuation due to adverse reactions were dizziness (4%) and somnolence (3%). In comparison, less than 1% of placebo patients withdrew due to dizziness and somnolence. Other reasons for discontinuation from the trials, occurring in greater frequency in the LYRICA group than in the placebo group, were confusion (2%), as well as peripheral edema, asthenia, ataxia, and abnormal gait (1% each).
- Most Common Adverse Reactions
- Table 4 lists all adverse reactions, regardless of causality, occurring in ≥ 1% of patients with neuropathic pain associated with postherpetic neuralgia in the combined LYRICA group for which the incidence was greater in this combined LYRICA group than in the placebo group. In addition, an event is included, even if the incidence in the all LYRICA group is not greater than in the placebo group, if the incidence of the event in the 600 mg/day group is more than twice that in the placebo group. A majority of pregabalin-treated patients in clinical studies had adverse reactions with a maximum intensity of "mild" or "moderate". Overall, 12.4% of all pregabalin-treated patients and 9.0% of all placebo-treated patients had at least one severe event while 8% of pregabalin-treated patients and 4.3% of placebo-treated patients had at least one severe treatment-related adverse event.
- Controlled Add-On Studies in Adjunctive Therapy for Adult Patients with Partial Onset Seizures
- Adverse Reactions Leading to Discontinuation
- Approximately 15% of patients receiving LYRICA and 6% of patients receiving placebo in add-on epilepsy trials discontinued prematurely due to adverse reactions. In the LYRICA treatment group, the adverse reactions most frequently leading to discontinuation were dizziness (6%), ataxia (4%), and somnolence (3%). In comparison, <1% of patients in the placebo group withdrew due to each of these events. Other adverse reactions that led to discontinuation of at least 1% of patients in the LYRICA group and at least twice as frequently compared to the placebo group were asthenia, diplopia, blurred vision, thinking abnormal, nausea, tremor, vertigo, headache, and confusion (which each led to withdrawal in 2% or less of patients).
- Most Common Adverse Reactions
- Table 5 lists all dose-related adverse reactions occurring in at least 2% of all LYRICA-treated patients. Dose-relatedness was defined as the incidence of the adverse event in the 600 mg/day group was at least 2% greater than the rate in both the placebo and 150 mg/day groups. In these studies, 758 patients received LYRICA and 294 patients received placebo for up to 12 weeks. Because patients were also treated with 1 to 3 other AEDs, it is not possible to determine whether the following adverse reactions can be ascribed to LYRICA alone, or the combination of LYRICA and other AEDs. A majority of pregabalin-treated patients in clinical studies had adverse reactions with a maximum intensity of "mild" or "moderate".
- Controlled Studies with Fibromyalgia
- Adverse Reactions Leading to Discontinuation
- In clinical trials of patients with fibromyalgia, 19% of patients treated with pregabalin (150–600 mg/day) and 10% of patients treated with placebo discontinued prematurely due to adverse reactions. In the pregabalin treatment group, the most common reasons for discontinuation due to adverse reactions were dizziness (6%) and somnolence (3%). In comparison, <1% of placebo-treated patients withdrew due to dizziness and somnolence. Other reasons for discontinuation from the trials, occurring with greater frequency in the pregabalin treatment group than in the placebo treatment group, were fatigue, headache, balance disorder, and weight increased. Each of these adverse reactions led to withdrawal in approximately 1% of patients.
- Most Common Adverse Reactions
- Table 6 lists all adverse reactions, regardless of causality, occurring in ≥2% of patients with fibromyalgia in the 'all pregabalin' treatment group for which the incidence was greater than in the placebo treatment group. A majority of pregabalin-treated patients in clinical studies experienced adverse reactions with a maximum intensity of "mild" or "moderate".
- Controlled Studies in Neuropathic Pain Associated with Spinal Cord Injury
- Adverse Reactions Leading to Discontinuation
- In clinical trials of patients with neuropathic pain associated with spinal cord injury, 13% of patients treated with pregabalin and 10% of patients treated with placebo discontinued prematurely due to adverse reactions. In the pregabalin treatment group, the most common reasons for discontinuation due to adverse reactions were somnolence (3%) and edema (2%). In comparison, none of the placebo-treated patients withdrew due to somnolence and edema. Other reasons for discontinuation from the trials, occurring with greater frequency in the pregabalin treatment group than in the placebo treatment group, were fatigue and balance disorder. Each of these adverse reactions led to withdrawal in less than 2% of patients.
- Most Common Adverse Reactions
- Table 7 lists all adverse reactions, regardless of causality, occurring in ≥2% of patients with neuropathic pain associated with spinal cord injury in the controlled trials. A majority of pregabalin-treated patients in clinical studies experienced adverse reactions with a maximum intensity of "mild" or "moderate".
- Other Adverse Reactions Observed During the Clinical Studies of LYRICA
- Following is a list of treatment-emergent adverse reactions reported by patients treated with LYRICA during all clinical trials. The listing does not include those events already listed in the previous tables or elsewhere in labeling, those events for which a drug cause was remote, those events which were so general as to be uninformative, and those events reported only once which did not have a substantial probability of being acutely life-threatening.
- Events are categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse reactions are those occurring on one or more occasions in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are those occurring in fewer than 1/1000 patients.
- Frequent: Abdominal pain, Allergic reaction, Fever, Infrequent: Abscess, Cellulitis, Chills, Malaise, Neck rigidity, Overdose, Pelvic pain, Photosensitivity reaction, Rare: Anaphylactoid reaction, Ascites, Granuloma, Hangover effect, Intentional Injury, Retroperitoneal Fibrosis, Shock
- Infrequent: Deep thrombophlebitis, Heart failure, Hypotension, Postural hypotension, Retinal vascular disorder, Syncope; Rare: ST Depressed, Ventricular Fibrillation
- Frequent: Gastroenteritis, Increased appetite; Infrequent: Cholecystitis, Cholelithiasis, Colitis, Dysphagia, Esophagitis, Gastritis, Gastrointestinal hemorrhage, Melena, Mouth ulceration, Pancreatitis, Rectal hemorrhage, Tongue edema; Rare: Aphthous stomatitis, Esophageal Ulcer, Periodontal abscess
- Frequent: Ecchymosis; Infrequent: Anemia, Eosinophilia, Hypochromic anemia, Leukocytosis, Leukopenia, Lymphadenopathy, Thrombocytopenia; Rare: Myelofibrosis, Polycythemia, Prothrombin decreased, Purpura, Thrombocythemia
- Rare: Glucose Tolerance Decreased, Urate Crystalluria
- Frequent: Arthralgia, Leg cramps, Myalgia, Myasthenia; Infrequent: Arthrosis; Rare: Chondrodystrophy, Generalized Spasm
- Frequent: Anxiety, Depersonalization, Hypertonia, Hypoesthesia, Libido decreased, Nystagmus, Paresthesia, Sedation, Stupor, Twitching; Infrequent: Abnormal dreams, Agitation, Apathy, Aphasia, Circumoral paresthesia, Dysarthria, Hallucinations, Hostility, Hyperalgesia, Hyperesthesia, Hyperkinesia, Hypokinesia, Hypotonia, Libido increased, Myoclonus, Neuralgia, Rare: Addiction, Cerebellar syndrome, Cogwheel rigidity, Coma, Delirium, Delusions, Dysautonomia, Dyskinesia, Dystonia, Encephalopathy, Extrapyramidal syndrome, Guillain-Barré syndrome, Hypalgesia, Intracranial hypertension, Manic reaction, Paranoid reaction, Peripheral neuritis, Personality disorder, Psychotic depression, Schizophrenic reaction, Sleep disorder, Torticollis, Trismus
- Rare: Apnea, Atelectasis, Bronchiolitis, Hiccup, Laryngismus, Lung edema, Lung fibrosis, Yawn
- Frequent: Pruritus, Infrequent: Alopecia, Dry skin, Eczema, Hirsutism, Skin ulcer, Urticaria, Vesiculobullous rash; Rare: Angioedema, Exfoliative dermatitis, Lichenoid dermatitis, Melanosis, Nail Disorder, Petechial rash, Purpuric rash, Pustular rash, Skin atrophy, Skin necrosis, Skin nodule, Stevens-Johnson syndrome, Subcutaneous nodule
- Frequent: Conjunctivitis, Diplopia, Otitis media, Tinnitus; Infrequent: Abnormality of accommodation, Blepharitis, Dry eyes, Eye hemorrhage, Hyperacusis, Photophobia, Retinal edema, Taste loss, Taste perversion; Rare: Anisocoria, Blindness, Corneal ulcer, Exophthalmos, Extraocular palsy, Iritis, Keratitis, Keratoconjunctivitis, Miosis, Mydriasis, Night blindness, Ophthalmoplegia, Optic atrophy, Papilledema, Parosmia, Ptosis, Uveitis
- Frequent: Anorgasmia, Impotence, Urinary frequency, Urinary incontinence; Infrequent: Abnormal ejaculation, Albuminuria, Amenorrhea, Dysmenorrhea, Dysuria, Hematuria, Kidney calculus, Leukorrhea, Menorrhagia, Metrorrhagia, Nephritis, Oliguria, Urinary retention, Urine abnormality; Rare: Acute kidney failure, Balanitis, Bladder Neoplasm, Cervicitis, Dyspareunia, Epididymitis, Female lactation, Glomerulitis, Ovarian disorder, Pyelonephritis
- The overall adverse event profile of pregabalin was similar between women and men. There are insufficient data to support a statement regarding the distribution of adverse experience reports by race.
- Headache
- Nausea, Diarrhea
- Gynecomastia, Breast Enlargement
## Postmarketing Experience
- The following adverse reactions have been identified during postapproval use of LYRICA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- In addition, there are post-marketing reports of events related to reduced lower gastrointestinal tract function (e.g., intestinal obstruction, paralytic ileus, constipation) when LYRICA was co-administered with medications that have the potential to produce constipation, such as opioid analgesics. There are also post-marketing reports of respiratory failure and coma in patients taking pregabalin and other CNS depressant medications.
# Drug Interactions
- Since LYRICA is predominantly excreted unchanged in the urine, undergoes negligible metabolism in humans (<2% of a dose recovered in urine as metabolites), and does not bind to plasma proteins, its pharmacokinetics are unlikely to be affected by other agents through metabolic interactions or protein binding displacement. In vitro and in vivo studies showed that LYRICA is unlikely to be involved in significant pharmacokinetic drug interactions. Specifically, there are no pharmacokinetic interactions between pregabalin and the following antiepileptic drugs: carbamazepine, valproic acid, lamotrigine, phenytoin, phenobarbital, and topiramate. Important pharmacokinetic interactions would also not be expected to occur between LYRICA and commonly used antiepileptic drugs.
- Pharmacodynamics
- Multiple oral doses of LYRICA were co-administered with oxycodone, lorazepam, or ethanol. Although no pharmacokinetic interactions were seen, additive effects on cognitive and gross motor functioning were seen when LYRICA was co-administered with these drugs. No clinically important effects on respiration were seen.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- Increased incidences of fetal structural abnormalities and other manifestations of developmental toxicity, including lethality, growth retardation, and nervous and reproductive system functional impairment, were observed in the offspring of rats and rabbits given pregabalin during pregnancy, at doses that produced plasma pregabalin exposures (AUC) ≥5 times human exposure at the maximum recommended dose (MRD) of 600 mg/day.
- When pregnant rats were given pregabalin (500, 1250, or 2500 mg/kg) orally throughout the period of organogenesis, incidences of specific skull alterations attributed to abnormally advanced ossification (premature fusion of the jugal and nasal sutures) were increased at ≥1250 mg/kg, and incidences of skeletal variations and retarded ossification were increased at all doses. Fetal body weights were decreased at the highest dose. The low dose in this study was associated with a plasma exposure (AUC) approximately 17 times human exposure at the MRD of 600 mg/day. A no-effect dose for rat embryo-fetal developmental toxicity was not established.
- When pregnant rabbits were given LYRICA (250, 500, or 1250 mg/kg) orally throughout the period of organogenesis, decreased fetal body weight and increased incidences of skeletal malformations, visceral variations, and retarded ossification were observed at the highest dose. The no-effect dose for developmental toxicity in rabbits (500 mg/kg) was associated with a plasma exposure approximately 16 times human exposure at the MRD.
- In a study in which female rats were dosed with LYRICA (50, 100, 250, 1250, or 2500 mg/kg) throughout gestation and lactation, offspring growth was reduced at ≥ 100 mg/kg and offspring survival was decreased at ≥250 mg/kg. The effect on offspring survival was pronounced at doses ≥1250 mg/kg, with 100% mortality in high-dose litters. When offspring were tested as adults, neurobehavioral abnormalities (decreased auditory startle responding) were observed at ≥250 mg/kg and reproductive impairment (decreased fertility and litter size) was seen at 1250 mg/kg. The no-effect dose for pre- and postnatal developmental toxicity in rats (50 mg/kg) produced a plasma exposure approximately 2 times human exposure at the MRD.
- There are no adequate and well-controlled studies in pregnant women. Use LYRICA during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- To provide information regarding the effects of in utero exposure to LYRICA, physicians are advised to recommend that pregnant patients taking LYRICA enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website /.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Pregabalin in women who are pregnant.
### Labor and Delivery
- The effects of LYRICA on labor and delivery in pregnant women are unknown. In the prenatal-postnatal study in rats, pregabalin prolonged gestation and induced dystocia at exposures ≥50 times the mean human exposure (AUC (0–24) of 123 µg∙hr/mL) at the maximum recommended clinical dose of 600 mg/day.
### Nursing Mothers
- It is not known if pregabalin is excreted in human milk; it is, however, present in the milk of rats. Because many drugs are excreted in human milk, and because of the potential for tumorigenicity shown for pregabalin in animal studies, decide whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
- The safety and efficacy of pregabalin in pediatric patients have not been established.
- In studies in which pregabalin (50 to 500 mg/kg) was orally administered to young rats from early in the postnatal period (Postnatal Day 7) through sexual maturity, neurobehavioral abnormalities (deficits in learning and memory, altered locomotor activity, decreased auditory startle responding and habituation) and reproductive impairment (delayed sexual maturation and decreased fertility in males and females) were observed at doses ≥50 mg/kg. The neurobehavioral changes of acoustic startle persisted at ≥250 mg/kg and locomotor activity and water maze performance at ≥500 mg/kg in animals tested after cessation of dosing and, thus, were considered to represent long-term effects. The low effect dose for developmental neurotoxicity and reproductive impairment in juvenile rats (50 mg/kg) was associated with a plasma pregabalin exposure (AUC) approximately equal to human exposure at the maximum recommended dose of 600 mg/day. A no-effect dose was not established.
### Geriatic Use
- In controlled clinical studies of LYRICA in neuropathic pain associated with diabetic peripheral neuropathy, 246 patients were 65 to 74 years of age, and 73 patients were 75 years of age or older.
- In controlled clinical studies of LYRICA in neuropathic pain associated with postherpetic neuralgia, 282 patients were 65 to 74 years of age, and 379 patients were 75 years of age or older.
- In controlled clinical studies of LYRICA in epilepsy, there were only 10 patients 65 to 74 years of age, and 2 patients who were 75 years of age or older.
- No overall differences in safety and efficacy were observed between these patients and younger patients.
- In controlled clinical studies of LYRICA in fibromyalgia, 106 patients were 65 years of age or older. Although the adverse reaction profile was similar between the two age groups, the following neurological adverse reactions were more frequent in patients 65 years of age or older: dizziness, blurred vision, balance disorder, tremor, confusional state, coordination abnormal, and lethargy.
- LYRICA is known to be substantially excreted by the kidney, and the risk of toxic reactions to LYRICA may be greater in patients with impaired renal function. Because LYRICA is eliminated primarily by renal excretion, adjust the dose for elderly patients with renal impairment.
### Gender
There is no FDA guidance on the use of Pregabalin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Pregabalin with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Pregabalin in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Pregabalin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Pregabalin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Pregabalin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Pregabalin in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Pregabalin in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- There is limited experience with overdose of LYRICA. The highest reported accidental overdose of LYRICA during the clinical development program was 8000 mg, and there were no notable clinical consequences.
### Management
- There is no specific antidote for overdose with LYRICA. If indicated, elimination of unabsorbed drug may be attempted by emesis or gastric lavage; observe usual precautions to maintain the airway. General supportive care of the patient is indicated including monitoring of vital signs and observation of the clinical status of the patient. Contact a Certified Poison Control Center for up-to-date information on the management of overdose with LYRICA.
- Although hemodialysis has not been performed in the few known cases of overdose, it may be indicated by the patient's clinical state or in patients with significant renal impairment. Standard hemodialysis procedures result in significant clearance of pregabalin (approximately 50% in 4 hours).
## Chronic Overdose
There is limited information regarding Chronic Overdose of Pregabalin in the drug label.
# Pharmacology
## Mechanism of Action
- LYRICA (pregabalin) binds with high affinity to the alpha2-delta site (an auxiliary subunit of voltage-gated calcium channels) in central nervous system tissues. Although the mechanism of action of pregabalin has not been fully elucidated, results with genetically modified mice and with compounds structurally related to pregabalin (such as gabapentin) suggest that binding to the alpha2-delta subunit may be involved in pregabalin's anti-nociceptive and antiseizure effects in animals. In animal models of nerve damage, pregabalin has been shown to reduce calcium-dependent release of pro-nociceptive neurotransmitters in the spinal cord, possibly by disrupting alpha2-delta containing-calcium channel trafficking and/or reducing calcium currents. Evidence from other animal models of nerve damage and persistent pain suggest the anti-nociceptive activities of pregabalin may also be mediated through interactions with descending noradrenergic and serotonergic pathways originating from the brainstem that modulate pain transmission in the spinal cord.
- While pregabalin is a structural derivative of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), it does not bind directly to GABAA, GABAB, or benzodiazepine receptors, does not augment GABAA responses in cultured neurons, does not alter rat brain GABA concentration or have acute effects on GABA uptake or degradation. However, in cultured neurons prolonged application of pregabalin increases the density of GABA transporter protein and increases the rate of functional GABA transport. Pregabalin does not block sodium channels, is not active at opiate receptors, and does not alter cyclooxygenase enzyme activity. It is inactive at serotonin and dopamine receptors and does not inhibit dopamine, serotonin, or noradrenaline reuptake.
## Structure
- Pregabalin is described chemically as (S)-3-(aminomethyl)-5-methylhexanoic acid. The molecular formula is C8H17NO2 and the molecular weight is 159.23. The chemical structure of pregabalin is:
- Pregabalin is a white to off-white, crystalline solid with a pKa1 of 4.2 and a pKa2 of 10.6. It is freely soluble in water and both basic and acidic aqueous solutions. The log of the partition coefficient (n-octanol/0.05M phosphate buffer) at pH 7.4 is – 1.35.
- LYRICA (pregabalin) Capsules are administered orally and are supplied as imprinted hard-shell capsules containing 25, 50, 75, 100, 150, 200, 225, and 300 mg of pregabalin, along with lactose monohydrate, cornstarch, and talc as inactive ingredients. The capsule shells contain gelatin and titanium dioxide. In addition, the orange capsule shells contain red iron oxide and the white capsule shells contain sodium lauryl sulfate and colloidal silicon dioxide. Colloidal silicon dioxide is a manufacturing aid that may or may not be present in the capsule shells. The imprinting ink contains shellac, black iron oxide, propylene glycol, and potassium hydroxide.
- LYRICA (pregabalin) oral solution, 20 mg/mL, is administered orally and is supplied as a clear, colorless solution contained in a 16 fluid ounce white HDPE bottle with a polyethylene-lined closure. The oral solution contains 20 mg/mL of pregabalin, along with methylparaben, propylparaben, monobasic sodium phosphate anhydrous, dibasic sodium phosphate anhydrous, sucralose, artificial strawberry #11545 and purified water as inactive ingredients.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Pregabalin in the drug label.
## Pharmacokinetics
- Pregabalin is well absorbed after oral administration, is eliminated largely by renal excretion, and has an elimination half-life of about 6 hours.
- Absorption and Distribution
- Following oral administration of LYRICA capsules under fasting conditions, peak plasma concentrations occur within 1.5 hours. Pregabalin oral bioavailability is ≥90% and is independent of dose. Following single- (25 to 300 mg) and multiple- dose (75 to 900 mg/day) administration, maximum plasma concentrations (Cmax) and area under the plasma concentration-time curve (AUC) values increase linearly. Following repeated administration, steady state is achieved within 24 to 48 hours. Multiple-dose pharmacokinetics can be predicted from single-dose data.
- The rate of pregabalin absorption is decreased when given with food, resulting in a decrease in Cmax of approximately 25% to 30% and an increase in Tmax to approximately 3 hours. However, administration of pregabalin with food has no clinically relevant effect on the total absorption of pregabalin. Therefore, pregabalin can be taken with or without food.
- Pregabalin does not bind to plasma proteins. The apparent volume of distribution of pregabalin following oral administration is approximately 0.5 L/kg. Pregabalin is a substrate for system L transporter which is responsible for the transport of large amino acids across the blood brain barrier. Although there are no data in humans, pregabalin has been shown to cross the blood brain barrier in mice, rats, and monkeys. In addition, pregabalin has been shown to cross the placenta in rats and is present in the milk of lactating rats.
- Metabolism and Elimination
- Pregabalin undergoes negligible metabolism in humans. Following a dose of radiolabeled pregabalin, approximately 90% of the administered dose was recovered in the urine as unchanged pregabalin. The N-methylated derivative of pregabalin, the major metabolite of pregabalin found in urine, accounted for 0.9% of the dose. In preclinical studies, pregabalin (S-enantiomer) did not undergo racemization to the R-enantiomer in mice, rats, rabbits, or monkeys.
- Pregabalin is eliminated from the systemic circulation primarily by renal excretion as unchanged drug with a mean elimination half-life of 6.3 hours in subjects with normal renal function. Mean renal clearance was estimated to be 67.0 to 80.9 mL/min in young healthy subjects. Because pregabalin is not bound to plasma proteins this clearance rate indicates that renal tubular reabsorption is involved. Pregabalin elimination is nearly proportional to creatinine clearance (CLcr).
- Pharmacokinetics in Special Populations
- Race
- In population pharmacokinetic analyses of the clinical studies in various populations, the pharmacokinetics of LYRICA were not significantly affected by race (Caucasians, Blacks, and Hispanics).
- Gender
- Population pharmacokinetic analyses of the clinical studies showed that the relationship between daily dose and LYRICA drug exposure is similar between genders.
- Renal Impairment and Hemodialysis
- Pregabalin clearance is nearly proportional to creatinine clearance (CLcr). Dosage reduction in patients with renal dysfunction is necessary. Pregabalin is effectively removed from plasma by hemodialysis. Following a 4-hour hemodialysis treatment, plasma pregabalin concentrations are reduced by approximately 50%. For patients on hemodialysis, dosing must be modified.
- Elderly
- Pregabalin oral clearance tended to decrease with increasing age. This decrease in pregabalin oral clearance is consistent with age-related decreases in CLcr. Reduction of pregabalin dose may be required in patients who have age-related compromised renal function.
- Pediatric Pharmacokinetics
- Pharmacokinetics of pregabalin have not been adequately studied in pediatric patients.
- Drug Interactions
- In Vitro Studies
Pregabalin, at concentrations that were, in general, 10-times those attained in clinical trials, does not inhibit human CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 enzyme systems. In vitro drug interaction studies demonstrate that pregabalin does not induce CYP1A2 or CYP3A4 activity. Therefore, an increase in the metabolism of coadministered CYP1A2 substrates (e.g. theophylline, caffeine) or CYP 3A4 substrates (e.g., midazolam, testosterone) is not anticipated.
- Pregabalin, at concentrations that were, in general, 10-times those attained in clinical trials, does not inhibit human CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 enzyme systems. In vitro drug interaction studies demonstrate that pregabalin does not induce CYP1A2 or CYP3A4 activity. Therefore, an increase in the metabolism of coadministered CYP1A2 substrates (e.g. theophylline, caffeine) or CYP 3A4 substrates (e.g., midazolam, testosterone) is not anticipated.
- In Vivo Studies
The drug interaction studies described in this section were conducted in healthy adults, and across various patient populations.
- The drug interaction studies described in this section were conducted in healthy adults, and across various patient populations.
- Gabapentin
- The pharmacokinetic interactions of pregabalin and gabapentin were investigated in 12 healthy subjects following concomitant single-dose administration of 100-mg pregabalin and 300-mg gabapentin and in 18 healthy subjects following concomitant multiple-dose administration of 200-mg pregabalin every 8 hours and 400-mg gabapentin every 8 hours. Gabapentin pharmacokinetics following single- and multiple-dose administration were unaltered by pregabalin coadministration. The extent of pregabalin absorption was unaffected by gabapentin coadministration, although there was a small reduction in rate of absorption.
- Oral Contraceptive
- Pregabalin coadministration (200 mg three times a day) had no effect on the steady-state pharmacokinetics of norethindrone and ethinyl estradiol (1 mg/35 µg, respectively) in healthy subjects.
- Lorazepam
- Multiple-dose administration of pregabalin (300 mg twice a day) in healthy subjects had no effect on the rate and extent of lorazepam single-dose pharmacokinetics and single-dose administration of lorazepam (1 mg) had no effect on the steady-state pharmacokinetics of pregabalin.
- Oxycodone
- Multiple-dose administration of pregabalin (300 mg twice a day) in healthy subjects had no effect on the rate and extent of oxycodone single-dose pharmacokinetics. Single-dose administration of oxycodone (10 mg) had no effect on the steady-state pharmacokinetics of pregabalin.
- Ethanol
- Multiple-dose administration of pregabalin (300 mg twice a day) in healthy subjects had no effect on the rate and extent of ethanol single-dose pharmacokinetics and single-dose administration of ethanol (0.7 g/kg) had no effect on the steady-state pharmacokinetics of pregabalin.
- Phenytoin, carbamazepine, valproic acid, and lamotrigine
- Steady-state trough plasma concentrations of phenytoin, carbamazepine and carbamazepine 10,11 epoxide, valproic acid, and lamotrigine were not affected by concomitant pregabalin (200 mg three times a day) administration.
- Population pharmacokinetic analyses in patients treated with pregabalin and various concomitant medications suggest the following:
## Nonclinical Toxicology
- Carcinogenesis
- A dose-dependent increase in the incidence of malignant vascular tumors (hemangiosarcomas) was observed in two strains of mice (B6C3F1 and CD-1) given pregabalin (200, 1000, or 5000 mg/kg) in the diet for two years. Plasma pregabalin exposure (AUC) in mice receiving the lowest dose that increased hemangiosarcomas was approximately equal to the human exposure at the maximum recommended dose (MRD) of 600 mg/day. A no-effect dose for induction of hemangiosarcomas in mice was not established. No evidence of carcinogenicity was seen in two studies in Wistar rats following dietary administration of pregabalin for two years at doses (50, 150, or 450 mg/kg in males and 100, 300, or 900 mg/kg in females) that were associated with plasma exposures in males and females up to approximately 14 and 24 times, respectively, human exposure at the MRD.
- Mutagenesis
- Pregabalin was not mutagenic in bacteria or in mammalian cells in vitro, was not clastogenic in mammalian systems in vitro and in vivo, and did not induce unscheduled DNA synthesis in mouse or rat hepatocytes.
- Impairment of Fertility
- In fertility studies in which male rats were orally administered pregabalin (50 to 2500 mg/kg) prior to and during mating with untreated females, a number of adverse reproductive and developmental effects were observed. These included decreased sperm counts and sperm motility, increased sperm abnormalities, reduced fertility, increased preimplantation embryo loss, decreased litter size, decreased fetal body weights, and an increased incidence of fetal abnormalities.
- Effects on sperm and fertility parameters were reversible in studies of this duration (3–4 months). The no-effect dose for male reproductive toxicity in these studies (100 mg/kg) was associated with a plasma pregabalin exposure (AUC) approximately 3 times human exposure at the maximum recommended dose (MRD) of 600 mg/day.
- In addition, adverse reactions on reproductive organ (testes, epididymides) histopathology were observed in male rats exposed to pregabalin (500 to 1250 mg/kg) in general toxicology studies of four weeks or greater duration. The no-effect dose for male reproductive organ histopathology in rats (250 mg/kg) was associated with a plasma exposure approximately 8 times human exposure at the MRD.
- In a fertility study in which female rats were given pregabalin (500, 1250, or 2500 mg/kg) orally prior to and during mating and early gestation, disrupted estrous cyclicity and an increased number of days to mating were seen at all doses, and embryolethality occurred at the highest dose. The low dose in this study produced a plasma exposure approximately 9 times that in humans receiving the MRD. A no-effect dose for female reproductive toxicity in rats was not established.
- Human Data
- In a double-blind, placebo-controlled clinical trial to assess the effect of pregabalin on sperm motility, 30 healthy male subjects were exposed to pregabalin at a dose of 600 mg/day. After 3 months of treatment (one complete sperm cycle), the difference between placebo- and pregabalin-treated subjects in mean percent sperm with normal motility was <4% and neither group had a mean change from baseline of more than 2%. Effects on other male reproductive parameters in humans have not been adequately studied.
- Dermatopathy
- Skin lesions ranging from erythema to necrosis were seen in repeated-dose toxicology studies in both rats and monkeys. The etiology of these skin lesions is unknown. At the maximum recommended human dose (MRD) of 600 mg/day, there is a 2-fold safety margin for the dermatological lesions. The more severe dermatopathies involving necrosis were associated with pregabalin exposures (as expressed by plasma AUCs) of approximately 3 to 8 times those achieved in humans given the MRD. No increase in incidence of skin lesions was observed in clinical studies.
- Ocular Lesions
- Ocular lesions (characterized by retinal atrophy and/or corneal inflammation/mineralization) were observed in two lifetime carcinogenicity studies in Wistar rats. These findings were observed at plasma pregabalin exposures (AUC) ≥2 times those achieved in humans given the maximum recommended dose of 600 mg/day. A no-effect dose for ocular lesions was not established. Similar lesions were not observed in lifetime carcinogenicity studies in two strains of mice or in monkeys treated for 1 year.
# Clinical Studies
- The efficacy of the maximum recommended dose of LYRICA for the management of neuropathic pain associated with diabetic peripheral neuropathy was established in three double-blind, placebo-controlled, multicenter studies with three times a day dosing, two of which studied the maximum recommended dose. Patients were enrolled with either Type 1 or Type 2 diabetes mellitus and a diagnosis of painful distal symmetrical sensorimotor polyneuropathy for 1 to 5 years. A total of 89% of patients completed Studies DPN 1 and DPN 2. The patients had a minimum mean baseline pain score of ≥4 on an 11-point numerical pain rating scale ranging from 0 (no pain) to 10 (worst possible pain). The baseline mean pain scores across the two studies ranged from 6.1 to 6.7. Patients were permitted up to 4 grams of acetaminophen per day as needed for pain, in addition to pregabalin. Patients recorded their pain daily in a diary.
- Study DPN 1: This 5-week study compared LYRICA 25, 100, or 200 mg three times a day with placebo. Treatment with LYRICA 100 and 200 mg three times a day statistically significantly improved the endpoint mean pain score and increased the proportion of patients with at least a 50% reduction in pain score from baseline. There was no evidence of a greater effect on pain scores of the 200 mg three times a day dose than the 100 mg three times a day dose, but there was evidence of dose dependent adverse reactions. For a range of levels of improvement in pain intensity from baseline to study endpoint, Figure 1 shows the fraction of patients achieving that level of improvement. The figure is cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%. Patients who did not complete the study were assigned 0% improvement. Some patients experienced a decrease in pain as early as Week 1, which persisted throughout the study.
- Figure 1: Patients Achieving Various Levels of Improvement in Pain Intensity – Study DPN 1
- Study DPN 2: This 8-week study compared LYRICA 100 mg three times a day with placebo. Treatment with LYRICA 100 mg three times a day statistically significantly improved the endpoint mean pain score and increased the proportion of patients with at least a 50% reduction in pain score from baseline. For various levels of improvement in pain intensity from baseline to study endpoint, Figure 2 shows the fraction of patients achieving that level of improvement. The figure is cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%. Patients who did not complete the study were assigned 0% improvement. Some patients experienced a decrease in pain as early as Week 1, which persisted throughout the study.
- Figure 2: Patients Achieving Various Levels of Improvement in Pain Intensity–Study DPN 2
- The efficacy of LYRICA for the management of postherpetic neuralgia was established in three double-blind, placebo-controlled, multicenter studies. These studies enrolled patients with neuralgia persisting for at least 3 months following healing of herpes zoster rash and a minimum baseline score of ≥4 on an 11-point numerical pain rating scale ranging from 0 (no pain) to 10 (worst possible pain). Seventy-three percent of patients completed the studies. The baseline mean pain scores across the 3 studies ranged from 6 to 7. Patients were permitted up to 4 grams of acetaminophen per day as needed for pain, in addition to pregabalin. Patients recorded their pain daily in a diary.
- Study PHN 1: This 13-week study compared LYRICA 75, 150, and 300 mg twice daily with placebo. Patients with creatinine clearance (CLcr) between 30 to 60 mL/min were randomized to 75 mg, 150 mg, or placebo twice daily. Patients with creatinine clearance greater than 60 mL/min were randomized to 75 mg, 150 mg, 300 mg or placebo twice daily. In patients with creatinine clearance greater than 60 mL/min treatment with all doses of LYRICA statistically significantly improved the endpoint mean pain score and increased the proportion of patients with at least a 50% reduction in pain score from baseline. Despite differences in dosing based on renal function, patients with creatinine clearance between 30 to 60 mL/min tolerated LYRICA less well than patients with creatinine clearance greater than 60 mL/min as evidenced by higher rates of discontinuation due to adverse reactions. For various levels of improvement in pain intensity from baseline to study endpoint, Figure 3 shows the fraction of patients achieving that level of improvement. The figure is cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%. Patients who did not complete the study were assigned 0% improvement. Some patients experienced a decrease in pain as early as Week 1, which persisted throughout the study.
- Figure 3: Patients Achieving Various Levels of Improvement in Pain Intensity– Study PHN 1
- Study PHN 2: This 8-week study compared LYRICA 100 or 200 mg three times a day with placebo, with doses assigned based on creatinine clearance. Patients with creatinine clearance between 30 to 60 mL/min were treated with 100 mg three times a day, and patients with creatinine clearance greater than 60 mL/min were treated with 200 mg three times daily. Treatment with LYRICA statistically significantly improved the endpoint mean pain score and increased the proportion of patients with at least a 50% reduction in pain score from baseline. For various levels of improvement in pain intensity from baseline to study endpoint, Figure 4 shows the fraction of patients achieving those levels of improvement. The figure is cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%. Patients who did not complete the study were assigned 0% improvement. Some patients experienced a decrease in pain as early as Week 1, which persisted throughout the study.
- Figure 4: Patients Achieving Various Levels of Improvement in Pain Intensity – Study PHN 2
- Study PHN 3: This 8-week study compared LYRICA 50 or 100 mg three times a day with placebo with doses assigned regardless of creatinine clearance. Treatment with LYRICA 50 and 100 mg three times a day statistically significantly improved the endpoint mean pain score and increased the proportion of patients with at least a 50% reduction in pain score from baseline. Patients with creatinine clearance between 30 to 60 mL/min tolerated LYRICA less well than patients with creatinine clearance greater than 60 mL/min as evidenced by markedly higher rates of discontinuation due to adverse reactions. For various levels of improvement in pain intensity from baseline to study endpoint, Figure 5 shows the fraction of patients achieving that level of improvement. The figure is cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%. Patients who did not complete the study were assigned 0% improvement. Some patients experienced a decrease in pain as early as Week 1, which persisted throughout the study.
- Figure 5: Patients Achieving Various Levels of Improvement in Pain Intensity– Study PHN 3
- The efficacy of LYRICA as adjunctive therapy in partial onset seizures was established in three 12-week, randomized, double-blind, placebo-controlled, multicenter studies in adult patients. Patients were enrolled who had partial onset seizures with or without secondary generalization and were not adequately controlled with 1 to 3 concomitant antiepileptic drugs (AEDs). Patients taking gabapentin were required to discontinue gabapentin treatment 1 week prior to entering baseline. During an 8-week baseline period, patients had to experience at least 6 partial onset seizures with no seizure-free period exceeding 4 weeks. The mean duration of epilepsy was 25 years in these 3 studies and the mean and median baseline seizure frequencies were 22.5 and 10 seizures per month, respectively. Approximately half of the patients were taking 2 concurrent AEDs at baseline. Among the LYRICA-treated patients, 80% completed the double-blind phase of the studies.
- Table 8 shows median baseline seizure rates and median percent reduction in seizure frequency by dose.
- In the first study (E1), there was evidence of a dose-response relationship for total daily doses of Lyrica between 150 and 600 mg/day; a dose of 50 mg/day was not effective. In the first study (E1), each daily dose was divided into two equal doses (twice a day dosing). In the second study (E2), each daily dose was divided into three equal doses (three times a day dosing). In the third study (E3), the same total daily dose was divided into two equal doses for one group (twice a day dosing) and three equal doses for another group (three times a day dosing). While the three times a day dosing group in Study E3 performed numerically better than the twice a day dosing group, this difference was small and not statistically significant.
- A secondary outcome measure included the responder rate (proportion of patients with ≥50% reduction from baseline in partial seizure frequency). The following figure displays responder rate by dose for two of the studies.
- Subset evaluations of the antiseizure efficacy of LYRICA showed no clinically important differences as a function of age, gender, or race.
- The efficacy of LYRICA for management of fibromyalgia was established in one 14-week, double-blind, placebo-controlled, multicenter study (F1) and one six-month, randomized withdrawal study (F2). Studies F1 and F2 enrolled patients with a diagnosis of fibromyalgia using the American College of Rheumatology (ACR) criteria (history of widespread pain for 3 months, and pain present at 11 or more of the 18 specific tender point sites). The studies showed a reduction in pain by visual analog scale. In addition, improvement was demonstrated based on a patient global assessment (PGIC), and on the Fibromyalgia Impact Questionnaire (FIQ).
- Study F1: This 14-week study compared LYRICA total daily doses of 300 mg, 450 mg and 600 mg with placebo. Patients were enrolled with a minimum mean baseline pain score of greater than or equal to 4 on an 11-point numeric pain rating scale and a score of greater than or equal to 40 mm on the 100 mm pain visual analog scale (VAS). The baseline mean pain score in this trial was 6.7. Responders to placebo in an initial one-week run-in phase were not randomized into subsequent phases of the study. A total of 64% of patients randomized to LYRICA completed the study. There was no evidence of a greater effect on pain scores of the 600 mg daily dose than the 450 mg daily dose, but there was evidence of dose-dependent adverse reactions. Some patients experienced a decrease in pain as early as Week 1, which persisted throughout the study. The results are summarized in Figure 8 and Table 9.
- For various levels of improvement in pain intensity from baseline to study endpoint, Figure 8 shows the fraction of patients achieving that level of improvement. The figure is cumulative. Patients who did not complete the study were assigned 0% improvement. Some patients experienced a decrease in pain as early as Week 1, which persisted throughout the study.
- Figure 8: Patients Achieving Various Levels of Improvement in Pain Intensity – Fibromyalgia Study F1
- Study F2: This randomized withdrawal study compared LYRICA with placebo. Patients were titrated during a 6-week open-label dose optimization phase to a total daily dose of 300 mg, 450 mg, or 600 mg. Patients were considered to be responders if they had both: 1) at least a 50% reduction in pain (VAS) and, 2) rated their overall improvement on the PGIC as "much improved" or "very much improved." Those who responded to treatment were then randomized in the double-blind treatment phase to either the dose achieved in the open-label phase or to placebo. Patients were treated for up to 6 months following randomization. Efficacy was assessed by time to loss of therapeutic response, defined as 1) less than 30% reduction in pain (VAS) from open-label baseline during two consecutive visits of the double-blind phase, or 2) worsening of FM symptoms necessitating an alternative treatment. Fifty-four percent of patients were able to titrate to an effective and tolerable dose of LYRICA during the 6-week open-label phase. Of the patients entering the randomized treatment phase assigned to remain on LYRICA, 38% of patients completed 26 weeks of treatment versus 19% of placebo-treated patients.
- When considering return of pain or withdrawal due to adverse events as loss of response (LTR), treatment with LYRICA resulted in a longer time to loss of therapeutic response than treatment with placebo. Fifty-three percent of the pregabalin-treated subjects compared to 33% of placebo patients remained on study drug and maintained a therapeutic response to Week 26 of the study. Treatment with LYRICA also resulted in a longer time to loss of response based on the FIQ1, and longer time to loss of overall assessment of patient status, as measured by the PGIC2.
- Figure 9: Time to Loss of Therapeutic Response, Fibromyalgia Study F2 (Kaplan-Meier Analysis)
- The efficacy of LYRICA for the management of neuropathic pain associated with spinal cord injury was established in two double-blind, placebo-controlled, multicenter studies. Patients were enrolled with neuropathic pain associated with spinal cord injury that persisted continuously for at least three months or with relapses and remissions for at least six months. A total of 63% of patients completed study 1 and 84% completed study 2. The patients had a minimum mean baseline pain score of ≥4 on an 11-point numerical pain rating scale ranging from 0 (no pain) to 10 (worst possible pain). The baseline mean pain scores across the two studies ranged from 6.5 to 6.7.
- Patients were allowed to take opioids, non-opioid analgesics, antiepileptic drugs, muscle relaxants, and antidepressant drugs if the dose was stable for 30 days prior to screening. Patients were allowed to take acetaminophen and nonsteroidal anti-inflammatory drugs during the studies.
- Study SCI 1: This 12-week, randomized, double-blind, parallel-group, multicenter, flexible dose (150–600 mg/day) study compared pregabalin with placebo. The 12-week study consisted of a 3-week dose adjustment phase and a 9-week dose maintenance phase. Treatment with LYRICA 150–600 mg/day statistically significantly improved the endpoint weekly mean pain score, and increased the proportion of patients with at least a 30% and 50% reduction in pain score from baseline. The fraction of patients achieving various levels of improvement in pain intensity from baseline to Week 12 is presented in Figure 10. Some patients experienced a decrease in pain as early as week 1, which persisted throughout the study.
- Figure 10: Patients Achieving Various Levels of Improvement in Pain Intensity – Study SCI 1
- Study SCI 2: This 16-week, randomized, double-blind, placebo-controlled, parallel-group, multicenter, flexible dose (150–600 mg/day, in increments of 150 mg) study compared the efficacy, safety and tolerability of pregabalin with placebo. The 16-week study consisted of a 4-week dose adjustment phase and a 12-week dose maintenance phase. Treatment with LYRICA statistically significantly improved the endpoint weekly mean pain score, and increased the proportion of patients with at least a 30% and 50% reduction in pain score from baseline. The fraction of patients achieving various levels of improvement in pain intensity from baseline to Week 16 is presented in Figure 11. Some patients experienced a decrease in pain as early as week 1, which persisted throughout the study.
- Figure 11: Patients Achieving Various Levels of Improvement in Pain Intensity – Study SCI 2
# How Supplied
- 25 mg capsules:
- White, hard-gelatin capsule printed with black ink "Pfizer" on the cap, "PGN 25" on the body; available in:
- Bottles of 90: NDC 0071-1012-68
- 50 mg capsules:
- White, hard-gelatin capsule printed with black ink "Pfizer" on the cap, "PGN 50" and an ink band on the body, available in:
- Bottles of 90: NDC 0071-1013-68
- Unit-Dose Blister Packages of 100: NDC 0071-1013-41
- 75 mg capsules:
- White/orange hard gelatin capsule printed with black ink "Pfizer" on the cap, "PGN 75" on the body; available in:
- Bottles of 90: NDC 0071-1014-68
- Unit-Dose Blister Packages of 100: NDC 0071-1014-41
- 100 mg capsules:
- Orange, hard-gelatin capsule printed with black ink "Pfizer" on the cap, "PGN 100" on the body, available in:
- Bottles of 90: NDC 0071-1015-68
- Unit-Dose Blister Packages of 100: NDC 0071-1015-41
- 150 mg capsules:
- White hard gelatin capsule printed with black ink "Pfizer" on the cap, "PGN 150" on the body, available in:
- Bottles of 90: NDC 0071-1016-68
- Unit-Dose Blister Packages of 100: NDC 0071-1016-41
- 200 mg capsules:
- Light orange hard gelatin capsule printed with black ink "Pfizer" on the cap, "PGN 200" on the body, available in:
- Bottles of 90: NDC 0071-1017-68
- 225 mg capsules:
- White/light orange hard gelatin capsule printed with black ink "Pfizer" on the cap, "PGN 225" on the body; available in:
- Bottles of 90: NDC 0071-1019-68
- 300 mg capsules:
- White/orange hard gelatin capsule printed with black ink "Pfizer" on the cap, "PGN 300" on the body, available in:
- Bottles of 90: NDC 0071-1018-68
- 20 mg/mL oral solution:
- 16 fluid ounce white high density polyethylene (HDPE) bottle with a polyethylene-lined closure:
- 16 fluid ounce bottle NDC 0071-1020-01
- Storage and Handling
- Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).
## Storage
There is limited information regarding Pregabalin Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Inform patients of the availability of a Medication Guide, and instruct them to read the Medication Guide prior to taking LYRICA. Instruct patients to take LYRICA only as prescribed.
- Angioedema
- Advise patients that LYRICA may cause angioedema, with swelling of the face, mouth (lip, gum, tongue) and neck (larynx and pharynx) that can lead to life-threatening respiratory compromise. Instruct patients to discontinue LYRICA and immediately seek medical care if they experience these symptoms.
- Hypersensitivity
- Advise patients that LYRICA has been associated with hypersensitivity reactions such as wheezing, dyspnea, rash, hives, and blisters. Instruct patients to discontinue LYRICA and immediately seek medical care if they experience these symptoms.
- Suicidal Thinking and Behavior
- Patients, their caregivers, and families should be counseled that AEDs, including LYRICA, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Report behaviors of concern immediately to healthcare providers.
- Dizziness and Somnolence
- Counsel patients that LYRICA may cause dizziness, somnolence, blurred vision and other CNS signs and symptoms. Accordingly, advise patients not to drive, operate complex machinery, or engage in other hazardous activities until they have gained sufficient experience on LYRICA to gauge whether or not it affects their mental, visual, and/or motor performance adversely.
- Weight Gain and Edema
- Counsel patients that LYRICA may cause edema and weight gain. Advise patients that concomitant treatment with LYRICA and a thiazolidinedione antidiabetic agent may lead to an additive effect on edema and weight gain. For patients with preexisting cardiac conditions, this may increase the risk of heart failure.
- Abrupt or Rapid Discontinuation
- Advise patients to take LYRICA as prescribed. Abrupt or rapid discontinuation may result in insomnia, nausea, headache, anxiety, hyperhidrosis, or diarrhea.
- Ophthalmological Effects
- Counsel patients that LYRICA may cause visual disturbances. Inform patients that if changes in vision occur, they should notify their physician.
- Creatine Kinase Elevations
- Instruct patients to promptly report unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever.
- CNS Depressants
- Inform patients who require concomitant treatment with central nervous system depressants such as opiates or benzodiazepines that they may experience additive CNS side effects, such as somnolence.
- Alcohol
- Tell patients to avoid consuming alcohol while taking LYRICA, as LYRICA may potentiate the impairment of motor skills and sedating effects of alcohol.
- Use in Pregnancy
- Instruct patients to notify their physician if they become pregnant or intend to become pregnant during therapy, and to notify their physician if they are breast feeding or intend to breast feed during therapy.
- Encourage patients to enroll in the NAAED Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334.
- Male Fertility
- Inform men being treated with LYRICA who plan to father a child of the potential risk of male-mediated teratogenicity. In preclinical studies in rats, pregabalin was associated with an increased risk of male-mediated teratogenicity. The clinical significance of this finding is uncertain.
- Dermatopathy
- Instruct diabetic patients to pay particular attention to skin integrity while being treated with LYRICA. Some animals treated with pregabalin developed skin ulcerations, although no increased incidence of skin lesions associated with LYRICA was observed in clinical trials.
- Capsules and Oral Solution, CV
- Read this Medication Guide before you start taking LYRICA and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. If you have any questions about LYRICA, ask your healthcare provider or pharmacist.
- What is the most important information I should know about LYRICA?
- LYRICA may cause serious side effects including:
- Serious, even life-threatening, allergic reactions
- Suicidal thoughts or actions
- Swelling of your hands, legs and feet
- Dizziness and sleepiness
- These serious side effects are described below:
- Serious, even life-threatening, allergic reactions.
Stop taking LYRICA and call your healthcare provider right away if you have any of these signs of a serious allergic reaction:
swelling of your face, mouth, lips, gums, tongue, throat or neck
trouble breathing
rash, hives (raised bumps) or blisters
- Stop taking LYRICA and call your healthcare provider right away if you have any of these signs of a serious allergic reaction:
- swelling of your face, mouth, lips, gums, tongue, throat or neck
- trouble breathing
- rash, hives (raised bumps) or blisters
- Like other antiepileptic drugs, LYRICA may cause suicidal thoughts or actions in a very small number of people, about 1 in 500.
Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you:
thoughts about suicide or dying
attempts to commit suicide
new or worse depression
new or worse anxiety
feeling agitated or restless
panic attacks
trouble sleeping (insomnia)
new or worse irritability
acting aggressive, being angry, or violent
acting on dangerous impulses
an extreme increase in activity and talking (mania)
-ther unusual changes in behavior or mood
- Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you:
- thoughts about suicide or dying
- attempts to commit suicide
- new or worse depression
- new or worse anxiety
- feeling agitated or restless
- panic attacks
- trouble sleeping (insomnia)
- new or worse irritability
- acting aggressive, being angry, or violent
- acting on dangerous impulses
- an extreme increase in activity and talking (mania)
- other unusual changes in behavior or mood
- If you have suicidal thoughts or actions, do not stop LYRICA without first talking to a healthcare provider.
Stopping LYRICA suddenly can cause serious problems.
Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes.
- Stopping LYRICA suddenly can cause serious problems.
- Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes.
- How can I watch for early symptoms of suicidal thoughts and actions?
Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings.
Keep all follow-up visits with your healthcare provider as scheduled.
Call your healthcare provider between visits as needed, especially if you are worried about symptoms.
- Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings.
- Keep all follow-up visits with your healthcare provider as scheduled.
- Call your healthcare provider between visits as needed, especially if you are worried about symptoms.
- Swelling of your hands, legs and feet. This swelling can be a serious problem for people with heart problems.
- Dizziness and sleepiness.
Do not drive a car, work with machines, or do other dangerous activities until you know how LYRICA affects you. Ask your healthcare provider about when it will be okay to do these activities.
- Do not drive a car, work with machines, or do other dangerous activities until you know how LYRICA affects you. Ask your healthcare provider about when it will be okay to do these activities.
- What is LYRICA?
- LYRICA is a prescription medicine used in adults, 18 years and older, to treat:
pain from damaged nerves (neuropathic pain) that happens with diabetes
pain from damaged nerves (neuropathic pain) that follows healing of shingles
partial seizures when taken together with other seizure medicines
fibromyalgia (pain all over your body)
pain from damaged nerves (neuropathic pain) that follows spinal cord injury
LYRICA has not been studied in children under 18 years of age.
- pain from damaged nerves (neuropathic pain) that happens with diabetes
- pain from damaged nerves (neuropathic pain) that follows healing of shingles
- partial seizures when taken together with other seizure medicines
- fibromyalgia (pain all over your body)
- pain from damaged nerves (neuropathic pain) that follows spinal cord injury
- LYRICA has not been studied in children under 18 years of age.
- Who Should Not Take LYRICA?
- Do not take LYRICA if you are allergic to pregabalin or any of the ingredients in LYRICA.
See "What is the most important information I should know about LYRICA?" for the signs of an allergic reaction.
See the end of this leaflet for a complete list of ingredients in LYRICA.
- See "What is the most important information I should know about LYRICA?" for the signs of an allergic reaction.
- See the end of this leaflet for a complete list of ingredients in LYRICA.
- What should I tell my healthcare provider before taking LYRICA?
- Before taking LYRICA, tell your healthcare provider about all your medical conditions, including if you:
have or have had depression, mood problems or suicidal thoughts or behavior
have kidney problems or get kidney dialysis
have heart problems including heart failure
have a bleeding problem or a low blood platelet count
have abused prescription medicines, street drugs, or alcohol in the past
have ever had swelling of your face, mouth, tongue, lips, gums, neck, or throat (angioedema)
plan to father a child. Animal studies have shown that pregabalin, the active ingredient in LYRICA, made male animals less fertile and caused sperm to change. Also, in animal studies, birth defects were seen in the offspring (babies) of male animals treated with pregabalin. It is not known if these problems can happen in people who take LYRICA.
are pregnant or plan to become pregnant. It is not known if LYRICA will harm your unborn baby. You and your healthcare provider will have to decide if you should take LYRICA while you are pregnant. If you become pregnant while taking LYRICA, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy.
are breastfeeding. It is not known if LYRICA passes into breast milk and if it can harm your baby. You and your healthcare provider should discuss whether you should take LYRICA or breast-feed, but you should not do both.
- have or have had depression, mood problems or suicidal thoughts or behavior
- have kidney problems or get kidney dialysis
- have heart problems including heart failure
- have a bleeding problem or a low blood platelet count
- have abused prescription medicines, street drugs, or alcohol in the past
- have ever had swelling of your face, mouth, tongue, lips, gums, neck, or throat (angioedema)
- plan to father a child. Animal studies have shown that pregabalin, the active ingredient in LYRICA, made male animals less fertile and caused sperm to change. Also, in animal studies, birth defects were seen in the offspring (babies) of male animals treated with pregabalin. It is not known if these problems can happen in people who take LYRICA.
- are pregnant or plan to become pregnant. It is not known if LYRICA will harm your unborn baby. You and your healthcare provider will have to decide if you should take LYRICA while you are pregnant. If you become pregnant while taking LYRICA, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy.
- are breastfeeding. It is not known if LYRICA passes into breast milk and if it can harm your baby. You and your healthcare provider should discuss whether you should take LYRICA or breast-feed, but you should not do both.
- Tell your healthcare provider about all the medicines you take including prescription and non-prescription medicines, vitamins or herbal supplements. LYRICA and other medicines may affect each other causing side effects. Especially tell your healthcare provider if you take:
angiotensin converting enzyme (ACE) inhibitors, which are used to treat many conditions, including high blood pressure. You may have a higher chance for swelling and hives if these medicines are taken with LYRICA. See "What is the most important information I should know about LYRICA?"
Avandia (rosiglitazone), Avandamet (contains rosiglitazone and metformin), or Actos (pioglitazone) for diabetes. You may have a higher chance of weight gain or swelling of your hands or feet if these medicines are taken with LYRICA. See "What are the possible side effects of LYRICA."
any narcotic pain medicine (such as oxycodone), tranquilizers or medicines for anxiety (such as lorazepam). You may have a higher chance for dizziness and sleepiness if these medicines are taken with LYRICA.
any medicines that make you sleepy
- angiotensin converting enzyme (ACE) inhibitors, which are used to treat many conditions, including high blood pressure. You may have a higher chance for swelling and hives if these medicines are taken with LYRICA. See "What is the most important information I should know about LYRICA?"
- Avandia (rosiglitazone), Avandamet (contains rosiglitazone and metformin), or Actos (pioglitazone) for diabetes. You may have a higher chance of weight gain or swelling of your hands or feet if these medicines are taken with LYRICA. See "What are the possible side effects of LYRICA."
- any narcotic pain medicine (such as oxycodone), tranquilizers or medicines for anxiety (such as lorazepam). You may have a higher chance for dizziness and sleepiness if these medicines are taken with LYRICA.
- any medicines that make you sleepy
- Know the medicines you take. Keep a list of them with you to show your healthcare provider and pharmacist each time you get a new medicine. Do not start a new medicine without talking with your healthcare provider.
- How should I take LYRICA?
- Take LYRICA exactly as prescribed. Your healthcare provider will tell you how much LYRICA to take and when to take it. Take LYRICA at the same times each day.
LYRICA may be taken with or without food.
Your healthcare provider may change your dose. Do not change your dose without talking to your healthcare provider.
Do not stop taking LYRICA without talking to your healthcare provider. If you stop taking LYRICA suddenly you may have headaches, nausea, diarrhea, trouble sleeping, increased sweating, or you may feel anxious. If you have epilepsy and you stop taking LYRICA suddenly, you may have seizures more often. Talk with your healthcare provider about how to stop LYRICA slowly.
If you miss a dose, take it as soon as you remember. If it is almost time for your next dose, just skip the missed dose. Take the next dose at your regular time. Do not take two doses at the same time.
If you take too much LYRICA, call your healthcare provider or poison control center, or go to the nearest emergency room right away.
- LYRICA may be taken with or without food.
- Your healthcare provider may change your dose. Do not change your dose without talking to your healthcare provider.
- Do not stop taking LYRICA without talking to your healthcare provider. If you stop taking LYRICA suddenly you may have headaches, nausea, diarrhea, trouble sleeping, increased sweating, or you may feel anxious. If you have epilepsy and you stop taking LYRICA suddenly, you may have seizures more often. Talk with your healthcare provider about how to stop LYRICA slowly.
- If you miss a dose, take it as soon as you remember. If it is almost time for your next dose, just skip the missed dose. Take the next dose at your regular time. Do not take two doses at the same time.
- If you take too much LYRICA, call your healthcare provider or poison control center, or go to the nearest emergency room right away.
- What should I avoid while taking LYRICA?
- Do not drive a car, work with machines, or do other dangerous activities until you know how LYRICA affects you.
- Do not drink alcohol while taking LYRICA. LYRICA and alcohol can affect each other and increase side effects such as sleepiness and dizziness.
- What are the possible side effects of LYRICA?
- LYRICA may cause serious side effects, including:
See "What is the most important information I should know about LYRICA?"
muscle problems, muscle pain, soreness, or weakness. If you have these symptoms, especially if you feel sick and have a fever, tell your healthcare provider right away.
problems with your eyesight, including blurry vision. Call your healthcare provider if you have any changes in your eyesight.
weight gain. If you have diabetes, weight gain may affect the management of your diabetes. Weight gain can also be a serious problem for people with heart problems.
feeling "high"
- See "What is the most important information I should know about LYRICA?"
- muscle problems, muscle pain, soreness, or weakness. If you have these symptoms, especially if you feel sick and have a fever, tell your healthcare provider right away.
- problems with your eyesight, including blurry vision. Call your healthcare provider if you have any changes in your eyesight.
- weight gain. If you have diabetes, weight gain may affect the management of your diabetes. Weight gain can also be a serious problem for people with heart problems.
- feeling "high"
- The most common side effects of LYRICA are:
dizziness
blurry vision
weight gain
sleepiness
trouble concentrating
swelling of hands and feet
dry mouth
- dizziness
- blurry vision
- weight gain
- sleepiness
- trouble concentrating
- swelling of hands and feet
- dry mouth
- LYRICA caused skin sores in animal studies. Skin sores did not happen in studies in people. If you have diabetes, you should pay attention to your skin while taking LYRICA and tell your healthcare provider about any sores or skin problems.
- Tell your healthcare provider about any side effect that bothers you or that does not go away.
- These are not all the possible side effects of LYRICA. For more information, ask your healthcare provider or pharmacist.
- Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
- How should I store LYRICA?
- Store LYRICA capsules and oral solution at room temperature, 59°F to 86°F (15°C to 30°C) in its original package.
Safely throw away any LYRICA that is out of date or no longer needed.
Keep LYRICA and all medicines out of the reach of children.
- Safely throw away any LYRICA that is out of date or no longer needed.
- Keep LYRICA and all medicines out of the reach of children.
- General information about LYRICA
- Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use LYRICA for a condition for which it was not prescribed. Do not give LYRICA to other people, even if they have the same symptoms you have. It may harm them.
- This Medication Guide summarizes the most important information about LYRICA. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about LYRICA that is written for health professionals.
- You can also visit the LYRICA website at www.LYRICA.com or call 1-866-459-7422 (1-866-4LYRICA).
- What are the ingredients In LYRICA?
- Active ingredient: pregabalin
- Inactive ingredients:
LYRICA capsules: lactose monohydrate, cornstarch, talc
Capsule shell: gelatin and titanium dioxide; Orange capsule shell: red iron oxide; White capsule shell: sodium lauryl sulfate, colloidal silicon dioxide. Colloidal silicon dioxide is a manufacturing aid that may or may not be present in the capsule shells.
Imprinting ink: shellac, black iron oxide, propylene glycol, potassium hydroxide.
- LYRICA capsules: lactose monohydrate, cornstarch, talc
- Capsule shell: gelatin and titanium dioxide; Orange capsule shell: red iron oxide; White capsule shell: sodium lauryl sulfate, colloidal silicon dioxide. Colloidal silicon dioxide is a manufacturing aid that may or may not be present in the capsule shells.
- Imprinting ink: shellac, black iron oxide, propylene glycol, potassium hydroxide.
- LYRICA oral solution: methylparaben, propylparaben, monobasic sodium phosphate anhydrous, dibasic sodium phosphate anhydrous, sucralose, artificial strawberry #11545 and purified water.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
- This Medication Guide has been approved by the U.S. Food and Drug Administration.
# Precautions with Alcohol
- Avoid consuming alcohol while taking LYRICA, as LYRICA may potentiate the impairment of motor skills and sedating effects of alcohol.
# Brand Names
- LYRICA®
# Look-Alike Drug Names
- Lyrica® — Lopressor®
# Drug Shortage Status
# Price | Pregabalin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2]
# Disclaimer
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# Overview
Pregabalin is a GABA analogue that is FDA approved for the treatment of neuropathic pain associated with diabetic peripheral neuropathy (DPN), postherpetic neuralgia (PHN), adjunctive therapy for adult patients with partial onset seizures ,fibromyalgia, neuropathic pain associated with spinal cord injury. Common adverse reactions include dizziness, somnolence, dry mouth, edema, blurred vision, weight gain and abnormal thinking (primarily difficulty with concentration/attention).
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- LYRICA is indicated for:
- Management of neuropathic pain associated with diabetic peripheral neuropathy
- Management of postherpetic neuralgia
- Adjunctive therapy for adult patients with partial onset seizures
- Management of fibromyalgia
- Management of neuropathic pain associated with spinal cord injury
### Dosage And Administration
- LYRICA is given orally with or without food.
- When discontinuing LYRICA, taper gradually over a minimum of 1 week.
### Neuropathic Pain Associated with Diabetic Peripheral Neuropathy
- The maximum recommended dose of LYRICA is 100 mg three times a day (300 mg/day) in patients with creatinine clearance of at least 60 mL/min. Begin dosing at 50 mg three times a day (150 mg/day). The dose may be increased to 300 mg/day within 1 week based on efficacy and tolerability. Because LYRICA is eliminated primarily by renal excretion, adjust the dose in patients with reduced renal function.
- Although LYRICA was also studied at 600 mg/day, there is no evidence that this dose confers additional significant benefit and this dose was less well tolerated. In view of the dose-dependent adverse reactions, treatment with doses above 300 mg/day is not recommended.
### Postherpetic Neuralgia
- The recommended dose of LYRICA is 75 to 150 mg two times a day, or 50 to 100 mg three times a day (150 to 300 mg/day) in patients with creatinine clearance of at least 60 mL/min. Begin dosing at 75 mg two times a day, or 50 mg three times a day (150 mg/day). The dose may be increased to 300 mg/day within 1 week based on efficacy and tolerability. Because LYRICA is eliminated primarily by renal excretion, adjust the dose in patients with reduced renal function.
- Patients who do not experience sufficient pain relief following 2 to 4 weeks of treatment with 300 mg/day, and who are able to tolerate LYRICA, may be treated with up to 300 mg two times a day, or 200 mg three times a day (600 mg/day). In view of the dose-dependent adverse reactions and the higher rate of treatment discontinuation due to adverse reactions, reserve dosing above 300 mg/day for those patients who have on-going pain and are tolerating 300 mg daily.
### Adjunctive Therapy for Adult Patients with Partial Onset Seizures
- LYRICA at doses of 150 to 600 mg/day has been shown to be effective as adjunctive therapy in the treatment of partial onset seizures in adults. Both the efficacy and adverse event profiles of LYRICA have been shown to be dose-related. Administer the total daily dose in two or three divided doses. In general, it is recommended that patients be started on a total daily dose no greater than 150 mg/day (75 mg two times a day, or 50 mg three times a day). Based on individual patient response and tolerability, the dose may be increased to a maximum dose of 600 mg/day.
- Because LYRICA is eliminated primarily by renal excretion, adjust the dose in patients with reduced renal function.
- The effect of dose escalation rate on the tolerability of LYRICA has not been formally studied.
- The efficacy of add-on LYRICA in patients taking gabapentin has not been evaluated in controlled trials. Consequently, dosing recommendations for the use of LYRICA with gabapentin cannot be offered.
### Management of Fibromyalgia
- The recommended dose of LYRICA for fibromyalgia is 300 to 450 mg/day. Begin dosing at 75 mg two times a day (150 mg/day). The dose may be increased to 150 mg two times a day (300 mg/day) within 1 week based on efficacy and tolerability. Patients who do not experience sufficient benefit with 300 mg/day may be further increased to 225 mg two times a day (450 mg/day). Although LYRICA was also studied at 600 mg/day, there is no evidence that this dose confers additional benefit and this dose was less well tolerated. In view of the dose-dependent adverse reactions, treatment with doses above 450 mg/day is not recommended. Because LYRICA is eliminated primarily by renal excretion, adjust the dose in patients with reduced renal function.
### Neuropathic Pain Associated with Spinal Cord Injury
- The recommended dose range of LYRICA for the treatment of neuropathic pain associated with spinal cord injury is 150 to 600 mg/day. The recommended starting dose is 75 mg two times a day (150 mg/day). The dose may be increased to 150 mg two times a day (300 mg/day) within 1 week based on efficacy and tolerability. Patients who do not experience sufficient pain relief after 2 to 3 weeks of treatment with 150 mg two times a day and who tolerate LYRICA may be treated with up to 300 mg two times a day. Because LYRICA is eliminated primarily by renal excretion, adjust the dose in patients with reduced renal function.
### Patients with Renal Impairment
- In view of dose-dependent adverse reactions and since LYRICA is eliminated primarily by renal excretion, adjust the dose in patients with reduced renal function. Base the dose adjustment in patients with renal impairment on creatinine clearance (CLcr), as indicated in Table 1. To use this dosing table, an estimate of the patient's CLcr in mL/min is needed. CLcr in mL/min may be estimated from serum creatinine (mg/dL) determination using the Cockcroft and Gault equation:
- Next, refer to the Dosage and Administration section to determine the recommended total daily dose based on indication, for a patient with normal renal function (CLcr ≥60 mL/min). Then refer to Table 1 to determine the corresponding renal adjusted dose.
- (For example: A patient initiating LYRICA therapy for postherpetic neuralgia with normal renal function (CLcr ≥60 mL/min), receives a total daily dose of 150 mg/day pregabalin. Therefore, a renal impaired patient with a CLcr of 50 mL/min would receive a total daily dose of 75 mg/day pregabalin administered in two or three divided doses.)
- For patients undergoing hemodialysis, adjust the pregabalin daily dose based on renal function. In addition to the daily dose adjustment, administer a supplemental dose immediately following every 4-hour hemodialysis treatment (see Table 1).
### Oral Solution Concentration and Dispensing
- The oral solution is 20 mg pregabalin per milliliter (mL) and prescriptions should be written in milligrams (mg). The pharmacist will calculate the applicable dose in mL for dispensing (e.g., 150 mg equals 7.5 mL oral solution).
### Dosage Forms And Strengths
- Capsules: 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 225 mg, and 300 mg
- Oral Solution: 20 mg/mL
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pregabalin in adult patients.
### Non–Guideline-Supported Use
- 450 mg per day[1]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Pregabalin in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pregabalin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Pregabalin in pediatric patients.
# Contraindications
- LYRICA is contraindicated in patients with known hypersensitivity to pregabalin or any of its components. Angioedema and hypersensitivity reactions have occurred in patients receiving pregabalin therapy.
# Warnings
### Precautions
- Angioedema
- There have been postmarketing reports of angioedema in patients during initial and chronic treatment with LYRICA. Specific symptoms included swelling of the face, mouth (tongue, lips, and gums), and neck (throat and larynx). There were reports of life-threatening angioedema with respiratory compromise requiring emergency treatment. Discontinue LYRICA immediately in patients with these symptoms.
- Exercise caution when prescribing LYRICA to patients who have had a previous episode of angioedema. In addition, patients who are taking other drugs associated with angioedema (e.g., angiotensin converting enzyme inhibitors ACE-inhibitors) may be at increased risk of developing angioedema.
- Hypersensitivity
- There have been postmarketing reports of hypersensitivity in patients shortly after initiation of treatment with LYRICA. Adverse reactions included skin redness, blisters, hives, rash, dyspnea, and wheezing. Discontinue LYRICA immediately in patients with these symptoms.
- Withdrawal of Antiepileptic Drugs (AEDs)
- As with all AEDs, withdraw LYRICA gradually to minimize the potential of increased seizure frequency in patients with seizure disorders. If LYRICA is discontinued, taper the drug gradually over a minimum of 1 week.
- Suicidal Behavior and Ideation
- Antiepileptic drugs (AEDs), including LYRICA, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Monitor patients treated with any AED for any indication for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
- Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.
- The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
- The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5–100 years) in the clinical trials analyzed.
- Table 2 shows absolute and relative risk by indication for all evaluated AEDs.
- The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.
- Anyone considering prescribing LYRICA or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
- Inform patients, their caregivers, and families that LYRICA and other AEDs increase the risk of suicidal thoughts and behavior and advise them of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Report behaviors of concern immediately to healthcare providers.
- Peripheral Edema
- LYRICA treatment may cause peripheral edema. In short-term trials of patients without clinically significant heart or peripheral vascular disease, there was no apparent association between peripheral edema and cardiovascular complications such as hypertension or congestive heart failure. Peripheral edema was not associated with laboratory changes suggestive of deterioration in renal or hepatic function.
- In controlled clinical trials the incidence of peripheral edema was 6% in the LYRICA group compared with 2% in the placebo group. In controlled clinical trials, 0.5% of LYRICA patients and 0.2% placebo patients withdrew due to peripheral edema.
- Higher frequencies of weight gain and peripheral edema were observed in patients taking both LYRICA and a thiazolidinedione antidiabetic agent compared to patients taking either drug alone. The majority of patients using thiazolidinedione antidiabetic agents in the overall safety database were participants in studies of pain associated with diabetic peripheral neuropathy. In this population, peripheral edema was reported in 3% (2/60) of patients who were using thiazolidinedione antidiabetic agents only, 8% (69/859) of patients who were treated with LYRICA only, and 19% (23/120) of patients who were on both LYRICA and thiazolidinedione antidiabetic agents. Similarly, weight gain was reported in 0% (0/60) of patients on thiazolidinediones only; 4% (35/859) of patients on LYRICA only; and 7.5% (9/120) of patients on both drugs.
- As the thiazolidinedione class of antidiabetic drugs can cause weight gain and/or fluid retention, possibly exacerbating or leading to heart failure, exercise caution when co-administering LYRICA and these agents.
- Because there are limited data on congestive heart failure patients with New York Heart Association (NYHA) Class III or IV cardiac status, exercise caution when using LYRICA in these patients.
- Dizziness and Somnolence
- LYRICA may cause dizziness and somnolence. Inform patients that LYRICA-related dizziness and somnolence may impair their ability to perform tasks such as driving or operating machinery.
- In the LYRICA controlled trials, dizziness was experienced by 30% of LYRICA-treated patients compared to 8% of placebo-treated patients; somnolence was experienced by 23% of LYRICA-treated patients compared to 8% of placebo-treated patients. Dizziness and somnolence generally began shortly after the initiation of LYRICA therapy and occurred more frequently at higher doses. Dizziness and somnolence were the adverse reactions most frequently leading to withdrawal (4% each) from controlled studies. In LYRICA-treated patients reporting these adverse reactions in short-term, controlled studies, dizziness persisted until the last dose in 30% and somnolence persisted until the last dose in 42% of patients.
- Weight Gain
- LYRICA treatment may cause weight gain. In LYRICA controlled clinical trials of up to 14 weeks, a gain of 7% or more over baseline weight was observed in 9% of LYRICA-treated patients and 2% of placebo-treated patients. Few patients treated with LYRICA (0.3%) withdrew from controlled trials due to weight gain. LYRICA associated weight gain was related to dose and duration of exposure, but did not appear to be associated with baseline BMI, gender, or age. Weight gain was not limited to patients with edema.
- Although weight gain was not associated with clinically important changes in blood pressure in short-term controlled studies, the long-term cardiovascular effects of LYRICA-associated weight gain are unknown.
- Among diabetic patients, LYRICA-treated patients gained an average of 1.6 kg (range: -16 to 16 kg), compared to an average 0.3 kg (range: -10 to 9 kg) weight gain in placebo patients. In a cohort of 333 diabetic patients who received LYRICA for at least 2 years, the average weight gain was 5.2 kg.
- While the effects of LYRICA-associated weight gain on glycemic control have not been systematically assessed, in controlled and longer-term open label clinical trials with diabetic patients, LYRICA treatment did not appear to be associated with loss of glycemic control (as measured by HbA1C).
- Abrupt or Rapid Discontinuation
- Following abrupt or rapid discontinuation of LYRICA, some patients reported symptoms including insomnia, nausea, headache, anxiety, hyperhidrosis, and diarrhea. Taper LYRICA gradually over a minimum of 1 week rather than discontinuing the drug abruptly.
- Tumorigenic Potential
- In standard preclinical in vivo lifetime carcinogenicity studies of LYRICA, an unexpectedly high incidence of hemangiosarcoma was identified in two different strains of mice. The clinical significance of this finding is unknown. Clinical experience during LYRICA's premarketing development provides no direct means to assess its potential for inducing tumors in humans.
- In clinical studies across various patient populations, comprising 6396 patient-years of exposure in patients >12 years of age, new or worsening-preexisting tumors were reported in 57 patients. Without knowledge of the background incidence and recurrence in similar populations not treated with LYRICA, it is impossible to know whether the incidence seen in these cohorts is or is not affected by treatment.
- Ophthalmological Effects
- In controlled studies, a higher proportion of patients treated with LYRICA reported blurred vision (7%) than did patients treated with placebo (2%), which resolved in a majority of cases with continued dosing. Less than 1% of patients discontinued LYRICA treatment due to vision-related events (primarily blurred vision).
- Prospectively planned ophthalmologic testing, including visual acuity testing, formal visual field testing and dilated funduscopic examination, was performed in over 3600 patients. In these patients, visual acuity was reduced in 7% of patients treated with LYRICA, and 5% of placebo-treated patients. Visual field changes were detected in 13% of LYRICA-treated, and 12% of placebo-treated patients. Funduscopic changes were observed in 2% of LYRICA-treated and 2% of placebo-treated patients.
- Although the clinical significance of the ophthalmologic findings is unknown, inform patients to notify their physician if changes in vision occur. If visual disturbance persists, consider further assessment. Consider more frequent assessment for patients who are already routinely monitored for ocular conditions.
- Creatine Kinase Elevations
- LYRICA treatment was associated with creatine kinase elevations. Mean changes in creatine kinase from baseline to the maximum value were 60 U/L for LYRICA-treated patients and 28 U/L for the placebo patients. In all controlled trials across multiple patient populations, 1.5% of patients on LYRICA and 0.7% of placebo patients had a value of creatine kinase at least three times the upper limit of normal. Three LYRICA treated subjects had events reported as rhabdomyolysis in premarketing clinical trials. The relationship between these myopathy events and LYRICA is not completely understood because the cases had documented factors that may have caused or contributed to these events. Instruct patients to promptly report unexplained muscle pain, tenderness, or weakness, particularly if these muscle symptoms are accompanied by malaise or fever. Discontinue treatment with LYRICA if myopathy is diagnosed or suspected or if markedly elevated creatine kinase levels occur.
- Decreased Platelet Count
- LYRICA treatment was associated with a decrease in platelet count. LYRICA-treated subjects experienced a mean maximal decrease in platelet count of 20 × 103/µL, compared to 11 × 103/µL in placebo patients. In the overall database of controlled trials, 2% of placebo patients and 3% of LYRICA patients experienced a potentially clinically significant decrease in platelets, defined as 20% below baseline value and <<<150 × 103/µL. A single LYRICA treated subject developed severe thrombocytopenia with a platelet count less than 20 × 103/ µL. In randomized controlled trials, LYRICA was not associated with an increase in bleeding-related adverse reactions.
- PR Interval Prolongation
- LYRICA treatment was associated with PR interval prolongation. In analyses of clinical trial ECG data, the mean PR interval increase was 3–6 msec at LYRICA doses ≥300 mg/day. This mean change difference was not associated with an increased risk of PR increase ≥25% from baseline, an increased percentage of subjects with on-treatment PR >200 msec, or an increased risk of adverse reactions of second or third degree AV block.
- Subgroup analyses did not identify an increased risk of PR prolongation in patients with baseline PR prolongation or in patients taking other PR prolonging medications. However, these analyses cannot be considered definitive because of the limited number of patients in these categories.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- In all controlled and uncontrolled trials across various patient populations during the premarketing development of LYRICA, more than 10,000 patients have received LYRICA. Approximately 5000 patients were treated for 6 months or more, over 3100 patients were treated for 1 year or longer, and over 1400 patients were treated for at least 2 years.
- Adverse Reactions Most Commonly Leading to Discontinuation in All Premarketing Controlled Clinical Studies
- In premarketing controlled trials of all populations combined, 14% of patients treated with LYRICA and 7% of patients treated with placebo discontinued prematurely due to adverse reactions. In the LYRICA treatment group, the adverse reactions most frequently leading to discontinuation were dizziness (4%) and somnolence (4%). In the placebo group, 1% of patients withdrew due to dizziness and <1% withdrew due to somnolence. Other adverse reactions that led to discontinuation from controlled trials more frequently in the LYRICA group compared to the placebo group were ataxia, confusion, asthenia, thinking abnormal, blurred vision, incoordination, and peripheral edema (1% each).
- Most Common Adverse Reactions in All Premarketing Controlled Clinical Studies
- In premarketing controlled trials of all patient populations combined, dizziness, somnolence, dry mouth, edema, blurred vision, weight gain, and "thinking abnormal" (primarily difficulty with concentration/attention) were more commonly reported by subjects treated with LYRICA than by subjects treated with placebo (≥5% and twice the rate of that seen in placebo).
- Controlled Studies with Neuropathic Pain Associated with Diabetic Peripheral Neuropathy
- Adverse Reactions Leading to Discontinuation
- In clinical trials in patients with neuropathic pain associated with diabetic peripheral neuropathy, 9% of patients treated with LYRICA and 4% of patients treated with placebo discontinued prematurely due to adverse reactions. In the LYRICA treatment group, the most common reasons for discontinuation due to adverse reactions were dizziness (3%) and somnolence (2%). In comparison, <1% of placebo patients withdrew due to dizziness and somnolence. Other reasons for discontinuation from the trials, occurring with greater frequency in the LYRICA group than in the placebo group, were asthenia, confusion, and peripheral edema. Each of these events led to withdrawal in approximately 1% of patients.
- Most Common Adverse Reactions
- Table 3 lists all adverse reactions, regardless of causality, occurring in ≥1% of patients with neuropathic pain associated with diabetic neuropathy in the combined LYRICA group for which the incidence was greater in this combined LYRICA group than in the placebo group. A majority of pregabalin-treated patients in clinical studies had adverse reactions with a maximum intensity of "mild" or "moderate".
- Controlled Studies in Postherpetic Neuralgia
- Adverse Reactions Leading to Discontinuation
- In clinical trials in patients with postherpetic neuralgia, 14% of patients treated with LYRICA and 7% of patients treated with placebo discontinued prematurely due to adverse reactions. In the LYRICA treatment group, the most common reasons for discontinuation due to adverse reactions were dizziness (4%) and somnolence (3%). In comparison, less than 1% of placebo patients withdrew due to dizziness and somnolence. Other reasons for discontinuation from the trials, occurring in greater frequency in the LYRICA group than in the placebo group, were confusion (2%), as well as peripheral edema, asthenia, ataxia, and abnormal gait (1% each).
- Most Common Adverse Reactions
- Table 4 lists all adverse reactions, regardless of causality, occurring in ≥ 1% of patients with neuropathic pain associated with postherpetic neuralgia in the combined LYRICA group for which the incidence was greater in this combined LYRICA group than in the placebo group. In addition, an event is included, even if the incidence in the all LYRICA group is not greater than in the placebo group, if the incidence of the event in the 600 mg/day group is more than twice that in the placebo group. A majority of pregabalin-treated patients in clinical studies had adverse reactions with a maximum intensity of "mild" or "moderate". Overall, 12.4% of all pregabalin-treated patients and 9.0% of all placebo-treated patients had at least one severe event while 8% of pregabalin-treated patients and 4.3% of placebo-treated patients had at least one severe treatment-related adverse event.
- Controlled Add-On Studies in Adjunctive Therapy for Adult Patients with Partial Onset Seizures
- Adverse Reactions Leading to Discontinuation
- Approximately 15% of patients receiving LYRICA and 6% of patients receiving placebo in add-on epilepsy trials discontinued prematurely due to adverse reactions. In the LYRICA treatment group, the adverse reactions most frequently leading to discontinuation were dizziness (6%), ataxia (4%), and somnolence (3%). In comparison, <1% of patients in the placebo group withdrew due to each of these events. Other adverse reactions that led to discontinuation of at least 1% of patients in the LYRICA group and at least twice as frequently compared to the placebo group were asthenia, diplopia, blurred vision, thinking abnormal, nausea, tremor, vertigo, headache, and confusion (which each led to withdrawal in 2% or less of patients).
- Most Common Adverse Reactions
- Table 5 lists all dose-related adverse reactions occurring in at least 2% of all LYRICA-treated patients. Dose-relatedness was defined as the incidence of the adverse event in the 600 mg/day group was at least 2% greater than the rate in both the placebo and 150 mg/day groups. In these studies, 758 patients received LYRICA and 294 patients received placebo for up to 12 weeks. Because patients were also treated with 1 to 3 other AEDs, it is not possible to determine whether the following adverse reactions can be ascribed to LYRICA alone, or the combination of LYRICA and other AEDs. A majority of pregabalin-treated patients in clinical studies had adverse reactions with a maximum intensity of "mild" or "moderate".
- Controlled Studies with Fibromyalgia
- Adverse Reactions Leading to Discontinuation
- In clinical trials of patients with fibromyalgia, 19% of patients treated with pregabalin (150–600 mg/day) and 10% of patients treated with placebo discontinued prematurely due to adverse reactions. In the pregabalin treatment group, the most common reasons for discontinuation due to adverse reactions were dizziness (6%) and somnolence (3%). In comparison, <1% of placebo-treated patients withdrew due to dizziness and somnolence. Other reasons for discontinuation from the trials, occurring with greater frequency in the pregabalin treatment group than in the placebo treatment group, were fatigue, headache, balance disorder, and weight increased. Each of these adverse reactions led to withdrawal in approximately 1% of patients.
- Most Common Adverse Reactions
- Table 6 lists all adverse reactions, regardless of causality, occurring in ≥2% of patients with fibromyalgia in the 'all pregabalin' treatment group for which the incidence was greater than in the placebo treatment group. A majority of pregabalin-treated patients in clinical studies experienced adverse reactions with a maximum intensity of "mild" or "moderate".
- Controlled Studies in Neuropathic Pain Associated with Spinal Cord Injury
- Adverse Reactions Leading to Discontinuation
- In clinical trials of patients with neuropathic pain associated with spinal cord injury, 13% of patients treated with pregabalin and 10% of patients treated with placebo discontinued prematurely due to adverse reactions. In the pregabalin treatment group, the most common reasons for discontinuation due to adverse reactions were somnolence (3%) and edema (2%). In comparison, none of the placebo-treated patients withdrew due to somnolence and edema. Other reasons for discontinuation from the trials, occurring with greater frequency in the pregabalin treatment group than in the placebo treatment group, were fatigue and balance disorder. Each of these adverse reactions led to withdrawal in less than 2% of patients.
- Most Common Adverse Reactions
- Table 7 lists all adverse reactions, regardless of causality, occurring in ≥2% of patients with neuropathic pain associated with spinal cord injury in the controlled trials. A majority of pregabalin-treated patients in clinical studies experienced adverse reactions with a maximum intensity of "mild" or "moderate".
- Other Adverse Reactions Observed During the Clinical Studies of LYRICA
- Following is a list of treatment-emergent adverse reactions reported by patients treated with LYRICA during all clinical trials. The listing does not include those events already listed in the previous tables or elsewhere in labeling, those events for which a drug cause was remote, those events which were so general as to be uninformative, and those events reported only once which did not have a substantial probability of being acutely life-threatening.
- Events are categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse reactions are those occurring on one or more occasions in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are those occurring in fewer than 1/1000 patients.
- Frequent: Abdominal pain, Allergic reaction, Fever, Infrequent: Abscess, Cellulitis, Chills, Malaise, Neck rigidity, Overdose, Pelvic pain, Photosensitivity reaction, Rare: Anaphylactoid reaction, Ascites, Granuloma, Hangover effect, Intentional Injury, Retroperitoneal Fibrosis, Shock
- Infrequent: Deep thrombophlebitis, Heart failure, Hypotension, Postural hypotension, Retinal vascular disorder, Syncope; Rare: ST Depressed, Ventricular Fibrillation
- Frequent: Gastroenteritis, Increased appetite; Infrequent: Cholecystitis, Cholelithiasis, Colitis, Dysphagia, Esophagitis, Gastritis, Gastrointestinal hemorrhage, Melena, Mouth ulceration, Pancreatitis, Rectal hemorrhage, Tongue edema; Rare: Aphthous stomatitis, Esophageal Ulcer, Periodontal abscess
- Frequent: Ecchymosis; Infrequent: Anemia, Eosinophilia, Hypochromic anemia, Leukocytosis, Leukopenia, Lymphadenopathy, Thrombocytopenia; Rare: Myelofibrosis, Polycythemia, Prothrombin decreased, Purpura, Thrombocythemia
- Rare: Glucose Tolerance Decreased, Urate Crystalluria
- Frequent: Arthralgia, Leg cramps, Myalgia, Myasthenia; Infrequent: Arthrosis; Rare: Chondrodystrophy, Generalized Spasm
- Frequent: Anxiety, Depersonalization, Hypertonia, Hypoesthesia, Libido decreased, Nystagmus, Paresthesia, Sedation, Stupor, Twitching; Infrequent: Abnormal dreams, Agitation, Apathy, Aphasia, Circumoral paresthesia, Dysarthria, Hallucinations, Hostility, Hyperalgesia, Hyperesthesia, Hyperkinesia, Hypokinesia, Hypotonia, Libido increased, Myoclonus, Neuralgia, Rare: Addiction, Cerebellar syndrome, Cogwheel rigidity, Coma, Delirium, Delusions, Dysautonomia, Dyskinesia, Dystonia, Encephalopathy, Extrapyramidal syndrome, Guillain-Barré syndrome, Hypalgesia, Intracranial hypertension, Manic reaction, Paranoid reaction, Peripheral neuritis, Personality disorder, Psychotic depression, Schizophrenic reaction, Sleep disorder, Torticollis, Trismus
- Rare: Apnea, Atelectasis, Bronchiolitis, Hiccup, Laryngismus, Lung edema, Lung fibrosis, Yawn
- Frequent: Pruritus, Infrequent: Alopecia, Dry skin, Eczema, Hirsutism, Skin ulcer, Urticaria, Vesiculobullous rash; Rare: Angioedema, Exfoliative dermatitis, Lichenoid dermatitis, Melanosis, Nail Disorder, Petechial rash, Purpuric rash, Pustular rash, Skin atrophy, Skin necrosis, Skin nodule, Stevens-Johnson syndrome, Subcutaneous nodule
- Frequent: Conjunctivitis, Diplopia, Otitis media, Tinnitus; Infrequent: Abnormality of accommodation, Blepharitis, Dry eyes, Eye hemorrhage, Hyperacusis, Photophobia, Retinal edema, Taste loss, Taste perversion; Rare: Anisocoria, Blindness, Corneal ulcer, Exophthalmos, Extraocular palsy, Iritis, Keratitis, Keratoconjunctivitis, Miosis, Mydriasis, Night blindness, Ophthalmoplegia, Optic atrophy, Papilledema, Parosmia, Ptosis, Uveitis
- Frequent: Anorgasmia, Impotence, Urinary frequency, Urinary incontinence; Infrequent: Abnormal ejaculation, Albuminuria, Amenorrhea, Dysmenorrhea, Dysuria, Hematuria, Kidney calculus, Leukorrhea, Menorrhagia, Metrorrhagia, Nephritis, Oliguria, Urinary retention, Urine abnormality; Rare: Acute kidney failure, Balanitis, Bladder Neoplasm, Cervicitis, Dyspareunia, Epididymitis, Female lactation, Glomerulitis, Ovarian disorder, Pyelonephritis
- The overall adverse event profile of pregabalin was similar between women and men. There are insufficient data to support a statement regarding the distribution of adverse experience reports by race.
- Headache
- Nausea, Diarrhea
- Gynecomastia, Breast Enlargement
## Postmarketing Experience
- The following adverse reactions have been identified during postapproval use of LYRICA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- In addition, there are post-marketing reports of events related to reduced lower gastrointestinal tract function (e.g., intestinal obstruction, paralytic ileus, constipation) when LYRICA was co-administered with medications that have the potential to produce constipation, such as opioid analgesics. There are also post-marketing reports of respiratory failure and coma in patients taking pregabalin and other CNS depressant medications.
# Drug Interactions
- Since LYRICA is predominantly excreted unchanged in the urine, undergoes negligible metabolism in humans (<2% of a dose recovered in urine as metabolites), and does not bind to plasma proteins, its pharmacokinetics are unlikely to be affected by other agents through metabolic interactions or protein binding displacement. In vitro and in vivo studies showed that LYRICA is unlikely to be involved in significant pharmacokinetic drug interactions. Specifically, there are no pharmacokinetic interactions between pregabalin and the following antiepileptic drugs: carbamazepine, valproic acid, lamotrigine, phenytoin, phenobarbital, and topiramate. Important pharmacokinetic interactions would also not be expected to occur between LYRICA and commonly used antiepileptic drugs.
- Pharmacodynamics
- Multiple oral doses of LYRICA were co-administered with oxycodone, lorazepam, or ethanol. Although no pharmacokinetic interactions were seen, additive effects on cognitive and gross motor functioning were seen when LYRICA was co-administered with these drugs. No clinically important effects on respiration were seen.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- Increased incidences of fetal structural abnormalities and other manifestations of developmental toxicity, including lethality, growth retardation, and nervous and reproductive system functional impairment, were observed in the offspring of rats and rabbits given pregabalin during pregnancy, at doses that produced plasma pregabalin exposures (AUC) ≥5 times human exposure at the maximum recommended dose (MRD) of 600 mg/day.
- When pregnant rats were given pregabalin (500, 1250, or 2500 mg/kg) orally throughout the period of organogenesis, incidences of specific skull alterations attributed to abnormally advanced ossification (premature fusion of the jugal and nasal sutures) were increased at ≥1250 mg/kg, and incidences of skeletal variations and retarded ossification were increased at all doses. Fetal body weights were decreased at the highest dose. The low dose in this study was associated with a plasma exposure (AUC) approximately 17 times human exposure at the MRD of 600 mg/day. A no-effect dose for rat embryo-fetal developmental toxicity was not established.
- When pregnant rabbits were given LYRICA (250, 500, or 1250 mg/kg) orally throughout the period of organogenesis, decreased fetal body weight and increased incidences of skeletal malformations, visceral variations, and retarded ossification were observed at the highest dose. The no-effect dose for developmental toxicity in rabbits (500 mg/kg) was associated with a plasma exposure approximately 16 times human exposure at the MRD.
- In a study in which female rats were dosed with LYRICA (50, 100, 250, 1250, or 2500 mg/kg) throughout gestation and lactation, offspring growth was reduced at ≥ 100 mg/kg and offspring survival was decreased at ≥250 mg/kg. The effect on offspring survival was pronounced at doses ≥1250 mg/kg, with 100% mortality in high-dose litters. When offspring were tested as adults, neurobehavioral abnormalities (decreased auditory startle responding) were observed at ≥250 mg/kg and reproductive impairment (decreased fertility and litter size) was seen at 1250 mg/kg. The no-effect dose for pre- and postnatal developmental toxicity in rats (50 mg/kg) produced a plasma exposure approximately 2 times human exposure at the MRD.
- There are no adequate and well-controlled studies in pregnant women. Use LYRICA during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- To provide information regarding the effects of in utero exposure to LYRICA, physicians are advised to recommend that pregnant patients taking LYRICA enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Pregabalin in women who are pregnant.
### Labor and Delivery
- The effects of LYRICA on labor and delivery in pregnant women are unknown. In the prenatal-postnatal study in rats, pregabalin prolonged gestation and induced dystocia at exposures ≥50 times the mean human exposure (AUC (0–24) of 123 µg∙hr/mL) at the maximum recommended clinical dose of 600 mg/day.
### Nursing Mothers
- It is not known if pregabalin is excreted in human milk; it is, however, present in the milk of rats. Because many drugs are excreted in human milk, and because of the potential for tumorigenicity shown for pregabalin in animal studies, decide whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
- The safety and efficacy of pregabalin in pediatric patients have not been established.
- In studies in which pregabalin (50 to 500 mg/kg) was orally administered to young rats from early in the postnatal period (Postnatal Day 7) through sexual maturity, neurobehavioral abnormalities (deficits in learning and memory, altered locomotor activity, decreased auditory startle responding and habituation) and reproductive impairment (delayed sexual maturation and decreased fertility in males and females) were observed at doses ≥50 mg/kg. The neurobehavioral changes of acoustic startle persisted at ≥250 mg/kg and locomotor activity and water maze performance at ≥500 mg/kg in animals tested after cessation of dosing and, thus, were considered to represent long-term effects. The low effect dose for developmental neurotoxicity and reproductive impairment in juvenile rats (50 mg/kg) was associated with a plasma pregabalin exposure (AUC) approximately equal to human exposure at the maximum recommended dose of 600 mg/day. A no-effect dose was not established.
### Geriatic Use
- In controlled clinical studies of LYRICA in neuropathic pain associated with diabetic peripheral neuropathy, 246 patients were 65 to 74 years of age, and 73 patients were 75 years of age or older.
- In controlled clinical studies of LYRICA in neuropathic pain associated with postherpetic neuralgia, 282 patients were 65 to 74 years of age, and 379 patients were 75 years of age or older.
- In controlled clinical studies of LYRICA in epilepsy, there were only 10 patients 65 to 74 years of age, and 2 patients who were 75 years of age or older.
- No overall differences in safety and efficacy were observed between these patients and younger patients.
- In controlled clinical studies of LYRICA in fibromyalgia, 106 patients were 65 years of age or older. Although the adverse reaction profile was similar between the two age groups, the following neurological adverse reactions were more frequent in patients 65 years of age or older: dizziness, blurred vision, balance disorder, tremor, confusional state, coordination abnormal, and lethargy.
- LYRICA is known to be substantially excreted by the kidney, and the risk of toxic reactions to LYRICA may be greater in patients with impaired renal function. Because LYRICA is eliminated primarily by renal excretion, adjust the dose for elderly patients with renal impairment.
### Gender
There is no FDA guidance on the use of Pregabalin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Pregabalin with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Pregabalin in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Pregabalin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Pregabalin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Pregabalin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Pregabalin in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Pregabalin in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- There is limited experience with overdose of LYRICA. The highest reported accidental overdose of LYRICA during the clinical development program was 8000 mg, and there were no notable clinical consequences.
### Management
- There is no specific antidote for overdose with LYRICA. If indicated, elimination of unabsorbed drug may be attempted by emesis or gastric lavage; observe usual precautions to maintain the airway. General supportive care of the patient is indicated including monitoring of vital signs and observation of the clinical status of the patient. Contact a Certified Poison Control Center for up-to-date information on the management of overdose with LYRICA.
- Although hemodialysis has not been performed in the few known cases of overdose, it may be indicated by the patient's clinical state or in patients with significant renal impairment. Standard hemodialysis procedures result in significant clearance of pregabalin (approximately 50% in 4 hours).
## Chronic Overdose
There is limited information regarding Chronic Overdose of Pregabalin in the drug label.
# Pharmacology
## Mechanism of Action
- LYRICA (pregabalin) binds with high affinity to the alpha2-delta site (an auxiliary subunit of voltage-gated calcium channels) in central nervous system tissues. Although the mechanism of action of pregabalin has not been fully elucidated, results with genetically modified mice and with compounds structurally related to pregabalin (such as gabapentin) suggest that binding to the alpha2-delta subunit may be involved in pregabalin's anti-nociceptive and antiseizure effects in animals. In animal models of nerve damage, pregabalin has been shown to reduce calcium-dependent release of pro-nociceptive neurotransmitters in the spinal cord, possibly by disrupting alpha2-delta containing-calcium channel trafficking and/or reducing calcium currents. Evidence from other animal models of nerve damage and persistent pain suggest the anti-nociceptive activities of pregabalin may also be mediated through interactions with descending noradrenergic and serotonergic pathways originating from the brainstem that modulate pain transmission in the spinal cord.
- While pregabalin is a structural derivative of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), it does not bind directly to GABAA, GABAB, or benzodiazepine receptors, does not augment GABAA responses in cultured neurons, does not alter rat brain GABA concentration or have acute effects on GABA uptake or degradation. However, in cultured neurons prolonged application of pregabalin increases the density of GABA transporter protein and increases the rate of functional GABA transport. Pregabalin does not block sodium channels, is not active at opiate receptors, and does not alter cyclooxygenase enzyme activity. It is inactive at serotonin and dopamine receptors and does not inhibit dopamine, serotonin, or noradrenaline reuptake.
## Structure
- Pregabalin is described chemically as (S)-3-(aminomethyl)-5-methylhexanoic acid. The molecular formula is C8H17NO2 and the molecular weight is 159.23. The chemical structure of pregabalin is:
- Pregabalin is a white to off-white, crystalline solid with a pKa1 of 4.2 and a pKa2 of 10.6. It is freely soluble in water and both basic and acidic aqueous solutions. The log of the partition coefficient (n-octanol/0.05M phosphate buffer) at pH 7.4 is – 1.35.
- LYRICA (pregabalin) Capsules are administered orally and are supplied as imprinted hard-shell capsules containing 25, 50, 75, 100, 150, 200, 225, and 300 mg of pregabalin, along with lactose monohydrate, cornstarch, and talc as inactive ingredients. The capsule shells contain gelatin and titanium dioxide. In addition, the orange capsule shells contain red iron oxide and the white capsule shells contain sodium lauryl sulfate and colloidal silicon dioxide. Colloidal silicon dioxide is a manufacturing aid that may or may not be present in the capsule shells. The imprinting ink contains shellac, black iron oxide, propylene glycol, and potassium hydroxide.
- LYRICA (pregabalin) oral solution, 20 mg/mL, is administered orally and is supplied as a clear, colorless solution contained in a 16 fluid ounce white HDPE bottle with a polyethylene-lined closure. The oral solution contains 20 mg/mL of pregabalin, along with methylparaben, propylparaben, monobasic sodium phosphate anhydrous, dibasic sodium phosphate anhydrous, sucralose, artificial strawberry #11545 and purified water as inactive ingredients.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Pregabalin in the drug label.
## Pharmacokinetics
- Pregabalin is well absorbed after oral administration, is eliminated largely by renal excretion, and has an elimination half-life of about 6 hours.
- Absorption and Distribution
- Following oral administration of LYRICA capsules under fasting conditions, peak plasma concentrations occur within 1.5 hours. Pregabalin oral bioavailability is ≥90% and is independent of dose. Following single- (25 to 300 mg) and multiple- dose (75 to 900 mg/day) administration, maximum plasma concentrations (Cmax) and area under the plasma concentration-time curve (AUC) values increase linearly. Following repeated administration, steady state is achieved within 24 to 48 hours. Multiple-dose pharmacokinetics can be predicted from single-dose data.
- The rate of pregabalin absorption is decreased when given with food, resulting in a decrease in Cmax of approximately 25% to 30% and an increase in Tmax to approximately 3 hours. However, administration of pregabalin with food has no clinically relevant effect on the total absorption of pregabalin. Therefore, pregabalin can be taken with or without food.
- Pregabalin does not bind to plasma proteins. The apparent volume of distribution of pregabalin following oral administration is approximately 0.5 L/kg. Pregabalin is a substrate for system L transporter which is responsible for the transport of large amino acids across the blood brain barrier. Although there are no data in humans, pregabalin has been shown to cross the blood brain barrier in mice, rats, and monkeys. In addition, pregabalin has been shown to cross the placenta in rats and is present in the milk of lactating rats.
- Metabolism and Elimination
- Pregabalin undergoes negligible metabolism in humans. Following a dose of radiolabeled pregabalin, approximately 90% of the administered dose was recovered in the urine as unchanged pregabalin. The N-methylated derivative of pregabalin, the major metabolite of pregabalin found in urine, accounted for 0.9% of the dose. In preclinical studies, pregabalin (S-enantiomer) did not undergo racemization to the R-enantiomer in mice, rats, rabbits, or monkeys.
- Pregabalin is eliminated from the systemic circulation primarily by renal excretion as unchanged drug with a mean elimination half-life of 6.3 hours in subjects with normal renal function. Mean renal clearance was estimated to be 67.0 to 80.9 mL/min in young healthy subjects. Because pregabalin is not bound to plasma proteins this clearance rate indicates that renal tubular reabsorption is involved. Pregabalin elimination is nearly proportional to creatinine clearance (CLcr).
- Pharmacokinetics in Special Populations
- Race
- In population pharmacokinetic analyses of the clinical studies in various populations, the pharmacokinetics of LYRICA were not significantly affected by race (Caucasians, Blacks, and Hispanics).
- Gender
- Population pharmacokinetic analyses of the clinical studies showed that the relationship between daily dose and LYRICA drug exposure is similar between genders.
- Renal Impairment and Hemodialysis
- Pregabalin clearance is nearly proportional to creatinine clearance (CLcr). Dosage reduction in patients with renal dysfunction is necessary. Pregabalin is effectively removed from plasma by hemodialysis. Following a 4-hour hemodialysis treatment, plasma pregabalin concentrations are reduced by approximately 50%. For patients on hemodialysis, dosing must be modified.
- Elderly
- Pregabalin oral clearance tended to decrease with increasing age. This decrease in pregabalin oral clearance is consistent with age-related decreases in CLcr. Reduction of pregabalin dose may be required in patients who have age-related compromised renal function.
- Pediatric Pharmacokinetics
- Pharmacokinetics of pregabalin have not been adequately studied in pediatric patients.
- Drug Interactions
- In Vitro Studies
Pregabalin, at concentrations that were, in general, 10-times those attained in clinical trials, does not inhibit human CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 enzyme systems. In vitro drug interaction studies demonstrate that pregabalin does not induce CYP1A2 or CYP3A4 activity. Therefore, an increase in the metabolism of coadministered CYP1A2 substrates (e.g. theophylline, caffeine) or CYP 3A4 substrates (e.g., midazolam, testosterone) is not anticipated.
- Pregabalin, at concentrations that were, in general, 10-times those attained in clinical trials, does not inhibit human CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 enzyme systems. In vitro drug interaction studies demonstrate that pregabalin does not induce CYP1A2 or CYP3A4 activity. Therefore, an increase in the metabolism of coadministered CYP1A2 substrates (e.g. theophylline, caffeine) or CYP 3A4 substrates (e.g., midazolam, testosterone) is not anticipated.
- In Vivo Studies
The drug interaction studies described in this section were conducted in healthy adults, and across various patient populations.
- The drug interaction studies described in this section were conducted in healthy adults, and across various patient populations.
- Gabapentin
- The pharmacokinetic interactions of pregabalin and gabapentin were investigated in 12 healthy subjects following concomitant single-dose administration of 100-mg pregabalin and 300-mg gabapentin and in 18 healthy subjects following concomitant multiple-dose administration of 200-mg pregabalin every 8 hours and 400-mg gabapentin every 8 hours. Gabapentin pharmacokinetics following single- and multiple-dose administration were unaltered by pregabalin coadministration. The extent of pregabalin absorption was unaffected by gabapentin coadministration, although there was a small reduction in rate of absorption.
- Oral Contraceptive
- Pregabalin coadministration (200 mg three times a day) had no effect on the steady-state pharmacokinetics of norethindrone and ethinyl estradiol (1 mg/35 µg, respectively) in healthy subjects.
- Lorazepam
- Multiple-dose administration of pregabalin (300 mg twice a day) in healthy subjects had no effect on the rate and extent of lorazepam single-dose pharmacokinetics and single-dose administration of lorazepam (1 mg) had no effect on the steady-state pharmacokinetics of pregabalin.
- Oxycodone
- Multiple-dose administration of pregabalin (300 mg twice a day) in healthy subjects had no effect on the rate and extent of oxycodone single-dose pharmacokinetics. Single-dose administration of oxycodone (10 mg) had no effect on the steady-state pharmacokinetics of pregabalin.
- Ethanol
- Multiple-dose administration of pregabalin (300 mg twice a day) in healthy subjects had no effect on the rate and extent of ethanol single-dose pharmacokinetics and single-dose administration of ethanol (0.7 g/kg) had no effect on the steady-state pharmacokinetics of pregabalin.
- Phenytoin, carbamazepine, valproic acid, and lamotrigine
- Steady-state trough plasma concentrations of phenytoin, carbamazepine and carbamazepine 10,11 epoxide, valproic acid, and lamotrigine were not affected by concomitant pregabalin (200 mg three times a day) administration.
- Population pharmacokinetic analyses in patients treated with pregabalin and various concomitant medications suggest the following:
## Nonclinical Toxicology
- Carcinogenesis
- A dose-dependent increase in the incidence of malignant vascular tumors (hemangiosarcomas) was observed in two strains of mice (B6C3F1 and CD-1) given pregabalin (200, 1000, or 5000 mg/kg) in the diet for two years. Plasma pregabalin exposure (AUC) in mice receiving the lowest dose that increased hemangiosarcomas was approximately equal to the human exposure at the maximum recommended dose (MRD) of 600 mg/day. A no-effect dose for induction of hemangiosarcomas in mice was not established. No evidence of carcinogenicity was seen in two studies in Wistar rats following dietary administration of pregabalin for two years at doses (50, 150, or 450 mg/kg in males and 100, 300, or 900 mg/kg in females) that were associated with plasma exposures in males and females up to approximately 14 and 24 times, respectively, human exposure at the MRD.
- Mutagenesis
- Pregabalin was not mutagenic in bacteria or in mammalian cells in vitro, was not clastogenic in mammalian systems in vitro and in vivo, and did not induce unscheduled DNA synthesis in mouse or rat hepatocytes.
- Impairment of Fertility
- In fertility studies in which male rats were orally administered pregabalin (50 to 2500 mg/kg) prior to and during mating with untreated females, a number of adverse reproductive and developmental effects were observed. These included decreased sperm counts and sperm motility, increased sperm abnormalities, reduced fertility, increased preimplantation embryo loss, decreased litter size, decreased fetal body weights, and an increased incidence of fetal abnormalities.
- Effects on sperm and fertility parameters were reversible in studies of this duration (3–4 months). The no-effect dose for male reproductive toxicity in these studies (100 mg/kg) was associated with a plasma pregabalin exposure (AUC) approximately 3 times human exposure at the maximum recommended dose (MRD) of 600 mg/day.
- In addition, adverse reactions on reproductive organ (testes, epididymides) histopathology were observed in male rats exposed to pregabalin (500 to 1250 mg/kg) in general toxicology studies of four weeks or greater duration. The no-effect dose for male reproductive organ histopathology in rats (250 mg/kg) was associated with a plasma exposure approximately 8 times human exposure at the MRD.
- In a fertility study in which female rats were given pregabalin (500, 1250, or 2500 mg/kg) orally prior to and during mating and early gestation, disrupted estrous cyclicity and an increased number of days to mating were seen at all doses, and embryolethality occurred at the highest dose. The low dose in this study produced a plasma exposure approximately 9 times that in humans receiving the MRD. A no-effect dose for female reproductive toxicity in rats was not established.
- Human Data
- In a double-blind, placebo-controlled clinical trial to assess the effect of pregabalin on sperm motility, 30 healthy male subjects were exposed to pregabalin at a dose of 600 mg/day. After 3 months of treatment (one complete sperm cycle), the difference between placebo- and pregabalin-treated subjects in mean percent sperm with normal motility was <4% and neither group had a mean change from baseline of more than 2%. Effects on other male reproductive parameters in humans have not been adequately studied.
- Dermatopathy
- Skin lesions ranging from erythema to necrosis were seen in repeated-dose toxicology studies in both rats and monkeys. The etiology of these skin lesions is unknown. At the maximum recommended human dose (MRD) of 600 mg/day, there is a 2-fold safety margin for the dermatological lesions. The more severe dermatopathies involving necrosis were associated with pregabalin exposures (as expressed by plasma AUCs) of approximately 3 to 8 times those achieved in humans given the MRD. No increase in incidence of skin lesions was observed in clinical studies.
- Ocular Lesions
- Ocular lesions (characterized by retinal atrophy [including loss of photoreceptor cells] and/or corneal inflammation/mineralization) were observed in two lifetime carcinogenicity studies in Wistar rats. These findings were observed at plasma pregabalin exposures (AUC) ≥2 times those achieved in humans given the maximum recommended dose of 600 mg/day. A no-effect dose for ocular lesions was not established. Similar lesions were not observed in lifetime carcinogenicity studies in two strains of mice or in monkeys treated for 1 year.
# Clinical Studies
- The efficacy of the maximum recommended dose of LYRICA for the management of neuropathic pain associated with diabetic peripheral neuropathy was established in three double-blind, placebo-controlled, multicenter studies with three times a day dosing, two of which studied the maximum recommended dose. Patients were enrolled with either Type 1 or Type 2 diabetes mellitus and a diagnosis of painful distal symmetrical sensorimotor polyneuropathy for 1 to 5 years. A total of 89% of patients completed Studies DPN 1 and DPN 2. The patients had a minimum mean baseline pain score of ≥4 on an 11-point numerical pain rating scale ranging from 0 (no pain) to 10 (worst possible pain). The baseline mean pain scores across the two studies ranged from 6.1 to 6.7. Patients were permitted up to 4 grams of acetaminophen per day as needed for pain, in addition to pregabalin. Patients recorded their pain daily in a diary.
- Study DPN 1: This 5-week study compared LYRICA 25, 100, or 200 mg three times a day with placebo. Treatment with LYRICA 100 and 200 mg three times a day statistically significantly improved the endpoint mean pain score and increased the proportion of patients with at least a 50% reduction in pain score from baseline. There was no evidence of a greater effect on pain scores of the 200 mg three times a day dose than the 100 mg three times a day dose, but there was evidence of dose dependent adverse reactions. For a range of levels of improvement in pain intensity from baseline to study endpoint, Figure 1 shows the fraction of patients achieving that level of improvement. The figure is cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%. Patients who did not complete the study were assigned 0% improvement. Some patients experienced a decrease in pain as early as Week 1, which persisted throughout the study.
- Figure 1: Patients Achieving Various Levels of Improvement in Pain Intensity – Study DPN 1
- Study DPN 2: This 8-week study compared LYRICA 100 mg three times a day with placebo. Treatment with LYRICA 100 mg three times a day statistically significantly improved the endpoint mean pain score and increased the proportion of patients with at least a 50% reduction in pain score from baseline. For various levels of improvement in pain intensity from baseline to study endpoint, Figure 2 shows the fraction of patients achieving that level of improvement. The figure is cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%. Patients who did not complete the study were assigned 0% improvement. Some patients experienced a decrease in pain as early as Week 1, which persisted throughout the study.
- Figure 2: Patients Achieving Various Levels of Improvement in Pain Intensity–Study DPN 2
- The efficacy of LYRICA for the management of postherpetic neuralgia was established in three double-blind, placebo-controlled, multicenter studies. These studies enrolled patients with neuralgia persisting for at least 3 months following healing of herpes zoster rash and a minimum baseline score of ≥4 on an 11-point numerical pain rating scale ranging from 0 (no pain) to 10 (worst possible pain). Seventy-three percent of patients completed the studies. The baseline mean pain scores across the 3 studies ranged from 6 to 7. Patients were permitted up to 4 grams of acetaminophen per day as needed for pain, in addition to pregabalin. Patients recorded their pain daily in a diary.
- Study PHN 1: This 13-week study compared LYRICA 75, 150, and 300 mg twice daily with placebo. Patients with creatinine clearance (CLcr) between 30 to 60 mL/min were randomized to 75 mg, 150 mg, or placebo twice daily. Patients with creatinine clearance greater than 60 mL/min were randomized to 75 mg, 150 mg, 300 mg or placebo twice daily. In patients with creatinine clearance greater than 60 mL/min treatment with all doses of LYRICA statistically significantly improved the endpoint mean pain score and increased the proportion of patients with at least a 50% reduction in pain score from baseline. Despite differences in dosing based on renal function, patients with creatinine clearance between 30 to 60 mL/min tolerated LYRICA less well than patients with creatinine clearance greater than 60 mL/min as evidenced by higher rates of discontinuation due to adverse reactions. For various levels of improvement in pain intensity from baseline to study endpoint, Figure 3 shows the fraction of patients achieving that level of improvement. The figure is cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%. Patients who did not complete the study were assigned 0% improvement. Some patients experienced a decrease in pain as early as Week 1, which persisted throughout the study.
- Figure 3: Patients Achieving Various Levels of Improvement in Pain Intensity– Study PHN 1
- Study PHN 2: This 8-week study compared LYRICA 100 or 200 mg three times a day with placebo, with doses assigned based on creatinine clearance. Patients with creatinine clearance between 30 to 60 mL/min were treated with 100 mg three times a day, and patients with creatinine clearance greater than 60 mL/min were treated with 200 mg three times daily. Treatment with LYRICA statistically significantly improved the endpoint mean pain score and increased the proportion of patients with at least a 50% reduction in pain score from baseline. For various levels of improvement in pain intensity from baseline to study endpoint, Figure 4 shows the fraction of patients achieving those levels of improvement. The figure is cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%. Patients who did not complete the study were assigned 0% improvement. Some patients experienced a decrease in pain as early as Week 1, which persisted throughout the study.
- Figure 4: Patients Achieving Various Levels of Improvement in Pain Intensity – Study PHN 2
- Study PHN 3: This 8-week study compared LYRICA 50 or 100 mg three times a day with placebo with doses assigned regardless of creatinine clearance. Treatment with LYRICA 50 and 100 mg three times a day statistically significantly improved the endpoint mean pain score and increased the proportion of patients with at least a 50% reduction in pain score from baseline. Patients with creatinine clearance between 30 to 60 mL/min tolerated LYRICA less well than patients with creatinine clearance greater than 60 mL/min as evidenced by markedly higher rates of discontinuation due to adverse reactions. For various levels of improvement in pain intensity from baseline to study endpoint, Figure 5 shows the fraction of patients achieving that level of improvement. The figure is cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%. Patients who did not complete the study were assigned 0% improvement. Some patients experienced a decrease in pain as early as Week 1, which persisted throughout the study.
- Figure 5: Patients Achieving Various Levels of Improvement in Pain Intensity– Study PHN 3
- The efficacy of LYRICA as adjunctive therapy in partial onset seizures was established in three 12-week, randomized, double-blind, placebo-controlled, multicenter studies in adult patients. Patients were enrolled who had partial onset seizures with or without secondary generalization and were not adequately controlled with 1 to 3 concomitant antiepileptic drugs (AEDs). Patients taking gabapentin were required to discontinue gabapentin treatment 1 week prior to entering baseline. During an 8-week baseline period, patients had to experience at least 6 partial onset seizures with no seizure-free period exceeding 4 weeks. The mean duration of epilepsy was 25 years in these 3 studies and the mean and median baseline seizure frequencies were 22.5 and 10 seizures per month, respectively. Approximately half of the patients were taking 2 concurrent AEDs at baseline. Among the LYRICA-treated patients, 80% completed the double-blind phase of the studies.
- Table 8 shows median baseline seizure rates and median percent reduction in seizure frequency by dose.
- In the first study (E1), there was evidence of a dose-response relationship for total daily doses of Lyrica between 150 and 600 mg/day; a dose of 50 mg/day was not effective. In the first study (E1), each daily dose was divided into two equal doses (twice a day dosing). In the second study (E2), each daily dose was divided into three equal doses (three times a day dosing). In the third study (E3), the same total daily dose was divided into two equal doses for one group (twice a day dosing) and three equal doses for another group (three times a day dosing). While the three times a day dosing group in Study E3 performed numerically better than the twice a day dosing group, this difference was small and not statistically significant.
- A secondary outcome measure included the responder rate (proportion of patients with ≥50% reduction from baseline in partial seizure frequency). The following figure displays responder rate by dose for two of the studies.
- Subset evaluations of the antiseizure efficacy of LYRICA showed no clinically important differences as a function of age, gender, or race.
- The efficacy of LYRICA for management of fibromyalgia was established in one 14-week, double-blind, placebo-controlled, multicenter study (F1) and one six-month, randomized withdrawal study (F2). Studies F1 and F2 enrolled patients with a diagnosis of fibromyalgia using the American College of Rheumatology (ACR) criteria (history of widespread pain for 3 months, and pain present at 11 or more of the 18 specific tender point sites). The studies showed a reduction in pain by visual analog scale. In addition, improvement was demonstrated based on a patient global assessment (PGIC), and on the Fibromyalgia Impact Questionnaire (FIQ).
- Study F1: This 14-week study compared LYRICA total daily doses of 300 mg, 450 mg and 600 mg with placebo. Patients were enrolled with a minimum mean baseline pain score of greater than or equal to 4 on an 11-point numeric pain rating scale and a score of greater than or equal to 40 mm on the 100 mm pain visual analog scale (VAS). The baseline mean pain score in this trial was 6.7. Responders to placebo in an initial one-week run-in phase were not randomized into subsequent phases of the study. A total of 64% of patients randomized to LYRICA completed the study. There was no evidence of a greater effect on pain scores of the 600 mg daily dose than the 450 mg daily dose, but there was evidence of dose-dependent adverse reactions. Some patients experienced a decrease in pain as early as Week 1, which persisted throughout the study. The results are summarized in Figure 8 and Table 9.
- For various levels of improvement in pain intensity from baseline to study endpoint, Figure 8 shows the fraction of patients achieving that level of improvement. The figure is cumulative. Patients who did not complete the study were assigned 0% improvement. Some patients experienced a decrease in pain as early as Week 1, which persisted throughout the study.
- Figure 8: Patients Achieving Various Levels of Improvement in Pain Intensity – Fibromyalgia Study F1
- Study F2: This randomized withdrawal study compared LYRICA with placebo. Patients were titrated during a 6-week open-label dose optimization phase to a total daily dose of 300 mg, 450 mg, or 600 mg. Patients were considered to be responders if they had both: 1) at least a 50% reduction in pain (VAS) and, 2) rated their overall improvement on the PGIC as "much improved" or "very much improved." Those who responded to treatment were then randomized in the double-blind treatment phase to either the dose achieved in the open-label phase or to placebo. Patients were treated for up to 6 months following randomization. Efficacy was assessed by time to loss of therapeutic response, defined as 1) less than 30% reduction in pain (VAS) from open-label baseline during two consecutive visits of the double-blind phase, or 2) worsening of FM symptoms necessitating an alternative treatment. Fifty-four percent of patients were able to titrate to an effective and tolerable dose of LYRICA during the 6-week open-label phase. Of the patients entering the randomized treatment phase assigned to remain on LYRICA, 38% of patients completed 26 weeks of treatment versus 19% of placebo-treated patients.
- When considering return of pain or withdrawal due to adverse events as loss of response (LTR), treatment with LYRICA resulted in a longer time to loss of therapeutic response than treatment with placebo. Fifty-three percent of the pregabalin-treated subjects compared to 33% of placebo patients remained on study drug and maintained a therapeutic response to Week 26 of the study. Treatment with LYRICA also resulted in a longer time to loss of response based on the FIQ1, and longer time to loss of overall assessment of patient status, as measured by the PGIC2.
- Figure 9: Time to Loss of Therapeutic Response, Fibromyalgia Study F2 (Kaplan-Meier Analysis)
- The efficacy of LYRICA for the management of neuropathic pain associated with spinal cord injury was established in two double-blind, placebo-controlled, multicenter studies. Patients were enrolled with neuropathic pain associated with spinal cord injury that persisted continuously for at least three months or with relapses and remissions for at least six months. A total of 63% of patients completed study 1 and 84% completed study 2. The patients had a minimum mean baseline pain score of ≥4 on an 11-point numerical pain rating scale ranging from 0 (no pain) to 10 (worst possible pain). The baseline mean pain scores across the two studies ranged from 6.5 to 6.7.
- Patients were allowed to take opioids, non-opioid analgesics, antiepileptic drugs, muscle relaxants, and antidepressant drugs if the dose was stable for 30 days prior to screening. Patients were allowed to take acetaminophen and nonsteroidal anti-inflammatory drugs during the studies.
- Study SCI 1: This 12-week, randomized, double-blind, parallel-group, multicenter, flexible dose (150–600 mg/day) study compared pregabalin with placebo. The 12-week study consisted of a 3-week dose adjustment phase and a 9-week dose maintenance phase. Treatment with LYRICA 150–600 mg/day statistically significantly improved the endpoint weekly mean pain score, and increased the proportion of patients with at least a 30% and 50% reduction in pain score from baseline. The fraction of patients achieving various levels of improvement in pain intensity from baseline to Week 12 is presented in Figure 10. Some patients experienced a decrease in pain as early as week 1, which persisted throughout the study.
- Figure 10: Patients Achieving Various Levels of Improvement in Pain Intensity – Study SCI 1
- Study SCI 2: This 16-week, randomized, double-blind, placebo-controlled, parallel-group, multicenter, flexible dose (150–600 mg/day, in increments of 150 mg) study compared the efficacy, safety and tolerability of pregabalin with placebo. The 16-week study consisted of a 4-week dose adjustment phase and a 12-week dose maintenance phase. Treatment with LYRICA statistically significantly improved the endpoint weekly mean pain score, and increased the proportion of patients with at least a 30% and 50% reduction in pain score from baseline. The fraction of patients achieving various levels of improvement in pain intensity from baseline to Week 16 is presented in Figure 11. Some patients experienced a decrease in pain as early as week 1, which persisted throughout the study.
- Figure 11: Patients Achieving Various Levels of Improvement in Pain Intensity – Study SCI 2
# How Supplied
- 25 mg capsules:
- White, hard-gelatin capsule printed with black ink "Pfizer" on the cap, "PGN 25" on the body; available in:
- Bottles of 90: NDC 0071-1012-68
- 50 mg capsules:
- White, hard-gelatin capsule printed with black ink "Pfizer" on the cap, "PGN 50" and an ink band on the body, available in:
- Bottles of 90: NDC 0071-1013-68
- Unit-Dose Blister Packages of 100: NDC 0071-1013-41
- 75 mg capsules:
- White/orange hard gelatin capsule printed with black ink "Pfizer" on the cap, "PGN 75" on the body; available in:
- Bottles of 90: NDC 0071-1014-68
- Unit-Dose Blister Packages of 100: NDC 0071-1014-41
- 100 mg capsules:
- Orange, hard-gelatin capsule printed with black ink "Pfizer" on the cap, "PGN 100" on the body, available in:
- Bottles of 90: NDC 0071-1015-68
- Unit-Dose Blister Packages of 100: NDC 0071-1015-41
- 150 mg capsules:
- White hard gelatin capsule printed with black ink "Pfizer" on the cap, "PGN 150" on the body, available in:
- Bottles of 90: NDC 0071-1016-68
- Unit-Dose Blister Packages of 100: NDC 0071-1016-41
- 200 mg capsules:
- Light orange hard gelatin capsule printed with black ink "Pfizer" on the cap, "PGN 200" on the body, available in:
- Bottles of 90: NDC 0071-1017-68
- 225 mg capsules:
- White/light orange hard gelatin capsule printed with black ink "Pfizer" on the cap, "PGN 225" on the body; available in:
- Bottles of 90: NDC 0071-1019-68
- 300 mg capsules:
- White/orange hard gelatin capsule printed with black ink "Pfizer" on the cap, "PGN 300" on the body, available in:
- Bottles of 90: NDC 0071-1018-68
- 20 mg/mL oral solution:
- 16 fluid ounce white high density polyethylene (HDPE) bottle with a polyethylene-lined closure:
- 16 fluid ounce bottle NDC 0071-1020-01
- Storage and Handling
- Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).
## Storage
There is limited information regarding Pregabalin Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Inform patients of the availability of a Medication Guide, and instruct them to read the Medication Guide prior to taking LYRICA. Instruct patients to take LYRICA only as prescribed.
- Angioedema
- Advise patients that LYRICA may cause angioedema, with swelling of the face, mouth (lip, gum, tongue) and neck (larynx and pharynx) that can lead to life-threatening respiratory compromise. Instruct patients to discontinue LYRICA and immediately seek medical care if they experience these symptoms.
- Hypersensitivity
- Advise patients that LYRICA has been associated with hypersensitivity reactions such as wheezing, dyspnea, rash, hives, and blisters. Instruct patients to discontinue LYRICA and immediately seek medical care if they experience these symptoms.
- Suicidal Thinking and Behavior
- Patients, their caregivers, and families should be counseled that AEDs, including LYRICA, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Report behaviors of concern immediately to healthcare providers.
- Dizziness and Somnolence
- Counsel patients that LYRICA may cause dizziness, somnolence, blurred vision and other CNS signs and symptoms. Accordingly, advise patients not to drive, operate complex machinery, or engage in other hazardous activities until they have gained sufficient experience on LYRICA to gauge whether or not it affects their mental, visual, and/or motor performance adversely.
- Weight Gain and Edema
- Counsel patients that LYRICA may cause edema and weight gain. Advise patients that concomitant treatment with LYRICA and a thiazolidinedione antidiabetic agent may lead to an additive effect on edema and weight gain. For patients with preexisting cardiac conditions, this may increase the risk of heart failure.
- Abrupt or Rapid Discontinuation
- Advise patients to take LYRICA as prescribed. Abrupt or rapid discontinuation may result in insomnia, nausea, headache, anxiety, hyperhidrosis, or diarrhea.
- Ophthalmological Effects
- Counsel patients that LYRICA may cause visual disturbances. Inform patients that if changes in vision occur, they should notify their physician.
- Creatine Kinase Elevations
- Instruct patients to promptly report unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever.
- CNS Depressants
- Inform patients who require concomitant treatment with central nervous system depressants such as opiates or benzodiazepines that they may experience additive CNS side effects, such as somnolence.
- Alcohol
- Tell patients to avoid consuming alcohol while taking LYRICA, as LYRICA may potentiate the impairment of motor skills and sedating effects of alcohol.
- Use in Pregnancy
- Instruct patients to notify their physician if they become pregnant or intend to become pregnant during therapy, and to notify their physician if they are breast feeding or intend to breast feed during therapy.
- Encourage patients to enroll in the NAAED Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334.
- Male Fertility
- Inform men being treated with LYRICA who plan to father a child of the potential risk of male-mediated teratogenicity. In preclinical studies in rats, pregabalin was associated with an increased risk of male-mediated teratogenicity. The clinical significance of this finding is uncertain.
- Dermatopathy
- Instruct diabetic patients to pay particular attention to skin integrity while being treated with LYRICA. Some animals treated with pregabalin developed skin ulcerations, although no increased incidence of skin lesions associated with LYRICA was observed in clinical trials.
- Capsules and Oral Solution, CV
- Read this Medication Guide before you start taking LYRICA and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. If you have any questions about LYRICA, ask your healthcare provider or pharmacist.
- What is the most important information I should know about LYRICA?
- LYRICA may cause serious side effects including:
- Serious, even life-threatening, allergic reactions
- Suicidal thoughts or actions
- Swelling of your hands, legs and feet
- Dizziness and sleepiness
- These serious side effects are described below:
- Serious, even life-threatening, allergic reactions.
Stop taking LYRICA and call your healthcare provider right away if you have any of these signs of a serious allergic reaction:
swelling of your face, mouth, lips, gums, tongue, throat or neck
trouble breathing
rash, hives (raised bumps) or blisters
- Stop taking LYRICA and call your healthcare provider right away if you have any of these signs of a serious allergic reaction:
- swelling of your face, mouth, lips, gums, tongue, throat or neck
- trouble breathing
- rash, hives (raised bumps) or blisters
- Like other antiepileptic drugs, LYRICA may cause suicidal thoughts or actions in a very small number of people, about 1 in 500.
Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you:
thoughts about suicide or dying
attempts to commit suicide
new or worse depression
new or worse anxiety
feeling agitated or restless
panic attacks
trouble sleeping (insomnia)
new or worse irritability
acting aggressive, being angry, or violent
acting on dangerous impulses
an extreme increase in activity and talking (mania)
other unusual changes in behavior or mood
- Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you:
- thoughts about suicide or dying
- attempts to commit suicide
- new or worse depression
- new or worse anxiety
- feeling agitated or restless
- panic attacks
- trouble sleeping (insomnia)
- new or worse irritability
- acting aggressive, being angry, or violent
- acting on dangerous impulses
- an extreme increase in activity and talking (mania)
- other unusual changes in behavior or mood
- If you have suicidal thoughts or actions, do not stop LYRICA without first talking to a healthcare provider.
Stopping LYRICA suddenly can cause serious problems.
Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes.
- Stopping LYRICA suddenly can cause serious problems.
- Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes.
- How can I watch for early symptoms of suicidal thoughts and actions?
Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings.
Keep all follow-up visits with your healthcare provider as scheduled.
Call your healthcare provider between visits as needed, especially if you are worried about symptoms.
- Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings.
- Keep all follow-up visits with your healthcare provider as scheduled.
- Call your healthcare provider between visits as needed, especially if you are worried about symptoms.
- Swelling of your hands, legs and feet. This swelling can be a serious problem for people with heart problems.
- Dizziness and sleepiness.
Do not drive a car, work with machines, or do other dangerous activities until you know how LYRICA affects you. Ask your healthcare provider about when it will be okay to do these activities.
- Do not drive a car, work with machines, or do other dangerous activities until you know how LYRICA affects you. Ask your healthcare provider about when it will be okay to do these activities.
- What is LYRICA?
- LYRICA is a prescription medicine used in adults, 18 years and older, to treat:
pain from damaged nerves (neuropathic pain) that happens with diabetes
pain from damaged nerves (neuropathic pain) that follows healing of shingles
partial seizures when taken together with other seizure medicines
fibromyalgia (pain all over your body)
pain from damaged nerves (neuropathic pain) that follows spinal cord injury
LYRICA has not been studied in children under 18 years of age.
- pain from damaged nerves (neuropathic pain) that happens with diabetes
- pain from damaged nerves (neuropathic pain) that follows healing of shingles
- partial seizures when taken together with other seizure medicines
- fibromyalgia (pain all over your body)
- pain from damaged nerves (neuropathic pain) that follows spinal cord injury
- LYRICA has not been studied in children under 18 years of age.
- Who Should Not Take LYRICA?
- Do not take LYRICA if you are allergic to pregabalin or any of the ingredients in LYRICA.
See "What is the most important information I should know about LYRICA?" for the signs of an allergic reaction.
See the end of this leaflet for a complete list of ingredients in LYRICA.
- See "What is the most important information I should know about LYRICA?" for the signs of an allergic reaction.
- See the end of this leaflet for a complete list of ingredients in LYRICA.
- What should I tell my healthcare provider before taking LYRICA?
- Before taking LYRICA, tell your healthcare provider about all your medical conditions, including if you:
have or have had depression, mood problems or suicidal thoughts or behavior
have kidney problems or get kidney dialysis
have heart problems including heart failure
have a bleeding problem or a low blood platelet count
have abused prescription medicines, street drugs, or alcohol in the past
have ever had swelling of your face, mouth, tongue, lips, gums, neck, or throat (angioedema)
plan to father a child. Animal studies have shown that pregabalin, the active ingredient in LYRICA, made male animals less fertile and caused sperm to change. Also, in animal studies, birth defects were seen in the offspring (babies) of male animals treated with pregabalin. It is not known if these problems can happen in people who take LYRICA.
are pregnant or plan to become pregnant. It is not known if LYRICA will harm your unborn baby. You and your healthcare provider will have to decide if you should take LYRICA while you are pregnant. If you become pregnant while taking LYRICA, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy.
are breastfeeding. It is not known if LYRICA passes into breast milk and if it can harm your baby. You and your healthcare provider should discuss whether you should take LYRICA or breast-feed, but you should not do both.
- have or have had depression, mood problems or suicidal thoughts or behavior
- have kidney problems or get kidney dialysis
- have heart problems including heart failure
- have a bleeding problem or a low blood platelet count
- have abused prescription medicines, street drugs, or alcohol in the past
- have ever had swelling of your face, mouth, tongue, lips, gums, neck, or throat (angioedema)
- plan to father a child. Animal studies have shown that pregabalin, the active ingredient in LYRICA, made male animals less fertile and caused sperm to change. Also, in animal studies, birth defects were seen in the offspring (babies) of male animals treated with pregabalin. It is not known if these problems can happen in people who take LYRICA.
- are pregnant or plan to become pregnant. It is not known if LYRICA will harm your unborn baby. You and your healthcare provider will have to decide if you should take LYRICA while you are pregnant. If you become pregnant while taking LYRICA, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy.
- are breastfeeding. It is not known if LYRICA passes into breast milk and if it can harm your baby. You and your healthcare provider should discuss whether you should take LYRICA or breast-feed, but you should not do both.
- Tell your healthcare provider about all the medicines you take including prescription and non-prescription medicines, vitamins or herbal supplements. LYRICA and other medicines may affect each other causing side effects. Especially tell your healthcare provider if you take:
angiotensin converting enzyme (ACE) inhibitors, which are used to treat many conditions, including high blood pressure. You may have a higher chance for swelling and hives if these medicines are taken with LYRICA. See "What is the most important information I should know about LYRICA?"
Avandia (rosiglitazone), Avandamet (contains rosiglitazone and metformin), or Actos (pioglitazone) for diabetes. You may have a higher chance of weight gain or swelling of your hands or feet if these medicines are taken with LYRICA. See "What are the possible side effects of LYRICA."
any narcotic pain medicine (such as oxycodone), tranquilizers or medicines for anxiety (such as lorazepam). You may have a higher chance for dizziness and sleepiness if these medicines are taken with LYRICA.
any medicines that make you sleepy
- angiotensin converting enzyme (ACE) inhibitors, which are used to treat many conditions, including high blood pressure. You may have a higher chance for swelling and hives if these medicines are taken with LYRICA. See "What is the most important information I should know about LYRICA?"
- Avandia (rosiglitazone), Avandamet (contains rosiglitazone and metformin), or Actos (pioglitazone) for diabetes. You may have a higher chance of weight gain or swelling of your hands or feet if these medicines are taken with LYRICA. See "What are the possible side effects of LYRICA."
- any narcotic pain medicine (such as oxycodone), tranquilizers or medicines for anxiety (such as lorazepam). You may have a higher chance for dizziness and sleepiness if these medicines are taken with LYRICA.
- any medicines that make you sleepy
- Know the medicines you take. Keep a list of them with you to show your healthcare provider and pharmacist each time you get a new medicine. Do not start a new medicine without talking with your healthcare provider.
- How should I take LYRICA?
- Take LYRICA exactly as prescribed. Your healthcare provider will tell you how much LYRICA to take and when to take it. Take LYRICA at the same times each day.
LYRICA may be taken with or without food.
Your healthcare provider may change your dose. Do not change your dose without talking to your healthcare provider.
Do not stop taking LYRICA without talking to your healthcare provider. If you stop taking LYRICA suddenly you may have headaches, nausea, diarrhea, trouble sleeping, increased sweating, or you may feel anxious. If you have epilepsy and you stop taking LYRICA suddenly, you may have seizures more often. Talk with your healthcare provider about how to stop LYRICA slowly.
If you miss a dose, take it as soon as you remember. If it is almost time for your next dose, just skip the missed dose. Take the next dose at your regular time. Do not take two doses at the same time.
If you take too much LYRICA, call your healthcare provider or poison control center, or go to the nearest emergency room right away.
- LYRICA may be taken with or without food.
- Your healthcare provider may change your dose. Do not change your dose without talking to your healthcare provider.
- Do not stop taking LYRICA without talking to your healthcare provider. If you stop taking LYRICA suddenly you may have headaches, nausea, diarrhea, trouble sleeping, increased sweating, or you may feel anxious. If you have epilepsy and you stop taking LYRICA suddenly, you may have seizures more often. Talk with your healthcare provider about how to stop LYRICA slowly.
- If you miss a dose, take it as soon as you remember. If it is almost time for your next dose, just skip the missed dose. Take the next dose at your regular time. Do not take two doses at the same time.
- If you take too much LYRICA, call your healthcare provider or poison control center, or go to the nearest emergency room right away.
- What should I avoid while taking LYRICA?
- Do not drive a car, work with machines, or do other dangerous activities until you know how LYRICA affects you.
- Do not drink alcohol while taking LYRICA. LYRICA and alcohol can affect each other and increase side effects such as sleepiness and dizziness.
- What are the possible side effects of LYRICA?
- LYRICA may cause serious side effects, including:
See "What is the most important information I should know about LYRICA?"
muscle problems, muscle pain, soreness, or weakness. If you have these symptoms, especially if you feel sick and have a fever, tell your healthcare provider right away.
problems with your eyesight, including blurry vision. Call your healthcare provider if you have any changes in your eyesight.
weight gain. If you have diabetes, weight gain may affect the management of your diabetes. Weight gain can also be a serious problem for people with heart problems.
feeling "high"
- See "What is the most important information I should know about LYRICA?"
- muscle problems, muscle pain, soreness, or weakness. If you have these symptoms, especially if you feel sick and have a fever, tell your healthcare provider right away.
- problems with your eyesight, including blurry vision. Call your healthcare provider if you have any changes in your eyesight.
- weight gain. If you have diabetes, weight gain may affect the management of your diabetes. Weight gain can also be a serious problem for people with heart problems.
- feeling "high"
- The most common side effects of LYRICA are:
dizziness
blurry vision
weight gain
sleepiness
trouble concentrating
swelling of hands and feet
dry mouth
- dizziness
- blurry vision
- weight gain
- sleepiness
- trouble concentrating
- swelling of hands and feet
- dry mouth
- LYRICA caused skin sores in animal studies. Skin sores did not happen in studies in people. If you have diabetes, you should pay attention to your skin while taking LYRICA and tell your healthcare provider about any sores or skin problems.
- Tell your healthcare provider about any side effect that bothers you or that does not go away.
- These are not all the possible side effects of LYRICA. For more information, ask your healthcare provider or pharmacist.
- Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
- How should I store LYRICA?
- Store LYRICA capsules and oral solution at room temperature, 59°F to 86°F (15°C to 30°C) in its original package.
Safely throw away any LYRICA that is out of date or no longer needed.
Keep LYRICA and all medicines out of the reach of children.
- Safely throw away any LYRICA that is out of date or no longer needed.
- Keep LYRICA and all medicines out of the reach of children.
- General information about LYRICA
- Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use LYRICA for a condition for which it was not prescribed. Do not give LYRICA to other people, even if they have the same symptoms you have. It may harm them.
- This Medication Guide summarizes the most important information about LYRICA. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about LYRICA that is written for health professionals.
- You can also visit the LYRICA website at www.LYRICA.com or call 1-866-459-7422 (1-866-4LYRICA).
- What are the ingredients In LYRICA?
- Active ingredient: pregabalin
- Inactive ingredients:
LYRICA capsules: lactose monohydrate, cornstarch, talc
Capsule shell: gelatin and titanium dioxide; Orange capsule shell: red iron oxide; White capsule shell: sodium lauryl sulfate, colloidal silicon dioxide. Colloidal silicon dioxide is a manufacturing aid that may or may not be present in the capsule shells.
Imprinting ink: shellac, black iron oxide, propylene glycol, potassium hydroxide.
- LYRICA capsules: lactose monohydrate, cornstarch, talc
- Capsule shell: gelatin and titanium dioxide; Orange capsule shell: red iron oxide; White capsule shell: sodium lauryl sulfate, colloidal silicon dioxide. Colloidal silicon dioxide is a manufacturing aid that may or may not be present in the capsule shells.
- Imprinting ink: shellac, black iron oxide, propylene glycol, potassium hydroxide.
- LYRICA oral solution: methylparaben, propylparaben, monobasic sodium phosphate anhydrous, dibasic sodium phosphate anhydrous, sucralose, artificial strawberry #11545 and purified water.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
- This Medication Guide has been approved by the U.S. Food and Drug Administration.
# Precautions with Alcohol
- Avoid consuming alcohol while taking LYRICA, as LYRICA may potentiate the impairment of motor skills and sedating effects of alcohol.
# Brand Names
- LYRICA®[2]
# Look-Alike Drug Names
- Lyrica® — Lopressor®[3]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Pregabalin | |
247e97ad96122361531325d2ff1082914a5339b8 | wikidoc | Prem Reddy | Prem Reddy
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Dr. Prem Reddy (born 1948) is a cardiologist, philanthropist and a major owner of Prime Healthcare Services, Inc., which owns several hospitals in California in the United States.
Prem Reddy was born in a rural village in Southern India. He and his wife immigrated to the United States in 1976.
Reddy, holding an MD, FACC, and FCCP is a board-certified physician in Internal Medicine and Cardiology. He is a Fellow of the American College of Cardiology and the American College of Chest Physicians. During his over two decades of practice, Dr. Reddy has performed more than 5,000
cardiac procedures (such as coronary angiography and angioplasty, and permanent pacemaker implantations).
# Business activity
Dr. Reddy founded Desert Valley Medical Group, a multi-specialty medical group, in 1985, which later became PrimeCare International, Inc. He also founded and served as CEO and Chairman of the Board of PrimeRX.Com, Inc.
In 2001 Reddy founded Prime Healthcare Services, Inc., which currently owns and operates eight acute care hospitals in Southern California. The company is reportedly seeking to purchase more hospitals in the near future.
An important aspect of the Reddy intervention in his hospitals is the improvement of services in the emergency room, as he claims these are the entrances to his hospitals.
# Alcohol
In a lawsuit won by two former nurses at the Desert Valley Hospital they claimed to have been improperly fired after they accused the hospital of inediaquote care and Reddy of working under the influence of alcohol. Reddy acknowledged having had an alcohol problem but said he never treated patients after drinking. | Prem Reddy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [2] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
Dr. Prem Reddy (born 1948) is a cardiologist, philanthropist and a major owner of Prime Healthcare Services, Inc., which owns several hospitals in California in the United States.
Prem Reddy was born in a rural village in Southern India. He and his wife immigrated to the United States in 1976.
Reddy, holding an MD, FACC, and FCCP is a board-certified physician in Internal Medicine and Cardiology. He is a Fellow of the American College of Cardiology and the American College of Chest Physicians. During his over two decades of practice, Dr. Reddy has performed more than 5,000 [1]
cardiac procedures (such as coronary angiography and angioplasty, and permanent pacemaker implantations).
# Business activity
Dr. Reddy founded Desert Valley Medical Group, a multi-specialty medical group, in 1985, which later became PrimeCare International, Inc. He also founded and served as CEO and Chairman of the Board of PrimeRX.Com, Inc.
In 2001 Reddy founded Prime Healthcare Services, Inc., which currently owns and operates eight acute care hospitals in Southern California. The company is reportedly seeking to purchase more hospitals in the near future.
An important aspect of the Reddy intervention in his hospitals is the improvement of services in the emergency room, as he claims these are the entrances to his hospitals.
# Alcohol
In a lawsuit won by two former nurses at the Desert Valley Hospital they claimed to have been improperly fired after they accused the hospital of inediaquote care and Reddy of working under the influence of alcohol. Reddy acknowledged having had an alcohol problem but said he never treated patients after drinking. [2] | https://www.wikidoc.org/index.php/Prem_Reddy | |
14cc8ba04db0d0f32bed4cfc5acef265e62305d8 | wikidoc | Presbyopia | Presbyopia
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
# Overview
Presbyopia (Greek word "presbys" (πρέσβυς), meaning "old person") is the eye's diminished ability to focus that occurs with aging. The most widely held theory is that it arises from the loss of elasticity of the crystalline lens, although changes in the lens's curvature from continual growth and loss of power of the ciliary muscles (the muscles that bend and straighten the lens) have also been postulated as its cause.
Presbyopia is not a disease as such, but a condition that affects everyone at a certain age. The first symptoms are usually noticed between the ages of 40-50, though in fact the ability to focus declines throughout life, from an accommodation of about 20 dioptres (ability to focus at 50 mm away) in a young person to 10 dioptres at 25 and levelling off at 0.5 to 1 dioptre at age 60 (ability to focus down to 1 -2 metres only). For those with good distance vision, it may start with difficulty reading fine print, particularly if the lighting is poor, or eyestrain when reading for long periods. Many advanced presbyopes complain that their arms have become "too short" to hold reading material at a comfortable distance.
In optics, the closest point at which an object can be brought into focus by the eye is called the eye's near point. A standard near point distance of 25 cm is typically assumed in the design of optical instruments, and in characterizing optical devices such as magnifying glasses.
Presbyopia, like other focus defects, becomes much less noticeable in bright sunlight. This is not the result of any mysterious 'healing effect' but just the consequence of the iris closing to a pinhole, so that depth of focus, regardless of actual ability to focus, is greatly enhanced, as in a pinhole camera which produces images without any lens at all. Another way of putting this is to say that the circle of confusion, or blurredness of image, is reduced, without improving focusing.
A delayed onset of seeking correction for presbyopia has been found among those with certain professions and those with miotic pupils. In particular, farmers and housewives seek correction later, whereas service workers and construction workers seek eyesight correction earlier.
# Focusing mechanism of the eye
There is some confusion in articles and even textbooks over how the focusing mechanism of the eye actually works. In the classic book, 'Eye and Brain' by Gregory, for example, the lens is said to be suspended by a membrane, the 'zonula', which holds it under tension. The tension is released, by contraction of the ciliary muscle, to allow the lens to fatten, for close vision. This would seem to imply that the ciliary muscle, which is outside the zonula must be circumferential, contracting like a sphincter, to slacken the tension of the zonula pulling outwards on the lens. This is consistent with the fact that our eyes seem to be in the 'relaxed' state when focusing at infinity, and also explains why no amount of effort seems to enable a myopic person to see further away. Many texts, though, describe the 'ciliary muscles' (which seem more likely to be just elastic ligaments and not under any form of nervous control) as pulling the lens taut in order to focus at close range. This has the counterintuitive effect of steepening the lens centrally (increasing its power) and flattening peripherally.
# Presbyopia and the 'payoff' for the nearsighted
Many people with myopia are able to read comfortably without eyeglasses or contact lenses even after age 40. Myopes considering refractive surgery are advised that surgically correcting their nearsightedness may actually be a disadvantage after the age of 40 when the eyes become presbyopic and lose their ability to accommodate or change focus because they will then need to use glasses for reading.
# Treatment
Presbyopia is not routinely curable - though tentative steps toward a possible cure suggest that this may be possible - but the loss of focusing ability can be compensated for by corrective lenses including eyeglasses or contact lenses. In subjects with other refractory problems, Convex lenses are used. In some cases, the addition of bifocals to an existing lens prescription is sufficient. As the ability to change focus worsens, the prescription needs to be changed accordingly.
Around the age of 65, the eyes have usually lost most of the elasticity. However, it will still be possible to read with the help of the appropriate prescription. Some may find it necessary to hold reading materials farther away, or require larger print and more light to read by. People who do not need glasses for distance vision may only need half glasses or reading glasses.
While bifocals and multifocals offer a working solution to everyday problems, they are hated by many, especially engineers, camera operators, and those used to having a good sharp distortion-free image in their work. Varifocals cause straight lines to look bent, and can leave some feeling dizzy after extended use. The power of simple, multiple prescriptions should not be underestimated. Reading glasses hastily prescribed may be fine for reading, but not good for shopping and generally walking around in. A slightly weaker prescription however, just powerful enough for reading using the full remaining accommodation of the eye, may feel much more comfortable for more general use too. Careful calculation of working ranges, together with a certain amount of trial and error, can restore undistorted vision for critical tasks for many people who do not find multifocals to their liking.
In order to reduce the need for bifocals or reading glasses, some people choose contact lenses to correct one eye for near and one eye for far with a method called "monovision". Monovision sometimes interferes with depth perception. There are also newer bifocal or multifocal contact lenses that attempt to correct both near and far vision with the same lens.
Eye exercises have been quoted as a way to delay the onset of Presbyopia. Go to: /~rsilver/presben.htm
## Surgery
New surgical procedures may also provide solutions for those who do not want to wear glasses or contacts, including the implantation of accommodative intraocular lenses (IOLs). Scleral expansion bands, which increase the space between the ciliary body and lens, have not been found to provide predictable or consistent results in the treatment of presbyopia. To read more about surgical procedures go to: | Presbyopia
Template:DiseaseDisorder infobox
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [2] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
# Overview
Presbyopia (Greek word "presbys" (πρέσβυς), meaning "old person") is the eye's diminished ability to focus that occurs with aging. The most widely held theory is that it arises from the loss of elasticity of the crystalline lens, although changes in the lens's curvature from continual growth and loss of power of the ciliary muscles (the muscles that bend and straighten the lens) have also been postulated as its cause.
Presbyopia is not a disease as such, but a condition that affects everyone at a certain age. The first symptoms are usually noticed between the ages of 40-50, though in fact the ability to focus declines throughout life, from an accommodation of about 20 dioptres (ability to focus at 50 mm away) in a young person to 10 dioptres at 25 and levelling off at 0.5 to 1 dioptre at age 60 (ability to focus down to 1 -2 metres only). For those with good distance vision, it may start with difficulty reading fine print, particularly if the lighting is poor, or eyestrain when reading for long periods. Many advanced presbyopes complain that their arms have become "too short" to hold reading material at a comfortable distance.[1]
In optics, the closest point at which an object can be brought into focus by the eye is called the eye's near point. A standard near point distance of 25 cm is typically assumed in the design of optical instruments, and in characterizing optical devices such as magnifying glasses.
Presbyopia, like other focus defects, becomes much less noticeable in bright sunlight. This is not the result of any mysterious 'healing effect' but just the consequence of the iris closing to a pinhole, so that depth of focus, regardless of actual ability to focus, is greatly enhanced, as in a pinhole camera which produces images without any lens at all. Another way of putting this is to say that the circle of confusion, or blurredness of image, is reduced, without improving focusing.
A delayed onset of seeking correction for presbyopia has been found among those with certain professions and those with miotic pupils.[2] In particular, farmers and housewives seek correction later, whereas service workers and construction workers seek eyesight correction earlier.
# Focusing mechanism of the eye
There is some confusion in articles and even textbooks over how the focusing mechanism of the eye actually works. In the classic book, 'Eye and Brain' by Gregory, for example, the lens is said to be suspended by a membrane, the 'zonula', which holds it under tension. The tension is released, by contraction of the ciliary muscle, to allow the lens to fatten, for close vision. This would seem to imply that the ciliary muscle, which is outside the zonula must be circumferential, contracting like a sphincter, to slacken the tension of the zonula pulling outwards on the lens. This is consistent with the fact that our eyes seem to be in the 'relaxed' state when focusing at infinity, and also explains why no amount of effort seems to enable a myopic person to see further away. Many texts, though, describe the 'ciliary muscles' (which seem more likely to be just elastic ligaments and not under any form of nervous control) as pulling the lens taut in order to focus at close range. This has the counterintuitive effect of steepening the lens centrally (increasing its power) and flattening peripherally.
# Presbyopia and the 'payoff' for the nearsighted
Many people with myopia are able to read comfortably without eyeglasses or contact lenses even after age 40. Myopes considering refractive surgery are advised that surgically correcting their nearsightedness may actually be a disadvantage after the age of 40 when the eyes become presbyopic and lose their ability to accommodate or change focus because they will then need to use glasses for reading.
# Treatment
Presbyopia is not routinely curable - though tentative steps toward a possible cure suggest that this may be possible - but the loss of focusing ability can be compensated for by corrective lenses including eyeglasses or contact lenses. In subjects with other refractory problems, Convex lenses are used. In some cases, the addition of bifocals to an existing lens prescription is sufficient. As the ability to change focus worsens, the prescription needs to be changed accordingly.
Around the age of 65, the eyes have usually lost most of the elasticity. However, it will still be possible to read with the help of the appropriate prescription. Some may find it necessary to hold reading materials farther away, or require larger print and more light to read by. People who do not need glasses for distance vision may only need half glasses or reading glasses.
While bifocals and multifocals offer a working solution to everyday problems, they are hated by many, especially engineers, camera operators, and those used to having a good sharp distortion-free image in their work. Varifocals cause straight lines to look bent, and can leave some feeling dizzy after extended use. The power of simple, multiple prescriptions should not be underestimated. Reading glasses hastily prescribed may be fine for reading, but not good for shopping and generally walking around in. A slightly weaker prescription however, just powerful enough for reading using the full remaining accommodation of the eye, may feel much more comfortable for more general use too. Careful calculation of working ranges, together with a certain amount of trial and error, can restore undistorted vision for critical tasks for many people who do not find multifocals to their liking.
In order to reduce the need for bifocals or reading glasses, some people choose contact lenses to correct one eye for near and one eye for far with a method called "monovision". Monovision sometimes interferes with depth perception. There are also newer bifocal or multifocal contact lenses that attempt to correct both near and far vision with the same lens.
[3]
Eye exercises have been quoted as a way to delay the onset of Presbyopia. Go to: http://www.cam.org/~rsilver/presben.htm
## Surgery
New surgical procedures may also provide solutions for those who do not want to wear glasses or contacts, including the implantation of accommodative intraocular lenses (IOLs). Scleral expansion bands, which increase the space between the ciliary body and lens, have not been found to provide predictable or consistent results in the treatment of presbyopia.[4] To read more about surgical procedures go to: http://www.allaboutvision.com/visionsurgery/presbyopia_surgery.htm | https://www.wikidoc.org/index.php/Presbyopia | |
655e871f5b279b9ddb87eca8a71a2a7058820615 | wikidoc | Presenilin | Presenilin
Presenilins are a family of related multi-pass transmembrane proteins which constitute the catalytic subunits of the gamma-secretase intramembrane protease complex. They were first identified in screens for mutations causing early onset forms of familial Alzheimer's Disease by Peter St George-Hyslop at the Centre for Research in Neurodegenerative Diseases at the University of Toronto, and now also at the University of Cambridge. Vertebrates have two presenilin genes, called PSEN1 (located on chromosome 14 in humans) that encodes presenilin 1 (PS-1) and PSEN2 (on chromosome 1 in humans) that codes for presenilin 2 (PS-2). Both genes show conservation between species, with little difference between rat and human presenilins. The nematode worm C. elegans has two genes that resemble the presenilins and appear to be functionally similar, sel-12 and hop-1.
Presenilins undergo cleavage in an alpha helical region of one of the cytoplasmic loops to produce a large N-terminal and a smaller C-terminal fragment that together form part of the functional protein. Cleavage of presenilin 1 can be prevented by a mutation that causes the loss of exon 9, and results in loss of function. Presenilins play a key role in the modulation of intracellular Ca2+ involved in presynaptic neurotransmitter release and long-term potentiation induction.
# Structure
The structure of presenilin-1 is still controversial, although recent research has produced a more widely accepted model. When first discovered, the PSEN1 gene was subjected to hydrophobicity analysis that predicted that the protein would contain ten trans-membrane domains. All previous models agreed that the first six putative membrane-spanning regions cross the membrane. These regions correspond to the N-terminal fragment of PS-1 but the structure of the C-terminal fragment was disputed. A recent paper by Spasic et al. provides strong evidence of a nine transmembrane structure with cleavage and assembly into the gamma-secretase complex prior to insertion into the plasma membrane. However, because this is a protein with large numbers of hydrophobic regions, it is unlikely that x-ray crystallography will provide definitive proof of the structure.
The structure of the presenilin-1 C-terminal catalytic fragment was determined using solution NMR. It is made up of alpha helices and is 176 amino acids in length. It was found that Alzheimer's patients carry mutations in the presenilin proteins (PSEN1; PSEN2).
# Function
Most cases of Alzheimer's disease are not hereditary. However, there is a small subset of cases that have an earlier age of onset and have a strong genetic element. In patients suffering from Alzheimer's disease (autosomal dominant hereditary), mutations in the presenilin proteins (PSEN1; PSEN2) or the amyloid precursor protein (APP) can be found. The majority of these cases carry mutant presenilin genes. An important part of the disease process in Alzheimer's disease is the accumulation of Amyloid beta (Aβ) protein. To form Aβ, APP must be cut by two enzymes, beta secretases and gamma secretase. Presenilin is the sub-component of gamma secretase that is responsible for the cutting of APP.
Gamma secretase can cut APP at several points within a small region of the protein, which results in Aβ of various lengths. The lengths associated with Alzheimer's disease are 40 and 42 amino acids long. Aβ 42 is more likely to aggregate to form plaques in the brain than Aβ 40. Presenilin mutations lead to an increase in the ratio of Aβ 42 produced compared to Aβ 40, although the total quantity of Aβ produced remains constant. This can come about by various effects of the mutations upon gamma secretase. Presenilins are also implicated in the processing of notch, an important developmental protein. Mice that have the PS1 gene knocked out die early in development from developmental abnormalities similar to those found when notch is disrupted.
The genes for the presenilins were found through linkage studies using mutations present in familial Alzheimer's cases in 1995.
The genetic inactivation of presenilins in hippocampal synapses has shown this selectively affects the long-term potentiation caused by theta with the inactivation in presynapse but not the postsynapse impairing short-term plasticity and synaptic facilitation. The release of glutamate was also reduced in presynaptic terminals by processes that involve modulation of intracellular Ca2+ release. This has been suggested to "represent a general convergent mechanism leading to neurodegeneration". | Presenilin
Presenilins are a family of related multi-pass transmembrane proteins which constitute the catalytic subunits of the gamma-secretase intramembrane protease complex. They were first identified in screens for mutations causing early onset forms of familial Alzheimer's Disease by Peter St George-Hyslop at the Centre for Research in Neurodegenerative Diseases at the University of Toronto, and now also at the University of Cambridge.[3] Vertebrates have two presenilin genes, called PSEN1 (located on chromosome 14 in humans) that encodes presenilin 1 (PS-1) and PSEN2 (on chromosome 1 in humans) that codes for presenilin 2 (PS-2).[4] Both genes show conservation between species, with little difference between rat and human presenilins. The nematode worm C. elegans has two genes that resemble the presenilins and appear to be functionally similar, sel-12 and hop-1.[5]
Presenilins undergo cleavage in an alpha helical region of one of the cytoplasmic loops to produce a large N-terminal and a smaller C-terminal fragment that together form part of the functional protein.[1] Cleavage of presenilin 1 can be prevented by a mutation that causes the loss of exon 9, and results in loss of function. Presenilins play a key role in the modulation of intracellular Ca2+ involved in presynaptic neurotransmitter release and long-term potentiation induction.[6]
# Structure
The structure of presenilin-1 is still controversial, although recent research has produced a more widely accepted model. When first discovered, the PSEN1 gene was subjected to hydrophobicity analysis that predicted that the protein would contain ten trans-membrane domains. All previous models agreed that the first six putative membrane-spanning regions cross the membrane. These regions correspond to the N-terminal fragment of PS-1 but the structure of the C-terminal fragment was disputed. A recent paper by Spasic et al.[7] provides strong evidence of a nine transmembrane structure with cleavage and assembly into the gamma-secretase complex prior to insertion into the plasma membrane. However, because this is a protein with large numbers of hydrophobic regions, it is unlikely that x-ray crystallography will provide definitive proof of the structure.
The structure of the presenilin-1 C-terminal catalytic fragment was determined using solution NMR. It is made up of alpha helices and is 176 amino acids in length.[1] It was found that Alzheimer's patients carry mutations in the presenilin proteins (PSEN1; PSEN2).[8]
# Function
Most cases of Alzheimer's disease are not hereditary. However, there is a small subset of cases that have an earlier age of onset and have a strong genetic element. In patients suffering from Alzheimer's disease (autosomal dominant hereditary), mutations in the presenilin proteins (PSEN1; PSEN2) or the amyloid precursor protein (APP) can be found. The majority of these cases carry mutant presenilin genes. An important part of the disease process in Alzheimer's disease is the accumulation of Amyloid beta (Aβ) protein. To form Aβ, APP must be cut by two enzymes, beta secretases and gamma secretase. Presenilin is the sub-component of gamma secretase that is responsible for the cutting of APP.
Gamma secretase can cut APP at several points within a small region of the protein, which results in Aβ of various lengths. The lengths associated with Alzheimer's disease are 40 and 42 amino acids long. Aβ 42 is more likely to aggregate to form plaques in the brain than Aβ 40. Presenilin mutations lead to an increase in the ratio of Aβ 42 produced compared to Aβ 40, although the total quantity of Aβ produced remains constant.[9] This can come about by various effects of the mutations upon gamma secretase.[10] Presenilins are also implicated in the processing of notch, an important developmental protein. Mice that have the PS1 gene knocked out die early in development from developmental abnormalities similar to those found when notch is disrupted.[11]
The genes for the presenilins were found through linkage studies using mutations present in familial Alzheimer's cases in 1995.[3]
The genetic inactivation of presenilins in hippocampal synapses has shown this selectively affects the long-term potentiation caused by theta with the inactivation in presynapse but not the postsynapse impairing short-term plasticity and synaptic facilitation.[6] The release of glutamate was also reduced in presynaptic terminals by processes that involve modulation of intracellular Ca2+ release.[6] This has been suggested to "represent a general convergent mechanism leading to neurodegeneration".[6] | https://www.wikidoc.org/index.php/Presenilin | |
8f5cab24bb71fa9cd7914233fec839f3c915f069 | wikidoc | Presque vu | Presque vu
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
The tip of the tongue (TOT) phenomenon is an instance of knowing something that cannot immediately be recalled. TOT is a near-universal experience with memory recollection involving difficulty retrieving a well-known word or familiar name. When experiencing TOT, people feel that the blocked word is on the verge of being recovered. Despite failure in finding the word, people have the feeling that the blocked word is figuratively "on the tip of the tongue." Inaccessibility and the sense of imminence are two key features of an operational definition of TOTs (A.S. Brown, 1991).
# History of Tip of the Tongue
The experience of TOT appeared in non-academic literature as early as 1885. Anton Chekhov's short story "A Horsey Name" is about the main character's tip-of-the-tongue experience involving a surname. In 1890, pioneering psychologist William James discussed the phenomenon in his text The Principles of Psychology. James described the TOT state as "a gap that is intensely active".
In 1966, Harvard psychologists Roger Brown and David McNeill reported the first empirical investigation of the tip-of-the-tongue state. They recounted, "he signs of it were unmistakable" and "he would appear to be in mild torment, something like on the brink of a sneeze, and if he found the word his relief was considerable." They also found that TOT is a fairly universal phenomenon, TOTs occur about once a week and increase as you age, and they're often caused by proper names. Further, people experiencing TOT are often able to access the first letter of the "target word" fairly accurately and they also bring up words related to the "target word." Finally, R. Brown and McNeill have some good news: target words are retrieved during the experience of a TOT phenomenon about half of the time (A.S. Brown, 1991).
Although it is not explicitly called by this name it is interesting to note that TOT is briefly considered by Aristotle in "On Memory and Reminiscence", in his discussion on recollection. (453a, 28)
# Recent TOT literature
## Universality
Cognitive psychologist Bennett Schwartz examined fifty-one languages and found that forty-five of them include expressions using the word tongue to describe the TOT state. Some languages use multiple metaphors. In Korean, the metaphor "going round and round at the end of the tongue" is used, as well as "caught in the throat." French speakers use the "tongue" metaphor. In some languages, tongue is often replaced by lip, "I got it (the word) right on my lips", the concept remaining identical, and having an obvious relation to the tongue. The results of the language survey suggest that the use of the "tongue" metaphor is not idiomatic to English but instead a commonality of the TOT phenomenon. Research involving diaries kept of TOT experiences show that college students have approximately one or two TOTs per week, while elderly adults have about two to four TOTs per week (Schacter, 2001). TOTs occur most frequently for names of people, but for common words as well.
## Etiology and the TOT in different psychology subdisciplines
A second major landmark study of TOTs was a review paper by A.S. Brown (1991), who detailed the pertinent research that had been done on TOTs for the 25-year period since R. Brown and McNeill (1966). In most sections of his review, A.S. Brown raised theoretical questions about TOTs that warrant further study, but most remain untested today. Instead of duplicating this coverage, Schwartz (1999) explored the etiology of the phenomenon. Schwartz considers TOTs in light of Tulving’s (1989) critique of the doctrine of concordance and how it applies to the etiology of TOTs. The doctrine of concordance states that cognitive processes, behavior, and phenomenological experience are highly correlated. In Tulving’s view, cognitive processes should not be confused with the study of phenomenological experiences. For example, the cognitive process of “retrieval” is not the same thing as or comparable to the experience of “recollection.”
The TOT has been studied using three different subdisciplines as approaches: psycholinguistics, memory perspectives, and metacognition. The first two are consistent with concordance and argue for direct access (a view that TOTs and word retrieval are caused by the same retrieval processes), while the metacognitive approach challenges concordance.
Most research to date concerning TOTs has come from the psycholinguistic perspective. This perspective focuses on TOTs as a temporary breakdown in lexical retrieval. This approach has linked TOTs to other errors in spoken language, such as slips of the tongue and spoonerisms. Researchers from the memory perspective have viewed TOTs as a marker of retrieval processes gone awry. Metacognitive models focus on the role that monitoring and controlling processes play in cognition. This approach views TOTs as inferences based on non-target information that is accessible to rememberers.
The direct-access views of the psycholinguistic and memory perspectives fall into three basic hypotheses.
- The first is the blocking hypothesis which states that TOTs occur because the rememberers recognize blocking words as incorrect but cannot retrieve the correct but inhibited target.
- The second is the incomplete activation hypothesis which views that TOTs are caused by the sensitivity to the existence of an unrecalled target in memory, accompanied by the failure to retrieve the target into conscious memory.
- The third hypothesis is the transmission deficit model which states that TOTs are brought about when the semantic representation of the word is activated, but there is a failure to prime the complete phonological representation of the target word.
The psycholinguistic approach views TOTs as a "window" on word retrieval (Schwartz, 1999). In 2000, Deborah Burke and Lori James reported on their research employing a repetition priming paradigm that utilized prime words that shared phonological components with potential TOT target words. They concluded that their results "support the transmission deficit model that the weak connections among phonological representations that cause TOTs are strengthened by production of phonologically related words" (Burke & James, 2000, p. 1378).
Providing support for the direct-access views are research subjects recognition of TOT targets and their ability to give partial information of TOT targets. Recognition of the correct target following a TOT experience is much greater than recognition of the correct target when subjects are not experiencing a TOT. And research subjects can usually recall phonological information related to the TOT targets, such as the first letter of the word, the number of syllables, and the syllabic stress.
# TOT and Neurobiology
## Neural basis of TOT
The anterior cingulate and right middle frontal cortices are two neural areas implicated in the TOT phenomenon. One study showed that, relative to successful retrieval or unsuccessful retrieval not accompanied by a TOT, retrieval failures accompanied by TOTs elicited a selective response in anterior cingulate-prefrontal cortices. The study also found that while attempting to retrieve information, subjects rely heavily on visual spatial clues in correctly retrieving the information. For example, some subjects in the study that were trying to recall a name described looking at the person's face in attempting to retrieve the name. Also, when trying to recall the name of an author, the subjects described attempting to read the name of the author from an imagined book. The authors of the study suggest that "the extent that the subjects in our fMRI study used a visual imagery strategy when in a TOT condition, the activation observed in right inferior PFC could constitute the neural correlates of these efforts to resolve these retrieval failures" (Maril et al., 2001, p. 657).
## Three stage neural network model
File:Neural network.svg
One theory of why the tip of the tongue phenomenon occurs comes from Petro Gopych (2001), a professor at the Kharkiv National University. Gopych’s model proposes three stages in word recall process.
- Word node selection
This first stage involves actually selecting which word we are trying to recall. When specifying the word, we identify the learned artificial neural network (ANN) which contains information about the target word, and then activate that part.
- This first stage involves actually selecting which word we are trying to recall. When specifying the word, we identify the learned artificial neural network (ANN) which contains information about the target word, and then activate that part.
- Word retrieval
According to Gopych, free recall exhibits positive and negative outputs randomly in the learned ANN. When trying to recall a specific word, otherwise known as cued recall, the retrieval process depicts a “spike” of these outputs with a fixed part of the true information (specific word). The result of attempts to retrieve the word from the learned ANN is an output of positive and negative units.
- According to Gopych, free recall exhibits positive and negative outputs randomly in the learned ANN. When trying to recall a specific word, otherwise known as cued recall, the retrieval process depicts a “spike” of these outputs with a fixed part of the true information (specific word). The result of attempts to retrieve the word from the learned ANN is an output of positive and negative units.
- Comparison of patterns
The pattern of outputs determined by the retrieval attempts is compared to a reference pattern from metamemory. If the sample pattern matches the reference pattern, the searching stops because the word that was searched for is recalled. If there is no match, the retrieval process (stage 2) starts over again and a pattern of outputs enters the ANN. This continues until the reference pattern is detected or the process is stopped independently.
- The pattern of outputs determined by the retrieval attempts is compared to a reference pattern from metamemory. If the sample pattern matches the reference pattern, the searching stops because the word that was searched for is recalled. If there is no match, the retrieval process (stage 2) starts over again and a pattern of outputs enters the ANN. This continues until the reference pattern is detected or the process is stopped independently.
Gopych believes that the problem in recalling a specified word comes from a damaged ANN. He suggests that the stored semantic information is damaged or incompletely selected. The severity of the damage determines the power of the TOT.
Gopych’s three stage neural network theory can be used to explain many aspects of TOT including semantic priming, immediate, delay, or eventually full TOT resolution, age dependence in TOTs, recollection of the first letter of the target word, and many more. Using the number of attempts of memory retrieval, the duration of time intervals between successive sets of spikes, and the duration of single neuron spikes, the retrieval chronometry can be determined. Gopych’s theory also supports Tulving’s challenge to the doctrine of concordance.
# TOT across the lifespan
TOT research in children has mainly focused on when they begin to experience TOTs and what the experience is like for them (Brown, 1991). Wellman (1977) found evidence that children between kindergarten and third grade (ages 4-7) did experience TOTs, though very rarely. They were able to recall pieces of the target word, words that sound like it or rhymed with it, and long words that included it. Further, they would tell researchers that they knew the word, but were having trouble remembering it. Like adults, they also became uncomfortable and frustrated by the experience. Finally, his findings suggest that TOTs occur more often in third graders (ages 6-7) than they do in kindergarteners and first graders.
More research has been done with TOTs in older adults. In terms of subjective estimates, research has found that older adults report experiencing TOTs about as often as younger adults (Brown, 1991). However, studies by Burke et al. (1991) and Cohen and Faulkner (1986) with more objective measurements received different results. Their participants kept diaries for four weeks, recording their TOT experiences, and young adults were found to experience significantly fewer TOTs than older adults. Other TOT literature has found that older adults remember less information about the target word and bring up fewer related words during the TOT experience and are less active in resolving the TOT experience (Brown, 1991). | Presque vu
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [2] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
The tip of the tongue (TOT) phenomenon is an instance of knowing something that cannot immediately be recalled. TOT is a near-universal experience with memory recollection involving difficulty retrieving a well-known word or familiar name. When experiencing TOT, people feel that the blocked word is on the verge of being recovered. Despite failure in finding the word, people have the feeling that the blocked word is figuratively "on the tip of the tongue." Inaccessibility and the sense of imminence are two key features of an operational definition of TOTs (A.S. Brown, 1991).
# History of Tip of the Tongue
The experience of TOT appeared in non-academic literature as early as 1885. Anton Chekhov's short story "A Horsey Name" is about the main character's tip-of-the-tongue experience involving a surname. In 1890, pioneering psychologist William James discussed the phenomenon in his text The Principles of Psychology. James described the TOT state as "a gap that is intensely active".
In 1966, Harvard psychologists Roger Brown and David McNeill reported the first empirical investigation of the tip-of-the-tongue state. They recounted, "[t]he signs of it were unmistakable" and "he [a research participant] would appear to be in mild torment, something like on the brink of a sneeze, and if he found the word his relief was considerable." They also found that TOT is a fairly universal phenomenon, TOTs occur about once a week and increase as you age, and they're often caused by proper names. Further, people experiencing TOT are often able to access the first letter of the "target word" fairly accurately and they also bring up words related to the "target word." Finally, R. Brown and McNeill have some good news: target words are retrieved during the experience of a TOT phenomenon about half of the time (A.S. Brown, 1991).
Although it is not explicitly called by this name it is interesting to note that TOT is briefly considered by Aristotle in "On Memory and Reminiscence", in his discussion on recollection. (453a, 28)
# Recent TOT literature
## Universality
Cognitive psychologist Bennett Schwartz examined fifty-one languages and found that forty-five of them include expressions using the word tongue to describe the TOT state. Some languages use multiple metaphors. In Korean, the metaphor "going round and round at the end of the tongue" is used, as well as "caught in the throat." French speakers use the "tongue" metaphor. In some languages, tongue is often replaced by lip, "I got it (the word) right on my lips", the concept remaining identical, and having an obvious relation to the tongue. The results of the language survey suggest that the use of the "tongue" metaphor is not idiomatic to English but instead a commonality of the TOT phenomenon. Research involving diaries kept of TOT experiences show that college students have approximately one or two TOTs per week, while elderly adults have about two to four TOTs per week (Schacter, 2001). TOTs occur most frequently for names of people, but for common words as well.
## Etiology and the TOT in different psychology subdisciplines
A second major landmark study of TOTs was a review paper by A.S. Brown (1991), who detailed the pertinent research that had been done on TOTs for the 25-year period since R. Brown and McNeill (1966). In most sections of his review, A.S. Brown raised theoretical questions about TOTs that warrant further study, but most remain untested today. Instead of duplicating this coverage, Schwartz (1999) explored the etiology of the phenomenon. Schwartz considers TOTs in light of Tulving’s (1989) critique of the doctrine of concordance and how it applies to the etiology of TOTs. The doctrine of concordance states that cognitive processes, behavior, and phenomenological experience are highly correlated. In Tulving’s view, cognitive processes should not be confused with the study of phenomenological experiences. For example, the cognitive process of “retrieval” is not the same thing as or comparable to the experience of “recollection.”
The TOT has been studied using three different subdisciplines as approaches: psycholinguistics, memory perspectives, and metacognition. The first two are consistent with concordance and argue for direct access (a view that TOTs and word retrieval are caused by the same retrieval processes), while the metacognitive approach challenges concordance.
Most research to date concerning TOTs has come from the psycholinguistic perspective. This perspective focuses on TOTs as a temporary breakdown in lexical retrieval. This approach has linked TOTs to other errors in spoken language, such as slips of the tongue and spoonerisms. Researchers from the memory perspective have viewed TOTs as a marker of retrieval processes gone awry. Metacognitive models focus on the role that monitoring and controlling processes play in cognition. This approach views TOTs as inferences based on non-target information that is accessible to rememberers.
The direct-access views of the psycholinguistic and memory perspectives fall into three basic hypotheses.
- The first is the blocking hypothesis which states that TOTs occur because the rememberers recognize blocking words as incorrect but cannot retrieve the correct but inhibited target.
- The second is the incomplete activation hypothesis which views that TOTs are caused by the sensitivity to the existence of an unrecalled target in memory, accompanied by the failure to retrieve the target into conscious memory.
- The third hypothesis is the transmission deficit model which states that TOTs are brought about when the semantic representation of the word is activated, but there is a failure to prime the complete phonological representation of the target word.
The psycholinguistic approach views TOTs as a "window" on word retrieval (Schwartz, 1999). In 2000, Deborah Burke and Lori James reported on their research employing a repetition priming paradigm that utilized prime words that shared phonological components with potential TOT target words. They concluded that their results "support the transmission deficit model that the weak connections among phonological representations that cause TOTs are strengthened by production of phonologically related words" (Burke & James, 2000, p. 1378).
Providing support for the direct-access views are research subjects recognition of TOT targets and their ability to give partial information of TOT targets. Recognition of the correct target following a TOT experience is much greater than recognition of the correct target when subjects are not experiencing a TOT. And research subjects can usually recall phonological information related to the TOT targets, such as the first letter of the word, the number of syllables, and the syllabic stress.
# TOT and Neurobiology
## Neural basis of TOT
Template:Cerebrum map
The anterior cingulate and right middle frontal cortices are two neural areas implicated in the TOT phenomenon. One study showed that, relative to successful retrieval or unsuccessful retrieval not accompanied by a TOT, retrieval failures accompanied by TOTs elicited a selective response in anterior cingulate-prefrontal cortices. The study also found that while attempting to retrieve information, subjects rely heavily on visual spatial clues in correctly retrieving the information. For example, some subjects in the study that were trying to recall a name described looking at the person's face in attempting to retrieve the name. Also, when trying to recall the name of an author, the subjects described attempting to read the name of the author from an imagined book. The authors of the study suggest that "the extent that the subjects in our fMRI study used a visual imagery strategy when in a TOT condition, the activation observed in right inferior PFC could constitute the neural correlates of these efforts to resolve these retrieval failures" (Maril et al., 2001, p. 657).
## Three stage neural network model
File:Neural network.svg
One theory of why the tip of the tongue phenomenon occurs comes from Petro Gopych (2001), a professor at the Kharkiv National University. Gopych’s model proposes three stages in word recall process.
- Word node selection
This first stage involves actually selecting which word we are trying to recall. When specifying the word, we identify the learned artificial neural network (ANN) which contains information about the target word, and then activate that part.
- This first stage involves actually selecting which word we are trying to recall. When specifying the word, we identify the learned artificial neural network (ANN) which contains information about the target word, and then activate that part.
- Word retrieval
According to Gopych, free recall exhibits positive and negative outputs randomly in the learned ANN. When trying to recall a specific word, otherwise known as cued recall, the retrieval process depicts a “spike” of these outputs with a fixed part of the true information (specific word). The result of attempts to retrieve the word from the learned ANN is an output of positive and negative units.
- According to Gopych, free recall exhibits positive and negative outputs randomly in the learned ANN. When trying to recall a specific word, otherwise known as cued recall, the retrieval process depicts a “spike” of these outputs with a fixed part of the true information (specific word). The result of attempts to retrieve the word from the learned ANN is an output of positive and negative units.
- Comparison of patterns
The pattern of outputs determined by the retrieval attempts is compared to a reference pattern from metamemory. If the sample pattern matches the reference pattern, the searching stops because the word that was searched for is recalled. If there is no match, the retrieval process (stage 2) starts over again and a pattern of outputs enters the ANN. This continues until the reference pattern is detected or the process is stopped independently.
- The pattern of outputs determined by the retrieval attempts is compared to a reference pattern from metamemory. If the sample pattern matches the reference pattern, the searching stops because the word that was searched for is recalled. If there is no match, the retrieval process (stage 2) starts over again and a pattern of outputs enters the ANN. This continues until the reference pattern is detected or the process is stopped independently.
Gopych believes that the problem in recalling a specified word comes from a damaged ANN. He suggests that the stored semantic information is damaged or incompletely selected. The severity of the damage determines the power of the TOT.
Gopych’s three stage neural network theory can be used to explain many aspects of TOT including semantic priming, immediate, delay, or eventually full TOT resolution, age dependence in TOTs, recollection of the first letter of the target word, and many more. Using the number of attempts of memory retrieval, the duration of time intervals between successive sets of spikes, and the duration of single neuron spikes, the retrieval chronometry can be determined. Gopych’s theory also supports Tulving’s challenge to the doctrine of concordance.
# TOT across the lifespan
TOT research in children has mainly focused on when they begin to experience TOTs and what the experience is like for them (Brown, 1991). Wellman (1977) found evidence that children between kindergarten and third grade (ages 4-7) did experience TOTs, though very rarely. They were able to recall pieces of the target word, words that sound like it or rhymed with it, and long words that included it. Further, they would tell researchers that they knew the word, but were having trouble remembering it. Like adults, they also became uncomfortable and frustrated by the experience. Finally, his findings suggest that TOTs occur more often in third graders (ages 6-7) than they do in kindergarteners and first graders.
More research has been done with TOTs in older adults. In terms of subjective estimates, research has found that older adults report experiencing TOTs about as often as younger adults (Brown, 1991). However, studies by Burke et al. (1991) and Cohen and Faulkner (1986) with more objective measurements received different results. Their participants kept diaries for four weeks, recording their TOT experiences, and young adults were found to experience significantly fewer TOTs than older adults. Other TOT literature has found that older adults remember less information about the target word and bring up fewer related words during the TOT experience and are less active in resolving the TOT experience (Brown, 1991). | https://www.wikidoc.org/index.php/Presque_vu | |
9e083a544e7d5a81a98b46eb8353061685c7391c | wikidoc | Prevotella | Prevotella
# Overview
Prevotella is a genus of Gram-negative bacteria.
Bacteroides melaninogenicus has been reclassified and split into Prevotella melaninogenica and Prevotella intermedia.
Prevotella spp. are members of the oral and vaginal flora, and are recovered from anaerobic infections of the respiratory tract. These infections include aspiration pneumonia, lung abscess, pulmonary empyema, and chronic otitis media and sinusitis. They have been isolated from abscesses and burns in the vicinity of the mouth, bites, paronychia, urinary tract infection, brain abscesses, osteomyelitis, and bacteremia associated with upper respiratory tract infections. Prevotella spp. predominate in periodontal disease and periodontal abscesses.
In a study of gut bacteria of children in Burkina Faso (in Africa), Prevotella made up 53% of the gut bacteria, but were absent in age-matched European children. Studies also indicate that long-term diet is strongly associated with the gut microbiome composition—those who eat plenty of protein and animal fats typical of Western diet have predominantly Bacteroides bacteria, while for those who consume more carbohydrates, especially fibre, the Prevotella species dominate.
P. copri is possibly connected to rheumatoid arthritis.
A recent study on Prevotella derived from humans compared the gene repertoires of its species derived from different body sites of human. It also reported an open pan- genome showing vast diversity of gene pool.
# Species
- Prevotella albensis
- Prevotella amnii
- Prevotella bergensis
- Prevotella bivia
- Prevotella brevis
- Prevotella bryantii
- Prevotella buccae
- Prevotella buccalis
- Prevotella copri
- Prevotella dentalis
- Prevotella denticola
- Prevotella disiens
- Prevotella histicola
- Prevotella intermedia
- Prevotella maculosa
- Prevotella marshii
- Prevotella melaninogenica
- Prevotella micans
- Prevotella multiformis
- Prevotella nigrescens
- Prevotella oralis
- Prevotella oris
- Prevotella oulorum
- Prevotella pallens
- Prevotella salivae
- Prevotella stercorea
- Prevotella tannerae
- Prevotella timonensis
- Prevotella veroralis | Prevotella
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Prevotella is a genus of Gram-negative bacteria.
Bacteroides melaninogenicus has been reclassified and split into Prevotella melaninogenica and Prevotella intermedia.[1]
Prevotella spp. are members of the oral and vaginal flora, and are recovered from anaerobic infections of the respiratory tract. These infections include aspiration pneumonia, lung abscess, pulmonary empyema, and chronic otitis media and sinusitis. They have been isolated from abscesses and burns in the vicinity of the mouth, bites, paronychia, urinary tract infection, brain abscesses, osteomyelitis, and bacteremia associated with upper respiratory tract infections. Prevotella spp. predominate in periodontal disease and periodontal abscesses. [2]
In a study of gut bacteria of children in Burkina Faso (in Africa), Prevotella made up 53% of the gut bacteria, but were absent in age-matched European children.[3] Studies also indicate that long-term diet is strongly associated with the gut microbiome composition—those who eat plenty of protein and animal fats typical of Western diet have predominantly Bacteroides bacteria, while for those who consume more carbohydrates, especially fibre, the Prevotella species dominate.[4]
P. copri is possibly connected to rheumatoid arthritis.[5]
A recent study on Prevotella derived from humans compared the gene repertoires of its species derived from different body sites of human. It also reported an open pan- genome showing vast diversity of gene pool. [6]
# Species
- Prevotella albensis
- Prevotella amnii
- Prevotella bergensis
- Prevotella bivia
- Prevotella brevis
- Prevotella bryantii
- Prevotella buccae
- Prevotella buccalis
- Prevotella copri
- Prevotella dentalis
- Prevotella denticola
- Prevotella disiens
- Prevotella histicola
- Prevotella intermedia
- Prevotella maculosa
- Prevotella marshii
- Prevotella melaninogenica
- Prevotella micans
- Prevotella multiformis
- Prevotella nigrescens
- Prevotella oralis
- Prevotella oris
- Prevotella oulorum
- Prevotella pallens
- Prevotella salivae
- Prevotella stercorea
- Prevotella tannerae
- Prevotella timonensis
- Prevotella veroralis | https://www.wikidoc.org/index.php/Prevotella | |
0803e72aff0263b0b5bb9fb1dffe5d42cee480bd | wikidoc | Ziconotide | Ziconotide
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Black Box Warning
# Overview
Ziconotide is an N-type calcium channel antagonist that is FDA approved for the {{{indicationType}}} of severe chronic pain in patients for whom intrathecal therapy is warranted, and who are intolerant of or refractory to other treatment, such as systemic analgesics, adjunctive therapies, or intrathecal morphine. There is a Black Box Warning for this drug as shown here. Common adverse reactions include dizziness, nausea, confusional state, nystagmus.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- PRIALT (ziconotide) solution, intrathecal infusion is indicated for the management of severe chronic pain in adult patients for whom intrathecal therapy is warranted, and who are intolerant of or refractory to other treatment, such as systemic analgesics, adjunctive therapies, or intrathecal morphine.
- Dose Initiation
- Initiate dosing with PRIALT via intrathecal device at no more than 2.4 mcg/day (0.1 mcg/hr).
- Dose Titration
- Titrate doses by up to 2.4 mcg/day (0.1 mcg/hr) at intervals of no more than 2 to 3 times per week based on analgesic response and adverse events. Dose increases in increments of less than 2.4 mcg/day (0.1 mcg/hr) and less frequently than 2 to 3 times per week may be used. For each dose titration, assess the dosing requirements and adjust the pump infusion flow rate as required to achieve the new dosing.
- The maximum recommended dose is 19.2 mcg/day (0.8 mcg/hr).
- Adjust the dose of intrathecal PRIALT according to the severity of pain, the patient’s response to therapy, and the occurrence of adverse reactions.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ziconotide in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ziconotide in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Ziconotide in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ziconotide in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ziconotide in pediatric patients.
# Contraindications
- PRIALT is contraindicated in patients with a known hypersensitivity to ziconotide or any of its formulation components.
- PRIALT is contraindicated in patients with any other concomitant treatment or medical condition that would render intrathecal administration hazardous. Contraindications to the use of intrathecal analgesia include the presence of infection at the microinfusion injection site, uncontrolled bleeding diathesis, and spinal canal obstruction that impairs circulation of CSF.
- PRIALT is contraindicated in patients with a pre-existing history of psychosis.
# Warnings
### Precautions
- Cognitive and Neuropsychiatric Adverse Reactions
- ere psychiatric symptoms and neurological impairment may occur during treatment with PRIALT. PRIALT is contraindicated in patients with a pre-existing history of psychosis. Monitor all patients frequently for evidence of cognitive impairment, hallucinations, or changes in mood or consciousness. PRIALT therapy can be interrupted or discontinued abruptly without evidence of withdrawal effects in the event of serious neurological or psychiatric signs or symptoms.
- Events of acute psychiatric disturbances such as hallucinations (12%), paranoid reactions (3%), hostility (2%), delirium (2%), psychosis (1%), and manic reactions (0.4%) have been reported in patients treated with PRIALT. Patients with pretreatment psychiatric disorders may be at an increased risk. PRIALT may cause or worsen depression with the risk of suicide in susceptible patients. In placebo-controlled trials, there was a higher incidence of suicide, suicide attempts, and suicide ideations in PRIALT-treated patients than in the placebo group (0.27/patient year for PRIALT patients and 0.10/patient year for placebo patients).
- Management of psychiatric complications may need to include discontinuation of PRIALT, treatment with psychotherapeutic agents and/or short-term hospitalization. Before drug is reinitiated, careful evaluation must be performed on an individual basis.
- Use of PRIALT has been associated with cognitive impairment and decreased alertness/unresponsiveness. The following cognitive adverse reaction rates were reported: confusion (33%), memory impairment (22%), speech disorder (14%), aphasia (12%), thinking abnormal (8%), and amnesia (1%). Cognitive impairment may appear gradually after several weeks of treatment. Reduce the dose of PRIALT or discontinue the use of PRIALT if signs or symptoms of cognitive impairment develop, but other contributing causes must also be considered. The cognitive effects of PRIALT are generally reversible within 2 weeks after drug discontinuation. The median time to reversal of the individual cognitive effects ranged from 3 to 15 days. The elderly (≥ 65 years of age) are at higher risk for confusion.
- There may be additive effects on cognitive impairment and decreased alertness when PRIALT is used in conjunction with other CNS-depressant drugs that may necessitate dosage adjustments.
- Meningitis and Other Infections
- Meningitis can occur due to inadvertent contamination of the microinfusion device and other means such as CSF seeding due to hematogenous or direct spread from an infected pump pocket or catheter tract. While meningitis is rare with an internal microinfusion device and surgically-implanted catheter, the incidence increases substantially with external devices. In PRIALT clinical trials, meningitis occurred in 3% (40) of patients in the PRIALT group using either internal or external microinfusion devices and 1% (1 case) of patients in the placebo group.
- The risk of meningitis was particularly high in patients with external microinfusion devices and catheters, occurring in 38 out of 41 patients (93%), 37 of whom received PRIALT and one who received placebo.
- Patients, caregivers, and healthcare providers must be particularly vigilant for the signs and symptoms of meningitis, including but not limited to fever, headache, stiff neck, altered mental status (e.g., lethargy, confusion, disorientation), nausea or vomiting, and occasionally seizures. Serious infection or meningitis can occur within 24 hours of a breach in sterility such as a disconnected catheter, the most common cause of meningitis with external microinfusion devices. The patient and health care provider must be familiar with the handling of the external microinfusion device and care of the catheter skin exit site.
- Strict aseptic procedures must be used during the preparation of the PRIALT solution and refilling of the microinfusion device to decrease the risk of introducing contaminants or other environmental pathogens into the reservoir. In suspected cases (especially in immuno-compromised patients) or in confirmed cases of meningitis, CSF cultures must be obtained and appropriate antibiotic therapy must be promptly instituted. Treatment of meningitis usually requires removal of the microinfusion system, catheter, and any other foreign body materials within the intrathecal space and, therefore, discontinuation of PRIALT therapy.
- Reduced Level of Consciousness
- Patients have become unresponsive or stuporous while receiving PRIALT. The incidence of unresponsiveness or stupor in clinical trials was 2% in PRIALT-treated patients. During these episodes, patients sometimes appear to be conscious and breathing is not depressed. If reduced levels of consciousness occur, discontinue PRIALT until the event resolves, and other etiologies (e.g., meningitis) must be considered. There is no known pharmacologic antagonist for this effect. Patients taking concomitant antiepileptics, neuroleptics, sedatives, or diuretics may be at higher risk of depressed levels of consciousness. If altered consciousness occurs, discontinue other CNS-depressant drugs as clinically appropriate.
- Elevation of Serum Creatine Kinase
- In clinical studies, 40% of PRIALT-treated patients had serum creatine kinase (CK) levels above the upper limit of normal (ULN), and 11% had CK levels that were greater than three times the ULN. In cases where CK was fractionated, only the muscle isoenzyme (MM) was elevated. The time to occurrence was sporadic, but the greatest incidence of CK elevation was during the first two months of treatment. One case of symptomatic myopathy with EMG findings, and two cases of acute renal failure associated with rhabdomyolysis and extreme CK elevations (17,000–27,000 IU/L) have been reported in PRIALT-treated patients.
- Therefore, monitor serum CK in patients undergoing treatment with PRIALT periodically (e.g., every other week for the first month and monthly as appropriate thereafter). Evaluate patients clinically and obtain CK measurements in the setting of new neuromuscular symptoms (e.g., myalgias, myasthenia, muscle cramps, asthenia) or a reduction in physical activity. If these symptoms continue and CK levels remain elevated or continue to rise, reduce the dose or discontinue the use of PRIALT.
- Withdrawal From Opiates
- PRIALT is not an opiate and cannot prevent or relieve the symptoms associated with the withdrawal of opiates.
- To avoid withdrawal syndrome when opiate withdrawal is necessary, do not abruptly reduce or withdraw opioid medications.
- For patients being withdrawn from intrathecal opiates or intrathecal opiate infusion, gradually taper over a few weeks and replace with a pharmacologically equivalent dose of oral opiates.
- Driving and Operating Machinery
- Use of PRIALT has been associated with cognitive impairment and decreased alertness/unresponsiveness. Therefore, caution patients against engaging in hazardous activities that require complete mental alertness or motor coordination such as operating machinery or driving a motor vehicle.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates in clinical practice.
- A total of 1254 adult patients received PRIALT as a continuous infusion in acute and severe chronic pain trials with an exposure of 662 patient-years. The mean duration of treatment was 193 days with 173 patients (14%) treated for at least 1 year. The average final dose was 17.6 mcg/day (0.73 mcg/hr).
- The most frequently reported adverse reactions (≥ 25%) in clinical trials were dizziness, nausea, confusional state and nystagmus. Slower titration of PRIALT may result in fewer serious adverse reactions and discontinuation of PRIALT for adverse reactions.
- Adverse reactions during the slow titration placebo-controlled trial that occurred in 5% or greater of patients and more commonly with PRIALT than with placebo are summarized in Table 1.
The following adverse reactions assessed as related to PRIALT have been reported in 2% or greater of patients participating in the clinical studies:
Fall, fatigue, lethargy, peripheral edema
Hypotension, orthostatic hypotension
Abdominal pain, constipation, dry mouth, nausea aggravated
Appetite decreased
Muscle cramp, muscle weakness, myalgia, pain in limb
Aphasia, areflexia, balance impaired, burning sensation, coordination abnormal, disturbance in attention, dizziness postural, dysarthria, dysgeusia, hypoaesthesia, mental impairment, paraesthesia, sedation, speech disorder, agitation, anxiety, cognitive disorder, confusional state, depression, depression aggravated, disorientation, hallucination, hallucination auditory, hallucination visual, insomnia, irritability, mood disorder, nervousness, paranoia
Diplopia, visual disturbance
Dysuria, urinary hesitation
Blood creatine phosphokinase increased
- The following medically important adverse reactions occurred in less than 2% of patients were assessed by the clinical investigators as related to PRIALT: acute renal failure, atrial fibrillation, cerebrovascular accident, sepsis, meningitis, psychotic disorder, suicidal ideation, respiratory distress, rhabdomyolysis, electrocardiogram abnormal, stupor, loss of consciousness, clonic convulsion and grand mal convulsion. Fatal aspiration pneumonia and suicide attempt were reported in less than 1% of patients.
## Postmarketing Experience
- The following adverse events have been reported during post-approval use of PRIALT. Because these events are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure: Hypersensitivity reactions including angioedema, serious skin reactions including bullous dermatitis, skin ulcers, skin exfoliation, and burning skin sensation.
# Drug Interactions
- Formal PK drug-drug interaction studies have not been performed with PRIALT. As ziconotide is a peptide, it is expected to be completely degraded by endopeptidases and exopeptidases (Phase I hydrolytic enzymes) widely located throughout the body, and not by other Phase I biotransformation processes (including the cytochrome P450 system) or by Phase II conjugation reactions. Thus, intrathecal administration, low plasma ziconotide concentrations, and metabolism by ubiquitous peptidases make metabolic interactions of other drugs with ziconotide unlikely. Further, as ziconotide is not highly bound in plasma (approximately 50%) and has low plasma exposure following intrathecal administration, clinically relevant plasma protein displacement reactions involving ziconotide and co-administered medications are unlikely.
- Over 90% of patients treated with intrathecal PRIALT used systemic opiates and in the slow titration study, 98% of patients received opioids.
- The combination of PRIALT with intrathecal opiates has not been studied in placebo-controlled clinical trials and is not recommended.
- Interaction with CNS Depressants
- Almost all patients in the PRIALT clinical trials received concomitant non-intrathecal medication. Most patients received several concomitant drugs, including antidepressants (66%), anxiolytics (52%), antiepileptics (47%), neuroleptics (46%), and sedatives (34%). The use of drugs with CNS-depressant activities may be associated with an increased incidence of CNS adverse reactions such as dizziness and confusion.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- Ziconotide was embryolethal in rats when given as a continuous intravenous infusion during the major period of organogenesis as evidenced by significant increases in post-implantation loss because of an absence or a reduced number of live fetuses. Estimated exposure for embryolethality in the rat was approximately 700-fold above the expected exposure resulting from the maximum recommended human daily intrathecal dose of 0.8 mcg/hr (19.2 mcg/day). Ziconotide was not teratogenic in female rats when given as a continuous intravenous infusion at doses up to 30 mg/kg/day or in female rabbits up to 5 mg/kg/day during the major period of organ development. Estimated exposures in the female rat and rabbit were approximately 26,000-fold and 940-fold higher than the expected exposure resulting from the maximum recommended human daily dose of 0.8 mcg/hr (19.2 mcg/day) based on plasma exposure. Maternal toxicity in the rat and rabbit, as evidenced by decreased body weight gain and food consumption, was present at all dose levels. Maternal toxicity in the rat led to reduced fetal weights and transient, delayed ossification of the pubic bones at doses ≥ 15 mg/kg/day, which is approximately 8900-fold higher than the expected exposure resulting from the maximum recommended human daily intrathecal dose of 0.8 mcg/hr (19.2 mcg/day) based on plasma exposure. The no observable adverse effect level (NOAEL) for embryo-fetal development in rats was 0.5 mg/kg/day and in rabbits was 5 mg/kg/day. Estimated NOAEL exposures in the rat and rabbit were approximately 400-fold and 940-fold higher than the expected exposure resulting from the maximum recommended human daily intrathecal dose of 0.8 mcg/hr (19.2 mcg/day) based on plasma exposure.
- In a pre- and post-natal study in rats, ziconotide given as a continuous intravenous infusion did not affect pup development or reproductive performance up to a dose of 10 mg/kg/day, which is approximately 3800-fold higher than the expected exposure resulting from the maximum recommended human daily intrathecal dose of 0.8 mcg/hr (19.2 mcg/day) based on plasma exposure. Maternal toxicity, as evidenced by clinical observations, and decreases in body weight gain and food consumption were observed at all doses.
- No adequate and well-controlled studies have been conducted in pregnant women. Because animal studies are not always predictive of human response, PRIALT should be used during pregnancy only if the potential benefit justifies risk to the fetus.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ziconotide in women who are pregnant.
### Labor and Delivery
- The effect of PRIALT on labor and delivery in humans is not known.
### Nursing Mothers
- It is not known whether PRIALT is excreted in human breast milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from PRIALT, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
- Safety and effectiveness in pediatric patients have not been established.
### Geriatic Use
- Of the total number of subjects in clinical studies of PRIALT, 22% were 65 and over, while 7% were 75 and over. In all trials, there was a higher incidence of confusion in older patients (42% for ≥ 65 year old versus 29% for < 65 year old subgroups). Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, the dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.
### Gender
There is no FDA guidance on the use of Ziconotide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Ziconotide with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Ziconotide in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Ziconotide in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ziconotide in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Ziconotide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intrathecal
### Monitoring
There is limited information regarding Monitoring of Ziconotide in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Ziconotide in the drug label.
# Overdosage
## Acute Overdose
- The maximum recommended intrathecal PRIALT dose is 19.2 mcg/day. The maximum intrathecal dose of PRIALT in clinical trials was 912 mcg/day. In some patients who received intrathecal doses greater than the maximum recommended dose, exaggerated pharmacological effects (e.g., ataxia, nystagmus, dizziness, stupor, unresponsiveness, spinal myoclonus, confusion, sedation, hypotension, word-finding difficulties, garbled speech, nausea, and vomiting) were observed. There was no indication of respiratory depression. Overdoses may occur due to pump programming errors or incorrect drug concentration preparations. In these cases, patients were observed and ziconotide was either temporarily discontinued or permanently withdrawn. Most patients recovered within 24 hours after withdrawal of drug. In the event of an overdose, elimination of ziconotide from CSF would be expected to remain constant (CSF t½=4.6 hours). Therefore, within 24 hours of stopping therapy, the ziconotide CSF concentration should be less than 5% of peak levels.
- There is no known antidote to ziconotide. General medical supportive measures should be administered to patients who receive an overdose until the exaggerated pharmacological effects of the drug have resolved. Treatment for an overdose is hospitalization, when needed, and symptom-related supportive care. Ziconotide does not bind to opiate receptors and its pharmacological effects are not blocked by opioid antagonists.
- In the event of an inadvertent intravenous or epidural administration, adverse reactions could include severe hypotension, which can be treated with a recumbent posture and blood pressure support as required. The half-life of PRIALT in serum is 1.3 hours.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Ziconotide in the drug label.
# Pharmacology
## Mechanism of Action
- Ziconotide binds to N-type calcium channels located on the primary nociceptive (A-δ and C) afferent nerves in the superficial layers (Rexed laminae I and II) of the dorsal horn in the spinal cord. Although the mechanism of action of ziconotide has not been established in humans, results in animals suggest that its binding blocks N-type calcium channels, which leads to a blockade of excitatory neurotransmitter release from the primary afferent nerve terminals and antinociception.
## Structure
- PRIALT contains ziconotide, a synthetic equivalent of a naturally occurring conopeptide found in the piscivorous marine snail, Conus magus. Ziconotide is a 25 amino acid, polybasic peptide containing three disulfide bridges with a molecular weight of 2639 daltons and a molecular formula of C102H172N36O32S7. The amino acid sequence and disulfide bridging pattern are given below:
- Ziconotide is a hydrophilic molecule that is freely soluble in water and is practically insoluble in methyl t-butyl ether.
- PRIALT is formulated as a sterile, preservative-free, isotonic solution for intrathecal administration using an appropriate microinfusion device . Each 1 or 5 mL vial of PRIALT (100 mcg/mL) respectively contains 100 or 500 mcg of ziconotide acetate, and the 20 mL vial of PRIALT (25 mcg/mL) contains 500 mcg of ziconotide acetate, with L-methionine and sodium chloride as excipients at pH 4.0–5.0. Each vial is intended for single use only, either undiluted or after dilution to the appropriate concentration with 0.9% Sodium Chloride Injection, USP (preservative free).
## Pharmacodynamics
- Interaction with Opioids
- Ziconotide does not bind to opioid receptors and its pharmacological effects are not blocked by opioid antagonists. In animal models, intrathecal ziconotide potentiated opioid-induced reduction in gastrointestinal (GI) motility, but did not potentiate morphine-induced respiratory depression. In rats receiving ziconotide, additive analgesic effects were observed with concurrent administration of morphine, baclofen, or clonidine. Concurrent administration of intrathecal ziconotide and morphine did not prevent the development of morphine tolerance in rats.
## Pharmacokinetics
- The cerebrospinal fluid (CSF) pharmacokinetics (PK) of ziconotide have been studied after one-hour intrathecal infusions of 1 to 10 mcg of PRIALT to patients with chronic pain. The plasma PK following intravenous infusion (0.3 to 10 mcg/kg/day) have also been studied. Both intrathecal and intravenous data are shown below (Table 2).
- Following one-hour intrathecal administration of 1 to 10 mcg of PRIALT, both total exposure (AUC; range: 83.6 to 608 ngh/mL) and peak exposure (Cmax; range: 16.4 to 132 ng/mL) values in the CSF were variable and dose-dependent, but appeared approximately dose-proportional. During 5 or 6 days of continuous intrathecal infusions of PRIALT at infusion rates ranging from 0.1 to 7.0 mcg/hr in patients with chronic pain, plasma ziconotide levels could not be quantified in 56% of patients using an assay with a lower limit of detection of approximately 0.04 ng/mL. Predictably, patients requiring higher intrathecal infusion dose rates were more likely to have quantifiable ziconotide levels in plasma. Plasma ziconotide levels, when detectable, remain constant after many months of intrathecal PRIALT infusion in patients followed for up to 9 months.
- Distribution
- Ziconotide is about 50% bound to human plasma proteins. The mean CSF volume of distribution (Vd) of ziconotide following intrathecal administration approximates the estimated total CSF volume (140 mL).
- Metabolism
- Ziconotide is cleaved by endopeptidases and exopeptidases at multiple sites on the peptide. Following passage from the CSF into the systemic circulation during continuous intrathecal administration, ziconotide is expected to be susceptible to proteolytic cleavage by various ubiquitous peptidases/proteases present in most organs (e.g., kidney, liver, lung, muscle, etc.), and thus readily degraded to peptide fragments and their individual constituent free amino acids. Human and animal CSF and blood exhibit minimal hydrolytic activity toward ziconotide in vitro. The biological activity of the various expected proteolytic degradation products of ziconotide has not been assessed.
- Elimination
- Minimal amounts of ziconotide (< 1%) were recovered in human urine following intravenous infusion. The terminal half-life of ziconotide in CSF after an intrathecal administration was around 4.6 hours (range 2.9 to 6.5 hours). Mean CSF clearance (CL) of ziconotide approximates adult human CSF turnover rate (0.3 to 0.4 mL/min).
- Special Populations
- No formal studies were conducted to assess the effect of demographic factors (age, race, gender, and weight), renal or hepatic dysfunction, or to assess the effect of concomitant drugs on the pharmacokinetics of ziconotide due to the low systemic exposure of ziconotide following intrathecal administration.
## Nonclinical Toxicology
- No carcinogenicity studies have been conducted in animals.
- Ziconotide was negative in the in vitro bacterial reverse mutation assay, in vitro mouse lymphoma assay, in vivo mouse micronucleus assay, and in the in vitro Syrian hamster embryo (SHE) cell transformation assay.
- Ziconotide did not affect male fertility in rats when administered as a continuous intravenous infusion at a dose of up to 10 mg/kg/day when administered for approximately 8 weeks, including a 28-day pre-mating period, or female fertility at a dose of 3 mg/kg/day when administered for approximately 6 weeks, including a 14-day pre-mating period. Estimated exposures for the male and female rats were approximately 6500-fold and 1700-fold higher, respectively, than the expected exposure resulting from the maximum recommended human daily intrathecal dose of 0.8 mcg/hr (19.2 mcg/day) based on plasma exposure.
- Female fertility in rats was significantly affected following continuous intravenous infusion at a dose of 10 mg/kg/day. Significant reductions in corpora lutea, implantation sites, and number of live fetuses were observed.
# Clinical Studies
- The efficacy of intrathecal PRIALT in the management of severe chronic pain was studied in three double-blind, placebo-controlled, multicenter studies in a total of 457 patients (268 PRIALT, 189 placebo) using two different titration schedules. The slow titration schedule tested dose increases 2 to 3 times per week with a maximum dose of 19.2 mcg/day (0.8 mcg/hr) at 21 days. The fast titration schedule used daily increases up to a maximum dose of 57.6 mcg/day (2.4 mcg/hr) in 5 to 6 days but resulted in less tolerability and substantially more frequent adverse events.
- A randomized, double-blind, placebo-controlled study of PRIALT was conducted in adult patients with severe chronic pain not adequately controlled with intrathecally delivered analgesics including morphine, bupivacaine and/or clonidine; or who were intolerant to analgesics and/or systemic analgesics using the 21-day slow titration schedule. All prior intrathecal medications were discontinued over a one to three week period, and patients were maintained on a stable regimen of non-intrathecal analgesics, including opiates, for at least 7 days prior to randomization. Dosing with PRIALT was started at 2.4 mcg/day (0.1 mcg/hr) and the dose was increased by 2.4 mcg/day (0.1 mcg/hr) two to three times/week (minimum titration interval 24 hours) to a maximum dose of 19.2 mcg/day (0.8 mcg/hr) as needed for management of pain. The final mean dose at the end of the trial at 21 days was 6.9 mcg/day (0.29 mcg/hr).
- Using a 100 mm Visual Analog Scale of Pain Intensity (VASPI) where 100 mm represented the worst possible pain, mean baseline pain scores were 81 in both the PRIALT and placebo groups. The primary efficacy variable was the mean percent change in the VASPI score from baseline to day 21. In the intent-to-treat efficacy analysis, there was a statistically significant difference between groups in the mean percent change in VASPI score from baseline with the PRIALT group having a 12% mean improvement at Week 3 compared to a 5% mean improvement in the placebo group. The 95% confidence interval for the treatment difference (PRIALT–placebo) was 0.4%, 13%.
- The effect of intrathecal PRIALT on pain was variable over the time period of treatment for some patients. Patients exhibited various degrees of improvement in pain after three weeks of treatment compared with baseline pain assessment. Figure 1 depicts the fraction of patients by their degree of improvement. The figure is cumulative, so that patients whose change from baseline is, for example, 30%, are also included at every level of improvement below 30%. Patients who did not have a VASPI score recorded at Week 3 (Study days 17–23, inclusive) were assigned 0% improvement. The improvement in the proportion of “responders,” defined as having a ≥ 30% improvement from baseline in VASPI, was 16% in the PRIALT group compared to 12% in the placebo group, for a net difference of 4%. The use of non-intrathecal opioids decreased by 24% in the PRIALT group and by 17% in the placebo group.
# How Supplied
- PRIALT is supplied as a 25 mcg/mL solution in a single-use 20 mL glass vial and as a 100 mcg/mL solution in single-use glass vials containing 1 mL or 5 mL of solution. One vial is packaged per carton.
- Presentation (NDC)
- 25 mcg/mL: 20 mL vial (18860-723-10). Only the undiluted 25 mcg/mL formulation should be used for PRIALT naïve pump priming.
- 100 mcg/mL: 1 mL vial (18860-720-10) and 5 mL vial (18860-722-10)
- Storage
- Refrigerate PRIALT during transit.
- Store PRIALT at 2°C to 8°C (36°F to 46°F).
- PRIALT, once diluted aseptically with saline, may be stored at 2°C to 8°C for 24 hours.
- Do NOT freeze PRIALT.
- Protect from light.
## Storage
There is limited information regarding Ziconotide Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise patients that psychiatric symptoms (paranoia, hostility, mania, depressive, suicidal) and cognitive symptoms (confusion, memory problems, speech disorder) may occur during treatment with PRIALT.
- Caution patients against engaging in hazardous activity requiring complete mental alertness or motor coordination such as operating machinery or driving a motor vehicle during treatment with PRIALT.
- Caution patients about possible combined effects with other CNS-depressant drugs. Dosage adjustments may be necessary when PRIALT is administered with such agents because of the potentially additive effects.
- Advise patients to contact a physician if the patient experiences new or worsening muscle pain, soreness, weakness with or without darkened urine.
- Instruct patients and their caregivers to contact a physician immediately if the patient has any of the following
- A change in mental status (e.g., lethargy, confusion, disorientation, decreased alertness)
- A change in mood, perception (hallucinations, including unusual tactile sensations in the oral cavity)
- Symptoms of depression or suicidal ideation
- Nausea, vomiting, seizures, fever, headache, and/or stiff neck, as these may be symptoms of developing meningitis
- Decreased level of consciousness, unresponsiveness or stupor
- New muscular symptoms (e.g., muscle cramps, myalgias)
- Withdrawal symptoms (e.g., nausea, insomnia, flu-like symptoms) as a result of abruptly discontinuing opioid therapy
- Development of serious skin reaction (e.g., bullous dermatitis, skin ulcers, skin exfoliation)
- For use only in the Medtronic SynchroMed® II Infusion System and CADD-Micro Ambulatory Infusion Pump.
# Precautions with Alcohol
- Alcohol-Ziconotide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- PRIALT®
# Look-Alike Drug Names
There is limited information regarding Ziconotide Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Ziconotide
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2]
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# Black Box Warning
# Overview
Ziconotide is an N-type calcium channel antagonist that is FDA approved for the {{{indicationType}}} of severe chronic pain in patients for whom intrathecal therapy is warranted, and who are intolerant of or refractory to other treatment, such as systemic analgesics, adjunctive therapies, or intrathecal morphine. There is a Black Box Warning for this drug as shown here. Common adverse reactions include dizziness, nausea, confusional state, nystagmus.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- PRIALT (ziconotide) solution, intrathecal infusion is indicated for the management of severe chronic pain in adult patients for whom intrathecal therapy is warranted, and who are intolerant of or refractory to other treatment, such as systemic analgesics, adjunctive therapies, or intrathecal morphine.
- Dose Initiation
- Initiate dosing with PRIALT via intrathecal device at no more than 2.4 mcg/day (0.1 mcg/hr).
- Dose Titration
- Titrate doses by up to 2.4 mcg/day (0.1 mcg/hr) at intervals of no more than 2 to 3 times per week based on analgesic response and adverse events. Dose increases in increments of less than 2.4 mcg/day (0.1 mcg/hr) and less frequently than 2 to 3 times per week may be used. For each dose titration, assess the dosing requirements and adjust the pump infusion flow rate as required to achieve the new dosing.
- The maximum recommended dose is 19.2 mcg/day (0.8 mcg/hr).
- Adjust the dose of intrathecal PRIALT according to the severity of pain, the patient’s response to therapy, and the occurrence of adverse reactions.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ziconotide in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ziconotide in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Ziconotide in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ziconotide in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ziconotide in pediatric patients.
# Contraindications
- PRIALT is contraindicated in patients with a known hypersensitivity to ziconotide or any of its formulation components.
- PRIALT is contraindicated in patients with any other concomitant treatment or medical condition that would render intrathecal administration hazardous. Contraindications to the use of intrathecal analgesia include the presence of infection at the microinfusion injection site, uncontrolled bleeding diathesis, and spinal canal obstruction that impairs circulation of CSF.
- PRIALT is contraindicated in patients with a pre-existing history of psychosis.
# Warnings
### Precautions
- Cognitive and Neuropsychiatric Adverse Reactions
- ere psychiatric symptoms and neurological impairment may occur during treatment with PRIALT. PRIALT is contraindicated in patients with a pre-existing history of psychosis. Monitor all patients frequently for evidence of cognitive impairment, hallucinations, or changes in mood or consciousness. PRIALT therapy can be interrupted or discontinued abruptly without evidence of withdrawal effects in the event of serious neurological or psychiatric signs or symptoms.
- Events of acute psychiatric disturbances such as hallucinations (12%), paranoid reactions (3%), hostility (2%), delirium (2%), psychosis (1%), and manic reactions (0.4%) have been reported in patients treated with PRIALT. Patients with pretreatment psychiatric disorders may be at an increased risk. PRIALT may cause or worsen depression with the risk of suicide in susceptible patients. In placebo-controlled trials, there was a higher incidence of suicide, suicide attempts, and suicide ideations in PRIALT-treated patients than in the placebo group (0.27/patient year for PRIALT patients and 0.10/patient year for placebo patients).
- Management of psychiatric complications may need to include discontinuation of PRIALT, treatment with psychotherapeutic agents and/or short-term hospitalization. Before drug is reinitiated, careful evaluation must be performed on an individual basis.
- Use of PRIALT has been associated with cognitive impairment and decreased alertness/unresponsiveness. The following cognitive adverse reaction rates were reported: confusion (33%), memory impairment (22%), speech disorder (14%), aphasia (12%), thinking abnormal (8%), and amnesia (1%). Cognitive impairment may appear gradually after several weeks of treatment. Reduce the dose of PRIALT or discontinue the use of PRIALT if signs or symptoms of cognitive impairment develop, but other contributing causes must also be considered. The cognitive effects of PRIALT are generally reversible within 2 weeks after drug discontinuation. The median time to reversal of the individual cognitive effects ranged from 3 to 15 days. The elderly (≥ 65 years of age) are at higher risk for confusion.
- There may be additive effects on cognitive impairment and decreased alertness when PRIALT is used in conjunction with other CNS-depressant drugs that may necessitate dosage adjustments.
- Meningitis and Other Infections
- Meningitis can occur due to inadvertent contamination of the microinfusion device and other means such as CSF seeding due to hematogenous or direct spread from an infected pump pocket or catheter tract. While meningitis is rare with an internal microinfusion device and surgically-implanted catheter, the incidence increases substantially with external devices. In PRIALT clinical trials, meningitis occurred in 3% (40) of patients in the PRIALT group using either internal or external microinfusion devices and 1% (1 case) of patients in the placebo group.
- The risk of meningitis was particularly high in patients with external microinfusion devices and catheters, occurring in 38 out of 41 patients (93%), 37 of whom received PRIALT and one who received placebo.
- Patients, caregivers, and healthcare providers must be particularly vigilant for the signs and symptoms of meningitis, including but not limited to fever, headache, stiff neck, altered mental status (e.g., lethargy, confusion, disorientation), nausea or vomiting, and occasionally seizures. Serious infection or meningitis can occur within 24 hours of a breach in sterility such as a disconnected catheter, the most common cause of meningitis with external microinfusion devices. The patient and health care provider must be familiar with the handling of the external microinfusion device and care of the catheter skin exit site.
- Strict aseptic procedures must be used during the preparation of the PRIALT solution and refilling of the microinfusion device to decrease the risk of introducing contaminants or other environmental pathogens into the reservoir. In suspected cases (especially in immuno-compromised patients) or in confirmed cases of meningitis, CSF cultures must be obtained and appropriate antibiotic therapy must be promptly instituted. Treatment of meningitis usually requires removal of the microinfusion system, catheter, and any other foreign body materials within the intrathecal space and, therefore, discontinuation of PRIALT therapy.
- Reduced Level of Consciousness
- Patients have become unresponsive or stuporous while receiving PRIALT. The incidence of unresponsiveness or stupor in clinical trials was 2% in PRIALT-treated patients. During these episodes, patients sometimes appear to be conscious and breathing is not depressed. If reduced levels of consciousness occur, discontinue PRIALT until the event resolves, and other etiologies (e.g., meningitis) must be considered. There is no known pharmacologic antagonist for this effect. Patients taking concomitant antiepileptics, neuroleptics, sedatives, or diuretics may be at higher risk of depressed levels of consciousness. If altered consciousness occurs, discontinue other CNS-depressant drugs as clinically appropriate.
- Elevation of Serum Creatine Kinase
- In clinical studies, 40% of PRIALT-treated patients had serum creatine kinase (CK) levels above the upper limit of normal (ULN), and 11% had CK levels that were greater than three times the ULN. In cases where CK was fractionated, only the muscle isoenzyme (MM) was elevated. The time to occurrence was sporadic, but the greatest incidence of CK elevation was during the first two months of treatment. One case of symptomatic myopathy with EMG findings, and two cases of acute renal failure associated with rhabdomyolysis and extreme CK elevations (17,000–27,000 IU/L) have been reported in PRIALT-treated patients.
- Therefore, monitor serum CK in patients undergoing treatment with PRIALT periodically (e.g., every other week for the first month and monthly as appropriate thereafter). Evaluate patients clinically and obtain CK measurements in the setting of new neuromuscular symptoms (e.g., myalgias, myasthenia, muscle cramps, asthenia) or a reduction in physical activity. If these symptoms continue and CK levels remain elevated or continue to rise, reduce the dose or discontinue the use of PRIALT.
- Withdrawal From Opiates
- PRIALT is not an opiate and cannot prevent or relieve the symptoms associated with the withdrawal of opiates.
- To avoid withdrawal syndrome when opiate withdrawal is necessary, do not abruptly reduce or withdraw opioid medications.
- For patients being withdrawn from intrathecal opiates or intrathecal opiate infusion, gradually taper over a few weeks and replace with a pharmacologically equivalent dose of oral opiates.
- Driving and Operating Machinery
- Use of PRIALT has been associated with cognitive impairment and decreased alertness/unresponsiveness. Therefore, caution patients against engaging in hazardous activities that require complete mental alertness or motor coordination such as operating machinery or driving a motor vehicle.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates in clinical practice.
- A total of 1254 adult patients received PRIALT as a continuous infusion in acute and severe chronic pain trials with an exposure of 662 patient-years. The mean duration of treatment was 193 days with 173 patients (14%) treated for at least 1 year. The average final dose was 17.6 mcg/day (0.73 mcg/hr).
- The most frequently reported adverse reactions (≥ 25%) in clinical trials were dizziness, nausea, confusional state and nystagmus. Slower titration of PRIALT may result in fewer serious adverse reactions and discontinuation of PRIALT for adverse reactions.
- Adverse reactions during the slow titration placebo-controlled trial that occurred in 5% or greater of patients and more commonly with PRIALT than with placebo are summarized in Table 1.
The following adverse reactions assessed as related to PRIALT have been reported in 2% or greater of patients participating in the clinical studies:
Fall, fatigue, lethargy, peripheral edema
Hypotension, orthostatic hypotension
Abdominal pain, constipation, dry mouth, nausea aggravated
Appetite decreased
Muscle cramp, muscle weakness, myalgia, pain in limb
Aphasia, areflexia, balance impaired, burning sensation, coordination abnormal, disturbance in attention, dizziness postural, dysarthria, dysgeusia, hypoaesthesia, mental impairment, paraesthesia, sedation, speech disorder, agitation, anxiety, cognitive disorder, confusional state, depression, depression aggravated, disorientation, hallucination, hallucination auditory, hallucination visual, insomnia, irritability, mood disorder, nervousness, paranoia
Diplopia, visual disturbance
Dysuria, urinary hesitation
Blood creatine phosphokinase increased
- The following medically important adverse reactions occurred in less than 2% of patients were assessed by the clinical investigators as related to PRIALT: acute renal failure, atrial fibrillation, cerebrovascular accident, sepsis, meningitis, psychotic disorder, suicidal ideation, respiratory distress, rhabdomyolysis, electrocardiogram abnormal, stupor, loss of consciousness, clonic convulsion and grand mal convulsion. Fatal aspiration pneumonia and suicide attempt were reported in less than 1% of patients.
## Postmarketing Experience
- The following adverse events have been reported during post-approval use of PRIALT. Because these events are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure: Hypersensitivity reactions including angioedema, serious skin reactions including bullous dermatitis, skin ulcers, skin exfoliation, and burning skin sensation.
# Drug Interactions
- Formal PK drug-drug interaction studies have not been performed with PRIALT. As ziconotide is a peptide, it is expected to be completely degraded by endopeptidases and exopeptidases (Phase I hydrolytic enzymes) widely located throughout the body, and not by other Phase I biotransformation processes (including the cytochrome P450 system) or by Phase II conjugation reactions. Thus, intrathecal administration, low plasma ziconotide concentrations, and metabolism by ubiquitous peptidases make metabolic interactions of other drugs with ziconotide unlikely. Further, as ziconotide is not highly bound in plasma (approximately 50%) and has low plasma exposure following intrathecal administration, clinically relevant plasma protein displacement reactions involving ziconotide and co-administered medications are unlikely.
- Over 90% of patients treated with intrathecal PRIALT used systemic opiates and in the slow titration study, 98% of patients received opioids.
- The combination of PRIALT with intrathecal opiates has not been studied in placebo-controlled clinical trials and is not recommended.
- Interaction with CNS Depressants
- Almost all patients in the PRIALT clinical trials received concomitant non-intrathecal medication. Most patients received several concomitant drugs, including antidepressants (66%), anxiolytics (52%), antiepileptics (47%), neuroleptics (46%), and sedatives (34%). The use of drugs with CNS-depressant activities may be associated with an increased incidence of CNS adverse reactions such as dizziness and confusion.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- Ziconotide was embryolethal in rats when given as a continuous intravenous infusion during the major period of organogenesis as evidenced by significant increases in post-implantation loss because of an absence or a reduced number of live fetuses. Estimated exposure for embryolethality in the rat was approximately 700-fold above the expected exposure resulting from the maximum recommended human daily intrathecal dose of 0.8 mcg/hr (19.2 mcg/day). Ziconotide was not teratogenic in female rats when given as a continuous intravenous infusion at doses up to 30 mg/kg/day or in female rabbits up to 5 mg/kg/day during the major period of organ development. Estimated exposures in the female rat and rabbit were approximately 26,000-fold and 940-fold higher than the expected exposure resulting from the maximum recommended human daily dose of 0.8 mcg/hr (19.2 mcg/day) based on plasma exposure. Maternal toxicity in the rat and rabbit, as evidenced by decreased body weight gain and food consumption, was present at all dose levels. Maternal toxicity in the rat led to reduced fetal weights and transient, delayed ossification of the pubic bones at doses ≥ 15 mg/kg/day, which is approximately 8900-fold higher than the expected exposure resulting from the maximum recommended human daily intrathecal dose of 0.8 mcg/hr (19.2 mcg/day) based on plasma exposure. The no observable adverse effect level (NOAEL) for embryo-fetal development in rats was 0.5 mg/kg/day and in rabbits was 5 mg/kg/day. Estimated NOAEL exposures in the rat and rabbit were approximately 400-fold and 940-fold higher than the expected exposure resulting from the maximum recommended human daily intrathecal dose of 0.8 mcg/hr (19.2 mcg/day) based on plasma exposure.
- In a pre- and post-natal study in rats, ziconotide given as a continuous intravenous infusion did not affect pup development or reproductive performance up to a dose of 10 mg/kg/day, which is approximately 3800-fold higher than the expected exposure resulting from the maximum recommended human daily intrathecal dose of 0.8 mcg/hr (19.2 mcg/day) based on plasma exposure. Maternal toxicity, as evidenced by clinical observations, and decreases in body weight gain and food consumption were observed at all doses.
- No adequate and well-controlled studies have been conducted in pregnant women. Because animal studies are not always predictive of human response, PRIALT should be used during pregnancy only if the potential benefit justifies risk to the fetus.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ziconotide in women who are pregnant.
### Labor and Delivery
- The effect of PRIALT on labor and delivery in humans is not known.
### Nursing Mothers
- It is not known whether PRIALT is excreted in human breast milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from PRIALT, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
- Safety and effectiveness in pediatric patients have not been established.
### Geriatic Use
- Of the total number of subjects in clinical studies of PRIALT, 22% were 65 and over, while 7% were 75 and over. In all trials, there was a higher incidence of confusion in older patients (42% for ≥ 65 year old versus 29% for < 65 year old subgroups). Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, the dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.
### Gender
There is no FDA guidance on the use of Ziconotide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Ziconotide with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Ziconotide in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Ziconotide in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ziconotide in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Ziconotide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intrathecal
### Monitoring
There is limited information regarding Monitoring of Ziconotide in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Ziconotide in the drug label.
# Overdosage
## Acute Overdose
- The maximum recommended intrathecal PRIALT dose is 19.2 mcg/day. The maximum intrathecal dose of PRIALT in clinical trials was 912 mcg/day. In some patients who received intrathecal doses greater than the maximum recommended dose, exaggerated pharmacological effects (e.g., ataxia, nystagmus, dizziness, stupor, unresponsiveness, spinal myoclonus, confusion, sedation, hypotension, word-finding difficulties, garbled speech, nausea, and vomiting) were observed. There was no indication of respiratory depression. Overdoses may occur due to pump programming errors or incorrect drug concentration preparations. In these cases, patients were observed and ziconotide was either temporarily discontinued or permanently withdrawn. Most patients recovered within 24 hours after withdrawal of drug. In the event of an overdose, elimination of ziconotide from CSF would be expected to remain constant (CSF t½=4.6 hours). Therefore, within 24 hours of stopping therapy, the ziconotide CSF concentration should be less than 5% of peak levels.
- There is no known antidote to ziconotide. General medical supportive measures should be administered to patients who receive an overdose until the exaggerated pharmacological effects of the drug have resolved. Treatment for an overdose is hospitalization, when needed, and symptom-related supportive care. Ziconotide does not bind to opiate receptors and its pharmacological effects are not blocked by opioid antagonists.
- In the event of an inadvertent intravenous or epidural administration, adverse reactions could include severe hypotension, which can be treated with a recumbent posture and blood pressure support as required. The half-life of PRIALT in serum is 1.3 hours.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Ziconotide in the drug label.
# Pharmacology
## Mechanism of Action
- Ziconotide binds to N-type calcium channels located on the primary nociceptive (A-δ and C) afferent nerves in the superficial layers (Rexed laminae I and II) of the dorsal horn in the spinal cord. Although the mechanism of action of ziconotide has not been established in humans, results in animals suggest that its binding blocks N-type calcium channels, which leads to a blockade of excitatory neurotransmitter release from the primary afferent nerve terminals and antinociception.
## Structure
- PRIALT contains ziconotide, a synthetic equivalent of a naturally occurring conopeptide found in the piscivorous marine snail, Conus magus. Ziconotide is a 25 amino acid, polybasic peptide containing three disulfide bridges with a molecular weight of 2639 daltons and a molecular formula of C102H172N36O32S7. The amino acid sequence and disulfide bridging pattern are given below:
- Ziconotide is a hydrophilic molecule that is freely soluble in water and is practically insoluble in methyl t-butyl ether.
- PRIALT is formulated as a sterile, preservative-free, isotonic solution for intrathecal administration using an appropriate microinfusion device [see Dosage and Administration (2)]. Each 1 or 5 mL vial of PRIALT (100 mcg/mL) respectively contains 100 or 500 mcg of ziconotide acetate, and the 20 mL vial of PRIALT (25 mcg/mL) contains 500 mcg of ziconotide acetate, with L-methionine and sodium chloride as excipients at pH 4.0–5.0. Each vial is intended for single use only, either undiluted or after dilution to the appropriate concentration with 0.9% Sodium Chloride Injection, USP (preservative free).
## Pharmacodynamics
- Interaction with Opioids
- Ziconotide does not bind to opioid receptors and its pharmacological effects are not blocked by opioid antagonists. In animal models, intrathecal ziconotide potentiated opioid-induced reduction in gastrointestinal (GI) motility, but did not potentiate morphine-induced respiratory depression. In rats receiving ziconotide, additive analgesic effects were observed with concurrent administration of morphine, baclofen, or clonidine. Concurrent administration of intrathecal ziconotide and morphine did not prevent the development of morphine tolerance in rats.
## Pharmacokinetics
- The cerebrospinal fluid (CSF) pharmacokinetics (PK) of ziconotide have been studied after one-hour intrathecal infusions of 1 to 10 mcg of PRIALT to patients with chronic pain. The plasma PK following intravenous infusion (0.3 to 10 mcg/kg/day) have also been studied. Both intrathecal and intravenous data are shown below (Table 2).
- Following one-hour intrathecal administration of 1 to 10 mcg of PRIALT, both total exposure (AUC; range: 83.6 to 608 ng•h/mL) and peak exposure (Cmax; range: 16.4 to 132 ng/mL) values in the CSF were variable and dose-dependent, but appeared approximately dose-proportional. During 5 or 6 days of continuous intrathecal infusions of PRIALT at infusion rates ranging from 0.1 to 7.0 mcg/hr in patients with chronic pain, plasma ziconotide levels could not be quantified in 56% of patients using an assay with a lower limit of detection of approximately 0.04 ng/mL. Predictably, patients requiring higher intrathecal infusion dose rates were more likely to have quantifiable ziconotide levels in plasma. Plasma ziconotide levels, when detectable, remain constant after many months of intrathecal PRIALT infusion in patients followed for up to 9 months.
- Distribution
- Ziconotide is about 50% bound to human plasma proteins. The mean CSF volume of distribution (Vd) of ziconotide following intrathecal administration approximates the estimated total CSF volume (140 mL).
- Metabolism
- Ziconotide is cleaved by endopeptidases and exopeptidases at multiple sites on the peptide. Following passage from the CSF into the systemic circulation during continuous intrathecal administration, ziconotide is expected to be susceptible to proteolytic cleavage by various ubiquitous peptidases/proteases present in most organs (e.g., kidney, liver, lung, muscle, etc.), and thus readily degraded to peptide fragments and their individual constituent free amino acids. Human and animal CSF and blood exhibit minimal hydrolytic activity toward ziconotide in vitro. The biological activity of the various expected proteolytic degradation products of ziconotide has not been assessed.
- Elimination
- Minimal amounts of ziconotide (< 1%) were recovered in human urine following intravenous infusion. The terminal half-life of ziconotide in CSF after an intrathecal administration was around 4.6 hours (range 2.9 to 6.5 hours). Mean CSF clearance (CL) of ziconotide approximates adult human CSF turnover rate (0.3 to 0.4 mL/min).
- Special Populations
- No formal studies were conducted to assess the effect of demographic factors (age, race, gender, and weight), renal or hepatic dysfunction, or to assess the effect of concomitant drugs on the pharmacokinetics of ziconotide due to the low systemic exposure of ziconotide following intrathecal administration.
## Nonclinical Toxicology
- No carcinogenicity studies have been conducted in animals.
- Ziconotide was negative in the in vitro bacterial reverse mutation assay, in vitro mouse lymphoma assay, in vivo mouse micronucleus assay, and in the in vitro Syrian hamster embryo (SHE) cell transformation assay.
- Ziconotide did not affect male fertility in rats when administered as a continuous intravenous infusion at a dose of up to 10 mg/kg/day when administered for approximately 8 weeks, including a 28-day pre-mating period, or female fertility at a dose of 3 mg/kg/day when administered for approximately 6 weeks, including a 14-day pre-mating period. Estimated exposures for the male and female rats were approximately 6500-fold and 1700-fold higher, respectively, than the expected exposure resulting from the maximum recommended human daily intrathecal dose of 0.8 mcg/hr (19.2 mcg/day) based on plasma exposure.
- Female fertility in rats was significantly affected following continuous intravenous infusion at a dose of 10 mg/kg/day. Significant reductions in corpora lutea, implantation sites, and number of live fetuses were observed.
# Clinical Studies
- The efficacy of intrathecal PRIALT in the management of severe chronic pain was studied in three double-blind, placebo-controlled, multicenter studies in a total of 457 patients (268 PRIALT, 189 placebo) using two different titration schedules. The slow titration schedule tested dose increases 2 to 3 times per week with a maximum dose of 19.2 mcg/day (0.8 mcg/hr) at 21 days. The fast titration schedule used daily increases up to a maximum dose of 57.6 mcg/day (2.4 mcg/hr) in 5 to 6 days but resulted in less tolerability and substantially more frequent adverse events.
- A randomized, double-blind, placebo-controlled study of PRIALT was conducted in adult patients with severe chronic pain not adequately controlled with intrathecally delivered analgesics including morphine, bupivacaine and/or clonidine; or who were intolerant to analgesics and/or systemic analgesics using the 21-day slow titration schedule. All prior intrathecal medications were discontinued over a one to three week period, and patients were maintained on a stable regimen of non-intrathecal analgesics, including opiates, for at least 7 days prior to randomization. Dosing with PRIALT was started at 2.4 mcg/day (0.1 mcg/hr) and the dose was increased by 2.4 mcg/day (0.1 mcg/hr) two to three times/week (minimum titration interval 24 hours) to a maximum dose of 19.2 mcg/day (0.8 mcg/hr) as needed for management of pain. The final mean dose at the end of the trial at 21 days was 6.9 mcg/day (0.29 mcg/hr).
- Using a 100 mm Visual Analog Scale of Pain Intensity (VASPI) where 100 mm represented the worst possible pain, mean baseline pain scores were 81 in both the PRIALT and placebo groups. The primary efficacy variable was the mean percent change in the VASPI score from baseline to day 21. In the intent-to-treat efficacy analysis, there was a statistically significant difference between groups in the mean percent change in VASPI score from baseline with the PRIALT group having a 12% mean improvement at Week 3 compared to a 5% mean improvement in the placebo group. The 95% confidence interval for the treatment difference (PRIALT–placebo) was 0.4%, 13%.
- The effect of intrathecal PRIALT on pain was variable over the time period of treatment for some patients. Patients exhibited various degrees of improvement in pain after three weeks of treatment compared with baseline pain assessment. Figure 1 depicts the fraction of patients by their degree of improvement. The figure is cumulative, so that patients whose change from baseline is, for example, 30%, are also included at every level of improvement below 30%. Patients who did not have a VASPI score recorded at Week 3 (Study days 17–23, inclusive) were assigned 0% improvement. The improvement in the proportion of “responders,” defined as having a ≥ 30% improvement from baseline in VASPI, was 16% in the PRIALT group compared to 12% in the placebo group, for a net difference of 4%. The use of non-intrathecal opioids decreased by 24% in the PRIALT group and by 17% in the placebo group.
# How Supplied
- PRIALT is supplied as a 25 mcg/mL solution in a single-use 20 mL glass vial and as a 100 mcg/mL solution in single-use glass vials containing 1 mL or 5 mL of solution. One vial is packaged per carton.
- Presentation (NDC)
- 25 mcg/mL: 20 mL vial (18860-723-10). Only the undiluted 25 mcg/mL formulation should be used for PRIALT naïve pump priming.
- 100 mcg/mL: 1 mL vial (18860-720-10) and 5 mL vial (18860-722-10)
- Storage
- Refrigerate PRIALT during transit.
- Store PRIALT at 2°C to 8°C (36°F to 46°F).
- PRIALT, once diluted aseptically with saline, may be stored at 2°C to 8°C for 24 hours.
- Do NOT freeze PRIALT.
- Protect from light.
## Storage
There is limited information regarding Ziconotide Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise patients that psychiatric symptoms (paranoia, hostility, mania, depressive, suicidal) and cognitive symptoms (confusion, memory problems, speech disorder) may occur during treatment with PRIALT.
- Caution patients against engaging in hazardous activity requiring complete mental alertness or motor coordination such as operating machinery or driving a motor vehicle during treatment with PRIALT.
- Caution patients about possible combined effects with other CNS-depressant drugs. Dosage adjustments may be necessary when PRIALT is administered with such agents because of the potentially additive effects.
- Advise patients to contact a physician if the patient experiences new or worsening muscle pain, soreness, weakness with or without darkened urine.
- Instruct patients and their caregivers to contact a physician immediately if the patient has any of the following
- A change in mental status (e.g., lethargy, confusion, disorientation, decreased alertness)
- A change in mood, perception (hallucinations, including unusual tactile sensations in the oral cavity)
- Symptoms of depression or suicidal ideation
- Nausea, vomiting, seizures, fever, headache, and/or stiff neck, as these may be symptoms of developing meningitis
- Decreased level of consciousness, unresponsiveness or stupor
- New muscular symptoms (e.g., muscle cramps, myalgias)
- Withdrawal symptoms (e.g., nausea, insomnia, flu-like symptoms) as a result of abruptly discontinuing opioid therapy
- Development of serious skin reaction (e.g., bullous dermatitis, skin ulcers, skin exfoliation)
- For use only in the Medtronic SynchroMed® II Infusion System and CADD-Micro Ambulatory Infusion Pump.
# Precautions with Alcohol
- Alcohol-Ziconotide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- PRIALT®[1]
# Look-Alike Drug Names
There is limited information regarding Ziconotide Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Prialt | |
66d4109fd3967f3b410896f4ffa771c7c2b77113 | wikidoc | Primordium | Primordium
A primordium, in embryology, is defined as an organ or tissue in its earliest recognizable stage of development. Cells of the primordium are called primordial cells.
A primordium can be considered as the simplest set of initial conditions capable of triggering growth.
# Primordium development in plants
Primordial development in plants is a very critical process for proper positioning and development of different plant organs. Different primordial types like the leaf and flower primordia arise from the shoot apical meristem. The process is intricately regulated by a set of genes that affect the positioning, growth and differentiation of the primordium.
The plant hormone Auxin has also been implicated in this process, with the new primordia being initiated at the site where the auxin concentration is the highest. Genes like SHOOTMERISTEMLESS (STM), CUP-SHAPED COTYLEDON (CUC) etc are involved in defining the borders of the newly formed primordium. | Primordium
Template:Cleanup
A primordium, in embryology, is defined as an organ or tissue in its earliest recognizable stage of development[1]. Cells of the primordium are called primordial cells.
A primordium can be considered as the simplest set of initial conditions capable of triggering growth.
# Primordium development in plants
Primordial development in plants is a very critical process for proper positioning and development of different plant organs. Different primordial types like the leaf and flower primordia arise from the shoot apical meristem. The process is intricately regulated by a set of genes that affect the positioning, growth and differentiation of the primordium.
The plant hormone Auxin has also been implicated in this process, with the new primordia being initiated at the site where the auxin concentration is the highest. Genes like SHOOTMERISTEMLESS (STM), CUP-SHAPED COTYLEDON (CUC) etc are involved in defining the borders of the newly formed primordium. [2] | https://www.wikidoc.org/index.php/Primordium | |
d3f22736ccf09fd8f3ac10492a67d1e52d779337 | wikidoc | Pritumumab | Pritumumab
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
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# Overview
Pritumumab is a human monoclonal antibody and which it is used to treat cancer. | Pritumumab
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Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
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# Overview
Pritumumab is a human monoclonal antibody and which it is used to treat cancer.
Template:Humanmonoclonals
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Template:WH
Template:WS | https://www.wikidoc.org/index.php/Pritumumab | |
f28b6af96e814285b459c2db0cc52652f970ec2b | wikidoc | Prohormone | Prohormone
A prohormone is a substance that is a precursor to a hormone, usually having minimal hormonal effect by itself. The term has been used in medical science since the middle of the 20th century. Examples of natural, human prohormones include proinsulin and pro-opiomelanocortin.
For peptide hormones, the conversion process from prohormone to hormone typically occurs after export to the endoplasmic reticulum and often requires multiple processing enzymes. For example, proinsulin is processed by PC 1/2, PC 3, and carboxypeptidase E to afford insulin. Proamylin, which is cosecreted with proinsulin, requires the above three factors and an amidating monoxygenase.
For small molecule hormones, the conversion is often one step, and is often used to regulate hormone levels.
# Prohormones of anabolic steroids
In the last two decades, prohormones have also been used by bodybuilders, athletes, and nonmedical users of anabolic steroids and other hormones to refer to substances that are expected to convert to active hormones in the body. The intent is to provide the putative benefits of taking an anabolic steroid without the legal or medical risks, and to achieve the hoped-for benefits or advantages without use of anabolic steroids themselves. Since prohormones are not anabolic steroids themselves, they are legally classified as dietary supplements and not subject to the much tighter regulatory requirements of the Food and Drug Administration (FDA) which apply to prescription hormones.
A typical prohormone is intended to be a precursor of an anabolic steroid like testosterone, which is taken in order to boost the body’s available hormone supply. These precursors are intended to be converted to full, active hormones via an enzymatic process that occurs during metabolism, typically resulting in the addition of whichever atoms happen to be missing from the chemical structure of the compound.
The use of prohormones has become popular among bodybuilders, since the effects can be similar (though normally much less drastic) to those achieved through the use of synthetic anabolic steroids, including gains in muscular strength and hypertrophy. There are currently many companies manufacturing prohormone products for this purpose.
Prohormones are legally sold in most parts of the world and were classified in the United States by the FDA as dietary supplements because they consist of compounds that occur naturally in the human body; however their use remains quite controversial and side effects are not uncommon. To date, prohormone products have been banned in the United States, however, most have not been thoroughly studied, and the health effects of prolonged use are mostly unknown.
On October 22nd, 2004, President Bush signed into law the Anabolic Steroid Control Act of 2004 (118 Stat. 1661).
The bill was written to become effective in 90 days, which was January 20, 2005. This legislation places both anabolic steroids and prohormones on a list of controlled substances (a new type of "regulatory control").
# Common types of prohormones on the market
- 4-androstenedione
Converts to: testosterone
Characteristics:
Research indicates a conversion rate of about 5.9%, which means that of the amount taken orally, 5.6% is converted to testosterone.
Relatively high rate of aromatization to estrogen, and consequently higher risk of side-effects such as gynecomastia brought on by excessive estrogen formation.
Exhibits significant androgenic properties, which may result in side effects such as male pattern baldness, acne, and enlarged prostate.
- Converts to: testosterone
- Characteristics:
Research indicates a conversion rate of about 5.9%, which means that of the amount taken orally, 5.6% is converted to testosterone.
Relatively high rate of aromatization to estrogen, and consequently higher risk of side-effects such as gynecomastia brought on by excessive estrogen formation.
Exhibits significant androgenic properties, which may result in side effects such as male pattern baldness, acne, and enlarged prostate.
- Research indicates a conversion rate of about 5.9%, which means that of the amount taken orally, 5.6% is converted to testosterone.
- Relatively high rate of aromatization to estrogen, and consequently higher risk of side-effects such as gynecomastia brought on by excessive estrogen formation.
- Exhibits significant androgenic properties, which may result in side effects such as male pattern baldness, acne, and enlarged prostate.
- 4-androstenediol (4-AD)
Converts to: testosterone
Characteristics:
Conversion rate of about 15.76%, almost triple that of androstenedione, due to utilization of a different enzymatic pathway.
No direct conversion to estrogen, though some secondary aromatization does occur through metabolism.
Appears to be less androgenic than its cousin, since it does not metabolize into the potent androgen dihydrotestosterone (DHT).
- Converts to: testosterone
- Characteristics:
Conversion rate of about 15.76%, almost triple that of androstenedione, due to utilization of a different enzymatic pathway.
No direct conversion to estrogen, though some secondary aromatization does occur through metabolism.
Appears to be less androgenic than its cousin, since it does not metabolize into the potent androgen dihydrotestosterone (DHT).
- Conversion rate of about 15.76%, almost triple that of androstenedione, due to utilization of a different enzymatic pathway.
- No direct conversion to estrogen, though some secondary aromatization does occur through metabolism.
- Appears to be less androgenic than its cousin, since it does not metabolize into the potent androgen dihydrotestosterone (DHT).
- 19-norandrostenedione
Converts to: nortestosterone (also called nandrolone)
Characteristics:
Only slightly less anabolic than testosterone.
Low rate of aromatization to estrogen.
Low occurrence of androgenic side effects.
- Converts to: nortestosterone (also called nandrolone)
- Characteristics:
Only slightly less anabolic than testosterone.
Low rate of aromatization to estrogen.
Low occurrence of androgenic side effects.
- Only slightly less anabolic than testosterone.
- Low rate of aromatization to estrogen.
- Low occurrence of androgenic side effects.
- 19-norandrostenediol
Converts to: nortestosterone
Characteristics:
Same as -dione, except (as with the andros), the conversion rate is higher.
- Converts to: nortestosterone
- Characteristics:
Same as -dione, except (as with the andros), the conversion rate is higher.
- Same as -dione, except (as with the andros), the conversion rate is higher.
- 1-androstenediol (1-AD)
Converts to: 1-testosterone, a 5-alpha reduced steroid reported to be 700% more anabolic and 200% more androgenic than testosterone; 1-testosterone is better (although rarely) described as dihydroboldenone, the 5-alpha reduced version of the veterinary steroid boldenone
Characteristics:
Very high conversion rate, because the liver serves primarily to "activate" the compound as it passes through rather than to break it down and excrete it, as is the case with other prohormones.
Cannot aromatize to estrogen either directly or through any of its metabolic products. However, 1-Testosterone, being a 5-alpha reduced steroid, is highly androgenic; it is very similar to Dihydrotestosterone (DHT). Many side effects associated with excessive levels of DHT, including male pattern baldness, testicular shrinkage, benign prostate hypertrophy and acne can occur with 1-AD usage. (Journal of Organic chem. vol, 27 1962 iss.1)
As with other -diols, 1-AD cannot convert directly to estrogen.
- Converts to: 1-testosterone, a 5-alpha reduced steroid reported to be 700% more anabolic and 200% more androgenic than testosterone; 1-testosterone is better (although rarely) described as dihydroboldenone, the 5-alpha reduced version of the veterinary steroid boldenone
- Characteristics:
Very high conversion rate, because the liver serves primarily to "activate" the compound as it passes through rather than to break it down and excrete it, as is the case with other prohormones.
Cannot aromatize to estrogen either directly or through any of its metabolic products. However, 1-Testosterone, being a 5-alpha reduced steroid, is highly androgenic; it is very similar to Dihydrotestosterone (DHT). Many side effects associated with excessive levels of DHT, including male pattern baldness, testicular shrinkage, benign prostate hypertrophy and acne can occur with 1-AD usage. (Journal of Organic chem. vol, 27 1962 iss.1)
As with other -diols, 1-AD cannot convert directly to estrogen.
- Very high conversion rate, because the liver serves primarily to "activate" the compound as it passes through rather than to break it down and excrete it, as is the case with other prohormones.
- Cannot aromatize to estrogen either directly or through any of its metabolic products. However, 1-Testosterone, being a 5-alpha reduced steroid, is highly androgenic; it is very similar to Dihydrotestosterone (DHT). Many side effects associated with excessive levels of DHT, including male pattern baldness, testicular shrinkage, benign prostate hypertrophy and acne can occur with 1-AD usage. (Journal of Organic chem. vol, 27 1962 iss.1)
- As with other -diols, 1-AD cannot convert directly to estrogen. | Prohormone
A prohormone is a substance that is a precursor to a hormone, usually having minimal hormonal effect by itself. The term has been used in medical science since the middle of the 20th century. Examples of natural, human prohormones include proinsulin and pro-opiomelanocortin.
For peptide hormones, the conversion process from prohormone to hormone typically occurs after export to the endoplasmic reticulum and often requires multiple processing enzymes. For example, proinsulin is processed by PC 1/2, PC 3, and carboxypeptidase E to afford insulin.[citation needed] Proamylin, which is cosecreted with proinsulin, requires the above three factors and an amidating monoxygenase.
For small molecule hormones, the conversion is often one step, and is often used to regulate hormone levels.
# Prohormones of anabolic steroids
In the last two decades, prohormones have also been used by bodybuilders, athletes, and nonmedical users of anabolic steroids and other hormones to refer to substances that are expected to convert to active hormones in the body. The intent is to provide the putative benefits of taking an anabolic steroid without the legal or medical risks, and to achieve the hoped-for benefits or advantages without use of anabolic steroids themselves. Since prohormones are not anabolic steroids themselves, they are legally classified as dietary supplements and not subject to the much tighter regulatory requirements of the Food and Drug Administration (FDA) which apply to prescription hormones.[citation needed]
A typical prohormone is intended to be a precursor of an anabolic steroid like testosterone, which is taken in order to boost the body’s available hormone supply. These precursors are intended to be converted to full, active hormones via an enzymatic process that occurs during metabolism, typically resulting in the addition of whichever atoms happen to be missing from the chemical structure of the compound.
The use of prohormones has become popular among bodybuilders, since the effects can be similar (though normally much less drastic) to those achieved through the use of synthetic anabolic steroids, including gains in muscular strength and hypertrophy. There are currently many companies manufacturing prohormone products for this purpose.
Prohormones are legally sold in most parts of the world and were classified in the United States by the FDA as dietary supplements[citation needed] because they consist of compounds that occur naturally in the human body; however their use remains quite controversial and side effects are not uncommon. To date, prohormone products have been banned in the United States, however, most have not been thoroughly studied, and the health effects of prolonged use are mostly unknown.[citation needed]
On October 22nd, 2004, President Bush signed into law the Anabolic Steroid Control Act of 2004 (118 Stat. 1661). [1]
The bill was written to become effective in 90 days, which was January 20, 2005. This legislation places both anabolic steroids and prohormones on a list of controlled substances (a new type of "regulatory control").[citation needed]
# Common types of prohormones on the market
- 4-androstenedione
Converts to: testosterone
Characteristics:
Research indicates a conversion rate of about 5.9%, which means that of the amount taken orally, 5.6% is converted to testosterone.
Relatively high rate of aromatization to estrogen, and consequently higher risk of side-effects such as gynecomastia brought on by excessive estrogen formation.
Exhibits significant androgenic properties, which may result in side effects such as male pattern baldness, acne, and enlarged prostate.
- Converts to: testosterone
- Characteristics:
Research indicates a conversion rate of about 5.9%, which means that of the amount taken orally, 5.6% is converted to testosterone.
Relatively high rate of aromatization to estrogen, and consequently higher risk of side-effects such as gynecomastia brought on by excessive estrogen formation.
Exhibits significant androgenic properties, which may result in side effects such as male pattern baldness, acne, and enlarged prostate.
- Research indicates a conversion rate of about 5.9%, which means that of the amount taken orally, 5.6% is converted to testosterone.
- Relatively high rate of aromatization to estrogen, and consequently higher risk of side-effects such as gynecomastia brought on by excessive estrogen formation.
- Exhibits significant androgenic properties, which may result in side effects such as male pattern baldness, acne, and enlarged prostate.
- 4-androstenediol (4-AD)
Converts to: testosterone
Characteristics:
Conversion rate of about 15.76%, almost triple that of androstenedione, due to utilization of a different enzymatic pathway.
No direct conversion to estrogen, though some secondary aromatization does occur through metabolism.
Appears to be less androgenic than its cousin, since it does not metabolize into the potent androgen dihydrotestosterone (DHT).
- Converts to: testosterone
- Characteristics:
Conversion rate of about 15.76%, almost triple that of androstenedione, due to utilization of a different enzymatic pathway.
No direct conversion to estrogen, though some secondary aromatization does occur through metabolism.
Appears to be less androgenic than its cousin, since it does not metabolize into the potent androgen dihydrotestosterone (DHT).
- Conversion rate of about 15.76%, almost triple that of androstenedione, due to utilization of a different enzymatic pathway.
- No direct conversion to estrogen, though some secondary aromatization does occur through metabolism.
- Appears to be less androgenic than its cousin, since it does not metabolize into the potent androgen dihydrotestosterone (DHT).
- 19-norandrostenedione
Converts to: nortestosterone (also called nandrolone)
Characteristics:
Only slightly less anabolic than testosterone.
Low rate of aromatization to estrogen.
Low occurrence of androgenic side effects.
- Converts to: nortestosterone (also called nandrolone)
- Characteristics:
Only slightly less anabolic than testosterone.
Low rate of aromatization to estrogen.
Low occurrence of androgenic side effects.
- Only slightly less anabolic than testosterone.
- Low rate of aromatization to estrogen.
- Low occurrence of androgenic side effects.
- 19-norandrostenediol
Converts to: nortestosterone
Characteristics:
Same as -dione, except (as with the andros), the conversion rate is higher.
- Converts to: nortestosterone
- Characteristics:
Same as -dione, except (as with the andros), the conversion rate is higher.
- Same as -dione, except (as with the andros), the conversion rate is higher.
- 1-androstenediol (1-AD)
Converts to: 1-testosterone, a 5-alpha reduced steroid reported to be 700% more anabolic and 200% more androgenic than testosterone; 1-testosterone is better (although rarely) described as dihydroboldenone, the 5-alpha reduced version of the veterinary steroid boldenone
Characteristics:
Very high conversion rate, because the liver serves primarily to "activate" the compound as it passes through rather than to break it down and excrete it, as is the case with other prohormones.
Cannot aromatize to estrogen either directly or through any of its metabolic products. However, 1-Testosterone, being a 5-alpha reduced steroid, is highly androgenic; it is very similar to Dihydrotestosterone (DHT). Many side effects associated with excessive levels of DHT, including male pattern baldness, testicular shrinkage, benign prostate hypertrophy and acne can occur with 1-AD usage. (Journal of Organic chem. vol, 27 1962 iss.1)
As with other -diols, 1-AD cannot convert directly to estrogen.
- Converts to: 1-testosterone, a 5-alpha reduced steroid reported to be 700% more anabolic and 200% more androgenic than testosterone; 1-testosterone is better (although rarely) described as dihydroboldenone, the 5-alpha reduced version of the veterinary steroid boldenone
- Characteristics:
Very high conversion rate, because the liver serves primarily to "activate" the compound as it passes through rather than to break it down and excrete it, as is the case with other prohormones.
Cannot aromatize to estrogen either directly or through any of its metabolic products. However, 1-Testosterone, being a 5-alpha reduced steroid, is highly androgenic; it is very similar to Dihydrotestosterone (DHT). Many side effects associated with excessive levels of DHT, including male pattern baldness, testicular shrinkage, benign prostate hypertrophy and acne can occur with 1-AD usage. (Journal of Organic chem. vol, 27 1962 iss.1)
As with other -diols, 1-AD cannot convert directly to estrogen.
- Very high conversion rate, because the liver serves primarily to "activate" the compound as it passes through rather than to break it down and excrete it, as is the case with other prohormones.
- Cannot aromatize to estrogen either directly or through any of its metabolic products. However, 1-Testosterone, being a 5-alpha reduced steroid, is highly androgenic; it is very similar to Dihydrotestosterone (DHT). Many side effects associated with excessive levels of DHT, including male pattern baldness, testicular shrinkage, benign prostate hypertrophy and acne can occur with 1-AD usage. (Journal of Organic chem. vol, 27 1962 iss.1)
- As with other -diols, 1-AD cannot convert directly to estrogen. | https://www.wikidoc.org/index.php/Pro-hormone | |
464b9d84c8cb65c3e884daaae667e924c7aacb29 | wikidoc | Proctology | Proctology
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
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# Overview
Proctology is a field in medicine dealing with diseases and disorders of the rectum, anus, colon and pelvic floor. The word Proctology is derived from the Greek words Proktos, meaning anus or hindparts, and Logos meaning science or study.
Physicians specializing in this field of medicine are more commonly called colorectal surgeons, as the term proctologist is outdated in the more traditional areas of medicine. A proctologist should be a surgeon by training. Proctologists often work closely with urologists.
In the United States, some surgeons (MDs) are certified by the American Board of Colon and Rectal Surgery, while some osteopathic surgeons (DOs), which are also equally licensed proctologists, are certified by the American Osteopathic Board of Proctology.
# Scope of the specialty
Proctological disorders include:
- varicosities or swelling, and inflammation of veins in the rectum and anus (Hemorrhoids)
- unnatural cracks or tears in the anus (Anal fissures)
- abnormal connections or passageways between the rectum or other anorectal area to the skin surface (Fistulas)
- severe constipation conditions
- fecal incontinence
- protrusion of the walls of the rectum through the anus (Rectal prolapse)
- birth defects such as the imperforate anus
- cancer of the colon and rectum (Colorectal cancer)
- anal cancer (rare)
- any injuries to the anus | Proctology
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [1] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
# Overview
Proctology is a field in medicine dealing with diseases and disorders of the rectum, anus, colon and pelvic floor. The word Proctology is derived from the Greek words Proktos, meaning anus or hindparts, and Logos meaning science or study.
Physicians specializing in this field of medicine are more commonly called colorectal surgeons, as the term proctologist is outdated in the more traditional areas of medicine. A proctologist should be a surgeon by training. Proctologists often work closely with urologists.
In the United States, some surgeons (MDs) are certified by the American Board of Colon and Rectal Surgery, while some osteopathic surgeons (DOs), which are also equally licensed proctologists, are certified by the American Osteopathic Board of Proctology.
# Scope of the specialty
Proctological disorders include:
- varicosities or swelling, and inflammation of veins in the rectum and anus (Hemorrhoids)
- unnatural cracks or tears in the anus (Anal fissures)
- abnormal connections or passageways between the rectum or other anorectal area to the skin surface (Fistulas)
- severe constipation conditions
- fecal incontinence
- protrusion of the walls of the rectum through the anus (Rectal prolapse)
- birth defects such as the imperforate anus
- cancer of the colon and rectum (Colorectal cancer)
- anal cancer (rare)
- any injuries to the anus | https://www.wikidoc.org/index.php/Proctologist | |
b05534afff24c49f1446023dca5bce3cec139547 | wikidoc | Proglumide | Proglumide
# Overview
Proglumide (Milid) is a drug which inhibits gastrointestinal motility and reduces gastric secretions.
Proglumide acts as a cholecystokinin antagonist. It was used mainly in the treatment of stomach ulcers, although it has now been largely replaced by newer drugs for this application.
An interesting side effect of proglumide is that it enhances the analgesia produced by opioid drugs, and can prevent or even reverse the development of tolerance to opioid drugs. This can make it a useful adjuvant treatment to use alongside opioid drugs in the treatment of chronic pain conditions such as cancer, where opioid analgesics may be required for long periods and development of tolerance reduces clinical efficacy of these drugs. | Proglumide
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Proglumide (Milid) is a drug which inhibits gastrointestinal motility and reduces gastric secretions.
Proglumide acts as a cholecystokinin antagonist.[1] It was used mainly in the treatment of stomach ulcers,[2][3] although it has now been largely replaced by newer drugs for this application.
An interesting side effect of proglumide is that it enhances the analgesia produced by opioid drugs,[4] and can prevent or even reverse the development of tolerance to opioid drugs.[5][6] This can make it a useful adjuvant treatment to use alongside opioid drugs in the treatment of chronic pain conditions such as cancer, where opioid analgesics may be required for long periods and development of tolerance reduces clinical efficacy of these drugs.[7][8]
Template:Pharma-stub | https://www.wikidoc.org/index.php/Proglumide | |
79ad52c852d241ef92f9e3557b934fae99d34d0b | wikidoc | Prohibitin | Prohibitin
Prohibitin, also known as PHB, is a protein that in humans is encoded by the PHB gene.
The Phb gene has also been described in animals, fungi, plants, and unicellular eukaryotes. Prohibitins are divided in two classes, termed Type-I and Type-II prohibitins, based on their similarity to yeast PHB1 and PHB2, respectively. Each organism has at least one copy of each type of prohibitin gene.
# Discovery
Prohibitins are evolutionarily conserved genes that are ubiquitously expressed. The human prohibitin gene, located on the BRCA1 chromosome region 17q21, was originally thought to be a negative regulator of cell proliferation and a tumor suppressor. This anti-proliferative activity was later attributed to the 3' UTR of the PHB gene, and not to the actual protein. Mutations in human PHB have been linked to sporadic breast cancer. However, over-expression of PHB has been associated with a reduction in the androgen receptor activity and a reduction in PSA gene expression resulting in a decrease of androgen-dependent growth of cancerous prostate cells.
Prohibitin is expressed as two transcripts with varying lengths of 3' untranslated region. The longer transcript is present at higher levels in proliferating tissues and cells, suggesting that this longer 3' untranslated region may function as a trans-acting regulatory RNA.
# Function
Prohibitins may have multiple functions including:
## Mitochondrial function and morphology
Prohibitins are assembled into a ring-like structure with 16–20 alternating Phb1 and Phb2 subunits in the inner mitochondrial membrane. The precise molecular function of the PHB complex is not clear, but a role as chaperone for respiration chain proteins or as a general structuring scaffold required for optimal mitochondrial morphology and function are suspected. Recently, prohibitins have been demonstrated to be positive, rather than negative, regulators of cell proliferation in both plants and mice.
## Transcriptional modulation
Both human prohibitins have also been suggested to be localized in the nucleus and modulate transcriptional activity by interacting with various transcription factors, including nuclear receptors, either directly or indirectly. However, little evidence for nuclear targeting and transcription factor-binding of prohibitins has been found in other organism (yeast, plants, C. elegans, etc.), indicating that this may be a specific function in mammalian cells.
# Clinical significance
Human prohibitin 1 has some activity as a virus receptor protein, having been identified as a receptor for Chikungunya Virus (CHIKV) and Dengue Virus 2 (DENV-2). Little else is known about the activity of the prohibitins in viral pathogenesis.
# Interactions
Prohibitin has been shown to interact with:
- ANXA2
- C-Raf,
- E2F1,
- HDAC1,
- P53,
- RB1,
- RBL1,
- RBL2,
- SMARCA2, and
- SMARCA4.
# Drugs that bind to prohibitin
- Aurilide
- Fluorizoline
- Rocaglamide A | Prohibitin
Prohibitin, also known as PHB, is a protein that in humans is encoded by the PHB gene.[1]
The Phb gene has also been described in animals, fungi, plants, and unicellular eukaryotes. Prohibitins are divided in two classes, termed Type-I and Type-II prohibitins, based on their similarity to yeast PHB1 and PHB2, respectively. Each organism has at least one copy of each type of prohibitin gene.[2][3]
# Discovery
Prohibitins are evolutionarily conserved genes that are ubiquitously expressed. The human prohibitin gene, located on the BRCA1 chromosome region 17q21, was originally thought to be a negative regulator of cell proliferation and a tumor suppressor. This anti-proliferative activity was later attributed to the 3' UTR of the PHB gene, and not to the actual protein. Mutations in human PHB have been linked to sporadic breast cancer. However, over-expression of PHB has been associated with a reduction in the androgen receptor activity and a reduction in PSA gene expression resulting in a decrease of androgen-dependent growth of cancerous prostate cells.[4]
Prohibitin is expressed as two transcripts with varying lengths of 3' untranslated region. The longer transcript is present at higher levels in proliferating tissues and cells, suggesting that this longer 3' untranslated region may function as a trans-acting regulatory RNA.[1]
# Function
Prohibitins may have multiple functions including:
## Mitochondrial function and morphology
Prohibitins are assembled into a ring-like structure with 16–20 alternating Phb1 and Phb2 subunits in the inner mitochondrial membrane.[5] The precise molecular function of the PHB complex is not clear, but a role as chaperone for respiration chain proteins or as a general structuring scaffold required for optimal mitochondrial morphology and function are suspected. Recently, prohibitins have been demonstrated to be positive, rather than negative, regulators of cell proliferation in both plants and mice.
## Transcriptional modulation
Both human prohibitins have also been suggested to be localized in the nucleus and modulate transcriptional activity by interacting with various transcription factors, including nuclear receptors, either directly or indirectly. However, little evidence for nuclear targeting and transcription factor-binding of prohibitins has been found in other organism (yeast, plants, C. elegans, etc.), indicating that this may be a specific function in mammalian cells.[6][7][8][9]
# Clinical significance
Human prohibitin 1 has some activity as a virus receptor protein, having been identified as a receptor for Chikungunya Virus (CHIKV)[10] and Dengue Virus 2 (DENV-2).[11] Little else is known about the activity of the prohibitins in viral pathogenesis.
# Interactions
Prohibitin has been shown to interact with:
- ANXA2[12]
- C-Raf,[13]
- E2F1,[13][14][15][16]
- HDAC1,[14][17]
- P53,[15]
- RB1,[13][18]
- RBL1,[18]
- RBL2,[18]
- SMARCA2,[16] and
- SMARCA4.[16]
# Drugs that bind to prohibitin
- Aurilide [19]
- Fluorizoline [20][21]
- Rocaglamide A [22] | https://www.wikidoc.org/index.php/Prohibitin | |
de33655a876cf6ebdf1365d1d64a5a5d91f04518 | wikidoc | Proinsulin | Proinsulin
Proinsulin is the prohormone precursor to insulin made in the beta cells of the islets of Langerhans, specialized regions of the pancreas. In humans, proinsulin is encoded by the INS gene. The islets of Langerhans only secrete between 1% and 3% of proinsulin intact. However, because proinsulin has a longer half life than insulin, it can account for anywhere from 5–30% of the insulin-like structures circulating in the blood. There are higher concentrations of proinsulin after meals and lower levels when a person is fasting. Additionally, while proinsulin and insulin have structural differences, proinsulin does demonstrate some affinity for the insulin receptor. Due to the relative similarities in structure, proinsulin can produce between 5% and 10% of the metabolic activity similarly induced by insulin.
Proinsulin is the final single chain protein structure secreted by cells before cleavage into mature insulin. Proinsulin was discovered by Professor Donald F. Steiner of the University of Chicago in 1967.
# Structure
Proinsulin is made up of 81 residues (in cows, 86 in humans), and formed by three distinct chains. The A chain, B chain, and the area connecting the two named the C peptide. The correct structure of proinsulin is crucial for the correct folding of mature insulin, as the placement of the C peptide sets the molecule up to create correctly positioned disulfide bonds in and between the A and B chains. There are three disulfide bonds that are necessary for mature insulin to be the correct structure. Two of these disulfide bonds are between the A and B chains, and one is an intra-A chain bond. The disulfide bonds occur between the seventh residues of the A and B chain, the 19th residue of the A chain and the 20th residue of the B chain, and the 6th and 11th residues of the A chain.
The C peptide is between the A and B chains of proinsulin. The connection between the A chain and C peptide is much more stable than the junction between the C peptide and B chain, with alpha helical features being exhibited near the C peptide-A chain connection. The C peptide-A chain junction occurs between residues 64 and 65 of proinsulin. These are lysine and arginine molecules, respectively. The C peptide-B chain connection is between two arginine residues at positions 31 and 32 of proinsulin.
There is conservation of much of the structure of proinsulin among mammalian species, with much of the residue changes seen from one species to another present in the C peptide. That said, the residues of the C peptide that are conserved across species interact with similarly conserved residues on the A and B chains. Thus, it is hypothesized that these conserved residues are important for the functionality of mature insulin.
- File:Proinsulin 3.png
# Synthesis and Post-translational Modification
Proinsulin is synthesized on membrane associated ribosomes found on the rough endoplasmic reticulum, where it is folded and its disulfide bonds are oxidized. It is then transported to the Golgi apparatus where it is packaged into secretory vesicles, and where it is processed by a series of proteases to form mature insulin. Mature insulin has 35 fewer amino acids; 4 are removed altogether, and the remaining 31 form the C-peptide. The C-peptide is abstracted from the center of the proinsulin sequence; the two other ends (the B chain and A chain) remain connected by disulfide bonds.
The post translational modification of proinsulin to mature insulin only occurs in the beta cells of the islets of Langerhans. When proinsulin is transported through the Golgi apparatus the C-peptide is cleaved. This cleavage occurs with the aid of two endoproteases. Type I endoproteases, PC1 and PC3, disrupt the C peptide-B chain connection. PC2, a type II endoprotease, cleaves the C peptide-A chain bond. The resulting molecule, now mature insulin, is stored as a hexamer in secretory vesicles and is stabilized with Zn^{2+} molecules until it is secreted.
- File:Proinsulin evolution.png
# Immunogenicity
When insulin was originally purified from bovine or porcine pancreata, all the proinsulin was not fully removed. When some people used these insulins, the proinsulin may have caused the body to react with a rash, to resist the insulin, or even to make dents or lumps in the skin at the place where the insulin was injected. This can be described as an iatrogenic injury due to slight differences between the proinsulin of different species. Since the late 1970s, when highly purified porcine insulin was introduced, and the level of insulin purity reached 99%, this ceased to be a significant clinical issue. It should also be noted that in respect of their influence on insulin pharmacokinetics, moderate concentrations of certain insulin antibodies may, in fact, be of positive advantage to all diabetics without endogenous insulin secretion (e.g. people with type 1 diabetes) because insulin binding antibodies effectively increase the insulin's clearance rate and distribution space and therefore helps to prolong its pharmacological and biological half lives.
# Medical Relevance
Historically, the focus of many insulin related metabolic diseases has focused on mature insulin. However, in recent years the importance of studying the structure and function of proinsulin in relation to these diseases has become increasingly clear.
## Diabetes Mellitus
Increased levels of proinsulin in the circulatory system relative to mature insulin concentrations can indicate impending insulin resistance and the development of type 2 diabetes. Additional problems with proinsulin that can lead to diabetes include mutations in the number of cysteines present, which could affect correct folding. If the mutation causes only a mild change it could simply stress the endoplasmic reticulum’s ability to properly fold the protein. This stress, after a while, would lead to a decrease in the number of β-cells producing mature insulin, and would then lead to diabetes mellitus.
## Neonatal Diabetes Mellitus
Postnatal proinsulin is crucial for metabolic regulation. However, proinsulin in neonates is important for normal development of the nerves of the eye, development of the heart, and general survival of embryonic cells. Regulation of the concentration of proinsulin during embryonic development is crucial, as too much or too little of the peptide can cause defects and death of the fetus. Thus far in the study of neonatal diabetes mellitus, only amino acid change mutations found in the B domain lead to the disease. | Proinsulin
Proinsulin is the prohormone precursor to insulin made in the beta cells of the islets of Langerhans, specialized regions of the pancreas. In humans, proinsulin is encoded by the INS gene.[1][2] The islets of Langerhans only secrete between 1% and 3% of proinsulin intact.[3] However, because proinsulin has a longer half life than insulin, it can account for anywhere from 5–30% of the insulin-like structures circulating in the blood.[3] There are higher concentrations of proinsulin after meals and lower levels when a person is fasting.[3] Additionally, while proinsulin and insulin have structural differences, proinsulin does demonstrate some affinity for the insulin receptor. Due to the relative similarities in structure, proinsulin can produce between 5% and 10% of the metabolic activity similarly induced by insulin.[3]
Proinsulin is the final single chain protein structure secreted by cells before cleavage into mature insulin.[4] Proinsulin was discovered by Professor Donald F. Steiner of the University of Chicago in 1967.[5]
# Structure
Proinsulin is made up of 81 residues (in cows, 86 in humans[6]), and formed by three distinct chains.[7] The A chain, B chain, and the area connecting the two named the C peptide.[7] The correct structure of proinsulin is crucial for the correct folding of mature insulin, as the placement of the C peptide sets the molecule up to create correctly positioned disulfide bonds in and between the A and B chains.[7][8] There are three disulfide bonds that are necessary for mature insulin to be the correct structure. Two of these disulfide bonds are between the A and B chains, and one is an intra-A chain bond.[7] The disulfide bonds occur between the seventh residues of the A and B chain, the 19th residue of the A chain and the 20th residue of the B chain, and the 6th and 11th residues of the A chain.[9]
The C peptide is between the A and B chains of proinsulin.[7] The connection between the A chain and C peptide is much more stable than the junction between the C peptide and B chain, with alpha helical features being exhibited near the C peptide-A chain connection.[10] The C peptide-A chain junction occurs between residues 64 and 65 of proinsulin. These are lysine and arginine molecules, respectively.[10] The C peptide-B chain connection is between two arginine residues at positions 31 and 32 of proinsulin.[10]
There is conservation of much of the structure of proinsulin among mammalian species, with much of the residue changes seen from one species to another present in the C peptide.[8][11] That said, the residues of the C peptide that are conserved across species interact with similarly conserved residues on the A and B chains.[8] Thus, it is hypothesized that these conserved residues are important for the functionality of mature insulin.[8]
- File:Proinsulin 3.png
# Synthesis and Post-translational Modification
Proinsulin is synthesized on membrane associated ribosomes found on the rough endoplasmic reticulum, where it is folded and its disulfide bonds are oxidized. It is then transported to the Golgi apparatus where it is packaged into secretory vesicles, and where it is processed by a series of proteases to form mature insulin. Mature insulin has 35 fewer amino acids; 4 are removed altogether, and the remaining 31 form the C-peptide. The C-peptide is abstracted from the center of the proinsulin sequence; the two other ends (the B chain and A chain) remain connected by disulfide bonds.
The post translational modification of proinsulin to mature insulin only occurs in the beta cells of the islets of Langerhans.[12] When proinsulin is transported through the Golgi apparatus the C-peptide is cleaved.[9] This cleavage occurs with the aid of two endoproteases.[13] Type I endoproteases, PC1 and PC3, disrupt the C peptide-B chain connection.[13] PC2, a type II endoprotease, cleaves the C peptide-A chain bond.[13] The resulting molecule, now mature insulin, is stored as a hexamer in secretory vesicles and is stabilized with <math>Zn^{2+} </math> molecules until it is secreted.[9]
- File:Proinsulin evolution.png
# Immunogenicity
When insulin was originally purified from bovine or porcine pancreata, all the proinsulin was not fully removed.[14][15] When some people used these insulins, the proinsulin may have caused the body to react with a rash, to resist the insulin, or even to make dents or lumps in the skin at the place where the insulin was injected. This can be described as an iatrogenic injury due to slight differences between the proinsulin of different species. Since the late 1970s, when highly purified porcine insulin was introduced, and the level of insulin purity reached 99%, this ceased to be a significant clinical issue.[16] It should also be noted that in respect of their influence on insulin pharmacokinetics, moderate concentrations of certain insulin antibodies may, in fact, be of positive advantage to all diabetics without endogenous insulin secretion (e.g. people with type 1 diabetes) because insulin binding antibodies effectively increase the insulin's clearance rate and distribution space and therefore helps to prolong its pharmacological and biological half lives.[17][clarification needed]
# Medical Relevance
Historically, the focus of many insulin related metabolic diseases has focused on mature insulin. However, in recent years the importance of studying the structure and function of proinsulin in relation to these diseases has become increasingly clear.
## Diabetes Mellitus
Increased levels of proinsulin in the circulatory system relative to mature insulin concentrations can indicate impending insulin resistance and the development of type 2 diabetes.[18] Additional problems with proinsulin that can lead to diabetes include mutations in the number of cysteines present, which could affect correct folding.[9] If the mutation causes only a mild change it could simply stress the endoplasmic reticulum’s ability to properly fold the protein.[9] This stress, after a while, would lead to a decrease in the number of β-cells producing mature insulin, and would then lead to diabetes mellitus.[9]
## Neonatal Diabetes Mellitus
Postnatal proinsulin is crucial for metabolic regulation. However, proinsulin in neonates is important for normal development of the nerves of the eye, development of the heart, and general survival of embryonic cells.[19] Regulation of the concentration of proinsulin during embryonic development is crucial, as too much or too little of the peptide can cause defects and death of the fetus.[19] Thus far in the study of neonatal diabetes mellitus, only amino acid change mutations found in the B domain lead to the disease.[9] | https://www.wikidoc.org/index.php/Proinsulin | |
e90d22c45512ee67497065c074fb019fac7191fe | wikidoc | Prokaryote | Prokaryote
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
The prokaryotes (Template:PronEng; singular prokaryote Template:IPA) are a group of organisms that lack a cell nucleus (= karyon), or any other membrane-bound organelles. They differ from the eukaryotes, which have a cell nucleus. Most are unicellular, but some prokaryotes are multicellular organisms. The word prokaryotes comes from the Old Greek pro- before + karyon nut or kernel, referring to the cell nucleus, + suffix -otos, pl. -otes; it is also spelled "procaryotes".
The prokaryotes are divided into two domains: the bacteria and the archaea. Archaea are a newly appointed domain of life. These organisms were originally thought to live only in inhospitable conditions such as extremes of temperature, pH, and radiation but have since been found in all types of habitats.
# Relationship to eukaryotes
A distinction between prokaryotes and eukaryotes (meaning true kernel, also spelled "eucaryotes") is that eukaryotes do have "true" nuclei containing their DNA, whereas the genetic material in prokaryotes is not membrane-bound. Eukaryotic organisms may, as in the case of amoebae, be unicellular or, as in the case of humans, be multicellular. The difference between the structure of prokaryotes and eukaryotes is so great that it is considered to be the most important distinction among groups of organisms. In 1977, Carl Woese proposed dividing prokaryotes into the Bacteria and Archaea (originally Eubacteria and Archaebacteria) because of the major differences in the structure and genetics between the two groups of organisms. This arrangement of Eukaryota (also called "Eukarya"), Bacteria, and Archaea is called the three-domain system replacing the traditional two-empire system. A criticism of this classification is that the word "prokaryote" itself is based on what these organisms are not (they are not eukaryotic), rather than what they are (either archaea or bacteria).
The cell structure of prokaryotes differs greatly from that of eukaryotes. The defining characteristic is the absence of a nucleus. Instead, the genomes of prokaryotes are held within an irregular DNA/protein complex in the cytosol called the nucleoid, which lacks a nuclear envelope. Prokaryotes generally lack membrane-bound cell compartments: such as mitochondria and chloroplasts. Instead processes such as oxidative phosphorylation and photosynthesis take place across the prokaryotic plasma membrane. However, prokaryotes do possess some internal structures, such as vacuole and cytoskeletons, and the bacterial order Planctomycetes have a membrane around their nucleoid and contain other membrane-bound cellular structures. Both eukaryotes and prokaryotes contain large RNA/protein structures called ribosomes, which produce protein. Prokaryotes are usually much smaller than eukaryotic cells.
Prokaryotes also differ from eukaryotes in that they contain only a single loop of stable chromosomal DNA stored in an area named the nucleoid, while eukaryote DNA is found on tightly bound and organized chromosomes. Although some eukaryotes have satellite DNA structures called plasmids, these are generally regarded as a prokaryote feature, and many important genes in prokaryotes are stored on plasmids.
Prokaryotes have a larger surface area to volume ratio giving them a higher metabolic rate, a higher growth rate and consequently a shorter generation time compared to Eukaryotes.
# Colonies
While prokaryotes are nearly always unicellular, some are capable of forming groups of cells called colonies. Unlike many eukaryotic multicellular organisms, each member of the colony is undifferentiated and capable of free-living (but consider cyanobacteria, a very successful prokaryotic group which does exhibit definite cell differentiation). Individuals that make up such bacterial colonies most often still act independently of one another. Colonies are formed by organisms that remain attached following cell division, sometimes through the help of a secreted slimy layer.
# Reproduction
Bacteria and archaea reproduce through asexual reproduction, usually by binary fission or budding. Genetic exchange and recombination still occur, but this is a form of horizontal gene transfer and is not a replicative process, simply involving DNA being transferred between two cells, as in bacterial conjugation.
# Structure
Recent research indicates that all prokaryotes actually do have cytoskeletons, albeit more primitive than those of eukaryotes. Besides homologues of actin and tubulin (MreB and FtsZ) the helically arranged building block of the flagellum, flagellin, is one of the most significant cytoskeletal proteins of bacteria as it provides structural backgrounds of chemotaxis, the basic cell physiological response of bacteria. At least some prokaryotes also contain intracellular structures which can be seen as primitive organelles. Membranous organelles (a.k.a. intracellular membranes) are known in some groups of prokaryotes, such as vacuoles or membrane systems devoted to special metabolic properties, e.g. photosynthesis or chemolithotrophy. Additionally, some species also contain protein-enclosed microcompartments mostly associated with special physiological properties (e.g. carboxysomes or gas vacuoles).
# Morphology of prokaryotic cells
Prokaryotic cells have various shapes; the three basic shapes are:
- Cocci - spherical
- Bacilli - rod shaped
- Spiral - curve (see Bacteria#Morphology)
# Environment
Prokaryotes are found in nearly all environments on earth. Archaea in particular seem to thrive in harsh conditions, such as high temperatures (thermophiles) or salinity (halophiles). Organisms such as these are referred to as extremophiles. Many prokaryotes live in or on the bodies of other organisms, including humans.
# Evolution of prokaryotes
It is generally accepted that the first living cells were some form of prokaryote and may have developed out of protobionts. Fossilized prokaryotes approximately 3.5 billion years old have been discovered (less than 1 billion years after the formation of the earth's crust), and prokaryotes are perhaps the most successful and abundant organism even today. Eukaryotes only formed later, from symbiosis of multiple prokaryote ancestors; their first evidence in the fossil record appears approximately 1.7 billion years ago, although genetic evidence suggests they could have formed as early as 3 billion years ago.
While Earth is the only place in the universe where life is known to exist, some have suggested evidence of life on Mars in the form of fossil or living prokaryotes; this is open to considerable debate and skepticism.
Prokaryotes diversified greatly throughout their long existence. The metabolism of prokaryotes is far more varied than that of eukaryotes, leading to many highly distinct types of prokaryotes. For example, in addition to using photosynthesis or organic compounds for energy like eukaryotes do, prokaryotes may obtain energy from inorganic chemicals such as hydrogen sulfide. This has enabled the bacteria to thrive and reproduce. Today, archaebacteria can be found in the cold of Antarctica and in the hot Yellowstone springs. | Prokaryote
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [1] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
The prokaryotes (Template:PronEng; singular prokaryote Template:IPA) are a group of organisms that lack a cell nucleus (= karyon), or any other membrane-bound organelles. They differ from the eukaryotes, which have a cell nucleus. Most are unicellular, but some prokaryotes are multicellular organisms. The word prokaryotes comes from the Old Greek pro- before + karyon nut or kernel, referring to the cell nucleus, + suffix -otos, pl. -otes; it is also spelled "procaryotes".[1]
The prokaryotes are divided into two domains: the bacteria and the archaea. Archaea are a newly appointed domain of life. These organisms were originally thought to live only in inhospitable conditions such as extremes of temperature, pH, and radiation but have since been found in all types of habitats.
# Relationship to eukaryotes
A distinction between prokaryotes and eukaryotes (meaning true kernel, also spelled "eucaryotes") is that eukaryotes do have "true" nuclei containing their DNA, whereas the genetic material in prokaryotes is not membrane-bound. Eukaryotic organisms may, as in the case of amoebae, be unicellular or, as in the case of humans, be multicellular. The difference between the structure of prokaryotes and eukaryotes is so great that it is considered to be the most important distinction among groups of organisms. In 1977, Carl Woese proposed dividing prokaryotes into the Bacteria and Archaea (originally Eubacteria and Archaebacteria) because of the major differences in the structure and genetics between the two groups of organisms. This arrangement of Eukaryota (also called "Eukarya"), Bacteria, and Archaea is called the three-domain system replacing the traditional two-empire system. A criticism of this classification is that the word "prokaryote" itself is based on what these organisms are not (they are not eukaryotic), rather than what they are (either archaea or bacteria).
The cell structure of prokaryotes differs greatly from that of eukaryotes. The defining characteristic is the absence of a nucleus. Instead, the genomes of prokaryotes are held within an irregular DNA/protein complex in the cytosol called the nucleoid, which lacks a nuclear envelope.[2] Prokaryotes generally lack membrane-bound cell compartments: such as mitochondria and chloroplasts. Instead processes such as oxidative phosphorylation and photosynthesis take place across the prokaryotic plasma membrane.[3] However, prokaryotes do possess some internal structures, such as vacuole and cytoskeletons,[4][5] and the bacterial order Planctomycetes have a membrane around their nucleoid and contain other membrane-bound cellular structures.[6] Both eukaryotes and prokaryotes contain large RNA/protein structures called ribosomes, which produce protein. Prokaryotes are usually much smaller than eukaryotic cells.[1]
Prokaryotes also differ from eukaryotes in that they contain only a single loop of stable chromosomal DNA stored in an area named the nucleoid, while eukaryote DNA is found on tightly bound and organized chromosomes. Although some eukaryotes have satellite DNA structures called plasmids, these are generally regarded as a prokaryote feature, and many important genes in prokaryotes are stored on plasmids.[1]
Prokaryotes have a larger surface area to volume ratio giving them a higher metabolic rate, a higher growth rate and consequently a shorter generation time compared to Eukaryotes.[1]
# Colonies
While prokaryotes are nearly always unicellular, some are capable of forming groups of cells called colonies. Unlike many eukaryotic multicellular organisms, each member of the colony is undifferentiated and capable of free-living (but consider cyanobacteria, a very successful prokaryotic group which does exhibit definite cell differentiation). Individuals that make up such bacterial colonies most often still act independently of one another. Colonies are formed by organisms that remain attached following cell division, sometimes through the help of a secreted slimy layer.
# Reproduction
Bacteria and archaea reproduce through asexual reproduction, usually by binary fission or budding. Genetic exchange and recombination still occur, but this is a form of horizontal gene transfer and is not a replicative process, simply involving DNA being transferred between two cells, as in bacterial conjugation.
# Structure
Recent research indicates that all prokaryotes actually do have cytoskeletons, albeit more primitive than those of eukaryotes. Besides homologues of actin and tubulin (MreB and FtsZ) the helically arranged building block of the flagellum, flagellin, is one of the most significant cytoskeletal proteins of bacteria as it provides structural backgrounds of chemotaxis, the basic cell physiological response of bacteria. At least some prokaryotes also contain intracellular structures which can be seen as primitive organelles. Membranous organelles (a.k.a. intracellular membranes) are known in some groups of prokaryotes, such as vacuoles or membrane systems devoted to special metabolic properties, e.g. photosynthesis or chemolithotrophy. Additionally, some species also contain protein-enclosed microcompartments mostly associated with special physiological properties (e.g. carboxysomes or gas vacuoles).
# Morphology of prokaryotic cells
Prokaryotic cells have various shapes; the three basic shapes are:[7]
- Cocci - spherical
- Bacilli - rod shaped
- Spiral - curve (see Bacteria#Morphology)
# Environment
Prokaryotes are found in nearly all environments on earth. Archaea in particular seem to thrive in harsh conditions, such as high temperatures (thermophiles) or salinity (halophiles). Organisms such as these are referred to as extremophiles. Many prokaryotes live in or on the bodies of other organisms, including humans.
# Evolution of prokaryotes
It is generally accepted that the first living cells were some form of prokaryote and may have developed out of protobionts. Fossilized prokaryotes approximately 3.5 billion years old have been discovered (less than 1 billion years after the formation of the earth's crust), and prokaryotes are perhaps the most successful and abundant organism even today. Eukaryotes only formed later, from symbiosis of multiple prokaryote ancestors; their first evidence in the fossil record appears approximately 1.7 billion years ago, although genetic evidence suggests they could have formed as early as 3 billion years ago.[8]
While Earth is the only place in the universe where life is known to exist, some have suggested evidence of life on Mars in the form of fossil or living prokaryotes;[9][10] this is open to considerable debate and skepticism.[11][12]
Prokaryotes diversified greatly throughout their long existence. The metabolism of prokaryotes is far more varied than that of eukaryotes, leading to many highly distinct types of prokaryotes. For example, in addition to using photosynthesis or organic compounds for energy like eukaryotes do, prokaryotes may obtain energy from inorganic chemicals such as hydrogen sulfide. This has enabled the bacteria to thrive and reproduce. Today, archaebacteria can be found in the cold of Antarctica and in the hot Yellowstone springs. | https://www.wikidoc.org/index.php/Prokaryote | |
4203c714d0cda3966334075e80c41eb2bbfd74cd | wikidoc | Prokinetic | Prokinetic
# Definition
Prokinetics are a class of drugs used on the digestive system. It includes all drugs whose primary effect is to augment the speed of intestinal transit, by increasing the frequency of contractions in the small intestine or making them stronger, but without disrupting their rhythm. They are mostly used to treat or prevent pathological reflux, or to speed up absorption of certain other drugs. Some of them can also be used to help in the treatment of nausea or other symptoms associated with dyspepsia.
Most of these drugs are grouped under ATC code A03F.
# Pharmacokinetics
Both cisapride and metoclopramide are serotonin receptor modulators.
Cisapride acts on 5HT4 receptor. Its metabolised by CYP3A4 so when combined with enzyme inhibitors as ketoconazole, erythromycin the increased serum level can produce prolonged QT interval in ECG and serious cardiac arrythmia.
Parasympathomimetics as bethanechol. They increase motility and secretions as well as motilin like agents e.g. erythromycin.
# Examples
Examples of this class of drug are:
- Domperidone
- Metoclopramide
- Cisapride
# Further reading
- Hardman JG, Limbird LE, Gilman AG. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 10th ed. New York: McGraw-Hill, 2001. ISBN 0-07-135469-7.
de:Prokinetikum | Prokinetic
# Definition
Prokinetics are a class of drugs used on the digestive system. It includes all drugs whose primary effect is to augment the speed of intestinal transit, by increasing the frequency of contractions in the small intestine or making them stronger, but without disrupting their rhythm. They are mostly used to treat or prevent pathological reflux, or to speed up absorption of certain other drugs. Some of them can also be used to help in the treatment of nausea or other symptoms associated with dyspepsia.
Most of these drugs are grouped under ATC code A03F.
# Pharmacokinetics
Both cisapride and metoclopramide are serotonin receptor modulators.
Cisapride acts on 5HT4 receptor. Its metabolised by CYP3A4 so when combined with enzyme inhibitors as ketoconazole, erythromycin the increased serum level can produce prolonged QT interval in ECG and serious cardiac arrythmia.
Parasympathomimetics as bethanechol. They increase motility and secretions as well as motilin like agents e.g. erythromycin.
# Examples
Examples of this class of drug are:
- Domperidone
- Metoclopramide
- Cisapride
# Further reading
- Hardman JG, Limbird LE, Gilman AG. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 10th ed. New York: McGraw-Hill, 2001. ISBN 0-07-135469-7.
Template:Propulsives
de:Prokinetikum | https://www.wikidoc.org/index.php/Prokinetic | |
83a7a620686dce9f23da9ad2439c5c55fc6eb7ee | wikidoc | Prometrium | Prometrium
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Prometrium® (Progesterone, USP) is a brand of micronized progesterone capsules from Solvay Pharmaceuticals, which has been FDA-approved for use in the United States. Solvay obtained US marketing rights from Schering-Plough Corporation in January 1998.
Synthesized from yams, prometrium® is identical in chemical structure to the progesterone which is naturally produced in a woman's body. The inactive ingredients in prometrium® capsules include peanut oil NF, gelatin NF, glycerin USP, lecithin NF, titanium dioxide USP and coloring
Prometrium® is used as a prescription drug in hormone replacement therapy -- or bioidentical hormone replacement therapy, to be more precise. Micronization of progesterone greatly improves its absorption when taken orally. Prior to the use of prometrium® micronized progesterone was only available from compounding pharmacies, but its production as an FDA-approved prescription drug by a major pharmaceutical company greatly increased availability.
Although prometrium® capsules are most often taken orally, they are also available as vaginal suppositories. | Prometrium
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [1] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
Prometrium® (Progesterone, USP) is a brand of micronized progesterone capsules from Solvay Pharmaceuticals, which has been FDA-approved for use in the United States[1]. Solvay obtained US marketing rights from Schering-Plough Corporation in January 1998.
Synthesized from yams, prometrium® is identical in chemical structure to the progesterone which is naturally produced in a woman's body. The inactive ingredients in prometrium® capsules include peanut oil NF, gelatin NF, glycerin USP, lecithin NF, titanium dioxide USP and coloring[2]
Prometrium® is used as a prescription drug in hormone replacement therapy -- or bioidentical hormone replacement therapy, to be more precise. Micronization of progesterone greatly improves its absorption when taken orally. Prior to the use of prometrium® micronized progesterone was only available from compounding pharmacies, but its production as an FDA-approved prescription drug by a major pharmaceutical company greatly increased availability.
Although prometrium® capsules are most often taken orally, they are also available as vaginal suppositories. | https://www.wikidoc.org/index.php/Prometrium | |
44ccf285e8a15d7af831a49700402252b4f9de37 | wikidoc | Propanidid | Propanidid
# Overview
Propanidid is an ultra short-acting phenylacetate general anesthetic. It was originally introduced by Bayer in 1963 but anaphylactic reactions caused it to be withdrawn shortly afterwards.
Even though Cremophor EL has been shown to cause anaphylactic reactions in humans in several cases (both when given intravenously and orally), it is still debated whether or not propanidid itself may have contributed to the reactions.
It has been argued that the toxic effects or reactions to Propanidid (and Althesin) were due to the drugs themselves. Several cases of negative reactions have been recorded for different drugs using Cremophor EL as solubilizer. This suggest that the negative reactions were mainly caused by Cremophor and not by the drug substances themselves. | Propanidid
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Propanidid is an ultra short-acting phenylacetate general anesthetic. It was originally introduced by Bayer in 1963[1] but anaphylactic reactions caused it to be withdrawn shortly afterwards.
Even though Cremophor EL has been shown to cause anaphylactic reactions in humans in several cases (both when given intravenously and orally), it is still debated whether or not propanidid itself may have contributed to the reactions.
It has been argued that the toxic effects or reactions to Propanidid (and Althesin) were due to the drugs themselves.[2] Several cases of negative reactions have been recorded for different drugs using Cremophor EL as solubilizer. This suggest that the negative reactions were mainly caused by Cremophor and not by the drug substances themselves. | https://www.wikidoc.org/index.php/Propanidid | |
198b3b53557ec4a68116a1152ce08a29cd7249c2 | wikidoc | Prosaposin | Prosaposin
Prosaposin, also known as PSAP, is a protein which in humans is encoded by the PSAP gene.
This highly conserved glycoprotein is a precursor for 4 cleavage products: saposins A, B, C, and D. Saposin is an acronym for Sphingolipid Activator PrOteINs. Each domain of the precursor protein is approximately 80 amino acid residues long with nearly identical placement of cysteine residues and glycosylation sites. Saposins A-D localize primarily to the lysosomal compartment where they facilitate the catabolism of glycosphingolipids with short oligosaccharide groups. The precursor protein exists both as a secretory protein and as an integral membrane protein and has neurotrophic activities.
Saposins A-D are required for the hydrolysis of certain sphingolipids by specific lysosomal hydrolases.
# Family members
- Saposin A was identified as an N-terminal domain in the prosaposin cDNA prior to its isolation. It is known to stimulate the enzymatic hydrolysis of 4-methlyumbelliferyl-β-glucoside, glucocerebroside, and galactocerebroside.
- Saposin B was the first to be discovered and was found to be required as a heat-stable factor for hydrolysis of sulfatides by arylsulfatase A. It is known by many different names, such as, sphingolipid activator protein-1 (SAP-1), sulfatide activator protein, GM1 ganglioside activator, dispersin, and nonspecific. It has been observed that this particular saposin activates many enzymes through interaction with the substrates not the enzymes themselves.
- Saposin C was the second saposin to be discovered and stimulates the hydrolysis of glycocerebroside by glycosylceramidase and galactocerebroside by galactosylceramidase.
- Saposin D is not well known to due lack of investigation at this point in time. It was predicted from the cDNA sequence of prosaposin, like saposin A. Enzymatic stimulation is very specific for this particular glycoprotein and it not understood completely.
- GM2A (GM2 ganglioside activator) has been viewed as a member of the SAP family and has been called SAP-3 (sphingolipid activator protein 3)
- Saposin A (PDB: 2DOB).
Saposin A (PDB: 2DOB).
- Saposin B (PDB: 1N69).
Saposin B (PDB: 1N69).
- Saposin C dimer in an open conformation (PDB: 2QYP).
Saposin C dimer in an open conformation (PDB: 2QYP).
- Saposin D (PDB: 2RB3).
Saposin D (PDB: 2RB3).
# Structure
Every saposin contains about 80 amino acid residues and has six equally placed cysteines, two prolines, and a glycosylation site (two in saposin A, one each in saposins B, C, and D). Since saposins characteristics of extreme heat-stability, adundance of disulfide linkages, and resistance to most proteases, they are assumed to be extremely compact and rigidly disulfide-linked molecules. Each saposin has an α-helical structure that is seen as being important for stimulation because this structure is maximal at a pH of 4.5; which is optimal for many lysosomal hydrolases. This helical structure is seen in all (especially with the first region), but saposin has been predicted to have β-sheet configuration due to it first 24 amino acids of the N-end.
# Function
They probably act by isolating the lipid substrate from the membrane surroundings, thus making it more accessible to the soluble degradative enzymes. which contains four Saposin-B domains, yielding the active saposins after proteolytic cleavage, and two Saposin-A domains that are removed in the activation reaction. The Saposin-B domains also occur in other proteins, many of them active in the lysis of membranes.
# Clinical significance
Mutations in this gene have been associated with Gaucher disease, Tay-Sachs disease, and metachromatic leukodystrophy. | Prosaposin
Prosaposin, also known as PSAP, is a protein which in humans is encoded by the PSAP gene.[1]
This highly conserved glycoprotein is a precursor for 4 cleavage products: saposins A, B, C, and D. Saposin is an acronym for Sphingolipid Activator PrO[S]teINs.[2] Each domain of the precursor protein is approximately 80 amino acid residues long with nearly identical placement of cysteine residues and glycosylation sites. Saposins A-D localize primarily to the lysosomal compartment where they facilitate the catabolism of glycosphingolipids with short oligosaccharide groups. The precursor protein exists both as a secretory protein and as an integral membrane protein and has neurotrophic activities.[1]
Saposins A-D are required for the hydrolysis of certain sphingolipids by specific lysosomal hydrolases.[3]
# Family members
- Saposin A was identified as an N-terminal domain in the prosaposin cDNA prior to its isolation. It is known to stimulate the enzymatic hydrolysis of 4-methlyumbelliferyl-β-glucoside, glucocerebroside, and galactocerebroside.[4]
- Saposin B was the first to be discovered and was found to be required as a heat-stable factor for hydrolysis of sulfatides by arylsulfatase A. It is known by many different names, such as, sphingolipid activator protein-1 (SAP-1), sulfatide activator protein, GM1 ganglioside activator, dispersin, and nonspecific.[5] It has been observed that this particular saposin activates many enzymes through interaction with the substrates not the enzymes themselves.
- Saposin C was the second saposin to be discovered and stimulates the hydrolysis of glycocerebroside by glycosylceramidase and galactocerebroside by galactosylceramidase.
- Saposin D is not well known to due lack of investigation at this point in time. It was predicted from the cDNA sequence of prosaposin, like saposin A. Enzymatic stimulation is very specific for this particular glycoprotein and it not understood completely.[3]
- GM2A (GM2 ganglioside activator) has been viewed as a member of the SAP family and has been called SAP-3 (sphingolipid activator protein 3)[6]
- Saposin A (PDB: 2DOB).[7]
Saposin A (PDB: 2DOB).[7]
- Saposin B (PDB: 1N69).[8]
Saposin B (PDB: 1N69).[8]
- Saposin C dimer in an open conformation (PDB: 2QYP).[9]
Saposin C dimer in an open conformation (PDB: 2QYP).[9]
- Saposin D (PDB: 2RB3).[9]
Saposin D (PDB: 2RB3).[9]
# Structure
Every saposin contains about 80 amino acid residues and has six equally placed cysteines, two prolines, and a glycosylation site (two in saposin A, one each in saposins B, C, and D).[3] Since saposins characteristics of extreme heat-stability, adundance of disulfide linkages, and resistance to most proteases, they are assumed to be extremely compact and rigidly disulfide-linked molecules. Each saposin has an α-helical structure that is seen as being important for stimulation because this structure is maximal at a pH of 4.5; which is optimal for many lysosomal hydrolases.[3] This helical structure is seen in all (especially with the first region), but saposin has been predicted to have β-sheet configuration due to it first 24 amino acids of the N-end.[5]
# Function
They probably act by isolating the lipid substrate from the membrane surroundings, thus making it more accessible to the soluble degradative enzymes. which contains four Saposin-B domains, yielding the active saposins after proteolytic cleavage, and two Saposin-A domains that are removed in the activation reaction. The Saposin-B domains also occur in other proteins, many of them active in the lysis of membranes.[10][11]
# Clinical significance
Mutations in this gene have been associated with Gaucher disease, Tay-Sachs disease, and metachromatic leukodystrophy.[2] | https://www.wikidoc.org/index.php/Prosaposin | |
06f53f5b43a93dd573324d937143a72221cf05f3 | wikidoc | Proscaline | Proscaline
Proscaline, or 4-propoxy-3,5-DMPEA is a psychedelic and hallucinogenic drug, used by some as an entheogen. It has structural and pharmacodynamic properties similar to the drugs mescaline and escaline.
# Chemistry
Proscaline is in a class of compounds commonly known as phenethylamines, and is the 4-propyloxy homologue of mescaline. The full name of the chemical is 4-propyloxy-3,5-dimethoxyphenethylamine.
# Effects
Proscaline produces psychedelic effects that can last 12 hours.
# Pharmacology
The mechanism that produces proscaline’s hallucinogenic and entheogenic effects is unknown.
# Dangers
The toxicity of proscaline is not known.
# Popularity
Proscaline is unknown on the black market. Limited accounts of proscaline can be found in journal articles, and in the book PiHKAL.
# Legality
Proscaline is unscheduled and unregulated in the United States, however its close similarity in structure and effects to mescaline could potentially subject possession and sale of proscaline to prosecution under the Federal Analog Act. This seems to be the tack the federal government is taking in the wake of the DEA's Operation Web Tryp. A series of Court Cases in the US involving the prosecution of several online vendors in ongoing as of 2004. | Proscaline
Template:Chembox/Top
Template:Chembox/Image
Template:Chembox/Bottom
Proscaline, or 4-propoxy-3,5-DMPEA is a psychedelic and hallucinogenic drug, used by some as an entheogen. It has structural and pharmacodynamic properties similar to the drugs mescaline and escaline.
# Chemistry
Proscaline is in a class of compounds commonly known as phenethylamines, and is the 4-propyloxy homologue of mescaline. The full name of the chemical is 4-propyloxy-3,5-dimethoxyphenethylamine.
# Effects
Proscaline produces psychedelic effects that can last 12 hours.
# Pharmacology
The mechanism that produces proscaline’s hallucinogenic and entheogenic effects is unknown.
# Dangers
The toxicity of proscaline is not known.
# Popularity
Proscaline is unknown on the black market. Limited accounts of proscaline can be found in journal articles, and in the book PiHKAL.
# Legality
Proscaline is unscheduled and unregulated in the United States, however its close similarity in structure and effects to mescaline could potentially subject possession and sale of proscaline to prosecution under the Federal Analog Act. This seems to be the tack the federal government is taking in the wake of the DEA's Operation Web Tryp. A series of Court Cases in the US involving the prosecution of several online vendors in ongoing as of 2004. | https://www.wikidoc.org/index.php/Proscaline | |
4a2ce92b7248eb34fed8072405c5672447e16689 | wikidoc | Prosthesis | Prosthesis
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
# Overview
In medicine, a prosthesis is an artificial extension that replaces a missing body part. It is part of the field of biomechatronics, the science of fusing mechanical devices with human muscle, skeleton, and nervous systems to assist or enhance motor control lost by trauma, disease, or defect. Prostheses are typically used to replace parts lost by injury (traumatic) or missing from birth (congenital) or to supplement defective body parts. In addition to the standard artificial limb for every-day use, many amputees have special limbs and devices to aid in the participation of sports and recreational activities.
# Mechanical and Electronic Components
In order for a robotic prosthetic limb to work, it must have several components to integrate it into the body's function:
Biosensors detect signals from the users nervous or muscular systems. It then relays this information to a controller located inside the device, and processes feedback from the limb and actuator (e.g., position, force) and sends it to the controller. Examples include wires that detect electrical activity on the skin, needle electrodes implanted in muscle, or solid-state electrode arrays with nerves growing through them.
Mechanical sensors process aspects affecting the device (e.g., limb position, applied force, load) and relay this information to the biosensor or controller. Examples: force meters and accelerometers.
The controller is connected to the user's nerve and muscular systems and the device itself. It sends intention commands from the user to the actuators of the device, and interprets feedback from the mechanical and biosensors to the user. The controller is also responsible for the monitoring and control of the movements of the device.
An actuator mimics the actions of a muscle in producing force and movement. Examples include a motor that aids or replaces original muscle tissue.
# Cosmesis
Though many prosthetics are clearly made of artificial materials, the practice of cosmesis, the creation of life-like limbs made from silicone or PVC, has grown in popularity. Such prosthetics, such as artificial hands, can now be made to mimic the appearance of real hands, complete with freckles, veins, hair, fingerprints and even tattoos. Custom-made cosmeses are generally more expensive (costing thousands of US dollars, depending on the level of detail), while standard cosmeses come ready-made in various sizes, though they are often not as realistic as their custom-made counterparts. Another option is the custom-made silicone cover, which can be made to match a person's skin tone but not details such as freckles or wrinkles. Cosmeses are attached to the body in any number of ways, using an adhesive, suction, form-fitting, stretchable skin, or a skin sleeve.
# Prosthetic Enhancement
Within science fiction, and, more recently, within the scientific community, there has been consideration given to using advanced prostheses to replace healthy body parts with artificial mechanisms and systems to improve function. The morality and desirability of such technologies is being debated. Body parts such as legs, arms, hands, feet, and others can be replaced.
The first experiment with a healthy individual appears to have been that by the British scientist Kevin Warwick. On 2002-03-14 an implant was interfaced directly into Warwick's nervous system. The electrode array contained around 100 electrodes, was placed in the median nerve. The signals produced were detailed enough that a robot arm was able to mimic the actions of Warwick's own arm and provide a form of touch feedback again via the implant
# Types
Some types of prosthetics include:
- Artificial limbs
- Breast prosthesis (after mastectomy)
- Cochlear implants
- Corrective lenses
- Craniofacial prosthesis
- Dental / Maxillofacial prosthetics (in cleft palate, dentures, dental restorations)
- Facial prosthetics
- Hair prosthesis
- Neuroprosthetics
- Ocular prosthetics
- Ostomies (colostomy, ileostomy, urostomy)
- Penile prosthetics
- Replacement joints (such as hips)
- Somato prosthetics
- Prosthetic testis
- Transtibial prosthesis | Prosthesis
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [1] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
# Overview
In medicine, a prosthesis is an artificial extension that replaces a missing body part. It is part of the field of biomechatronics, the science of fusing mechanical devices with human muscle, skeleton, and nervous systems to assist or enhance motor control lost by trauma, disease, or defect. Prostheses are typically used to replace parts lost by injury (traumatic) or missing from birth (congenital) or to supplement defective body parts. In addition to the standard artificial limb for every-day use, many amputees have special limbs and devices to aid in the participation of sports and recreational activities.
# Mechanical and Electronic Components
In order for a robotic prosthetic limb to work, it must have several components to integrate it into the body's function:
Biosensors detect signals from the users nervous or muscular systems. It then relays this information to a controller located inside the device, and processes feedback from the limb and actuator (e.g., position, force) and sends it to the controller. Examples include wires that detect electrical activity on the skin, needle electrodes implanted in muscle, or solid-state electrode arrays with nerves growing through them.
Mechanical sensors process aspects affecting the device (e.g., limb position, applied force, load) and relay this information to the biosensor or controller. Examples: force meters and accelerometers.
The controller is connected to the user's nerve and muscular systems and the device itself. It sends intention commands from the user to the actuators of the device, and interprets feedback from the mechanical and biosensors to the user. The controller is also responsible for the monitoring and control of the movements of the device.
An actuator mimics the actions of a muscle in producing force and movement. Examples include a motor that aids or replaces original muscle tissue.
# Cosmesis
Though many prosthetics are clearly made of artificial materials, the practice of cosmesis, the creation of life-like limbs made from silicone or PVC, has grown in popularity. Such prosthetics, such as artificial hands, can now be made to mimic the appearance of real hands, complete with freckles, veins, hair, fingerprints and even tattoos. Custom-made cosmeses are generally more expensive (costing thousands of US dollars, depending on the level of detail), while standard cosmeses come ready-made in various sizes, though they are often not as realistic as their custom-made counterparts. Another option is the custom-made silicone cover, which can be made to match a person's skin tone but not details such as freckles or wrinkles. Cosmeses are attached to the body in any number of ways, using an adhesive, suction, form-fitting, stretchable skin, or a skin sleeve.
# Prosthetic Enhancement
Within science fiction, and, more recently, within the scientific community, there has been consideration given to using advanced prostheses to replace healthy body parts with artificial mechanisms and systems to improve function. The morality and desirability of such technologies is being debated. Body parts such as legs, arms, hands, feet, and others can be replaced.
The first experiment with a healthy individual appears to have been that by the British scientist Kevin Warwick. On 2002-03-14 an implant was interfaced directly into Warwick's nervous system. The electrode array contained around 100 electrodes, was placed in the median nerve. The signals produced were detailed enough that a robot arm was able to mimic the actions of Warwick's own arm and provide a form of touch feedback again via the implant[1]
# Types
Some types of prosthetics include:
- Artificial limbs
- Breast prosthesis (after mastectomy)
- Cochlear implants
- Corrective lenses
- Craniofacial prosthesis
- Dental / Maxillofacial prosthetics (in cleft palate, dentures, dental restorations)
- Facial prosthetics
- Hair prosthesis
- Neuroprosthetics
- Ocular prosthetics
- Ostomies (colostomy, ileostomy, urostomy)
- Penile prosthetics
- Replacement joints (such as hips)
- Somato prosthetics
- Prosthetic testis
- Transtibial prosthesis | https://www.wikidoc.org/index.php/Prostheses | |
56e2f01c6e56672e83779377676978fb894f3f8f | wikidoc | Proteomics | Proteomics
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
Proteomics is the large-scale study of proteins, particularly their structures and functions. Proteins are vital parts of living organisms, as they are the main components of the physiological metabolic pathways of cells. The term "proteomics" was coined to make an analogy with genomics, the study of the genes. The word "proteome" is a blend of "protein" and "genome". The proteome is the entire complement of proteins, including the modifications made to a particular set of proteins, produced by an organism or system. This will vary with time and distinct requirements, or stresses, that a cell or organism undergoes.
# Complexity of the Problem
Proteomics is often considered the next step in the study of biological systems, after genomics. It is much more complicated than genomics, mostly because while an organism's genome is more or less constant, the proteome differs from cell to cell. This is because distinct genes are expressed in distinct cell types, meaning that even the basic set of proteins which are produced in a cell needs to be determined.
In the past this was done by mRNA analysis, but it is now known that mRNA is not always translated into protein, and the amount of protein produced for a given amount of mRNA depends on the gene it is transcribed from and on the current physiological state of the cell. Proteomics confirms the presence of the protein and provides a direct measure of the quantity present.
## Examples of post-translational modifications
### Phosphorylation
More importantly though, any particular protein may go through a wide variety of alterations, which will have critical effects to its function. For example, during cell signaling many enzymes and structural proteins can undergo phosphorylation. The addition of a phosphate to particular amino acids--most commonly serine & threonine, mediated by serine/threonine kinases, or, more rarely, tyrosine, mediated by tyrosine kinases--causes a protein to become a target for binding or interacting with a distinct set of other proteins that recognize the phosphorylated domain.
Because protein phosphorylation is one of the most-studied protein modifications, many "proteomic" efforts are geared to determining the set of phosphorylated proteins in a particular cell or tissue-type under particular circumstances. This alerts the scientist to the signaling pathways that may be active in that instance.
### Ubiquitination
Ubiquitin is a small protein that can be affixed to certain protein substrates by enzymes called E3 ubiquitin ligases. Determining which proteins are poly-ubiquitinated can be helpful in understanding how protein pathways are regulated. This is therefore an additional legitimate "proteomic" study. Similarly, once it is determined what substrates are ubiquitinated by each ligase, determining the set of ligases expressed in a particular cell type will be helpful.
### Additional modifications
Listing all the protein modifications that might be studied in a "Proteomics" project would require a discussion of most of biochemistry; therefore, a short list will serve here to illustrate the complexity of the problem. In addition to phosphorylation and ubiquitination, proteins can be subjected to methylation, acetylation, glycosylation, oxidation, nitrosylation, etc. Some proteins undergo ALL of these modifications, which nicely illustrates the potential complexity one has to deal with when studying protein structure and function.
## Distinct proteins are made under distinct settings
Even if one is studying a particular cell type, that cell may make different sets of proteins at different times, or under different conditions. Furthermore, as mentioned, any one protein can undergo a wide range of post-translational modifications.
Therefore a "proteomics" study can become quite complex very quickly, even if the object of the study is very restricted. In more ambitious settings, such as when a biomarker for a tumor is sought - when the proteomics scientist is obliged to study sera samples from multiple cancer patients - the amount of complexity that must be dealt with is as great as in any modern biological project.
# Rationale for proteomics
The key requirement in understanding protein function is to learn to correlate the vast array of potential protein modifications to particular phenotypic settings, and then determine if a particular post-translational modification is required for a function to occur.
# Limitations to genomic study
Scientists are very interested in proteomics because it gives a much better understanding of an organism than genomics. First, the level of transcription of a gene gives only a rough estimate of its level of expression into a protein. An mRNA produced in abundance may be degraded rapidly or translated inefficiently, resulting in a small amount of protein. Second, as mentioned above many proteins experience post-translational modifications that profoundly affect their activities; for example some proteins are not active until they become phosphorylated. Methods such as phosphoproteomics and glycoproteomics are used to study post-translational modifications. Third, many transcripts give rise to more than one protein, through alternative splicing or alternative post-translational modifications. Finally, many proteins form complexes with other proteins or RNA molecules, and only function in the presence of these other molecules.
# Methods of studying proteins
## Determining proteins which are post-translationally modified
One way in which a particular protein can be studied is to develop an antibody which is specific to that modification. For example, there are antibodies which only recognize certain proteins when they are tyrosine-phosphorylated; also, there are antibodies specific to other modifications. These can be used to determine the set of proteins that have undergone the modification of interest.
For sugar modifications, such as glycosylation of proteins, certain lectins have been discovered which bind sugars. These too can be used.
A more common way to determine post-translational modification of interest is to subject a complex mixture of proteins to electrophoresis in "two-dimensions", which simply means that the proteins are electrophoresed first in one direction, and then in another... this allows small differences in a protein to be visualized by separating a modified protein from its unmodified form. This methodology is known as "two-dimensional gel electrophoresis".
## Determining the existence of proteins in complex mixtures
Classically, antibodies to particular proteins or to their modified forms have been used in biochemistry and cell biology studies. These are among the most common tools used by practicing biologists today.
For more quantitative determinations of protein amounts, techniques such as ELISAs can be used.
For proteomic study, more recent techniques such as Matrix-assisted laser desorption/ionization have been employed for rapid determination of proteins in particular mixtures.
# Establishing protein-protein interactions
Most proteins function in collaboration with other proteins, and one goal of proteomics is to identify which proteins interact. This is especially useful in determining potential partners in cell signaling cascades.
Several methods are available to probe protein-protein interactions. The traditional method is yeast two-hybrid analysis. New methods include protein microarrays, immunoaffinity chromatography followed by mass spectrometry, and experimental methods such as phage display and computational methods.
# Practical applications of proteomics
One of the most promising developments to come from the study of human genes and proteins has been the identification of potential new drugs for the treatment of disease. This relies on genome and proteome information to identify proteins associated with a disease, which computer software can then use as targets for new drugs. For example, if a certain protein is implicated in a disease, its 3D structure provides the information to design drugs to interfere with the action of the protein. A molecule that fits the active site of an enzyme, but cannot be released by the enzyme, will inactivate the enzyme. This is the basis of new drug-discovery tools, which aim to find new drugs to inactivate proteins involved in disease. As genetic differences among individuals are found, researchers expect to use these techniques to develop personalized drugs that are more effective for the individual.
A computer technique which attempts to fit millions of small molecules to the three-dimensional structure of a protein is called "virtual ligand screening". The computer rates the quality of the fit to various sites in the protein, with the goal of either enhancing or disabling the function of the protein, depending on its function in the cell. A good example of this is the identification of new drugs to target and inactivate the HIV-1 protease. The HIV-1 protease is an enzyme that cleaves a very large HIV protein into smaller, functional proteins. The virus cannot survive without this enzyme; therefore, it is one of the most effective protein targets for killing HIV.
## Biomarkers
Understanding the proteome, the structure and function of each protein and the complexities of protein-protein interactions will be critical for developing the most effective diagnostic techniques and disease treatments in the future.
An interesting use of proteomics is using specific protein biomarkers to diagnose disease. A number of techniques allow to test for proteins produced during a particular disease, which helps to diagnose the disease quickly. Techniques include western blot, immunohistochemical staining, enzyme linked immunosorbent assay (ELISA) or mass spectrometry. The following are some of the diseases that have characteristic biomarkers that physicians can use for diagnosis.
## Alzheimer's disease
In Alzheimer’s disease, elevations in beta secretase create amyloid/beta-protein, which causes plaque to build up in the patient's brain, which is thought to play a role in dementia. Targeting this enzyme decreases the amyloid/beta-protein and so slows the progression of the disease. A procedure to test for the increase in amyloid/beta-protein is immunohistochemical staining, in which antibodies bind to specific antigens or biological tissue of amyloid/beta-protein.
## Heart disease
Heart disease is commonly assessed using several key protein based biomarkers. Standard protein biomarkers for CVD include interleukin-6, interleukin-8, serum amyloid A protein, fibrinogen, and troponins. cTnI cardiac troponin I increases in concentration within 3 to 12 hours of initial cardiac injury and can be found elevated days after an acute myocardial infarction. A number of commercial antibody based assays as well as other methods are used in hospitals as primary tests for acute MI. | Proteomics
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Proteomics is the large-scale study of proteins, particularly their structures and functions.[1][2] Proteins are vital parts of living organisms, as they are the main components of the physiological metabolic pathways of cells. The term "proteomics" was coined to make an analogy with genomics, the study of the genes. The word "proteome" is a blend of "protein" and "genome". The proteome is the entire complement of proteins, including the modifications made to a particular set of proteins, produced by an organism or system. This will vary with time and distinct requirements, or stresses, that a cell or organism undergoes.
# Complexity of the Problem
Proteomics is often considered the next step in the study of biological systems, after genomics. It is much more complicated than genomics, mostly because while an organism's genome is more or less constant, the proteome differs from cell to cell. This is because distinct genes are expressed in distinct cell types, meaning that even the basic set of proteins which are produced in a cell needs to be determined.
In the past this was done by mRNA analysis, but it is now known that mRNA is not always translated into protein, and the amount of protein produced for a given amount of mRNA depends on the gene it is transcribed from and on the current physiological state of the cell. Proteomics confirms the presence of the protein and provides a direct measure of the quantity present.
## Examples of post-translational modifications
### Phosphorylation
More importantly though, any particular protein may go through a wide variety of alterations, which will have critical effects to its function. For example, during cell signaling many enzymes and structural proteins can undergo phosphorylation. The addition of a phosphate to particular amino acids--most commonly serine & threonine[3], mediated by serine/threonine kinases, or, more rarely, tyrosine, mediated by tyrosine kinases--causes a protein to become a target for binding or interacting with a distinct set of other proteins that recognize the phosphorylated domain.
Because protein phosphorylation is one of the most-studied protein modifications, many "proteomic" efforts are geared to determining the set of phosphorylated proteins in a particular cell or tissue-type under particular circumstances. This alerts the scientist to the signaling pathways that may be active in that instance.
### Ubiquitination
Ubiquitin is a small protein that can be affixed to certain protein substrates by enzymes called E3 ubiquitin ligases. Determining which proteins are poly-ubiquitinated can be helpful in understanding how protein pathways are regulated. This is therefore an additional legitimate "proteomic" study. Similarly, once it is determined what substrates are ubiquitinated by each ligase, determining the set of ligases expressed in a particular cell type will be helpful.
### Additional modifications
Listing all the protein modifications that might be studied in a "Proteomics" project would require a discussion of most of biochemistry; therefore, a short list will serve here to illustrate the complexity of the problem. In addition to phosphorylation and ubiquitination, proteins can be subjected to methylation, acetylation, glycosylation, oxidation, nitrosylation, etc. Some proteins undergo ALL of these modifications, which nicely illustrates the potential complexity one has to deal with when studying protein structure and function.
## Distinct proteins are made under distinct settings
Even if one is studying a particular cell type, that cell may make different sets of proteins at different times, or under different conditions. Furthermore, as mentioned, any one protein can undergo a wide range of post-translational modifications.
Therefore a "proteomics" study can become quite complex very quickly, even if the object of the study is very restricted. In more ambitious settings, such as when a biomarker for a tumor is sought - when the proteomics scientist is obliged to study sera samples from multiple cancer patients - the amount of complexity that must be dealt with is as great as in any modern biological project.
# Rationale for proteomics
The key requirement in understanding protein function is to learn to correlate the vast array of potential protein modifications to particular phenotypic settings, and then determine if a particular post-translational modification is required for a function to occur.
# Limitations to genomic study
Scientists are very interested in proteomics because it gives a much better understanding of an organism than genomics. First, the level of transcription of a gene gives only a rough estimate of its level of expression into a protein. An mRNA produced in abundance may be degraded rapidly or translated inefficiently, resulting in a small amount of protein. Second, as mentioned above many proteins experience post-translational modifications that profoundly affect their activities; for example some proteins are not active until they become phosphorylated. Methods such as phosphoproteomics and glycoproteomics are used to study post-translational modifications. Third, many transcripts give rise to more than one protein, through alternative splicing or alternative post-translational modifications. Finally, many proteins form complexes with other proteins or RNA molecules, and only function in the presence of these other molecules.
# Methods of studying proteins
## Determining proteins which are post-translationally modified
One way in which a particular protein can be studied is to develop an antibody which is specific to that modification. For example, there are antibodies which only recognize certain proteins when they are tyrosine-phosphorylated; also, there are antibodies specific to other modifications. These can be used to determine the set of proteins that have undergone the modification of interest.
For sugar modifications, such as glycosylation of proteins, certain lectins have been discovered which bind sugars. These too can be used.
A more common way to determine post-translational modification of interest is to subject a complex mixture of proteins to electrophoresis in "two-dimensions", which simply means that the proteins are electrophoresed first in one direction, and then in another... this allows small differences in a protein to be visualized by separating a modified protein from its unmodified form. This methodology is known as "two-dimensional gel electrophoresis".
## Determining the existence of proteins in complex mixtures
Classically, antibodies to particular proteins or to their modified forms have been used in biochemistry and cell biology studies. These are among the most common tools used by practicing biologists today.
For more quantitative determinations of protein amounts, techniques such as ELISAs can be used.
For proteomic study, more recent techniques such as Matrix-assisted laser desorption/ionization have been employed for rapid determination of proteins in particular mixtures.
# Establishing protein-protein interactions
Most proteins function in collaboration with other proteins, and one goal of proteomics is to identify which proteins interact. This is especially useful in determining potential partners in cell signaling cascades.
Several methods are available to probe protein-protein interactions. The traditional method is yeast two-hybrid analysis. New methods include protein microarrays, immunoaffinity chromatography followed by mass spectrometry, and experimental methods such as phage display and computational methods.
# Practical applications of proteomics
One of the most promising developments to come from the study of human genes and proteins has been the identification of potential new drugs for the treatment of disease. This relies on genome and proteome information to identify proteins associated with a disease, which computer software can then use as targets for new drugs. For example, if a certain protein is implicated in a disease, its 3D structure provides the information to design drugs to interfere with the action of the protein. A molecule that fits the active site of an enzyme, but cannot be released by the enzyme, will inactivate the enzyme. This is the basis of new drug-discovery tools, which aim to find new drugs to inactivate proteins involved in disease. As genetic differences among individuals are found, researchers expect to use these techniques to develop personalized drugs that are more effective for the individual.
A computer technique which attempts to fit millions of small molecules to the three-dimensional structure of a protein is called "virtual ligand screening". The computer rates the quality of the fit to various sites in the protein, with the goal of either enhancing or disabling the function of the protein, depending on its function in the cell. A good example of this is the identification of new drugs to target and inactivate the HIV-1 protease. The HIV-1 protease is an enzyme that cleaves a very large HIV protein into smaller, functional proteins. The virus cannot survive without this enzyme; therefore, it is one of the most effective protein targets for killing HIV.
## Biomarkers
Understanding the proteome, the structure and function of each protein and the complexities of protein-protein interactions will be critical for developing the most effective diagnostic techniques and disease treatments in the future.
An interesting use of proteomics is using specific protein biomarkers to diagnose disease. A number of techniques allow to test for proteins produced during a particular disease, which helps to diagnose the disease quickly. Techniques include western blot, immunohistochemical staining, enzyme linked immunosorbent assay (ELISA) or mass spectrometry. The following are some of the diseases that have characteristic biomarkers that physicians can use for diagnosis.
## Alzheimer's disease
In Alzheimer’s disease, elevations in beta secretase create amyloid/beta-protein, which causes plaque to build up in the patient's brain, which is thought to play a role in dementia. Targeting this enzyme decreases the amyloid/beta-protein and so slows the progression of the disease. A procedure to test for the increase in amyloid/beta-protein is immunohistochemical staining, in which antibodies bind to specific antigens or biological tissue of amyloid/beta-protein.
## Heart disease
Heart disease is commonly assessed using several key protein based biomarkers. Standard protein biomarkers for CVD include interleukin-6, interleukin-8, serum amyloid A protein, fibrinogen, and troponins. cTnI cardiac troponin I increases in concentration within 3 to 12 hours of initial cardiac injury and can be found elevated days after an acute myocardial infarction. A number of commercial antibody based assays as well as other methods are used in hospitals as primary tests for acute MI. | https://www.wikidoc.org/index.php/Proteomic | |
fdc263c9b18a43456a7c9dc844a4d968635f93e3 | wikidoc | Protirelin | Protirelin
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Protirelin is a diagnostic agent that is FDA approved for the diagnosis of thyroid function. Common adverse reactions include hypertension, hypotension, lightheadedness, flushing, abdominal discomfort, bad taste in mouth, nausea, xerostomia, headache, Urgent desire to urinate.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- TRH is indicated as an adjunctive agent in the diagnostic assessment of thyroid function. As an adjunct to other diagnostic procedures, testing with TRH (protirelin) may yield useful information in patients with pituitary or hypothalamic dysfunction.
- TRH is indicated as an adjunct to evaluate the effectiveness of thyrotropin suppression with a particular dose of T4 in patients with nodular or diffuse goiter. A normal TSH baseline value and a minimal difference between the 30 minute and baseline response to TRH injection would indicate adequate suppression of the pituitary secretion of TSH.
- TRH may be used, adjunctively, for adjustment of thyroid hormone dosage given to patients with primary hypothyroidism. A normal or slightly blunted TSH response, thirty minutes following TRH injection, would indicate adequate replacement therapy.
- TRH is intended for intravenous administration with the patient in the supine position. The drug is administered as a bolus over a period of 15 to 30 seconds, with the patient remaining supine until all scheduled post injection blood samples have been taken. Blood pressure should be measured before TRH is administered and at frequent intervals during the first 15 minutes thereafter . Have the patient urinate before injecting TRH.
- Adults: 500 μg. Doses between 200 and 500 μg have been used. 500 μg is considered the optimum dose to give the maximum response in the greatest number of patients. Doses greater than 500 μg are unlikely to elicit a greater TSH response.
- Children age 6 to 16 years: 7 μg/kg body weight up to a dose of 500 μg.
- Infants and children up to 6 years: Experience is limited in this age group; doses of 7μg/kg have been administered.
- One blood sample for TSH assay should be drawn immediately prior to the injection of TRH, and a second sample should be obtained 30 minutes after injection.
- The TSH response to TRH is reduced by repetitive administration of the drug. Accordingly, if the TRH test is repeated, an interval of seven days before testing is recommended.
- Elevated serum lipids may interfere with the TSH assay. Thus, fasting (except in patients with hypopituitarism) or a low-fat meal is recommended prior to the test.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Protirelin in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Protirelin in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Protirelin in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Protirelin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Protirelin in pediatric patients.
# Contraindications
There is limited information regarding Protirelin Contraindications in the drug label.
# Warnings
- Transient changes in blood pressure, either increases or decreases, frequently occur immediately following administration of TRH. Blood pressure should therefore be measured before TRH is administered and at frequent intervals during the first 15 minutes after its administration.
- Increases in systolic pressure (usually less than 30 mm Hg) and/or increases in diastolic pressure (usually less than 20 mm Hg) have been observed more frequently than decreases in pressure. These changes have not ordinarily persisted for more than 15 minutes nor have they required therapy. More severe degrees of hypertension or hypotension with or without syncope have been reported in a few patients. To minimize the incidence and/or severity of hypotension, the patient should be supine before, during, and after TRH administration. If a clinically important change in blood pressure occurs, monitoring of blood pressure should be continued until it returns to base-line levels.
- TRH should not be administered to patients in whom marked, rapid changes in blood pressure would be dangerous unless the potential benefit clearly outweighs the potential risk
### Precautions
- Thyroid hormones reduce the TSH response to TRH. Accordingly, patients in whom TRH is to be used diagnostically should be taken off liothyronine (T3) approximately seven days prior to testing and should be taken off thyroid medications containing levothyroxine (T4), e.g., desiccated thyroid, thyroglobulin, or liotrix, at least 14 days before testing. Hormone therapy is NOT to be discontinued when the test is used to evaluate the effectiveness of thyroid suppression with a particular dose of T4 in patients with nodular or diffuse goiter, or for adjustment of thyroid hormone dosage given to patients with primary hypothyroidism.
- Chronic administration of levodopa has been reported to inhibit the TSH response to TRH.
- It is not advisable to withdraw maintenance doses of adrenocortical drugs used in the therapy of known hypopituitarism. Several published reports have shown that prolonged treatment with glucocorticoids at physiologic doses has no significant effect on the TSH response to thyrotropin releasing hormone, but that the administration of pharmacologic doses of steroids reduces the TSH response. Therapeutic doses of acetylsalicylic acid (2 to 3.6 g/day) have been reported to inhibit the TSH response to protirelin. The ingestion of acetylsalicylic acid caused the peak level of TSH to decrease approximately 30% as compared to values obtained without acetylsalicylic acid administration. In both cases, the TSH peak occurred 30 minutes post-administration of protirelin.
# Adverse Reactions
## Clinical Trials Experience
- Side effects have been reported in about 50% of the patients tested with TRH. Generally, the side effects are moor, have occurred promptly, and have persisted for only a few minutes following injection.
- Marked changes in blood pressure, including both hypertension and hypotension with or without syncope, have been reported in a small number of patients.
- Breast enlargement and leakage in lactating women for up to two or three days.
- Headaches, sometimes severe, and transient amaurosis in patients with pituitary tumors. Rarely, convulsions may occur in patients with predisposing conditions, e.g., epilepsy, brain damage. Nausea; urge to urinate; flushed sensation; light-headedness; bad taste in mouth; abdominal discomfort; and dry mouth.
- Anxiety; sweating; tightness in the throat; pressure in the chest; tingling sensation; drowsiness; and allergic reactions.
- Pituitary apoplexy requiring acute neurosurgical intervention has been reported infrequently for patients with pituitary macroadenomas following the acute administration of protirelin injection in the setting of combined anterior pituitary function testing in conjunction with LHRH and insulin.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Protirelin in the drug label.
# Drug Interactions
There is limited information regarding Protirelin Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
There is no FDA guidance on usage of Protirelin in women who are pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Protirelin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Protirelin during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Protirelin with respect to nursing mothers.
### Pediatric Use
There is no FDA guidance on the use of Protirelin with respect to pediatric patients.
### Geriatic Use
There is no FDA guidance on the use of Protirelin with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Protirelin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Protirelin with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Protirelin in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Protirelin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Protirelin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Protirelin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
### Monitoring
There is limited information regarding Monitoring of Protirelin in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Protirelin in the drug label.
# Overdosage
There is limited information regarding Chronic Overdose of Protirelin in the drug label.
# Pharmacology
## Mechanism of Action
There is limited information regarding Protirelin Mechanism of Action in the drug label.
## Structure
- Chemically, TRH (protirelin) is identified as 5-oxo-L-prolyl-L-histidyl-L-proline amide. It is a synthetic tripeptide that is believed to be structurally identical to the naturally-occurring thyrotropin-releasing hormone produced by the hypothalamus. The CAS Registry Number is 24305-27-9. The structural formula is:
- TRH is supplied as a solution of 1 mL in a 5 mL vial. Each vial contains 500 mcg protirelin, 1.8 mg Methylparaben, 0.2 mg Propylparaben, and 9.0 mg Sodium Chloride. TRH is intended for intravenous administration following dilution with 1 mL sterile water for injection.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Protirelin in the drug label.
## Pharmacokinetics
- Pharmacologically, TRH increases the release of the thyroid stimulating hormone (TSH) from the anterior pituitary. Prolactin release is also increased. It has recently been observed that approximately 65% of acromegalic patients tested respond with a rise in circulating growth hormone levels; the clinical significance is as yet not clear. Following intravenous administration, the mean plasma half-life of protirelin in normal subjects is approximately five minutes. TSH levels rise rapidly and reach a peak at 20 to 30 minutes. The decline in TSH levels takes place more slowly, approaching baseline levels after approximately three hours
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Protirelin in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Protirelin in the drug label.
# How Supplied
There is limited information regarding Protirelin How Supplied in the drug label.
## Storage
There is limited information regarding Protirelin Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Protirelin in the drug label.
# Precautions with Alcohol
- Alcohol-Protirelin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Thyrel TRH
# Look-Alike Drug Names
There is limited information regarding Protirelin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Protirelin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aparna Vuppala, M.B.B.S. [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Protirelin is a diagnostic agent that is FDA approved for the diagnosis of thyroid function. Common adverse reactions include hypertension, hypotension, lightheadedness, flushing, abdominal discomfort, bad taste in mouth, nausea, xerostomia, headache, Urgent desire to urinate.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- TRH is indicated as an adjunctive agent in the diagnostic assessment of thyroid function. As an adjunct to other diagnostic procedures, testing with TRH (protirelin) may yield useful information in patients with pituitary or hypothalamic dysfunction.
- TRH is indicated as an adjunct to evaluate the effectiveness of thyrotropin suppression with a particular dose of T4 in patients with nodular or diffuse goiter. A normal TSH baseline value and a minimal difference between the 30 minute and baseline response to TRH injection would indicate adequate suppression of the pituitary secretion of TSH.
- TRH may be used, adjunctively, for adjustment of thyroid hormone dosage given to patients with primary hypothyroidism. A normal or slightly blunted TSH response, thirty minutes following TRH injection, would indicate adequate replacement therapy.
- TRH is intended for intravenous administration with the patient in the supine position. The drug is administered as a bolus over a period of 15 to 30 seconds, with the patient remaining supine until all scheduled post injection blood samples have been taken. Blood pressure should be measured before TRH is administered and at frequent intervals during the first 15 minutes thereafter . Have the patient urinate before injecting TRH.
- Adults: 500 μg. Doses between 200 and 500 μg have been used. 500 μg is considered the optimum dose to give the maximum response in the greatest number of patients. Doses greater than 500 μg are unlikely to elicit a greater TSH response.
- Children age 6 to 16 years: 7 μg/kg body weight up to a dose of 500 μg.
- Infants and children up to 6 years: Experience is limited in this age group; doses of 7μg/kg have been administered.
- One blood sample for TSH assay should be drawn immediately prior to the injection of TRH, and a second sample should be obtained 30 minutes after injection.
- The TSH response to TRH is reduced by repetitive administration of the drug. Accordingly, if the TRH test is repeated, an interval of seven days before testing is recommended.
- Elevated serum lipids may interfere with the TSH assay. Thus, fasting (except in patients with hypopituitarism) or a low-fat meal is recommended prior to the test.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Protirelin in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Protirelin in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Protirelin in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Protirelin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Protirelin in pediatric patients.
# Contraindications
There is limited information regarding Protirelin Contraindications in the drug label.
# Warnings
- Transient changes in blood pressure, either increases or decreases, frequently occur immediately following administration of TRH. Blood pressure should therefore be measured before TRH is administered and at frequent intervals during the first 15 minutes after its administration.
- Increases in systolic pressure (usually less than 30 mm Hg) and/or increases in diastolic pressure (usually less than 20 mm Hg) have been observed more frequently than decreases in pressure. These changes have not ordinarily persisted for more than 15 minutes nor have they required therapy. More severe degrees of hypertension or hypotension with or without syncope have been reported in a few patients. To minimize the incidence and/or severity of hypotension, the patient should be supine before, during, and after TRH administration. If a clinically important change in blood pressure occurs, monitoring of blood pressure should be continued until it returns to base-line levels.
- TRH should not be administered to patients in whom marked, rapid changes in blood pressure would be dangerous unless the potential benefit clearly outweighs the potential risk
### Precautions
- Thyroid hormones reduce the TSH response to TRH. Accordingly, patients in whom TRH is to be used diagnostically should be taken off liothyronine (T3) approximately seven days prior to testing and should be taken off thyroid medications containing levothyroxine (T4), e.g., desiccated thyroid, thyroglobulin, or liotrix, at least 14 days before testing. Hormone therapy is NOT to be discontinued when the test is used to evaluate the effectiveness of thyroid suppression with a particular dose of T4 in patients with nodular or diffuse goiter, or for adjustment of thyroid hormone dosage given to patients with primary hypothyroidism.
- Chronic administration of levodopa has been reported to inhibit the TSH response to TRH.
- It is not advisable to withdraw maintenance doses of adrenocortical drugs used in the therapy of known hypopituitarism. Several published reports have shown that prolonged treatment with glucocorticoids at physiologic doses has no significant effect on the TSH response to thyrotropin releasing hormone, but that the administration of pharmacologic doses of steroids reduces the TSH response. Therapeutic doses of acetylsalicylic acid (2 to 3.6 g/day) have been reported to inhibit the TSH response to protirelin. The ingestion of acetylsalicylic acid caused the peak level of TSH to decrease approximately 30% as compared to values obtained without acetylsalicylic acid administration. In both cases, the TSH peak occurred 30 minutes post-administration of protirelin.
# Adverse Reactions
## Clinical Trials Experience
- Side effects have been reported in about 50% of the patients tested with TRH. Generally, the side effects are moor, have occurred promptly, and have persisted for only a few minutes following injection.
- Marked changes in blood pressure, including both hypertension and hypotension with or without syncope, have been reported in a small number of patients.
- Breast enlargement and leakage in lactating women for up to two or three days.
- Headaches, sometimes severe, and transient amaurosis in patients with pituitary tumors. Rarely, convulsions may occur in patients with predisposing conditions, e.g., epilepsy, brain damage. Nausea; urge to urinate; flushed sensation; light-headedness; bad taste in mouth; abdominal discomfort; and dry mouth.
- Anxiety; sweating; tightness in the throat; pressure in the chest; tingling sensation; drowsiness; and allergic reactions.
- Pituitary apoplexy requiring acute neurosurgical intervention has been reported infrequently for patients with pituitary macroadenomas following the acute administration of protirelin injection in the setting of combined anterior pituitary function testing in conjunction with LHRH and insulin.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Protirelin in the drug label.
# Drug Interactions
There is limited information regarding Protirelin Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
There is no FDA guidance on usage of Protirelin in women who are pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Protirelin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Protirelin during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Protirelin with respect to nursing mothers.
### Pediatric Use
There is no FDA guidance on the use of Protirelin with respect to pediatric patients.
### Geriatic Use
There is no FDA guidance on the use of Protirelin with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Protirelin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Protirelin with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Protirelin in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Protirelin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Protirelin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Protirelin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
### Monitoring
There is limited information regarding Monitoring of Protirelin in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Protirelin in the drug label.
# Overdosage
There is limited information regarding Chronic Overdose of Protirelin in the drug label.
# Pharmacology
## Mechanism of Action
There is limited information regarding Protirelin Mechanism of Action in the drug label.
## Structure
- Chemically, TRH (protirelin) is identified as 5-oxo-L-prolyl-L-histidyl-L-proline amide. It is a synthetic tripeptide that is believed to be structurally identical to the naturally-occurring thyrotropin-releasing hormone produced by the hypothalamus. The CAS Registry Number is 24305-27-9. The structural formula is:
- TRH is supplied as a solution of 1 mL in a 5 mL vial. Each vial contains 500 mcg protirelin, 1.8 mg Methylparaben, 0.2 mg Propylparaben, and 9.0 mg Sodium Chloride. TRH is intended for intravenous administration following dilution with 1 mL sterile water for injection.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Protirelin in the drug label.
## Pharmacokinetics
- Pharmacologically, TRH increases the release of the thyroid stimulating hormone (TSH) from the anterior pituitary. Prolactin release is also increased. It has recently been observed that approximately 65% of acromegalic patients tested respond with a rise in circulating growth hormone levels; the clinical significance is as yet not clear. Following intravenous administration, the mean plasma half-life of protirelin in normal subjects is approximately five minutes. TSH levels rise rapidly and reach a peak at 20 to 30 minutes. The decline in TSH levels takes place more slowly, approaching baseline levels after approximately three hours
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Protirelin in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Protirelin in the drug label.
# How Supplied
There is limited information regarding Protirelin How Supplied in the drug label.
## Storage
There is limited information regarding Protirelin Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Protirelin in the drug label.
# Precautions with Alcohol
- Alcohol-Protirelin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Thyrel TRH
# Look-Alike Drug Names
There is limited information regarding Protirelin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Protirelin | |
601e2e3c4b4509557834a1602a18925d5a46f2b2 | wikidoc | Psilocybin | Psilocybin
Psilocybin (also known as psilocybine) is a psychedelic alkaloid of the tryptamine family, found in psilocybin mushrooms. It is considered mostly to be an entheogen and a tool in use to supplement various types of practices for transcendence including in meditation, psychonautics, and illicit psychedelic psychotherapy whether self administered or not. It can also be used as a recreational drug. Though Psilocybin rarely attracts much attention from mainstream media, when it does, the focus tends to be on the recreational use to the exclusion of any other purpose. It is present in hundreds of species of fungi, including those of the genus Psilocybe, such as Psilocybe cubensis and Psilocybe semilanceata, but also reportedly isolated from a dozen or so other genera. Psilocybin mushrooms are commonly called "magic mushrooms" or more simply "shrooms". The intensity and duration of entheogenic and recreational use of psilocybin mushrooms vary depending on species of mushrooms, dosage, individual physiology, and set and setting.
# Chemistry
Psilocybin is a prodrug that is converted into the pharmacologically active compound psilocin in the body by dephosphorylation. This chemical reaction takes place under strongly acidic conditions or enzymatically by phosphatases in the body. Psilocybin is a zwitterionic alkaloid that is soluble in water, moderately soluble in methanol and ethanol, and insoluble in most organic solvents.
Albert Hofmann was the first to recognize the importance and chemical structure of the pure compounds psilocybin and psilocin. Hofmann was aided in this process by his willingness to ingest extracts isolated from Psilocybe. Hofmann's colleagues at the University of Delaware were also trying to isolate the active principle, but were unsuccessful.
# Biology
Psilocybin is a naturally-occurring compound found in high concentrations in some species of Psilocybe and Panaeolus (collectively called "psilocybin mushrooms" or "psilocybian mushrooms"), and at low levels in a large number of species of the Agaricales. The spores of these mushrooms are completely free of both psilocybin and psilocin. The total potency varies greatly between species and even between specimens of one species in the same batch. Younger, smaller mushrooms are relatively higher in alkaloids and have a milder taste than larger, mature mushrooms. Mature mycelium contains some amount of psilocybin, which can be extracted with an acidic solution, usually of citric acid or ascorbic acid (Vitamin C). Young mycelium (recently germinated from spores) does not contain appreciable amounts of alkaloids. Most species of hallucinogenic mushrooms also contain small amounts of the psilocybin analogs baeocystin and norbaeocystin. Many types of psilocybin mushrooms bruise blue when handled or damaged — this is due to the oxidization of active compounds though bruising is not a definitive method of determining a mushrooms potency.
# Pharmacology
Psilocybin is rapidly dephosphorylated in the body to psilocin which then acts as a partial agonist at the 5-HT2A serotonin receptor in the brain where it mimics the effects of serotonin (5-HT). Psilocin is an 5-HT1A and 5-HT2A/2C agonist.
# Medicine
Psilocybin has been studied as a treatment for several disorders. In 1961, Timothy Leary and Richard Alpert ran the Harvard Psilocybin Project, carrying out a number of experiments concerning the use of psilocybin in the treatment of personality disorders and other uses in psychological counseling.
In the United States, an FDA-approved study supported by Multidisciplinary Association for Psychedelic Studies (MAPS) began in 2001 to study the effects of psilocybin on patients with obsessive-compulsive disorder. MAPS has also proposed studying psilocybin's potential application for the treatment of cluster headaches based on anecdotal evidence presented to them by a group of cluster headache sufferers. In 2006, the MAPS study found psilocybin effective in relieving obsessive compulsive disorder symptoms, in some cases for more than a few days.
In a current study of psilocybin, led by Charles Grob, 12 subjects are being administered with either the hallucinogen or a placebo in two separate sessions. Grob hopes to reduce the psychological distress that is associated with death by treating patients with psilocybin. "Lewis, Judith. "The Hallucinogenic Way to Die." LA Weekly. Mar. 2004:AlterNet
# Toxicity
The toxicity of psilocybin is relatively low; in rats, the oral LD50 is 280mg/kg — almost one and a half times that of the LD50 of caffeine. When administered intravenously in rabbits, Psilocybin's LD50 is approximately 12.5mg/kg. Death from psilocybin intake alone is unknown at recreational or medicinal levels.
The psilocybin content of psychoactive mushrooms is quite variable and depends on species, growth and drying conditions, and mushroom size.
# Effects
Psilocybin is absorbed through the lining of the mouth and stomach. Effects begin 10-40 minutes after ingestion of psilocybin-containing mushrooms if held in mouth for 20-60 minutes or if swallowed on an empty stomach, and last from 2-6 hours depending on dose, species, and individual metabolism. Typical recreational dosage is from 10-50mg psilocybin, approximately 1-5g dried mushroom or 10-50g wet mushrooms.
The effects of psilocybin are often pleasant, even ecstatic, including a deep sense of connection to others, confusion, hilarity, and a general feeling of connection to nature and the universe. Bad trips may occur when psychedelic compounds are taken in a non-supportive or inadequate environment, by an inexperienced person, in an unexpectedly high dose (see: set and setting), or when the substance triggers difficult areas of one's psyche.
At low doses, hallucinatory effects occur, including walls that seem to breathe, a vivid enhancement of colors and the animation of organic shapes. At higher doses, experiences tend to be less social and more entheogenic, often catalyzing intense spiritual experiences. For example, in the Marsh Chapel Experiment, which was run by a graduate student at Harvard Divinity School under the supervision of Timothy Leary, almost all of the graduate degree divinity student volunteers who received psilocybin reported profound religious experiences. (A brief video about the Marsh Chapel experiment can be viewed here.)
In 2006, a group of researchers from Johns Hopkins School of Medicine led by Roland R Griffiths conducted an experiment assessing the degree of mystical experience and attitudinal effects of the psilocybin experience; this report was published in the journal Psychopharmacology. Thirty-six volunteers without prior experience with hallucinogens were given psilocybin and methylphenidate (Ritalin) in separate sessions, the methylphenidate sessions serving as a control and active placebo; the tests were double-blind, with neither the subject nor the administrator knowing which drug was being administered. The degree of mystical experience was measured using a questionnaire on mystical experience developed by Ralph W Hood; 61% of subjects reported a "complete mystical experience" after their psilocybin session, while only 13% reported such an outcome after their experience with methylphenidate. Two months after taking psilocybin, 79% of the participants reported moderately to greatly increased life satisfaction and sense of well-being. About 36% of participants also had a strong to extreme “experience of fear” or dysphoria (I.E. a “bad trip”) at some point during the psilocybin session (which was not reported by any subject during the methylphenidate session), with about one-third of these (13% of the total) reporting that this dysphoria dominated the entire session. These negative effects were reported to be easily managed by the researchers and did not have a lasting negative effect on the subject’s sense of well-being. This research was widely covered in the major media outlets.. Most people who have used psilocybin report that if you believe you will have a "bad trip" then you will. The same people, also report the best way to have a "good trip" is respect the mushroom, believe it will be a "good trip", and use it more for spiritual enhancement, rather than taking the psilocybin just to get "messed up".
A very small number of people are unusually sensitive to psilocybin's effects, where doses as little as 0.25 grams of dried Psilocybe cubensis mushrooms (normally a threshold dose of around 2 mg psilocybin) can result in effects usually associated with medium and high doses. Likewise, there are some people who require relatively high doses of psilocybin to gain low-dose effects. Individual brain chemistry and metabolism plays a large role in determining a person's response to psilocybin.
Psilocybin is metabolized mostly in the liver where it becomes psilocin. It is broken down by the enzyme monoamine oxidase. MAO inhibitors have been known to sustain the effects of psilocybin for longer periods of time; people who are taking an MAOI for a medical condition (or are seeking to potentiate the mushroom experience) should be careful.
Mental and physical tolerance to psilocybin builds and dissipates quickly. Taking psilocybin more than three or four times in a week (especially two days in a row) can result in diminished effects. Tolerance dissipates after a few days, so frequent users often keep doses spaced five to seven days apart to avoid the effect.
## Adverse effects
Individuals that have relatives with schizophrenia should be very careful about consuming psilocybin or any hallucinogenic drug at all due to the risk of triggering a psychosis.
In extremely rare cases the use of hallucinogens may trigger a malady called Hallucinogen persisting perception disorder. (HPPD).
# Social and legal aspects
Psilocybin and psilocin are listed as Schedule I drugs under the United Nations 1971 Convention on Psychotropic Substances. Schedule I drugs are illicit drugs that are claimed to have no known therapeutic benefit. Parties to the treaty are required to restrict use of the drug to medical and scientific research under strictly controlled conditions. Most national drug laws have been amended to reflect this convention (for example, the US Psychotropic Substances Act, the UK Misuse of Drugs Act 1971, and the Canadian Controlled Drugs and Substances Act), with possession and use of psilocybin and psilocin being prohibited under almost all circumstances, and often carrying severe legal penalties.
Possession and use of psilocybin mushrooms, including the bluing species of Psilocybe, is therefore prohibited by extension. However, in many national, state, and provincial drug laws, there is a great deal of ambiguity about the legal status of psilocybin mushrooms and the spores of these mushrooms, as well as a strong element of selective enforcement in some places. For more details on the legal status of psilocybin mushrooms and Psilocybe spores, see: Psilocybe: Social and legal aspects.
Because of the ease of cultivating psilocybin mushrooms or gathering wild species, purified psilocybin is practically nonexistent on the illegal drug market. | Psilocybin
Psilocybin (also known as psilocybine) is a psychedelic alkaloid of the tryptamine family, found in psilocybin mushrooms. It is considered mostly to be an entheogen and a tool in use to supplement various types of practices for transcendence including in meditation, psychonautics, and illicit psychedelic psychotherapy whether self administered or not. It can also be used as a recreational drug. Though Psilocybin rarely attracts much attention from mainstream media, when it does, the focus tends to be on the recreational use to the exclusion of any other purpose. It is present in hundreds of species of fungi, including those of the genus Psilocybe, such as Psilocybe cubensis and Psilocybe semilanceata, but also reportedly isolated from a dozen or so other genera. Psilocybin mushrooms are commonly called "magic mushrooms" or more simply "shrooms". The intensity and duration of entheogenic and recreational use of psilocybin mushrooms vary depending on species of mushrooms, dosage, individual physiology, and set and setting.
# Chemistry
Psilocybin is a prodrug that is converted into the pharmacologically active compound psilocin in the body by dephosphorylation.[1] This chemical reaction takes place under strongly acidic conditions or enzymatically by phosphatases in the body. Psilocybin is a zwitterionic alkaloid that is soluble in water, moderately soluble in methanol and ethanol, and insoluble in most organic solvents.
Albert Hofmann was the first to recognize the importance and chemical structure of the pure compounds psilocybin and psilocin. Hofmann was aided in this process by his willingness to ingest extracts isolated from Psilocybe. Hofmann's colleagues at the University of Delaware were also trying to isolate the active principle, but were unsuccessful.[2]
# Biology
Psilocybin is a naturally-occurring compound found in high concentrations in some species of Psilocybe and Panaeolus (collectively called "psilocybin mushrooms" or "psilocybian mushrooms"), and at low levels in a large number of species of the Agaricales. The spores of these mushrooms are completely free of both psilocybin and psilocin. The total potency varies greatly between species and even between specimens of one species in the same batch. Younger, smaller mushrooms are relatively higher in alkaloids and have a milder taste than larger, mature mushrooms. Mature mycelium contains some amount of psilocybin, which can be extracted with an acidic solution, usually of citric acid or ascorbic acid (Vitamin C). Young mycelium (recently germinated from spores) does not contain appreciable amounts of alkaloids. Most species of hallucinogenic mushrooms also contain small amounts of the psilocybin analogs baeocystin and norbaeocystin. Many types of psilocybin mushrooms bruise blue when handled or damaged — this is due to the oxidization of active compounds though bruising is not a definitive method of determining a mushrooms potency.
# Pharmacology
Psilocybin is rapidly dephosphorylated in the body to psilocin which then acts as a partial agonist at the 5-HT2A serotonin receptor in the brain where it mimics the effects of serotonin (5-HT). Psilocin is an 5-HT1A and 5-HT2A/2C agonist.
# Medicine
Psilocybin has been studied as a treatment for several disorders. In 1961, Timothy Leary and Richard Alpert ran the Harvard Psilocybin Project, carrying out a number of experiments concerning the use of psilocybin in the treatment of personality disorders and other uses in psychological counseling.
In the United States, an FDA-approved study supported by Multidisciplinary Association for Psychedelic Studies (MAPS) began in 2001 to study the effects of psilocybin on patients with obsessive-compulsive disorder.[3] MAPS has also proposed studying psilocybin's potential application for the treatment of cluster headaches based on anecdotal evidence presented to them by a group of cluster headache sufferers.[4] In 2006, the MAPS study found psilocybin effective in relieving obsessive compulsive disorder symptoms, in some cases for more than a few days.[5]
In a current study of psilocybin, led by Charles Grob, 12 subjects are being administered with either the hallucinogen or a placebo in two separate sessions. Grob hopes to reduce the psychological distress that is associated with death by treating patients with psilocybin.[6][7] "Lewis, Judith. "The Hallucinogenic Way to Die." LA Weekly. Mar. 2004:AlterNet
# Toxicity
The toxicity of psilocybin is relatively low; in rats, the oral LD50 is 280mg/kg — almost one and a half times that of the LD50 of caffeine. When administered intravenously in rabbits, Psilocybin's LD50 is approximately 12.5mg/kg. [8] Death from psilocybin intake alone is unknown at recreational or medicinal levels.
The psilocybin content of psychoactive mushrooms is quite variable and depends on species, growth and drying conditions, and mushroom size.
# Effects
Psilocybin is absorbed through the lining of the mouth and stomach. Effects begin 10-40 minutes after ingestion of psilocybin-containing mushrooms if held in mouth for 20-60 minutes or if swallowed on an empty stomach, and last from 2-6 hours depending on dose, species, and individual metabolism.[9] Typical recreational dosage is from 10-50mg psilocybin, approximately 1-5g dried mushroom or 10-50g wet mushrooms.
The effects of psilocybin are often pleasant, even ecstatic, including a deep sense of connection to others, confusion, hilarity, and a general feeling of connection to nature and the universe. Bad trips may occur when psychedelic compounds are taken in a non-supportive or inadequate environment, by an inexperienced person, in an unexpectedly high dose (see: set and setting), or when the substance triggers difficult areas of one's psyche.
At low doses, hallucinatory effects occur, including walls that seem to breathe, a vivid enhancement of colors and the animation of organic shapes. At higher doses, experiences tend to be less social and more entheogenic, often catalyzing intense spiritual experiences. For example, in the Marsh Chapel Experiment, which was run by a graduate student at Harvard Divinity School under the supervision of Timothy Leary, almost all of the graduate degree divinity student volunteers who received psilocybin reported profound religious experiences. (A brief video about the Marsh Chapel experiment can be viewed here.)
In 2006, a group of researchers from Johns Hopkins School of Medicine led by Roland R Griffiths conducted an experiment assessing the degree of mystical experience and attitudinal effects of the psilocybin experience; this report was published in the journal Psychopharmacology. Thirty-six volunteers without prior experience with hallucinogens were given psilocybin and methylphenidate (Ritalin) in separate sessions, the methylphenidate sessions serving as a control and active placebo; the tests were double-blind, with neither the subject nor the administrator knowing which drug was being administered. The degree of mystical experience was measured using a questionnaire on mystical experience developed by Ralph W Hood; 61% of subjects reported a "complete mystical experience" after their psilocybin session, while only 13% reported such an outcome after their experience with methylphenidate. Two months after taking psilocybin, 79% of the participants reported moderately to greatly increased life satisfaction and sense of well-being. About 36% of participants also had a strong to extreme “experience of fear” or dysphoria (I.E. a “bad trip”) at some point during the psilocybin session (which was not reported by any subject during the methylphenidate session), with about one-third of these (13% of the total) reporting that this dysphoria dominated the entire session. These negative effects were reported to be easily managed by the researchers and did not have a lasting negative effect on the subject’s sense of well-being. [1] This research was widely covered in the major media outlets.[2]. Most people who have used psilocybin report that if you believe you will have a "bad trip" then you will. The same people, also report the best way to have a "good trip" is respect the mushroom, believe it will be a "good trip", and use it more for spiritual enhancement, rather than taking the psilocybin just to get "messed up".
A very small number of people are unusually sensitive to psilocybin's effects, where doses as little as 0.25 grams of dried Psilocybe cubensis mushrooms (normally a threshold dose of around 2 mg psilocybin) can result in effects usually associated with medium and high doses. Likewise, there are some people who require relatively high doses of psilocybin to gain low-dose effects. Individual brain chemistry and metabolism plays a large role in determining a person's response to psilocybin.
Psilocybin is metabolized mostly in the liver where it becomes psilocin. It is broken down by the enzyme monoamine oxidase. MAO inhibitors have been known to sustain the effects of psilocybin for longer periods of time; people who are taking an MAOI for a medical condition (or are seeking to potentiate the mushroom experience) should be careful.
Mental and physical tolerance to psilocybin builds and dissipates quickly. Taking psilocybin more than three or four times in a week (especially two days in a row) can result in diminished effects. Tolerance dissipates after a few days, so frequent users often keep doses spaced five to seven days apart to avoid the effect.
## Adverse effects
Individuals that have relatives with schizophrenia should be very careful about consuming psilocybin or any hallucinogenic drug at all due to the risk of triggering a psychosis. [10]
In extremely rare cases the use of hallucinogens may trigger a malady called Hallucinogen persisting perception disorder. (HPPD).[11]
# Social and legal aspects
Psilocybin and psilocin are listed as Schedule I drugs under the United Nations 1971 Convention on Psychotropic Substances.[3] Schedule I drugs are illicit drugs that are claimed to have no known therapeutic benefit. Parties to the treaty are required to restrict use of the drug to medical and scientific research under strictly controlled conditions. Most national drug laws have been amended to reflect this convention (for example, the US Psychotropic Substances Act, the UK Misuse of Drugs Act 1971, and the Canadian Controlled Drugs and Substances Act), with possession and use of psilocybin and psilocin being prohibited under almost all circumstances, and often carrying severe legal penalties.
Possession and use of psilocybin mushrooms, including the bluing species of Psilocybe, is therefore prohibited by extension. However, in many national, state, and provincial drug laws, there is a great deal of ambiguity about the legal status of psilocybin mushrooms and the spores of these mushrooms, as well as a strong element of selective enforcement in some places. For more details on the legal status of psilocybin mushrooms and Psilocybe spores, see: Psilocybe: Social and legal aspects.
Because of the ease of cultivating psilocybin mushrooms or gathering wild species, purified psilocybin is practically nonexistent on the illegal drug market. | https://www.wikidoc.org/index.php/Psilocybin | |
dbf3065443c8167c0494a001edda2a3186fe0f50 | wikidoc | Psoas sign | Psoas sign
# Overview
Elicited by the iliopsoas test, the psoas sign is an indicator of irritation to the iliopsoas group of hip flexors in the abdomen.
# Technique
The test is performed by passively extending the thigh of a patient with knees extended. In other words, the patient is positioned on his/her left side, and the right leg is extended behind the patient. If abdominal pain results, it is a positive psoas sign.
# Cause
Because the right iliopsoas muscle lies under the appendix when the patient is supine, a "positive psoas sign" may suggest appendicitis.
It could also be done by flexing the hip to 90 degrees -- with flexed knee -- asking the patient to actively flex their thigh against resistance.
# Video
# Related Chapters
- Abdominal exam
- Appendicitis
- Obturator sign
- Rovsing's sign | Psoas sign
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Elicited by the iliopsoas test, the psoas sign is an indicator of irritation to the iliopsoas group of hip flexors in the abdomen.
# Technique
The test is performed by passively extending the thigh of a patient with knees extended. In other words, the patient is positioned on his/her left side, and the right leg is extended behind the patient. If abdominal pain results, it is a positive psoas sign.
# Cause
Because the right iliopsoas muscle lies under the appendix when the patient is supine, a "positive psoas sign" may suggest appendicitis.
It could also be done by flexing the hip to 90 degrees -- with flexed knee -- asking the patient to actively flex their thigh against resistance.
# Video
# Related Chapters
- Abdominal exam
- Appendicitis
- Obturator sign
- Rovsing's sign
# External Links
- Acute appendicitis review in American Family Physician | https://www.wikidoc.org/index.php/Psoas_sign | |
dd21008621a699141eee580acc793b1efe7d14b0 | wikidoc | Psychiatry | Psychiatry
# Background
Psychiatry is a branch of medicine which exists to study, prevent, and treat mental disorders in humans. The art and science of the clinical application of psychiatry has been considered a bridge between the social world and those who are mentally ill. Both its research and clinical application are considered interdisciplinary. Because of this, various subspecialties and theoretical approaches exist in psychiatric research and practice. Psychiatrists can be considered physicians who specialize in the doctor-patient relationship who utilize some of medicine's newest classification schemes, diagnostic tools and treatments.
Ancient psychiatry originated in the 5th century BC with the ideology that psychotic disorders were supernatural in origin. At that time clergy were the individuals in society with the responsibility of "curing" mental disorders. By the middle ages psychiatric hospitals were first created as custodial institutions to house those with mental disorders. During the 18th century the idea arose that mental health institutions could utilize treatments. As a result of these early psychiatric interventions, the 19th century saw a massive increase in patient populations. This dramatic increase led to the decline of treatments offered in such institutions and hurt the reputation of psychiatry. The 20th century saw a rebirth of a biological understanding of mental disorders as well an introduction into disease classification. The shift of psychiatry to the hard sciences moved psychiatry into a different direction which resulted in an altered doctor-patient relationship. These changes were seen by many in society as negative and anti-psychiatry movements emerged. The shift in thinking, as well as the introduction of psychiatric medications, led to the dismantling of state psychiatric hospitals. While community treatment was seen as the single solution for those suffering from mental disorders, clinician's soon realized that it was only another treatment option following the drift of disturbed populations into homelessness and prisons. The dramatic changes associated with psychiatric diagnoses and treatments have pushed the field into recognizing the balance between the biological and social sciences and has called for a significant demand of research looking into the origins, classification, and treatment of mental disorders.
# Theory and focus
"Psychiatry, more than any other branch of medicine, forces its practitioners to wrestle with the nature of evidence, the validity of introspection, problems in communication, and other long-standing philosophical issues" (Psychiatry# note-Guze4|Guze, 1992, p.4).
Psychiatry, a word coined by Johann Christian Reil in 1808, has historically been seen as a specialty of medicine which acted as an intermediary between the world from a social context and the world from the perspective of those who are mentally ill. Those who practice psychiatry are different than most other mental health professionals and physicians in that they must be familiar with both the social and biological sciences. The discipline is interested in the operations of different organs and body systems as classified by the patient's subjective experiences and the objective physiology of the patient. Psychiatry exists to treat mental disorders which are conventionally divided into three very general categories; mental illness, severe learning disability, and personality disorder. While the focus of psychiatry has changed little throughout time, the diagnostic and treatment processes have evolved dramatically and continue to do so. Since the late 20th century, the field of psychiatry has continued to become more biological and less conceptually isolated from the field of medicine.
## Scope of practice
While the medical specialty of psychiatry utilizes research in the field of neuroscience, psychology, medicine, biology, biochemistry, and pharmacology, it has generally been considered a middle ground between neurology and psychology. Unlike other physicians and neurologists, psychiatrists specialize in the doctor-patient relationship and are trained in the use of psychotherapy and other therepautic communication techniques. Psychiatrists also differ from psychologists in that they are physicians and the entirety of their post-graduate training is revolved around the field of medicine. Psychiatrists can therefore prescribe medications, order laboratory tests, utilize neuroimaging in a clinical setting, and conduct physical examinations.
## Ethics
Like other professions, the World Psychiatric Association issues an ethical code to govern the conduct of psychiatrists. The psychiatric code of ethics, first set forth through the Declaration of Hawaii in 1977, has been expanded through a 1983 Vienna update and, in 1996, the broader Madrid Declaration. The code was further revised in Hamburg, 1999. The World Psychiatric Association code covers such matters as patient assessment, up-to-date knowledge, the human dignity of incapacitated patients, confidentiality, research ethics, sex selection, euthanasia, organ transplantation, torture, the death penalty, media relations, genetics, and ethnic or cultural discrimination. In establishing such ethical codes, the profession has responded to a number of controversies about the practice of psychiatry.
## Subspecialties
Various subspecialties and/or theoretical approaches exist which are related to the field of psychiatry. They include the following:
- Biological psychiatry; an approach to psychiatry that aims to understand mental disorder in terms of the biological function of the nervous system.
- Child and adolescent psychiatry; a branch of psychiatry that specialises in work with children, teenagers, and their families.
- Cross-cultural psychiatry; a branch of psychiatry concerned with the cultural and ethnic context of mental disorder and psychiatric services.
- Emergency psychiatry; the clinical application of psychiatry in emergency settings.
- Forensic psychiatry; the interface between law and psychiatry.
- Geriatric psychiatry; a branch of psychiatry dealing with the study, prevention, and treatment of mental disorders in humans with old age.
- Liaison psychiatry; the branch of psychiatry that specializes in the interface between other medical specialties and psychiatry.
- Neuropsychiatry; branch of medicine dealing with mental disorders attributable to diseases of the nervous system.
- Social psychiatry; a branch of psychiatry that focuses on the interpersonal and cultural context of mental disorder and mental wellbeing.
# History
## Ancient psychiatry
Starting in the 5th century BC, mental disorders, especially those disorders with psychotic traits, were considered supernatural in origin. This view existed throughout ancient Greece and ancient Rome|Rome. Early manuals written about mental disorders were created by the Greeks. In 4th century BC, Hippocrates theorized that physiological abnormalities may be the root of mental disorders. However further explorations of this perspective ceased shortly thereafter following the Decline of the Roman Empire|fall of the Roman Empire. Religious leaders and others returned to using early versions of exorcisms to treat mental disorders which often utilized cruel, harsh, and other barbarous methods.
## Middle ages through the 18th century
Psychiatric hospitals have existed to treat mental disorders since the Middle Ages but were utilized only as custodial institutions and did not provide any type of treatment. Founded in the 13th century, Bethlem Royal Hospital in London is one of the oldest psychiatric hospitals. By 1547 the City of London acquired the hospital and continued its function until 1948. In 1656, Louis XIV of France created a public system of hospitals for those suffering from mental disorders, but like in England, no real treatment was being applied. In 1758 English physician William Battie wrote the Treatise on Madness which called for treatments to be utilized in asylums. Thirty years later the new ruling monarch in England, George III of the United Kingdom|George III, was known to be suffering from a mental disorder. Following the King's remission in 1789, mental illness was seen as something which could be treated and cured. By 1792 French physician Philippe Pinel introduced Moral treatment|humane treatment approaches to those suffering from mental disorders. William Tuke adopted the methods outlined by Pinel and that same year Tuke opened the The Retreat|York Retreat in England. That institution became known as a model throughout the world for humane and moral treatment of patients suffering from mental disorders.
## 19th century
In 1800 the number of individuals in asylums in all of England and France was only in the low hundreds. By the late 1890s and early 1900s this number skyrocketed to the hundreds of thousands. The United States housed 150,000 patients in mental hospitals by 1904. German speaking countries housed more than 400 public and private sector asylums. These asylums were critical to the evolution of psychiatry as they provided a universal platform of practice throughout the world. Universities oftentimes played a part in the administration of the asylums. Due to the relationship between the universities and asylums, scores of competitive psychiatrists were being molded in Germany. Germany became known as the world leader in psychiatry during the nineteenth century. The country possessed more than 20 separate universities all competing with each other for scientific advancement. However, because of Germany's individual states and the lack of national regulation of asylums, the country had no organized centralization of asylums or psychiatry. Britain, like Germany, also lacked a centralized organization for the administration of asylums. This deficit hindered the diffusion of new ideas in medicine and psychiatry. By 1838, France created a national law which regulated both the mechanisms for admission into asylums and organized asylum services across the country. By 1840 asylums existing as therapeutic institutions existed throughout Europe and the United States.
However, the new and dominating ideas that mental illness could be "conquered" during the mid-nineteenth century all came crashing down. Psychiatrists and asylums were being pressured by an ever increasing patient population. The average number of patients in asylums in the United States jumped 927%. Numbers were similar in England and Germany. Overcrowding was rampant in France where asylums would commonly take in double their maximum capacity. Increases in asylum populations may have been a result of the transfer of care from families and poorhouses, but the specific reasons as to why the increase occurred is still debated today. No matter the cause, the pressure on asylums from the increase was taking its toll on the asylums and psychiatry as a specialty. Asylums were once again turning into custodial institutions and the reputation of psychiatry in the medical world had hit an extreme low.
## 20th century
### Disease classification and rebirth of biological psychiatry
The 20th century introduced a new psychiatry into the world. The different perspectives of looking at mental disorders began to be introduced. The career and beginnings of Emil Kraepelin somewhat model this hiatus of psychiatry between the different disciplines. Kraepelin initially was very attracted to psychology and ignored the ideas of anatomical psychiatry. Following his acceptance for a professorship of psychiatry, and later his work in a university psychiatric clinic, Kraepelin's insterest in pure psychology began to fade and he introduced a plan of a more comprehensive psychiatry. Kraepelin also began to study and promote the ideas of disease classification for mental disorders, an idea introduced by Karl Ludwig Kahlbaum. The initial ideas behind biological psychiatry, stating that these different disorders were all biological in nature, evolved into a new idea of "nerves" and psychiatry became a sort of rough neurology or neuropsychiatry. Following Sigmund Freud's death, ideas stemming from psychoanalytic theory also began to take root. The psychoanalytic theory became popular among psychiatrists because it allowed the patients to be treated in private practices instead of asylums. However the progress of psychiatry by the 1970s turned psychoanalytic theory into a marginal school of thought within the field.
This period of time saw the reemergence of biological psychiatry. Psychopharmacology became an integral part of psychiatry starting with Otto Loewi's discovery of the first neurotransmitter, acetylcholine. Neuroimaging was first utilized as a tool for psychiatry in the 1980s. The discovery of chlorpromazine's effectiveness in treating schizophrenia in 1952 revolutionized treatment of the disease, as did lithium carbonate's ability to stabilize mood highs and lows in bipolar disorder in 1948. While psychosocial issues were still seen as valid, psychotherapy was seen to be their "cure." Genetics were once again thought to play a role in mental illness. Molecular biology opened the door for specific genes causing mental disorders to be identified. By 1995 genes causing schizophrenia had been identified on chromosome 6 and those genes responsible for bipolar disorder on chromosomes 18 and 21.
### Anti-psychiatry and deinstitutionalization
The introduction of psychiatric medications and the use of laboratory tests altered the doctor-patient relationship between psychiatrists and their patients. Psychiatry's shift to the hard sciences had been interpreted as a lack of concern for patients. Anti-psychiatry had become more prevalent in the late twentieth century due to this and publications in the media which conceptualized mental disorders as myths. Others in the movement argued that psychiatry was a form of social control and demanded that institutionalized psychiatric care, stemming from Pinel's thereapeutic asylum, be abolished. Incidents of physical abuse by psychiatrists took place during the reign of some totalitarian regimes as part of a system to enforce political control with some of the abuse even continuing to our present day. Historical examples of the abuse of psychiatry took place in Nazi Germany , in the Soviet Union under Psikhushka, and in the apartheid system in South Africa.
Electroconvulsive therapy was one treatment that the anti-psychiatry movement wanted eliminated. They alleged that electroconvulsive therapy damaged the brain and it was used as a tool for discipline. While there is no evidence that brain damage was a result of electronconvulsive therapy, there have been isolated incidents where the use of electroconvulsive therapy was threatened to keep the patients "in line." The prevalence of psychiatric medication helped initiate deinstitutionalization, the process of discharging patients from psychiatric hospitals to the community. The pressure from the anti-psychiatry movements and the ideology of community treatment from the medical arena helped sustain deinstitutionalization. A mere thirty three years after deinstitutionalization started in the United States, only 19% of the patients in state hospitals remained. Mental health professionals envisioned a process wherein patients would be released into communities where they could participate in a normal life while living in a therapeutic atmosphere.
### Transinstitutionalization and the aftermath
In 1963, United States president John F. Kennedy introduced legislation delegating the National Institute of Mental Health to administer Community Mental Health Centers for those being discharged from state psychiatric hospitals. Later, though, the Community Mental Health Center's focus was diverted to provide psychotherapy sessions for those suffering from acute and/or mild mental disorders. Ultimately there were no arrangements made for actively ill patients who were being discharged from hospitals. Instead of being treated by the "community," those suffering from mental disorders drifted into homelessness or ended up in prisons and jails. Studies found that 33% of the homeless population and 14% of inmates in prisons and jails were already diagnosed with a mental illness.
In 1972, psychologist David Rosenhan published the Rosenhan experiment, a study analyzing the validity of psychiatric diagnoses. The study arranged for eight individuals with no history of psychopathology to attempt admission into psychiatric hospitals. The individuals included a graduate student, psychologists, an artist, a housewife, and two physicians, including one psychiatrist. All eight individuals were admitted with a diagnosis of schizophrenia or bipolar disorder. Psychiatrists then attempted to treat the individuals using psychiatric medication. All eight were discharged within 7 to 52 days. Rosenhan's study concluded that individuals with no presence of mental disorders could not be distinguished from those suffering from mental disorders. While critics such as Robert Spitzer placed doubt on the validity and credibility of the study, they also conceded that the consistency of psychiatric diagnoses needed improvement.
Psychiatry is one of the few medical specialties with a continuing, significant demand for research investigating its related diseases, classifications, origins, and treatments. Psychiatry falls into biology's fundamental belief that disease and health are different elements of an individual's adaptation to an environment. But psychiatry also recognizes that the environment of the human species is complex and includes physical, cultural, and relational elements. In addition to external factors, the human brain must recognize or organize an individual's hopes, fears, desires, fantasies and feelings. Psychiatry's difficult task is the attempt to envelop the understanding of these factors so that they can be studied both clinically and physiologically.
# Industry and academia
## Practitioners
As with most medical specialties, all physicians can diagnose mental disorders and prescribe treatments utilizing principles of psychiatry. Psychiatrists are physicians who specialize in psychiatry and are certified in treating mental illness using the biomedical approach to mental disorders. Psychiatrists may also go through significant training to conduct psychotherapy, psychoanalysis, and/or cognitive behavioral therapy, but it is their medical training, access to medical laboratories, and ability to prescribe medications that differentiates them from other mental health professionals.
## Research
Psychiatric research is, by its very nature, interdisciplinary. From a general perspective it studies and combines social, biological and psychological approaches and how those perspectives cause mental disorders. While practicing psychiatrists and other psychiatric researchers study outcomes from such a wide variety of fields, research institutions and publications exist that are dedicated to the interdisciplinary study of mental disorders within the psychiatric context. Under the supervision of institutional review boards, psychiatric researchers looks at a variety of topics such as neuroimaging, genetics, and psychopharmacology, which in turn help enhance diagnostic consistency, discover new treatment methods, and classify new mental disorders.
## Clinical application
### Diagnostic systems
Psychiatric diagnoses take place in a wide variety of settings and are performed by many different health professionals. Therefore, the diagnostic procedure may vary greatly based upon these factors. Typically, though, a psychiatric diagnosis utilizes a differential diagnosis procedure where mental status examinations and physical examinations are conducted, pathological, psychopathological and psychosocial histories obtained, neuroimages or other neurophysiological measurements are taken, and personality tests or cognitive tests may be administered. In addition psychiatrists are beginning to utilize genetics during the diagnostic process. Some endophenotypes being researched may predispose certain individuals to certain conditions.
Three main diagnostic manuals used to classify mental health conditions are in use today. The ICD-10 is produced and published by the World Health Organisation and includes a section on psychiatric conditions, and is used worldwide. The Diagnostic and Statistical Manual of Mental Disorders, produced and published by the American Psychiatric Association, is solely focused on mental health conditions and is the main classification tool in the United States. It is currently in its fourth revised edition and is also used worldwide. The Chinese Society of Psychiatry has also produced a diagnostic manual, the Chinese Classification of Mental Disorders.
The stated intention of diagnostic manuals is typically to develop replicable and clinically useful categories and criteria, to facilitate consensus and agreed standards, whilst being atheoretical as regards etiology. However, the categories are nevertheless based on particular psychiatric theories and data; they are broad and often specified by numerous possible combinations of symptoms, and many of the categories overlap in symptomology or typically occur together. While originally intended only as a guide for experienced clinicians trained in its use, the nomenclature is now widely used by clinicians, administrators and insurance companies in many countries.
### Treatment settings
In general, psychiatric treatments have changed over the past several decades. In the past, psychiatric patients were often hospitalized for six months or more, with some cases involving hospitalization for many years. Today, most people receiving psychiatric treatment are seen as outpatients. If hospitalization is required, the average hospital stay is around two to three weeks, with only a small number of people receiving long-term hospitalization.
Individuals with mental health conditions are commonly referred to as patients but may also be called clients, consumers, or service recipients. They may come under the care of a psychiatric physician or other psychiatric practitioners by various paths, the two most common being self-referral or referral by a primary-care physician. Alternatively, a person may be referred by hospital medical staff, by court order, involuntary commitment, or, in the UK and Australia, by sectioning under a mental health law.
Whatever the circumstance of a person's referral, a psychiatrist first assesses a person's mental and physical condition. This usually involves interviewing the person and often obtaining information from other sources such as other health and social care professionals, relatives, associates, law enforcement and emergency medical personnel and psychiatric rating scales. A physical examination is usually performed to establish or exclude other illnesses, such as thyroid dysfunction or brain tumors, or identify any signs of self-harm; this examination may be done by someone else other than the psychiatrist, especially if blood tests and medical imaging are performed.
Like all medications, psychiatric medications can have toxic effects in patients and hence often involve ongoing therapeutic drug monitoring, for instance full blood counts or, for patients taking lithium salts, serum levels of lithium, renal and thyroid function. Electroconvulsive therapy (ECT) is sometimes administered for serious and disabling conditions, especially those unresponsive to medication.
Psychiatric inpatients are people admitted to a hospital or clinic to receive psychiatric care. Some are admitted involuntarily, perhaps committed to a secure hospital, or in some jurisdictions to a facility within the prison system. In many countries including the USA and Canada, the criteria for involuntary admission vary with local jurisdiction. They may be as broad as having a mental health condition, or as narrow as being an immediate danger to themselves and/or others. Bed availability is often the real determinant of admission decisions to hard pressed public facilities. European Human Rights legislation restricts detention to medically-certified cases of mental disorder, and adds a right to timely judicial review of detention.
Voluntary commitment is also possible, and in some cases people seeking care are offered this option if a mental health professional feels inpatient care is needed, but is unable or unwilling to seek involuntary commitment. People who are voluntarily committed have more options in ending their commitment, but procedures on leaving the facility vary greatly.
Inpatient psychiatric wards may be secure (for those thought to have a particular risk of violence or self-harm) or unlocked/open. Some wards are mixed-sex whilst same-sex wards are increasingly favored to protect women inpatients.
Once in the care of a hospital, people are assessed, monitored, and often given medication and care from a multidisciplinary team, which may include physicians, psychiatric nurse practitioners, psychiatric nurses, clinical psychologists, psychotherapists, psychiatric social workers, occupational therapists and social workers. If a person receiving treatment in a psychiatric hospital is assessed as at particular risk of harming themselves or others, they may be put on constant or intermittent one-to-one supervision, and may be physically restrained or medicated. People on inpatient wards may be allowed leave for periods of time, either accompanied or on their own.
In many developed countries there has been a massive reduction in psychiatric beds since the mid 20th century, with the growth of community care. Standards of inpatient care remain a challenge in some public and private facilities, due to levels of funding, and facilities in developing countries are typically grossly inadequate for the same reason.
People receiving psychiatric care may do so on an inpatient or outpatient basis. Outpatient treatment involves periodic visits to a clinician for consultation in his or her office, usually for an appointment lasting thirty to sixty minutes. These consultations normally involve the psychiatric practitioner interviewing the person to update their assessment of the person's condition, and to provide psychotherapy or review medication. The frequency with which a psychiatric practitioner sees people in treatment varies widely, from days to months, depending on the type, severity and stability of each person's condition, and depending on what the clinician and client decide would be best. Increasingly, psychiatrists are limiting their practice to psychopharmacology (prescribing medications) with less time devoted to psychotherapy or "talk" therapies, or behavior modification. The role of psychiatrists is changing in community psychiatry, with many assuming more leadership roles, coordinating and supervising teams of allied health professionals and junior doctors in delivery of health services. | Psychiatry
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Background
Psychiatry is a branch of medicine which exists to study, prevent, and treat mental disorders in humans.[1][2][3] The art and science of the clinical application of psychiatry has been considered a bridge between the social world and those who are mentally ill.[4] Both its research and clinical application are considered interdisciplinary.[5] Because of this, various subspecialties and theoretical approaches exist in psychiatric research and practice. Psychiatrists can be considered physicians who specialize in the doctor-patient relationship[6] who utilize some of medicine's newest classification schemes, diagnostic tools and treatments.[7][8][9]
Ancient psychiatry originated in the 5th century BC with the ideology that psychotic disorders were supernatural in origin.[10] At that time clergy were the individuals in society with the responsibility of "curing" mental disorders.[10] By the middle ages psychiatric hospitals were first created as custodial institutions to house those with mental disorders.[11] During the 18th century the idea arose that mental health institutions could utilize treatments.[12] As a result of these early psychiatric interventions, the 19th century saw a massive increase in patient populations.[13] This dramatic increase led to the decline of treatments offered in such institutions and hurt the reputation of psychiatry.[14] The 20th century saw a rebirth of a biological understanding of mental disorders as well an introduction into disease classification.[15][16] The shift of psychiatry to the hard sciences moved psychiatry into a different direction which resulted in an altered doctor-patient relationship.[17] These changes were seen by many in society as negative and anti-psychiatry movements emerged.[18] The shift in thinking, as well as the introduction of psychiatric medications, led to the dismantling of state psychiatric hospitals.[19] While community treatment was seen as the single solution for those suffering from mental disorders, clinician's soon realized that it was only another treatment option following the drift of disturbed populations into homelessness and prisons.[20] The dramatic changes associated with psychiatric diagnoses and treatments have pushed the field into recognizing the balance between the biological and social sciences and has called for a significant demand of research looking into the origins, classification, and treatment of mental disorders.[21][22]
# Theory and focus
"Psychiatry, more than any other branch of medicine, forces its practitioners to wrestle with the nature of evidence, the validity of introspection, problems in communication, and other long-standing philosophical issues" (Psychiatry# note-Guze4|Guze, 1992, p.4).
Psychiatry, a word coined by Johann Christian Reil in 1808, has historically been seen as a specialty of medicine which acted as an intermediary between the world from a social context and the world from the perspective of those who are mentally ill.[4] Those who practice psychiatry are different than most other mental health professionals and physicians in that they must be familiar with both the social and biological sciences.[22] The discipline is interested in the operations of different organs and body systems as classified by the patient's subjective experiences and the objective physiology of the patient.[23] Psychiatry exists to treat mental disorders which are conventionally divided into three very general categories; mental illness, severe learning disability, and personality disorder.[24] While the focus of psychiatry has changed little throughout time, the diagnostic and treatment processes have evolved dramatically and continue to do so. Since the late 20th century, the field of psychiatry has continued to become more biological and less conceptually isolated from the field of medicine.[25]
## Scope of practice
While the medical specialty of psychiatry utilizes research in the field of neuroscience, psychology, medicine, biology, biochemistry, and pharmacology,[5] it has generally been considered a middle ground between neurology and psychology.[6] Unlike other physicians and neurologists, psychiatrists specialize in the doctor-patient relationship and are trained in the use of psychotherapy and other therepautic communication techniques.[6] Psychiatrists also differ from psychologists in that they are physicians and the entirety of their post-graduate training is revolved around the field of medicine.[26] Psychiatrists can therefore prescribe medications, order laboratory tests, utilize neuroimaging in a clinical setting, and conduct physical examinations.[27]
## Ethics
Like other professions, the World Psychiatric Association issues an ethical code to govern the conduct of psychiatrists. The psychiatric code of ethics, first set forth through the Declaration of Hawaii in 1977, has been expanded through a 1983 Vienna update and, in 1996, the broader Madrid Declaration. The code was further revised in Hamburg, 1999. The World Psychiatric Association code covers such matters as patient assessment, up-to-date knowledge, the human dignity of incapacitated patients, confidentiality, research ethics, sex selection, euthanasia,[28] organ transplantation, torture,[29][30] the death penalty, media relations, genetics, and ethnic or cultural discrimination.[31] In establishing such ethical codes, the profession has responded to a number of controversies about the practice of psychiatry.
## Subspecialties
Various subspecialties and/or theoretical approaches exist which are related to the field of psychiatry. They include the following:
- Biological psychiatry; an approach to psychiatry that aims to understand mental disorder in terms of the biological function of the nervous system.
- Child and adolescent psychiatry; a branch of psychiatry that specialises in work with children, teenagers, and their families.
- Cross-cultural psychiatry; a branch of psychiatry concerned with the cultural and ethnic context of mental disorder and psychiatric services.
- Emergency psychiatry; the clinical application of psychiatry in emergency settings.
- Forensic psychiatry; the interface between law and psychiatry.
- Geriatric psychiatry; a branch of psychiatry dealing with the study, prevention, and treatment of mental disorders in humans with old age.
- Liaison psychiatry; the branch of psychiatry that specializes in the interface between other medical specialties and psychiatry.
- Neuropsychiatry; branch of medicine dealing with mental disorders attributable to diseases of the nervous system.
- Social psychiatry; a branch of psychiatry that focuses on the interpersonal and cultural context of mental disorder and mental wellbeing.
# History
## Ancient psychiatry
Starting in the 5th century BC, mental disorders, especially those disorders with psychotic traits, were considered supernatural in origin.[10] This view existed throughout ancient Greece and ancient Rome|Rome.[10] Early manuals written about mental disorders were created by the Greeks.[32] In 4th century BC, Hippocrates theorized that physiological abnormalities may be the root of mental disorders.[10] However further explorations of this perspective ceased shortly thereafter following the Decline of the Roman Empire|fall of the Roman Empire.[10] Religious leaders and others returned to using early versions of exorcisms to treat mental disorders which often utilized cruel, harsh, and other barbarous methods.[10]
## Middle ages through the 18th century
Psychiatric hospitals have existed to treat mental disorders since the Middle Ages but were utilized only as custodial institutions and did not provide any type of treatment.[11] Founded in the 13th century, Bethlem Royal Hospital in London is one of the oldest psychiatric hospitals.[11] By 1547 the City of London acquired the hospital and continued its function until 1948.[33] In 1656, Louis XIV of France created a public system of hospitals for those suffering from mental disorders, but like in England, no real treatment was being applied.[33] In 1758 English physician William Battie wrote the Treatise on Madness which called for treatments to be utilized in asylums.[12] Thirty years later the new ruling monarch in England, George III of the United Kingdom|George III, was known to be suffering from a mental disorder.[10] Following the King's remission in 1789, mental illness was seen as something which could be treated and cured.[10] By 1792 French physician Philippe Pinel introduced Moral treatment|humane treatment approaches to those suffering from mental disorders.[10] William Tuke adopted the methods outlined by Pinel and that same year Tuke opened the The Retreat|York Retreat in England.[10] That institution became known as a model throughout the world for humane and moral treatment of patients suffering from mental disorders.[34]
## 19th century
In 1800 the number of individuals in asylums in all of England and France was only in the low hundreds.[35] By the late 1890s and early 1900s this number skyrocketed to the hundreds of thousands.[35] The United States housed 150,000 patients in mental hospitals by 1904.[35] German speaking countries housed more than 400 public and private sector asylums.[35] These asylums were critical to the evolution of psychiatry as they provided a universal platform of practice throughout the world.[35] Universities oftentimes played a part in the administration of the asylums.[36] Due to the relationship between the universities and asylums, scores of competitive psychiatrists were being molded in Germany.[36] Germany became known as the world leader in psychiatry during the nineteenth century.[35] The country possessed more than 20 separate universities all competing with each other for scientific advancement.[35] However, because of Germany's individual states and the lack of national regulation of asylums, the country had no organized centralization of asylums or psychiatry.[35] Britain, like Germany, also lacked a centralized organization for the administration of asylums.[37] This deficit hindered the diffusion of new ideas in medicine and psychiatry.[37] By 1838, France created a national law which regulated both the mechanisms for admission into asylums and organized asylum services across the country.[38] By 1840 asylums existing as therapeutic institutions existed throughout Europe and the United States.[13]
However, the new and dominating ideas that mental illness could be "conquered" during the mid-nineteenth century all came crashing down.[13] Psychiatrists and asylums were being pressured by an ever increasing patient population.[13] The average number of patients in asylums in the United States jumped 927%.[13] Numbers were similar in England and Germany.[13] Overcrowding was rampant in France where asylums would commonly take in double their maximum capacity.[39] Increases in asylum populations may have been a result of the transfer of care from families and poorhouses, but the specific reasons as to why the increase occurred is still debated today.[40][41] No matter the cause, the pressure on asylums from the increase was taking its toll on the asylums and psychiatry as a specialty. Asylums were once again turning into custodial institutions[42] and the reputation of psychiatry in the medical world had hit an extreme low.[14]
## 20th century
### Disease classification and rebirth of biological psychiatry
The 20th century introduced a new psychiatry into the world. The different perspectives of looking at mental disorders began to be introduced. The career and beginnings of Emil Kraepelin somewhat model this hiatus of psychiatry between the different disciplines.[15] Kraepelin initially was very attracted to psychology and ignored the ideas of anatomical psychiatry.[15] Following his acceptance for a professorship of psychiatry, and later his work in a university psychiatric clinic, Kraepelin's insterest in pure psychology began to fade and he introduced a plan of a more comprehensive psychiatry.[43][16] Kraepelin also began to study and promote the ideas of disease classification for mental disorders, an idea introduced by Karl Ludwig Kahlbaum.[16] The initial ideas behind biological psychiatry, stating that these different disorders were all biological in nature, evolved into a new idea of "nerves" and psychiatry became a sort of rough neurology or neuropsychiatry.[44] Following Sigmund Freud's death, ideas stemming from psychoanalytic theory also began to take root.[45] The psychoanalytic theory became popular among psychiatrists because it allowed the patients to be treated in private practices instead of asylums.[45] However the progress of psychiatry by the 1970s turned psychoanalytic theory into a marginal school of thought within the field.[45]
This period of time saw the reemergence of biological psychiatry. Psychopharmacology became an integral part of psychiatry starting with Otto Loewi's discovery of the first neurotransmitter, acetylcholine.[46] Neuroimaging was first utilized as a tool for psychiatry in the 1980s.[47] The discovery of chlorpromazine's effectiveness in treating schizophrenia in 1952 revolutionized treatment of the disease, [48] as did lithium carbonate's ability to stabilize mood highs and lows in bipolar disorder in 1948.[49] While psychosocial issues were still seen as valid, psychotherapy was seen to be their "cure."[50] Genetics were once again thought to play a role in mental illness.[46] Molecular biology opened the door for specific genes causing mental disorders to be identified.[46] By 1995 genes causing schizophrenia had been identified on chromosome 6 and those genes responsible for bipolar disorder on chromosomes 18 and 21.[46]
### Anti-psychiatry and deinstitutionalization
The introduction of psychiatric medications and the use of laboratory tests altered the doctor-patient relationship between psychiatrists and their patients.[17] Psychiatry's shift to the hard sciences had been interpreted as a lack of concern for patients.[17] Anti-psychiatry had become more prevalent in the late twentieth century due to this and publications in the media which conceptualized mental disorders as myths.[18] Others in the movement argued that psychiatry was a form of social control and demanded that institutionalized psychiatric care, stemming from Pinel's thereapeutic asylum, be abolished.[19] Incidents of physical abuse by psychiatrists took place during the reign of some totalitarian regimes as part of a system to enforce political control with some of the abuse even continuing to our present day.[51] Historical examples of the abuse of psychiatry took place in Nazi Germany [52], in the Soviet Union under Psikhushka, and in the apartheid system in South Africa.[53]
Electroconvulsive therapy was one treatment that the anti-psychiatry movement wanted eliminated.[54] They alleged that electroconvulsive therapy damaged the brain and it was used as a tool for discipline.[54] While there is no evidence that brain damage was a result of electronconvulsive therapy[55][56][57], there have been isolated incidents where the use of electroconvulsive therapy was threatened to keep the patients "in line."[54] The prevalence of psychiatric medication helped initiate deinstitutionalization,[58] the process of discharging patients from psychiatric hospitals to the community.[59] The pressure from the anti-psychiatry movements and the ideology of community treatment from the medical arena helped sustain deinstitutionalization.[58] A mere thirty three years after deinstitutionalization started in the United States, only 19% of the patients in state hospitals remained.[58] Mental health professionals envisioned a process wherein patients would be released into communities where they could participate in a normal life while living in a therapeutic atmosphere.[58]
### Transinstitutionalization and the aftermath
In 1963, United States president John F. Kennedy introduced legislation delegating the National Institute of Mental Health to administer Community Mental Health Centers for those being discharged from state psychiatric hospitals.[58] Later, though, the Community Mental Health Center's focus was diverted to provide psychotherapy sessions for those suffering from acute and/or mild mental disorders.[58] Ultimately there were no arrangements made for actively ill patients who were being discharged from hospitals.[58] Instead of being treated by the "community," those suffering from mental disorders drifted into homelessness or ended up in prisons and jails.[58][20] Studies found that 33% of the homeless population and 14% of inmates in prisons and jails were already diagnosed with a mental illness.[58][60]
In 1972, psychologist David Rosenhan published the Rosenhan experiment, a study analyzing the validity of psychiatric diagnoses.[61] The study arranged for eight individuals with no history of psychopathology to attempt admission into psychiatric hospitals. The individuals included a graduate student, psychologists, an artist, a housewife, and two physicians, including one psychiatrist. All eight individuals were admitted with a diagnosis of schizophrenia or bipolar disorder. Psychiatrists then attempted to treat the individuals using psychiatric medication. All eight were discharged within 7 to 52 days. Rosenhan's study concluded that individuals with no presence of mental disorders could not be distinguished from those suffering from mental disorders.[61] While critics such as Robert Spitzer placed doubt on the validity and credibility of the study, they also conceded that the consistency of psychiatric diagnoses needed improvement.[62]
Psychiatry is one of the few medical specialties with a continuing, significant demand for research investigating its related diseases, classifications, origins, and treatments.[21] Psychiatry falls into biology's fundamental belief that disease and health are different elements of an individual's adaptation to an environment.[63] But psychiatry also recognizes that the environment of the human species is complex and includes physical, cultural, and relational elements.[63] In addition to external factors, the human brain must recognize or organize an individual's hopes, fears, desires, fantasies and feelings.[63] Psychiatry's difficult task is the attempt to envelop the understanding of these factors so that they can be studied both clinically and physiologically.[63]
# Industry and academia
## Practitioners
As with most medical specialties, all physicians can diagnose mental disorders and prescribe treatments utilizing principles of psychiatry. Psychiatrists are physicians who specialize in psychiatry and are certified in treating mental illness using the biomedical approach to mental disorders.[64] Psychiatrists may also go through significant training to conduct psychotherapy, psychoanalysis, and/or cognitive behavioral therapy, but it is their medical training, access to medical laboratories, and ability to prescribe medications that differentiates them from other mental health professionals.[64]
## Research
Psychiatric research is, by its very nature, interdisciplinary. From a general perspective it studies and combines social, biological and psychological approaches and how those perspectives cause mental disorders.[65] While practicing psychiatrists and other psychiatric researchers study outcomes from such a wide variety of fields, research institutions and publications exist that are dedicated to the interdisciplinary study of mental disorders within the psychiatric context.[5][66][67][68] Under the supervision of institutional review boards, psychiatric researchers looks at a variety of topics such as neuroimaging, genetics, and psychopharmacology, which in turn help enhance diagnostic consistency, discover new treatment methods, and classify new mental disorders.[69]
## Clinical application
### Diagnostic systems
Psychiatric diagnoses take place in a wide variety of settings and are performed by many different health professionals. Therefore, the diagnostic procedure may vary greatly based upon these factors. Typically, though, a psychiatric diagnosis utilizes a differential diagnosis procedure where mental status examinations and physical examinations are conducted, pathological, psychopathological and psychosocial histories obtained, neuroimages or other neurophysiological measurements are taken, and personality tests or cognitive tests may be administered.[70][71][72][73][74][9][75] In addition psychiatrists are beginning to utilize genetics during the diagnostic process.[8] Some endophenotypes being researched may predispose certain individuals to certain conditions.[76][77]
Three main diagnostic manuals used to classify mental health conditions are in use today. The ICD-10 is produced and published by the World Health Organisation and includes a section on psychiatric conditions, and is used worldwide.[78] The Diagnostic and Statistical Manual of Mental Disorders, produced and published by the American Psychiatric Association, is solely focused on mental health conditions and is the main classification tool in the United States.[79] It is currently in its fourth revised edition and is also used worldwide.[79] The Chinese Society of Psychiatry has also produced a diagnostic manual, the Chinese Classification of Mental Disorders.[80]
The stated intention of diagnostic manuals is typically to develop replicable and clinically useful categories and criteria, to facilitate consensus and agreed standards, whilst being atheoretical as regards etiology.[79][7] However, the categories are nevertheless based on particular psychiatric theories and data; they are broad and often specified by numerous possible combinations of symptoms, and many of the categories overlap in symptomology or typically occur together.[81] While originally intended only as a guide for experienced clinicians trained in its use, the nomenclature is now widely used by clinicians, administrators and insurance companies in many countries.[82]
### Treatment settings
In general, psychiatric treatments have changed over the past several decades. In the past, psychiatric patients were often hospitalized for six months or more, with some cases involving hospitalization for many years. Today, most people receiving psychiatric treatment are seen as outpatients. If hospitalization is required, the average hospital stay is around two to three weeks, with only a small number of people receiving long-term hospitalization.
Individuals with mental health conditions are commonly referred to as patients but may also be called clients, consumers, or service recipients. They may come under the care of a psychiatric physician or other psychiatric practitioners by various paths, the two most common being self-referral or referral by a primary-care physician. Alternatively, a person may be referred by hospital medical staff, by court order, involuntary commitment, or, in the UK and Australia, by sectioning under a mental health law.
Whatever the circumstance of a person's referral, a psychiatrist first assesses a person's mental and physical condition. This usually involves interviewing the person and often obtaining information from other sources such as other health and social care professionals, relatives, associates, law enforcement and emergency medical personnel and psychiatric rating scales. A physical examination is usually performed to establish or exclude other illnesses, such as thyroid dysfunction or brain tumors, or identify any signs of self-harm; this examination may be done by someone else other than the psychiatrist, especially if blood tests and medical imaging are performed.
Like all medications, psychiatric medications can have toxic effects in patients and hence often involve ongoing therapeutic drug monitoring, for instance full blood counts or, for patients taking lithium salts, serum levels of lithium, renal and thyroid function. Electroconvulsive therapy (ECT) is sometimes administered for serious and disabling conditions, especially those unresponsive to medication.
Psychiatric inpatients are people admitted to a hospital or clinic to receive psychiatric care. Some are admitted involuntarily, perhaps committed to a secure hospital, or in some jurisdictions to a facility within the prison system. In many countries including the USA and Canada, the criteria for involuntary admission vary with local jurisdiction. They may be as broad as having a mental health condition, or as narrow as being an immediate danger to themselves and/or others. Bed availability is often the real determinant of admission decisions to hard pressed public facilities. European Human Rights legislation restricts detention to medically-certified cases of mental disorder, and adds a right to timely judicial review of detention.
Voluntary commitment is also possible, and in some cases people seeking care are offered this option if a mental health professional feels inpatient care is needed, but is unable or unwilling to seek involuntary commitment. People who are voluntarily committed have more options in ending their commitment, but procedures on leaving the facility vary greatly.
Inpatient psychiatric wards may be secure (for those thought to have a particular risk of violence or self-harm) or unlocked/open. Some wards are mixed-sex whilst same-sex wards are increasingly favored to protect women inpatients.
Once in the care of a hospital, people are assessed, monitored, and often given medication and care from a multidisciplinary team, which may include physicians, psychiatric nurse practitioners, psychiatric nurses, clinical psychologists, psychotherapists, psychiatric social workers, occupational therapists and social workers. If a person receiving treatment in a psychiatric hospital is assessed as at particular risk of harming themselves or others, they may be put on constant or intermittent one-to-one supervision, and may be physically restrained or medicated. People on inpatient wards may be allowed leave for periods of time, either accompanied or on their own.
In many developed countries there has been a massive reduction in psychiatric beds since the mid 20th century, with the growth of community care. Standards of inpatient care remain a challenge in some public and private facilities, due to levels of funding, and facilities in developing countries are typically grossly inadequate for the same reason.
People receiving psychiatric care may do so on an inpatient or outpatient basis. Outpatient treatment involves periodic visits to a clinician for consultation in his or her office, usually for an appointment lasting thirty to sixty minutes. These consultations normally involve the psychiatric practitioner interviewing the person to update their assessment of the person's condition, and to provide psychotherapy or review medication. The frequency with which a psychiatric practitioner sees people in treatment varies widely, from days to months, depending on the type, severity and stability of each person's condition, and depending on what the clinician and client decide would be best. Increasingly, psychiatrists are limiting their practice to psychopharmacology (prescribing medications) with less time devoted to psychotherapy or "talk" therapies, or behavior modification. The role of psychiatrists is changing in community psychiatry, with many assuming more leadership roles, coordinating and supervising teams of allied health professionals and junior doctors in delivery of health services. | https://www.wikidoc.org/index.php/Psychiatry | |
2a64e71af469fcb44262c1d6da2d826e77a1a4f2 | wikidoc | Psychonaut | Psychonaut
A psychonaut (from the Greek ψυχοναύτης, meaning literally a sailor of the mind/soul) is a person who uses altered states of consciousness, intentionally induced, to investigate his or her mind, and possibly address spiritual questions, through direct experience. Psychonauts tend to be pluralistic, willing to explore mystical traditions from established world religions, meditation, lucid dreaming, technologies such as brainwave entrainment and sensory deprivation, and often psychedelic drugs (entheogens). Because techniques that alter consciousness can be dangerous, and can induce a state of extreme susceptibility, psychonauts generally prefer to undertake these explorations either alone, or in the company of people they trust. Therefore, they are averse to using altered consciousness in a social or "party" context. Psychonauts generally regard the latter sort of use as irresponsible and dangerous.
Goals of psychonautic practices may be to answer questions about how the mind works, improve one's psychological state, answer existential or spiritual questions, or improve cognitive performance in everyday life.
# The term "psychonaut"
While some psychonauts abstain from psychoactive drugs and discourage their use, others encourage it, and the term "psychonaut" is often misinterpreted as implying frequent drug use. Most psychonauts maintain that their use of altered consciousness is different from social or recreational use, and their use may or may not have a religious or spiritual significance to them.
According to Jonathan Ott, the word psychonaut was originally coined by the German author Ernst Jünger.
# Use of the term
Psychonaut is a modern term used to describe one who uses trance technologies and, more specifically mind-altering substances, more for their ability to act as entheogens than for their inebriating (or social) effect. In effect, they are used as a means to achieve states of mind in which different perceptions, unhindered by everyday mental filters and processes, can arise. Psychonauts believe that when a mind-altering substance is used with this intent, its effects can be life altering and are not mere hallucinations. An alternate description is that while some aspects of the experience may be hallucinatory, the realizations caused by those hallucinations and the mental, emotional and long term impact of the experience are real, usually positive, and enduring.
The term is often associated with neoshamanic practices; however, many distinguish between the mental exploration of the psychonaut and authentic, healing-oriented shamanic practice.
# Associated concepts, technologies, and practices
## Concepts
### Brain function
Psychonautics may be considered an attempt to generate a user's manual for the human brain. Unlike psychology, which is concerned with understanding other people, psychonauts are more concerned with understanding themselves, and the process of self exploration; accordingly, they engage in direct exploration of themselves and their own thought processes.
As such, psychonauts seek to experientially understand mental process and functioning and employ such knowledge in their activities. Key to this is auto-modification of brain wave frequencies, which can lead to quite distinct perceptual states; a detailed examination and understanding of one's own thought processes, habits, and beliefs is also sought. Hallucinatory states, drug-induced or otherwise, are seen as a form of subliminal symbolism or as a real but distinct reality; as with other processes of the mind, psychonauts seek to understand these. These states often simultaneously dissociate the mind from the ego and offer a subjective view of one's mental processes. Psychological theories and concepts are also often taken into account, particularly those of Carl G. Jung and Abraham Maslow.
This is also ideally practically applied in bettering one's self through the knowledge of one's own thought processes; with this understanding and heightened perception of one's own internal dialogue, it is thought that one is more able to control his own ego, and detach oneself from what is seen as a herd mentality common to modern culture.
### Mythical archetypes and concepts
Psychonauts, as described in the Tibetan Book of the Dead, place emphasis on various mythical archetypes and concepts, believing that these are useful to coming to understand one's own thought patterns and the nature of existence, reflecting realities and meanings that should be understood, rather than being irrelevant fantasy. As in shamanic practice, the Axis mundi is often employed, often overlaid with chakras and other relevant concepts of bodily function; the Kabbalist Tree of Life and its chakra-like sephirot is one notable example of this in mythology. The nature of karma is often explored in trying to understand one's own situation, actions, and relation to the outside world.
### Metaphysics
Psychonauts are often interested in metaphysics, the branch of philosophy dealing with the ultimate nature of reality or existence; it is thought that in coming to some understanding of how the universe functions and the nature of existence, one would be better able to govern themselves accordingly and integrate their life experiences.
## Technologies and practices
### Hallucinogens/entheogens
The technology and practice most often associated with psychonauts is the use of psychedelic drugs for mental exploration. The method of use varies widely; such usage is often (but not always) entheogenic and informed by traditional shamanic uses of psychedelic drugs and rituals surrounding such usage.
Some psychedelics and dissociatives commonly used by psychonauts include:
- Psilocybin mushrooms like Psilocybe cubensis, also known as shrooms, Magic Mushrooms or Liberty Caps
- Psychoactive Cacti such as Peyote and San Pedro, which contain mescaline
- Salvia Divinorum, which contains salvinorin A
- Ayahuasca, which contains DMT
- DMT crystals, vaporized
- Hawaiian Baby Woodrose and Morning Glory seeds, which contain LSA
- LSD
- MDMA (Ecstasy, XTC, E, X)
Less common:
- Amanita muscaria
- Coca, although cocaine is almost never used in a psychonautic context.
- Ibogaine
- Ketamine
- 2C-I
- 2C-B
- 5-MeO-DiPT ("Foxy Methoxy")
- Kratom
- Opium
- PCP
- DXM
Though avoided by most modern psychonauts, certain species of the Nightshade family have been used for psychoactive purposes throughout human history. The most common of these is Datura stramonium, which is classified as a deliriant, not as a psychedelic or entheogen. Datura is rarely used by psychonauts because control and lucidity are lost in a delirious state, and the experience is often not remembered. Similarly, psychonauts often prefer to consume salvia via the "quid" method, rather than inducing an intense, short-lived trip associated with smoking extracts. With deliriants like datura, self-inflicted injury and even death are quite common.
### Cannabis
Cannabis is often used individually, or in combination with many hallucinogens to amplify and extend the experience.
### Dreams
As dreams are considered by psychonauts to be a window into thought processes, many keep dream journals in order to better remember dreams and further their understanding of their own symbolic internal dialogue. Many attempt to not only remember their dreams, but engage in lucid dreaming, in which one is consciously aware of their state while dreaming.
### Meditation
Certain types of meditation, such as those practiced in eastern religions. This can range from Zen-type meditation where the user focuses on their breath or a koan, or repeating/focusing on a mantra in one's head, as done in some forms of Raja Yoga. Transcendental Meditation is also practiced by some psychonauts.
### Ritual
Ritual is often employed for purposes of grounding and centering one's self, to set one's focus and intentions, and to instill a conception of the significance and depth of psychonautical practice. Repeated use of ritual may also train the brain to associate certain activities and states of consciousness with specific situations, creating deeper experiences and allowing one to more easily enter altered states of consciousness.
### Other
Other technologies and practices employed include:
- Sleep deprivation
- Isolation tank
- Sensory deprivation
- Sensory overload
- Sex
- Fasting
- Dark-room retreats
- Brainwave synchronization
- Brain wave entrainment
- Glossolalia
- Lucid dreaming
- Hypnosis
- Mind machines
- Dreamachine
- Astral Projection
# Controversy
Psychonautic practice, especially when it involves the use of psychedelic drugs, is regarded by some as risky, undesirable, and dangerous. Many mental illnesses (e.g. schizophrenia, autism, narcolepsy, attention deficit disorder, mania) are known to result from altered states of consciousness and thought patterns, and the intentional increase of the brain's pliability is considered by some to increase the risk of mental illness. Long-term use of psychedelic drugs may induce hallucinogen persisting perception disorder, and certain meditation practices can cause a similar condition known as kundalini syndrome. However, as altered-consciousness therapies have proven effective for improving peoples' overall health, the controlled and informed pursuit of at least psychonautic practices is generally considered safe.
Psychonauts tend to be libertarian in social ideology, with a firm commitment to individual responsibility. Therefore, they tend to be risk-averse in comparison to other categories of recreational drug users, placing a high value on the concept of set and setting. In general, they eschew the most dangerous and addictive drugs (e.g. alcohol, cocaine, methamphetamine, heroin), finding them to be crude, toxic, and devoid of educational value. The goal of meditative and psychedelic practice is to liberate and expand one's consciousness; the abuse of drugs is clearly contrary to that goal. Additionally, psychonauts are often more likely to use drugs with established shamanic traditions, since they have more evidence of safety.
# List of psychonauts
Scientists, philosophers and writers:
- Alan Watts
- Albert Hofmann
- Aldous Huxley
- Alexander Shulgin
- Allen Ginsberg
- Andrew Rutajit
- Ann Shulgin
- Bruce Eisner
- Carlos Castaneda
- Christian Rätsch
- Claude Rifat
- Daniel Jordan Argo
- Daniel Pinchbeck
- Daniel Lugo
- Dennis McKenna
- Dylan Rastall
- D. M. Turner
- Ernst Jünger
- Frank Greve
- Hunter S. Thompson
- Jack Herer
- Jack Kerouac
- James Arthur
- Jan Irvin
- Jeremy Narby
- John Lilly
- Jonathan Ott
- Mark Wise
- Maria Sabina
- Michael Hoffman
- Peter Carroll
- William S. Burroughs
- Ken Kesey
- Ralph Metzner
- Ram Dass
- Rick Doblin
- Rick Strassman
- Robert Anton Wilson
- Rupert Sheldrake
- Stanislav Grof
- Terence McKenna
- Thaddeus Golas
- Timothy Leary
- William James
Artists:
- Alex Grey
- Carl McCoy
- Jimi Hendrix
- Jim Morrison
- Lemmy | Psychonaut
A psychonaut (from the Greek ψυχοναύτης, meaning literally a sailor of the mind/soul) is a person who uses altered states of consciousness, intentionally induced, to investigate his or her mind, and possibly address spiritual questions, through direct experience. Psychonauts tend to be pluralistic, willing to explore mystical traditions from established world religions, meditation, lucid dreaming, technologies such as brainwave entrainment and sensory deprivation, and often psychedelic drugs (entheogens). Because techniques that alter consciousness can be dangerous, and can induce a state of extreme susceptibility, psychonauts generally prefer to undertake these explorations either alone, or in the company of people they trust. Therefore, they are averse to using altered consciousness in a social or "party" context. Psychonauts generally regard the latter sort of use as irresponsible and dangerous.
Goals of psychonautic practices may be to answer questions about how the mind works, improve one's psychological state, answer existential or spiritual questions, or improve cognitive performance in everyday life.
# The term "psychonaut"
While some psychonauts abstain from psychoactive drugs and discourage their use, others encourage it, and the term "psychonaut" is often misinterpreted as implying frequent drug use. Most psychonauts maintain that their use of altered consciousness is different from social or recreational use, and their use may or may not have a religious or spiritual significance to them.
According to Jonathan Ott, the word psychonaut was originally coined by the German author Ernst Jünger.
# Use of the term
Psychonaut is a modern term used to describe one who uses trance technologies and, more specifically mind-altering substances, more for their ability to act as entheogens than for their inebriating (or social) effect. In effect, they are used as a means to achieve states of mind in which different perceptions, unhindered by everyday mental filters and processes, can arise. Psychonauts believe that when a mind-altering substance is used with this intent, its effects can be life altering and are not mere hallucinations. An alternate description is that while some aspects of the experience may be hallucinatory, the realizations caused by those hallucinations and the mental, emotional and long term impact of the experience are real, usually positive, and enduring.
The term is often associated with neoshamanic practices; however, many distinguish between the mental exploration of the psychonaut and authentic, healing-oriented shamanic practice.
# Associated concepts, technologies, and practices
## Concepts
### Brain function
Psychonautics may be considered an attempt to generate a user's manual for the human brain. Unlike psychology, which is concerned with understanding other people, psychonauts are more concerned with understanding themselves, and the process of self exploration; accordingly, they engage in direct exploration of themselves and their own thought processes.
As such, psychonauts seek to experientially understand mental process and functioning and employ such knowledge in their activities. Key to this is auto-modification of brain wave frequencies, which can lead to quite distinct perceptual states; a detailed examination and understanding of one's own thought processes, habits, and beliefs is also sought. Hallucinatory states, drug-induced or otherwise, are seen as a form of subliminal symbolism or as a real but distinct reality; as with other processes of the mind, psychonauts seek to understand these. These states often simultaneously dissociate the mind from the ego and offer a subjective view of one's mental processes. Psychological theories and concepts are also often taken into account, particularly those of Carl G. Jung and Abraham Maslow.
This is also ideally practically applied in bettering one's self through the knowledge of one's own thought processes; with this understanding and heightened perception of one's own internal dialogue, it is thought that one is more able to control his own ego, and detach oneself from what is seen as a herd mentality common to modern culture.
### Mythical archetypes and concepts
Psychonauts, as described in the Tibetan Book of the Dead, place emphasis on various mythical archetypes and concepts, believing that these are useful to coming to understand one's own thought patterns and the nature of existence, reflecting realities and meanings that should be understood, rather than being irrelevant fantasy. As in shamanic practice, the Axis mundi is often employed, often overlaid with chakras and other relevant concepts of bodily function; the Kabbalist Tree of Life and its chakra-like sephirot is one notable example of this in mythology. The nature of karma is often explored in trying to understand one's own situation, actions, and relation to the outside world.
### Metaphysics
Psychonauts are often interested in metaphysics, the branch of philosophy dealing with the ultimate nature of reality or existence; it is thought that in coming to some understanding of how the universe functions and the nature of existence, one would be better able to govern themselves accordingly and integrate their life experiences.
## Technologies and practices
### Hallucinogens/entheogens
The technology and practice most often associated with psychonauts is the use of psychedelic drugs for mental exploration. The method of use varies widely; such usage is often (but not always) entheogenic and informed by traditional shamanic uses of psychedelic drugs and rituals surrounding such usage.
Some psychedelics and dissociatives commonly used by psychonauts include:
- Psilocybin mushrooms like Psilocybe cubensis, also known as shrooms, Magic Mushrooms or Liberty Caps
- Psychoactive Cacti such as Peyote and San Pedro, which contain mescaline
- Salvia Divinorum, which contains salvinorin A
- Ayahuasca, which contains DMT
- DMT crystals, vaporized
- Hawaiian Baby Woodrose and Morning Glory seeds, which contain LSA
- LSD
- MDMA (Ecstasy, XTC, E, X)
Less common:
- Amanita muscaria
- Coca, although cocaine is almost never used in a psychonautic context.
- Ibogaine
- Ketamine
- 2C-I
- 2C-B
- 5-MeO-DiPT ("Foxy Methoxy")
- Kratom
- Opium
- PCP
- DXM
Though avoided by most modern psychonauts, certain species of the Nightshade family have been used for psychoactive purposes throughout human history. The most common of these is Datura stramonium, which is classified as a deliriant, not as a psychedelic or entheogen. Datura is rarely used by psychonauts because control and lucidity are lost in a delirious state, and the experience is often not remembered. Similarly, psychonauts often prefer to consume salvia via the "quid" method, rather than inducing an intense, short-lived trip associated with smoking extracts. With deliriants like datura, self-inflicted injury and even death are quite common.
### Cannabis
Cannabis is often used individually, or in combination with many hallucinogens to amplify and extend the experience.
### Dreams
As dreams are considered by psychonauts to be a window into thought processes, many keep dream journals in order to better remember dreams and further their understanding of their own symbolic internal dialogue. Many attempt to not only remember their dreams, but engage in lucid dreaming, in which one is consciously aware of their state while dreaming.
### Meditation
Certain types of meditation, such as those practiced in eastern religions. This can range from Zen-type meditation where the user focuses on their breath or a koan, or repeating/focusing on a mantra in one's head, as done in some forms of Raja Yoga. Transcendental Meditation is also practiced by some psychonauts.
### Ritual
Ritual is often employed for purposes of grounding and centering one's self, to set one's focus and intentions, and to instill a conception of the significance and depth of psychonautical practice. Repeated use of ritual may also train the brain to associate certain activities and states of consciousness with specific situations, creating deeper experiences and allowing one to more easily enter altered states of consciousness.
### Other
Other technologies and practices employed include:
- Sleep deprivation
- Isolation tank
- Sensory deprivation
- Sensory overload
- Sex
- Fasting
- Dark-room retreats
- Brainwave synchronization
- Brain wave entrainment
- Glossolalia
- Lucid dreaming
- Hypnosis
- Mind machines
- Dreamachine
- Astral Projection
# Controversy
Psychonautic practice, especially when it involves the use of psychedelic drugs, is regarded by some as risky, undesirable, and dangerous. Many mental illnesses (e.g. schizophrenia, autism, narcolepsy, attention deficit disorder, mania) are known to result from altered states of consciousness and thought patterns, and the intentional increase of the brain's pliability is considered by some to increase the risk of mental illness. Long-term use of psychedelic drugs may induce hallucinogen persisting perception disorder, and certain meditation practices can cause a similar condition known as kundalini syndrome. However, as altered-consciousness therapies have proven effective for improving peoples' overall health, the controlled and informed pursuit of at least psychonautic practices is generally considered safe.
Psychonauts tend to be libertarian in social ideology, with a firm commitment to individual responsibility. Therefore, they tend to be risk-averse in comparison to other categories of recreational drug users, placing a high value on the concept of set and setting. In general, they eschew the most dangerous and addictive drugs (e.g. alcohol, cocaine, methamphetamine, heroin), finding them to be crude, toxic, and devoid of educational value. The goal of meditative and psychedelic practice is to liberate and expand one's consciousness; the abuse of drugs is clearly contrary to that goal. Additionally, psychonauts are often more likely to use drugs with established shamanic traditions, since they have more evidence of safety.
# List of psychonauts
Scientists, philosophers and writers:
- Alan Watts
- Albert Hofmann
- Aldous Huxley
- Alexander Shulgin
- Allen Ginsberg
- Andrew Rutajit
- Ann Shulgin
- Bruce Eisner
- Carlos Castaneda
- Christian Rätsch
- Claude Rifat
- Daniel Jordan Argo
- Daniel Pinchbeck
- Daniel Lugo
- Dennis McKenna
- Dylan Rastall
- D. M. Turner
- Ernst Jünger
- Frank Greve
- Hunter S. Thompson
- Jack Herer
- Jack Kerouac
- James Arthur
- Jan Irvin
- Jeremy Narby
- John Lilly
- Jonathan Ott
- Mark Wise
- Maria Sabina
- Michael Hoffman
- Peter Carroll
- William S. Burroughs
- Ken Kesey
- Ralph Metzner
- Ram Dass
- Rick Doblin
- Rick Strassman
- Robert Anton Wilson
- Rupert Sheldrake
- Stanislav Grof
- Terence McKenna
- Thaddeus Golas
- Timothy Leary
- William James
Artists:
- Alex Grey
- Carl McCoy
- Jimi Hendrix
- Jim Morrison
- Lemmy | https://www.wikidoc.org/index.php/Psychonaut | |
db9f198a0def586ff4c56a9e5061020f116911b8 | wikidoc | Pubic hair | Pubic hair
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
# Overview
Pubic hair is hair in the frontal genital area, the crotch, and sometimes at the top of the inside of the legs; these areas form the pubic region.
Although fine vellus hair is present in the area in childhood, the term pubic hair is generally restricted to the heavier, longer hair that develops with puberty as an effect of rising levels of androgens. Pubic hair is therefore part of the androgenic hair.
# Development of pubic hair
Before puberty, the genital area of both boys and girls has very fine vellus hair, referred to as Tanner stage 1 hair. As puberty begins, the body produces rising levels of the sex hormones known as androgens, and in response the skin of the genital area begins to produce thicker, often curlier, hair with a faster growth rate. The onset of pubic hair development is termed pubarche. The change for each hair follicle is relatively abrupt, but the extent of skin which grows androgenic hair gradually increases over several years.
In most females, pubic hair first appears along the edges of the labia majora (stage 2), and spreads forward to the mons (stage 3) over the next 2 years. By 2-3 years into puberty (roughly the time of menarche for most girls), the pubic triangle is densely filled. Within another 2 years pubic hair also grows from the near thighs in most young women, and sometimes a small amount up the line of the abdomen toward the umbilicus.
In males, the first pubic hair appears as a few sparse hairs on the scrotum or at the upper base of the penis (stage 2). Within a year, hairs around the base of the penis are too numerous to count (stage 3). Within 3 to 4 years, hair fills the pubic area (stage 4) and becomes much thicker and darker, and by 5 years extends to the near thighs and upwards on the abdomen toward the umbilicus (stage 5).
Other areas of the skin are similarly, though slightly less, sensitive to androgens and androgenic hair typically appears somewhat later. In rough sequence of sensitivity to androgens and appearance of androgenic hair, are the armpits (axillae), perianal area, upper lip, preauricular areas (sideburns), periareolar areas (nipples), middle of the chest, neck under the chin, remainder of chest and beard area, limbs and shoulders, back, and buttocks.
Although generally considered part of the process of puberty, pubarche is distinct and independent of the process of maturation of the gonads that leads to sexual maturation and fertility. Pubic hair can develop from adrenal androgens alone, and can develop even when the ovaries or testes are defective and nonfunctional. See puberty for details.
There is little if any difference in the capacity of male and female bodies to grow hair in response to androgens. The obvious sex-dimorphic difference in hair distribution in men and women is primarily a result of differences in the levels of androgen reached as maturity occurs.
Patterns of pubic hair vary. On some individuals, pubic hair is thick and/or coarse; on others it may be sparse and/or fine. Hair texture varies from tightly curled to entirely straight. Pubic hair patterns can also vary by race and ethnicity.
Pubic hair and axillary hair can vary in color considerably from the hair of the scalp. In most people it is darker, although it can also be lighter. On most women, the pubic patch is triangular and lies over the mons veneris, or mound of Venus. On many men, the pubic patch tapers upwards to a line of hair pointing towards the navel (see abdominal hair), roughly a more upward-pointing triangle. As with axillary (armpit) hair, pubic hair is associated with a concentration of sebaceous glands in the area. | Pubic hair
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [2] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
Template:Human hair
# Overview
Pubic hair is hair in the frontal genital area, the crotch, and sometimes at the top of the inside of the legs; these areas form the pubic region.
Although fine vellus hair is present in the area in childhood, the term pubic hair is generally restricted to the heavier, longer hair that develops with puberty as an effect of rising levels of androgens. Pubic hair is therefore part of the androgenic hair.
# Development of pubic hair
Before puberty, the genital area of both boys and girls has very fine vellus hair, referred to as Tanner stage 1 hair. As puberty begins, the body produces rising levels of the sex hormones known as androgens, and in response the skin of the genital area begins to produce thicker, often curlier, hair with a faster growth rate. The onset of pubic hair development is termed pubarche. The change for each hair follicle is relatively abrupt, but the extent of skin which grows androgenic hair gradually increases over several years.
In most females, pubic hair first appears along the edges of the labia majora (stage 2), and spreads forward to the mons (stage 3) over the next 2 years. By 2-3 years into puberty (roughly the time of menarche for most girls), the pubic triangle is densely filled. Within another 2 years pubic hair also grows from the near thighs in most young women, and sometimes a small amount up the line of the abdomen toward the umbilicus.
In males, the first pubic hair appears as a few sparse hairs on the scrotum or at the upper base of the penis (stage 2). Within a year, hairs around the base of the penis are too numerous to count (stage 3). Within 3 to 4 years, hair fills the pubic area (stage 4) and becomes much thicker and darker, and by 5 years extends to the near thighs and upwards on the abdomen toward the umbilicus (stage 5).
Other areas of the skin are similarly, though slightly less, sensitive to androgens and androgenic hair typically appears somewhat later. In rough sequence of sensitivity to androgens and appearance of androgenic hair, are the armpits (axillae), perianal area, upper lip, preauricular areas (sideburns), periareolar areas (nipples), middle of the chest, neck under the chin, remainder of chest and beard area, limbs and shoulders, back, and buttocks.
Although generally considered part of the process of puberty, pubarche is distinct and independent of the process of maturation of the gonads that leads to sexual maturation and fertility. Pubic hair can develop from adrenal androgens alone, and can develop even when the ovaries or testes are defective and nonfunctional. See puberty for details.
There is little if any difference in the capacity of male and female bodies to grow hair in response to androgens. The obvious sex-dimorphic difference in hair distribution in men and women is primarily a result of differences in the levels of androgen reached as maturity occurs.
Patterns of pubic hair vary. On some individuals, pubic hair is thick and/or coarse; on others it may be sparse and/or fine. Hair texture varies from tightly curled to entirely straight. Pubic hair patterns can also vary by race and ethnicity.
Pubic hair and axillary hair can vary in color considerably from the hair of the scalp. In most people it is darker, although it can also be lighter. On most women, the pubic patch is triangular and lies over the mons veneris, or mound of Venus. On many men, the pubic patch tapers upwards to a line of hair pointing towards the navel (see abdominal hair), roughly a more upward-pointing triangle. As with axillary (armpit) hair, pubic hair is associated with a concentration of sebaceous glands in the area. | https://www.wikidoc.org/index.php/Pubic_hair | |
55e72d3e989cd1f1a54f85cab2c2042eeb8bf83c | wikidoc | Pulse Asia | Pulse Asia
Pulse Asia, Inc. is a public opinion polling body in the Philippines. It was launched by professional academics recognized as experts in their respective fields of study. It monitors salient socio-economic, political and cultural issues in the minds of the Filipino public.
# Profile
According to its corporate profile, Pulse Asia sees the public pulse as a key ingredient in a democracy. It committed itself to the advancement of professional polling by Filipinos within the country, as well as in other parts of Asia. It uses prudence and academic rigor to explore innovations in the gathering, use and analysis of social data. It also probes new or under-explored areas of study, which bear significant relevance or interest to the public.
Pulse Asia has academic independence and has a professional team of high caliber. It initiates its own research studies based on a regular monitoring of prominent public concerns at a national, regional, local or sectoral level. It also solicits third-party sponsorship of or subscription to its research products and may also undertake specific surveys at the request of interested parties, but it will not undertake proprietary surveys where the client retains the exclusive right to the survey findings and withholds them from the public domain indefinitely. All Pulse Asia surveys are made available to the general public within a year from the time they are released to a client.
Pulse Asia endeavors at all times to serve the public interest in democratic governance by undertaking studies on social, economic, political and comprehensive policy issues and by making available to the widest audience the findings, analyses and policy recommendations of its independent, non-partisan and academic probes. In doing so, the company has these commitments: (1) All work done by Pulse Asia shall meet at least the generally accepted standards demanded of quality academic output; (2) Believing in the urgent necessity to facilitate the public's access to information, all studies done by the company shall automatically become public domain material within one year after their completion; and (3) Pulse Asia shall provide for a system of equitable access to information by materially assisting parties or individuals that are unable to adequately finance their demonstrably critical information needs.
# Team of analysts
- Prof. Felipe B. Miranda - professor of political science, University of the Philippines, founding fellow of the Social Weather Stations
- Mercedes R. Abad - president and general manager of TRENDS-MBL, Inc.
- Jose V. Abueva - former president of the University of the Philippines, now president of Kalayaan College
- Arsenio M. Balisacan - professor of economics, University of the Philippines
- Maria Rose Cynthia Banzon-Bautista - professor of sociology, University of the Philippines
- Emmanuel S. de Dios - former department of economics chairman, University of the Philippines School of Economics
- Ronald D. Holmes - executive director of the De La Salle University System and director of the De La Salle-Santiago Zobel School
- Jose P. de Jesus - is among the country's top technocrats, has served the Government in various capacities
- Romeo L. Manlapaz - teaches mathematics at the University of the Philippines
- Rosa Linda Tidalgo Miranda - executive director of the Center for Asia-Pacific Women in Politics
- Temario C. Rivera - professor of political science, University of the Philippines
- Ana Maria L. Tabunda - dean, University of the Philippines School of Statistics
- Zelda C. Zablan - professor of demography at the UP Population Institute
# Ulat ng Bayan Survey
## Pre-election poll
As early as June, 2006, Pulse Asia has already conducted a pre-election poll for the 2007 elections. The survey conducted from June 24 to July 8, 2006 shows that as of survey date, the following individuals end up within the winning circle of 12 senators: (1) former Senator Loren Legarda (48.6%); (2) Senator Francis N. Pangilinan (39.0%); (3) Senator Panfilo M. Lacson (34.9%); (4) Senator Manuel B. Villar, Jr. (34.2%); (5) Senator Ralph G. Recto (33.1%); (6) former Senator Vicente C. Sotto III (31.0%); (7) Atty. Aquilino Pimentel III (29.9%); (8) Taguig-Pateros Representative Alan Peter S. Cayetano (29.5%); (9) former Senator Greogorio B. Honasan (27.7%); (10) San Juan Mayor JV Ejercito-Estrada (23.8%); (11) Ilocos Norte Representative Imee R. Marcos (23.1%); and (12) former Senator John Henry Osmeña (22.7%). It also shows that the slots in the survey were in favor of the political opposition.
# Media releases
- Pulse Asia’s November 2006 Ulat ng Bayan Survey Media release on charter change
- Pulse Asia’s July 2006 Ulat ng Bayan Survey
- Pulse Asia Media Release (December 16, 2005) | Pulse Asia
Pulse Asia, Inc. is a public opinion polling body in the Philippines. It was launched by professional academics recognized as experts in their respective fields of study. It monitors salient socio-economic, political and cultural issues in the minds of the Filipino public.
# Profile
According to its corporate profile, Pulse Asia sees the public pulse as a key ingredient in a democracy. It committed itself to the advancement of professional polling by Filipinos within the country, as well as in other parts of Asia. It uses prudence and academic rigor to explore innovations in the gathering, use and analysis of social data. It also probes new or under-explored areas of study, which bear significant relevance or interest to the public.
Pulse Asia has academic independence and has a professional team of high caliber. It initiates its own research studies based on a regular monitoring of prominent public concerns at a national, regional, local or sectoral level. It also solicits third-party sponsorship of or subscription to its research products and may also undertake specific surveys at the request of interested parties, but it will not undertake proprietary surveys where the client retains the exclusive right to the survey findings and withholds them from the public domain indefinitely. All Pulse Asia surveys are made available to the general public within a year from the time they are released to a client.
Pulse Asia endeavors at all times to serve the public interest in democratic governance by undertaking studies on social, economic, political and comprehensive policy issues and by making available to the widest audience the findings, analyses and policy recommendations of its independent, non-partisan and academic probes. In doing so, the company has these commitments: (1) All work done by Pulse Asia shall meet at least the generally accepted standards demanded of quality academic output; (2) Believing in the urgent necessity to facilitate the public's access to information, all studies done by the company shall automatically become public domain material within one year after their completion; and (3) Pulse Asia shall provide for a system of equitable access to information by materially assisting parties or individuals that are unable to adequately finance their demonstrably critical information needs.
# Team of analysts
- Prof. Felipe B. Miranda - professor of political science, University of the Philippines, founding fellow of the Social Weather Stations
- Mercedes R. Abad - president and general manager of TRENDS-MBL, Inc.
- Jose V. Abueva - former president of the University of the Philippines, now president of Kalayaan College
- Arsenio M. Balisacan - professor of economics, University of the Philippines
- Maria Rose Cynthia Banzon-Bautista - professor of sociology, University of the Philippines
- Emmanuel S. de Dios - former department of economics chairman, University of the Philippines School of Economics
- Ronald D. Holmes - executive director of the De La Salle University System and director of the De La Salle-Santiago Zobel School
- Jose P. de Jesus - is among the country's top technocrats, has served the Government in various capacities
- Romeo L. Manlapaz - teaches mathematics at the University of the Philippines
- Rosa Linda Tidalgo Miranda - executive director of the Center for Asia-Pacific Women in Politics
- Temario C. Rivera - professor of political science, University of the Philippines
- Ana Maria L. Tabunda - dean, University of the Philippines School of Statistics
- Zelda C. Zablan - professor of demography at the UP Population Institute
# Ulat ng Bayan Survey
## Pre-election poll
As early as June, 2006, Pulse Asia has already conducted a pre-election poll for the 2007 elections. The survey conducted from June 24 to July 8, 2006 shows that as of survey date, the following individuals end up within the winning circle of 12 senators: (1) former Senator Loren Legarda (48.6%); (2) Senator Francis N. Pangilinan (39.0%); (3) Senator Panfilo M. Lacson (34.9%); (4) Senator Manuel B. Villar, Jr. (34.2%); (5) Senator Ralph G. Recto (33.1%); (6) former Senator Vicente C. Sotto III (31.0%); (7) Atty. Aquilino Pimentel III (29.9%); (8) Taguig-Pateros Representative Alan Peter S. Cayetano (29.5%); (9) former Senator Greogorio B. Honasan (27.7%); (10) San Juan Mayor JV Ejercito-Estrada (23.8%); (11) Ilocos Norte Representative Imee R. Marcos (23.1%); and (12) former Senator John Henry Osmeña (22.7%). [1] It also shows that the slots in the survey were in favor of the political opposition. [1]
# Media releases
- Pulse Asia’s November 2006 Ulat ng Bayan Survey Media release on charter change
- Pulse Asia’s July 2006 Ulat ng Bayan Survey
- Pulse Asia Media Release (December 16, 2005) | https://www.wikidoc.org/index.php/Pulse_Asia | |
0c8d0efc4ddb139b68db34a613e2cdaafd57a86f | wikidoc | Pustulosis | Pustulosis
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
# Overview
Pustulosis is highly inflammatory skin condition resulting in large fluid-filled blister-like areas - pustules. Pustulosis typically occurs on the palms of the hands and/or the soles of the feet. The skin of these areas peels and flakes exfoliates. | Pustulosis
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
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# Overview
Pustulosis is highly inflammatory skin condition resulting in large fluid-filled blister-like areas - pustules. Pustulosis typically occurs on the palms of the hands and/or the soles of the feet. The skin of these areas peels and flakes exfoliates.[1] | https://www.wikidoc.org/index.php/Pustulosis | |
eb0c144c3019b7aa8bdc56fac54d60f0092e4b5f | wikidoc | Pyocyanase | Pyocyanase
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
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Pyocyanase was the first antibiotic drug to be used in hospitals. It is no longer used today.
Rudolf Emmerich and Oscar Low, two German physicians who were the first to make an effective medication from microbes, conducted experiments in the 1890s, roughly 30 years after Louis Pasteur showed that many diseases were caused by bacteria. They proved that the germs that caused one disease may be the cure for another.
Emmerich and Low isolated germs from infected bandages that caused green infections in open wounds. The germ was a bacteria called Bacillus pycyoneus. They then mixed the isolate with other bacteria. They showed that Bacillus pycyoneus was able to destroy other strains of bacteria. The bacteria that it killed were those that caused cholera, typhoid, diphtheria, and anthrax.
From these experiments Emmerich and Low created a medication that they called pyocyanase. It was the first antibiotic to be used in hospitals. Unfortunately, its effectiveness was sporadic and did not work equally on all patients. As a result, the drug was eventually abandoned. | Pyocyanase
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [1] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
Pyocyanase was the first antibiotic drug to be used in hospitals. It is no longer used today.
Rudolf Emmerich and Oscar Low, two German physicians who were the first to make an effective medication from microbes, conducted experiments in the 1890s, roughly 30 years after Louis Pasteur showed that many diseases were caused by bacteria. They proved that the germs that caused one disease may be the cure for another.
Emmerich and Low isolated germs from infected bandages that caused green infections in open wounds. The germ was a bacteria called Bacillus pycyoneus. They then mixed the isolate with other bacteria. They showed that Bacillus pycyoneus was able to destroy other strains of bacteria. The bacteria that it killed were those that caused cholera, typhoid, diphtheria, and anthrax.
From these experiments Emmerich and Low created a medication that they called pyocyanase. It was the first antibiotic to be used in hospitals. Unfortunately, its effectiveness was sporadic and did not work equally on all patients. As a result, the drug was eventually abandoned.
Template:SIB
Template:Jb1
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Pyocyanase | |
1372db251a68b14c6b60709974cac324953741d5 | wikidoc | Pyrazolone | Pyrazolone
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
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# Overview
Pyrazolone, a five-membered-ring lactam, is a derivative of pyrazole that has an additional keto (=O) group.
It has a molecular formula of C3H4N2O.
Examples of derivatives include:
- Ampyrone
- Metamizole
- Phenazone
- Phenylbutazone | Pyrazolone
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [2] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
# Overview
Pyrazolone, a five-membered-ring lactam, is a derivative of pyrazole that has an additional keto (=O) group.
It has a molecular formula of C3H4N2O.
Examples of derivatives include:
- Ampyrone
- Metamizole
- Phenazone
- Phenylbutazone
# External links
- Pyrazolones at the US National Library of Medicine Medical Subject Headings (MeSH)
- Pubchem - 3-Pyrazolone
- Pubchem - 5-Pyrazolone
Template:SIB
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Pyrazolone | |
91fea60c8cc46424f1fef60089fd6962230a6758 | wikidoc | Pyrogallol | Pyrogallol
# Overview
Pyrogallol is an organic compound with the formula C6H3(OH)3. It is a white solid although because of its sensitivity toward oxygen, samples are typically brownish. It is one of three isomeric benzenetriols.
# Production, occurrence, reactions
It is produced in a manner it was first prepared by Scheele (1786): heating gallic acid. Presently gallic acid is obtained from tannin. Heating induces decarboxylation:
Because tannin is expensive, many alternative routes have been devised
An alternate preparation involves treating para-chlorophenoldisulphonic acid with potassium hydroxide, a variant on the time-honored route to phenols from sulfonic acids.
The aquatic plant Myriophyllum spicatum produces pyrogallic acid.
When in alkaline solution, it absorbs oxygen from the air, turning brown from a colourless solution. It can be used in this way to calculate the amount of oxygen in air, notably via the use of the Orsat apparatus.
# Uses
One can find its uses in hair dying, dying of suturing materials and for oxygen absorption in gas analysis. It also has antiseptic properties. Pyrogallol was also used as a developing agent in black-and-white developers, but its use is largely historical except for special purpose applications. (Hydroquinone is more commonly used today.)
# Safety
Pyrogallol use, e.g. in hair dye formulations, is declining because of concerns about its toxicity.
Its LD50 (oral, rat) is 300 mg/kg. | Pyrogallol
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Pyrogallol is an organic compound with the formula C6H3(OH)3. It is a white solid although because of its sensitivity toward oxygen, samples are typically brownish.[1] It is one of three isomeric benzenetriols.
# Production, occurrence, reactions
It is produced in a manner it was first prepared by Scheele (1786): heating gallic acid. Presently gallic acid is obtained from tannin. Heating induces decarboxylation:
Because tannin is expensive, many alternative routes have been devised
An alternate preparation involves treating para-chlorophenoldisulphonic acid with potassium hydroxide, a variant on the time-honored route to phenols from sulfonic acids.
The aquatic plant Myriophyllum spicatum produces pyrogallic acid.[2]
When in alkaline solution, it absorbs oxygen from the air, turning brown from a colourless solution. It can be used in this way to calculate the amount of oxygen in air, notably via the use of the Orsat apparatus.
# Uses
One can find its uses in hair dying, dying of suturing materials and for oxygen absorption in gas analysis. It also has antiseptic properties. Pyrogallol was also used as a developing agent in black-and-white developers, but its use is largely historical except for special purpose applications. (Hydroquinone is more commonly used today.)
# Safety
Pyrogallol use, e.g. in hair dye formulations, is declining because of concerns about its toxicity.[3]
Its LD50 (oral, rat) is 300 mg/kg.[1] | https://www.wikidoc.org/index.php/Pyrogallol | |
6485c2cf13dd49331b4ca80159494492091bd96b | wikidoc | Quadrupole | Quadrupole
A quadrupole is one of a sequence of configurations of — for example — electric charge or current, or gravitational mass that can exist in ideal form, but it is usually just part of a multipole expansion of a more complex structure reflecting various orders of complexity.
# Mathematical definition
The traceless quadrupole moment tensor of a system of charges (or masses, for example) is defined as
for a discrete system with individual charges q_n, or
for a continuous system with charge density \rho(x).
The quadrupole moment has 9 components, but because of the rotational symmetry and trace property, only 5 of these are independent. As with all types of moments except the monopole, the value of the quadrupole moment depends on the choice of the coordinate origin. For example, the basic dipole can have a quadrupole moment if the origin is shifted away from the center of the two charges. However, the quadrupole moment of the basic dipole can also be reduced to zero with a particular choice of the origin.
If each charge is the source of a "1/r" field, like the electric or gravitational field, the contribution to the field's potential from the quadrupole moment is:
where R is a vector with origin in the system of charges and n
is the unit vector in the direction of R. Here, k is a constant that depends on the type of field, and the units being used.
# Electric quadrupole
The classic example of an electric quadrupole is shown in the picture. There are two positive and two negative charges, arranged on the corners of a square. The monopole moment (just the total charge) of this arrangement is zero. Similarly, the dipole moment is zero, when the coordinate origin is at the center of the picture. The quadrupole moment of this arrangement, however, cannot be reduced to zero, regardless of where we place the coordinate origin. The electric potential of an electric charge quadrupole is given by
where \epsilon_0 is the electric permittivity.
# Magnetic quadrupole
All known magnetic sources give dipole fields. However, to make a magnetic quadrupole it is possible to place two identical bar magnets parallel to each other such that the North pole of one is next to the South of the other and vice versa. Such a configuration cancels the dipole moment and gives a quadrupole moment, and its field will decrease at large distances faster than that of a dipole.
Magnetic quadrupoles like the one depicted on the right are being used to focus particle beams in a particle accelerator. There are four steel pole tips, two opposing magnetic north poles and two opposing magnetic south poles. The steel is magnetized by a large electric current that flows in the coils of tubing wrapped around the poles.
Changing magnetic quadrupole moments give production of electromagnetic radiation.
# Gravitational quadrupole
The mass quadrupole is very analogous to the electric charge quadrupole, where the charge density is simply replaced by the mass density. The gravitational potential is then expressed as:
For example, because the Earth is rotating, it is oblate (flattened at the poles). This gives it a nonzero quadrupole moment. While the contribution to the Earth's gravitational field from this quadrupole is extremely important for artificial satellites close to Earth, it is less important for the Moon, because the \frac{1}{|\mathbf{R}|^3} term falls quickly.
The mass quadrupole moment is also important in General Relativity because, if it changes in time, it can produce gravitational radiation, similar to the electromagnetic radiation produced by change electric or magnetic quadrupoles. (In particular, the second time derivative must be nonzero.) The mass monopole represents the total mass-energy in a system, and does not change in time — thus it gives off no radiation. Similarly, the mass dipole represents the center of mass of a system, which also does not change in time — thus it also gives off no radiation. The mass quadrupole, however, can change in time, and is the lowest-order contribution to gravitational radiation.
The simplest and most important example of a radiating system is a pair of black holes with equal masses orbiting each other. If we place the coordinate origin right between the two black holes, and one black hole at unit distance along the x-axis, the system will have no dipole moment. Its quadrupole moment will simply be
where M is the mass of each hole, and x_i is the unit vector in the x-direction. As the system orbits, the x-vector will rotate, which means that it will have a nonzero second time derivative. Thus, the system will radiate gravitational waves. Energy lost in this way was indirectly detected in the Hulse-Taylor binary.
Just as electric charge and current multipoles contribute to the electromagnetic field, mass and mass-current multipoles contribute to the gravitational field in General Relativity, because GR also includes "gravitomagnetic" effects. Changing mass-current multipoles can also give off gravitational radiation. However, contributions from the current multipoles will typically be much smaller than that of the mass quadrupole. | Quadrupole
A quadrupole is one of a sequence of configurations of — for example — electric charge or current, or gravitational mass that can exist in ideal form, but it is usually just part of a multipole expansion of a more complex structure reflecting various orders of complexity.
# Mathematical definition
The traceless quadrupole moment tensor of a system of charges (or masses, for example) is defined as
for a discrete system with individual charges <math>q_n</math>, or
for a continuous system with charge density <math>\rho(x)</math>.
The quadrupole moment has 9 components, but because of the rotational symmetry and trace property, only 5 of these are independent. As with all types of moments except the monopole, the value of the quadrupole moment depends on the choice of the coordinate origin. For example, the basic dipole can have a quadrupole moment if the origin is shifted away from the center of the two charges. However, the quadrupole moment of the basic dipole can also be reduced to zero with a particular choice of the origin.
If each charge is the source of a "<math>1/r</math>" field, like the electric or gravitational field, the contribution to the field's potential from the quadrupole moment is:
where R is a vector with origin in the system of charges and n
is the unit vector in the direction of R. Here, k is a constant that depends on the type of field, and the units being used.
# Electric quadrupole
The classic example of an electric quadrupole is shown in the picture. There are two positive and two negative charges, arranged on the corners of a square. The monopole moment (just the total charge) of this arrangement is zero. Similarly, the dipole moment is zero, when the coordinate origin is at the center of the picture. The quadrupole moment of this arrangement, however, cannot be reduced to zero, regardless of where we place the coordinate origin. The electric potential of an electric charge quadrupole is given by [1]
where <math>\epsilon_0</math> is the electric permittivity.
# Magnetic quadrupole
All known magnetic sources give dipole fields. However, to make a magnetic quadrupole it is possible to place two identical bar magnets parallel to each other such that the North pole of one is next to the South of the other and vice versa. Such a configuration cancels the dipole moment and gives a quadrupole moment, and its field will decrease at large distances faster than that of a dipole.
Magnetic quadrupoles like the one depicted on the right are being used to focus particle beams in a particle accelerator. There are four steel pole tips, two opposing magnetic north poles and two opposing magnetic south poles. The steel is magnetized by a large electric current that flows in the coils of tubing wrapped around the poles.
Changing magnetic quadrupole moments give production of electromagnetic radiation.
# Gravitational quadrupole
The mass quadrupole is very analogous to the electric charge quadrupole, where the charge density is simply replaced by the mass density. The gravitational potential is then expressed as:
For example, because the Earth is rotating, it is oblate (flattened at the poles). This gives it a nonzero quadrupole moment. While the contribution to the Earth's gravitational field from this quadrupole is extremely important for artificial satellites close to Earth, it is less important for the Moon, because the <math>\frac{1}{|\mathbf{R}|^3}</math> term falls quickly.
The mass quadrupole moment is also important in General Relativity because, if it changes in time, it can produce gravitational radiation, similar to the electromagnetic radiation produced by change electric or magnetic quadrupoles. (In particular, the second time derivative must be nonzero.) The mass monopole represents the total mass-energy in a system, and does not change in time — thus it gives off no radiation. Similarly, the mass dipole represents the center of mass of a system, which also does not change in time — thus it also gives off no radiation. The mass quadrupole, however, can change in time, and is the lowest-order contribution to gravitational radiation.[2]
The simplest and most important example of a radiating system is a pair of black holes with equal masses orbiting each other. If we place the coordinate origin right between the two black holes, and one black hole at unit distance along the x-axis, the system will have no dipole moment. Its quadrupole moment will simply be
where M is the mass of each hole, and <math>x_i</math> is the unit vector in the x-direction. As the system orbits, the x-vector will rotate, which means that it will have a nonzero second time derivative. Thus, the system will radiate gravitational waves. Energy lost in this way was indirectly detected in the Hulse-Taylor binary.
Just as electric charge and current multipoles contribute to the electromagnetic field, mass and mass-current multipoles contribute to the gravitational field in General Relativity, because GR also includes "gravitomagnetic" effects. Changing mass-current multipoles can also give off gravitational radiation. However, contributions from the current multipoles will typically be much smaller than that of the mass quadrupole. | https://www.wikidoc.org/index.php/Quadrupole | |
7c4ab79f5f39b5d107e30403ea887247eb742351 | wikidoc | Quarantine | Quarantine
# Overview
Quarantine is voluntary or compulsory isolation, typically to contain the spread of something considered dangerous, often but not always disease. The word comes from the Italian (17th Century Venetian) language Italian quarantena, meaning forty day period.
# In practice
The quarantining of people often raises questions of civil rights, especially in cases of long confinement or segregation from society, such as that of Mary Mallon (aka Typhoid Mary), a typhoid fever carrier.
Some quarantine periods can be very short, such as in the case of a suspected anthrax attack, in which persons are allowed to leave as soon as they shed their potentially contaminated garments and undergo a decontamination shower. For example, an article entitled "Daily News workers quarantined" describes a brief quarantine that lasted until people could be showered in a decontamination tent. (Kelly Nankervis, Daily News).
The February/March 2003 issue of HazMat Magazine suggests that people be "locked in a room until proper decon could be performed", in the event of "suspect anthrax".
Standard-Times senior correspondent Steve Urbon (February 14 2003) describes such temporary quarantine powers:
Civil rights activists in some cases have objected to people being rounded up, stripped and showered against their will. But Capt. Chmiel said local health authorities have "certain powers to quarantine people."
The purpose of such quarantine-for-decontamination is to prevent the spread of contamination, and to contain the contamination such that others are not put at risk from a person fleeing a scene where contamination is suspect.
The first astronauts to visit the Moon were quarantined upon their return at a specially built Lunar Receiving Laboratory.
To reduce the risk of introducing rabies from Continental Europe, the United Kingdom used to require that when dogs, and most other animals, are introduced to the country, they spend six months in quarantine at an HM Customs and Excise pound; this policy was abolished at the beginning of the 21st century in favour of a scheme generally known as Pet Passports, where animals can avoid quarantine if they have documentation showing they are up to date on their appropriate vaccinations.
The United States puts immediate quarantines on imported products if the disease can be traced back to a certain shipment or product. All imports will also quarantined if the diseases breakout in other countries. Up until now it was becoming a less stricter policy but with the harmful chemicals and diseases coming from Chinese products it is becoming strict again.
# History
The discovery of the contagious nature of infectious diseases and the use of quarantine to limit the spread of contagious diseases was introduced by Abū Alī ibn Sīnā (Avicenna) in The Canon of Medicine, circa 1020.
The word "quarantine" originates from the Latin quaranti giorni, meaning 'forty days'. This is due to the 40 day isolation of ships and people prior to entering the city of Dubrovnik (aka Ragusa). This was practiced as a measure of disease prevention related to the plague (Black Death). Between 1348 and 1359 the Black Death wiped out an estimated 30% of Europe's population, as well as a significant percentage of Asia's population. The original document from 1377, which is kept in the Archives of Dubrovnik, states that before entering the city, newcomers had to spend 30 days in a restricted location (originally nearby islands) waiting to see whether the symptoms of plague would develop. Later on, isolation was prolonged to 40 days and was called quarantine.
Other diseases lent themselves to the practice of quarantine before and after the devastation of the Plague.
Those afflicted with leprosy were historically isolated from society, the attempts to check the invasion of syphilis in northern Europe about 1490, the advent of yellow fever in Spain at the beginning of the 19th century and the arrival of Asiatic cholera in 1831.
Venice took the lead in measures to check the spread of plague, having appointed three guardians of the public health in the first years of the Black Death (1348). The next record of preventive measures comes from Reggio in Modena in 1374. The first lazaret was founded by Venice in 1403, on a small island adjoining the city; in 1467 Genova followed the example of Venice; and in 1476 the old leper hospital of Marseille was converted into a plague hospital. The great lazaret of that city, perhaps the most complete of its kind, having been founded in 1526 on the island of Pomgue. The practice at all the Mediterranean lazarets was not different from the English procedure in the Levantine and North African trade. On the approach of cholera in 1831 some new lazarets were set up at western ports, notably a very extensive establishment near Bordeaux, afterwards turned to another use.
The plague had disappeared from England, never to return, for more than thirty years before the practice of quarantine against it was definitely established by an act of British Parliament of Queen Anne's reign (1710). The first act was called for, owing to an alarm, lest plague should be imported from Poland and the Baltics; the second act of 1721 was due to the disastrous prevalence of plague at Marseille and other places in Provence; it was renewed in 1733 owing to a fresh outbreak of the malady on the continent of Europe, and again in 1743, owing to the disastrous epidemic at Messina. In 1752 a rigorous quarantine clause was introduced into an act regulating the Levantine trade; and various arbitrary orders were issued during the next twenty years to meet the supposed danger of infection from the Baltics. Although no plague cases ever came to England all those years, the restrictions on traffic became more and more stringent (following the movements of medical dogma), and in 1788 a very oppressive Quarantine Act was passed, with provisions affecting cargoes in particular. The first year of the 19th century marked the turning-point in quarantine legislation; a parliamentary committee sat on the practice, and a more reasonable act arose on their report. In 1805 there was another new act, and in 1823-24 again an elaborate inquiry followed by an act making the quarantine only at discretion of the privy council, and at the same time recognizing yellow fever or other highly infectious disorder as calling for quarantine measures along with plague. The steady approach of cholera in 1831 was the last occasion in England of a thoroughgoing resort to quarantine restrictions. The pestilence invaded every country of Europe despite all efforts to keep it out. In England the experiment of hermetically sealing the ports was not seriously tried when cholera returned in 1849, 1853 and 1865-66. In 1847 the privy council ordered all arrivals with clean bills from the Black Sea and the Levant to be admitted to free pratique, provided there had been no case of plague during the voyage; and therewith the last remnant of the once formidable quarantine practice against plague may be said to have disappeared.
For a number of years after the passing of the first Quarantine Act (1710) the protective practices in England were of the most haphazard and arbitrary kind. In 1721 two vessels laden with cotton goods from Cyprus, then a seat of plague, were ordered to be burned with their cargoes, the owners receiving 23,935 as indemnity. By the clause in the Levant Trade Act of 1752 vessels for the United Kingdom with a foul bill (i.e. coming from a country where plague existed) had to repair to the lazarets of Malta, Venice, Messina, Leghorn, Genoa or Marseille, to perform their quarantine or to have their cargoes sufficiently opened and aired. Since 1741 Stangate Creek (on the Medway) had been made the quarantine station at home; but it would appear from the above clause that it was available only for vessels with clean bills. In 1755 lazarets in the form of floating hulks were established in England for the first time, the cleansing of cargo (particularly by exposure to dews) having been done previously on the ships deck. There was no medical inspection employed, but the whole routine left to the officers of customs and quarantine. In 1780, when plague was in Poland, even vessels with grain from the Baltic had to lie forty days in quarantine, and unpack and air the sacks; but owing to remonstrances, which came chiefly from Edinburgh and Leith, grain was from that date declared to be a nonsusceptible article. About 1788 an order of the council required every ship liable to quarantine, in case of meeting any vessel at sea, or within four leagues of the coast of Great Britain or Ireland, to hoist a yellow flag in the daytime and show a light at the main topmast head at night, under a penalty of 200 pounds. After 1800, ships from plague-countries (or with foul bills) were enabled to perform their quarantine on arrival in the Medway instead of taking a Mediterranean port on the way for that purpose; and about the same time an extensive lazaret was built on Chetney Hill near Chatham at an expense of 170,000 ponds, which was almost at once condemned owing to its marshy foundations, and the materials sold for 15,000 pounds. The use of floating hulks as lazarets continued as before. In 1800 two ships with hides from Mogador (Morocco) were ordered to be sunk with their cargoes at the Nore, the owners receiving 15,000 pounds. About this period it was merchandise that was chiefly suspected: there was a long schedule of susceptible articles, and these were first exposed on the ships deck for twenty-one days or less (six days for each instalment of the cargo), and then transported to the lazaret, where they were opened and aired forty days more. The whole detention of the vessel was from sixty to sixty-five days, including the time for reshipment of her cargo. Pilots had to pass fifteen days on board a convalescent ship. The expenses may be estimated from one or two examples. In 1820 the Asia, 763 tons, arrived in the Medway with a foul bill from Alexandria, laden with linseed; her freight was 1475 and her quarantine dues 610. The same year the Pilato, 495 tons, making the same voyage, paid 200 quarantine dues on a freight of 1060. In 1823 the expenses of the quarantine service (at various ports) were 26,090, and the dues paid by shipping (nearly all with clean bills) 22,000. A return for the United Kingdom and colonies in 1849 showed, among other details, that the expenses of the lazaret at Malta for ten years from 1839 to 1848 had been 53,553. From 1846 onwards the establishments in the United Kingdom were gradually reduced, while the last vestige of the British quarantine law was removed by the Public Health Act of 1896, which repealed the Quarantine Act of 1825 (with dependent clauses of other acts), and transferred from the privy council to the Local Government Board the powers to deal with ships arriving infected with yellow fever or plague, the powers to deal with cholera ships having been already transferred by the Public Health Act of 1875.
The British regulations of 9th November 1896 applied to yellow fever, plague and cholera. Officers of the Customs, as well as of Coast Guard and Board of Trade (for signalling), were empowered to take the initial steps. They certified in writing the master of a supposed infected ship, and detained the vessel provisionally for not more than twelve hours, giving notice meanwhile to the port sanitary authority. The medical officer of the port boarded the ship and examined every person in it. Every person found infected was certified of the fact, removed to a hospital provided (if his condition allow), and kept under the orders of the medical officer. If the sick could be removed, the vessel remained under his orders. Every person suspected (owing to his or her immediate attendance on the sick) could be detained on board for 48 hours or removed to the hospital for a similar period. All others were free to land on giving the addresses of their destinations to be sent to the respective local authorities, so that the dispersed passengers and crew could be kept individually under observation for a few days. The ship was then disinfected, dead bodies buried at sea, infected clothing, bedding, etc., destroyed or disinfected, and bilge-water and water-ballast (subject to exceptions) pumped out at a suitable distance before the ship entered a dock or basin. Mails were subject to no detention. A stricken ship within 3 miles of the shore had to fly at the main mast a yellow and black flag borne quarterly from sunrise to sunset.
## International Conventions
Since 1852 several conferences have been held between delegates of the European powers, with a view to uniform action in keeping out infection from the East and preventing its spread within Europe; all but that of 1897 were occupied with cholera. No result came of those at Paris (1852), Constantinople (1866), Vienna (1874), and Rome (1885), but each of the subsequent ones has been followed by an international convention on the part of nearly one-half of the governments represented. The general effect has been an abandonment of the high quarantine doctrine of constructive infection of a ship as coming from a scheduled port, and an approximation to the principles advocated by Great Britain for many years. The principal countries which retained the old system at the time were Spain, Portugal, Turkey, Greece and Russia (the British possessions at the time, Gibraltar, Malta and Cyprus, being under the same influence). The aim of each international sanitary convention had been to bind the governments to a uniform minimum of preventive action, with further restrictions permissible to individual countries. The minimum specified by international conventions were very nearly the same as the British practice, which had been in turn adapted to continental opinion in the matter of the importation of rags.
The Venice convention of 1892 was on cholera by the Suez Canal route; that of Dresden, 1893, on cholera within European countries; that of Paris, 1894, on cholera by the pilgrim traffic; and that of Venice, in 1897, was in connection with the outbreak of plague in the East, and the conference met to settle on an international basis the steps to be taken to prevent, if possible, its spread into Europe.
One of the first points to be dealt with in 1897 was to settle the incubation period for this disease, and the period to be adopted for administrative purposes. It was admitted that the incubation period was, as a rule, a comparatively short one, namely, of some three or four days. After much discussion ten days was accepted by a very large majority. The principle of disease notification was unanimously adopted. Each government had to notify to other governments on the existence of plague within their several jurisdictions, and at the same time state the measures of prevention which are being carried out to prevent its diffusion. The area deemed to be infected was limited to the actual district or village where the disease prevailed, and no locality was deemed to be infected merely because of the importation into it of a few cases of plague while there has been no diffusion of the malady. As regards the precautions to be taken on land frontiers, it was decided that during the prevalence of plague every country had the inherent right to close its land frontiers against traffic. As regards the Red Sea, it was decided after discussion that a healthy vessel could pass through the Suez Canal, and continue its voyage in the Mediterranean during the period of incubation of the disease the prevention of which is in question. It was also agreed that vessels passing through the Canal in quarantine might, subject to the use of the electric light, coal in quarantine at Port Said by night as well as by day, and that passengers might embark in quarantine at that port. Infected vessels, if these carry a doctor and are provided with a disinfecting stove, have a right to navigate the Canal, in quarantine, subject only to the landing of those who were suffering from plague.
## 1900s
The United States had isolation facilities at every port of entry in the 1950s and 60s. The last federal order of involuntary quarantine, prior to the 2007 tuberculosis scare, was issued in 1963.
# Other uses
U.S. President John F. Kennedy euphemistically referred to the U.S. Navy's interdiction of shipping en route to Cuba during the Cuban missile crisis as a "quarantine" rather than a blockade, because a quarantine is a legal act in peacetime, whereas a blockade is defined as an act of aggression under the U.N. Charter.
In computer science, it describes putting files infected by computer viruses into a special directory, so as to eliminate the threat they pose, without irreversibly deleting them.
# Notable quarantines
- Eyam was a village in Britain that chose to isolate itself to stop the spread of the Plague northward in 1665. They were hindered in this by the time's limited knowledge of the disease: what caused it, what forms infection took, what animal vectors carried it, how it spread.
- Mary Mallon AKA "Typhoid Mary" was quarantined in New York in the early 20th Century. She was an asymptomatic Typhoid carrier and was considered a public health hazard.
- The 1972 outbreak of smallpox in Yugoslavia was the final outbreak of smallpox in Europe. The WHO fought the outbreak with extensive quarantine, and the government instituted martial law.
- Ted DeVita had severe aplastic anemia and lived in a sterile hospital environment for 8 years due to his compromised immune system.
- David Vetter suffered from a rare genetic disorder and lived his entire life in an isolated sterile environment.
- The astronauts on Apollo 11 were put into quarantine for a couple of days in the Lunar Receiving Laboratory to make sure that they didn't carry any unknown diseases from the moon.
- Robert Daniels was quarantined for having the deadliest form of Tuberculosis in an Arizona hospital, partly for not wearing a mask during his time in the outside world when he was diagnosed with the disease.
- During World-war II (1942) the British forces tested out their biological weapons programme on Gruinard Island and infected it with Anthrax. The quarantine was lifted in 1990 when the island was declared safe and a flock of sheep were released onto the island.
- Andrew Speaker was placed under U.S. Federal quarantine in 2007 after flying to Europe while knowing he had tuberculosis, then flying back after learning it was an extensively drug resistant strain. He is the first person since 1963 to be under Federal quarantine.
# Notes
- ↑ David W. Tschanz, MSPH, PhD (August 2003). "Arab Roots of European Medicine", Heart Views 4 (2).
- ↑ NPR.org | Quarantine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Quarantine is voluntary or compulsory isolation, typically to contain the spread of something considered dangerous, often but not always disease. The word comes from the Italian (17th Century Venetian) language Italian quarantena, meaning forty day period.
# In practice
The quarantining of people often raises questions of civil rights, especially in cases of long confinement or segregation from society, such as that of Mary Mallon (aka Typhoid Mary), a typhoid fever carrier.
Some quarantine periods can be very short, such as in the case of a suspected anthrax attack, in which persons are allowed to leave as soon as they shed their potentially contaminated garments and undergo a decontamination shower. For example, an article entitled "Daily News workers quarantined" describes a brief quarantine that lasted until people could be showered in a decontamination tent. (Kelly Nankervis, Daily News).
The February/March 2003 issue of HazMat Magazine suggests that people be "locked in a room until proper decon could be performed", in the event of "suspect anthrax".
Standard-Times senior correspondent Steve Urbon (February 14 2003) describes such temporary quarantine powers:
Civil rights activists in some cases have objected to people being rounded up, stripped and showered against their will. But Capt. Chmiel said local health authorities have "certain powers to quarantine people."
The purpose of such quarantine-for-decontamination is to prevent the spread of contamination, and to contain the contamination such that others are not put at risk from a person fleeing a scene where contamination is suspect.
The first astronauts to visit the Moon were quarantined upon their return at a specially built Lunar Receiving Laboratory.
To reduce the risk of introducing rabies from Continental Europe, the United Kingdom used to require that when dogs, and most other animals, are introduced to the country, they spend six months in quarantine at an HM Customs and Excise pound; this policy was abolished at the beginning of the 21st century in favour of a scheme generally known as Pet Passports, where animals can avoid quarantine if they have documentation showing they are up to date on their appropriate vaccinations.
The United States puts immediate quarantines on imported products if the disease can be traced back to a certain shipment or product. All imports will also quarantined if the diseases breakout in other countries. Up until now it was becoming a less stricter policy but with the harmful chemicals and diseases coming from Chinese products it is becoming strict again.
# History
The discovery of the contagious nature of infectious diseases and the use of quarantine to limit the spread of contagious diseases was introduced by Abū Alī ibn Sīnā (Avicenna) in The Canon of Medicine, circa 1020.[1]
The word "quarantine" originates from the Latin quaranti giorni, meaning 'forty days'. This is due to the 40 day isolation of ships and people prior to entering the city of Dubrovnik (aka Ragusa). This was practiced as a measure of disease prevention related to the plague (Black Death). Between 1348 and 1359 the Black Death wiped out an estimated 30% of Europe's population, as well as a significant percentage of Asia's population. The original document from 1377, which is kept in the Archives of Dubrovnik, states that before entering the city, newcomers had to spend 30 days in a restricted location (originally nearby islands) waiting to see whether the symptoms of plague would develop. Later on, isolation was prolonged to 40 days and was called quarantine.
Other diseases lent themselves to the practice of quarantine before and after the devastation of the Plague.
Those afflicted with leprosy were historically isolated from society, the attempts to check the invasion of syphilis in northern Europe about 1490, the advent of yellow fever in Spain at the beginning of the 19th century and the arrival of Asiatic cholera in 1831.
Venice took the lead in measures to check the spread of plague, having appointed three guardians of the public health in the first years of the Black Death (1348). The next record of preventive measures comes from Reggio in Modena in 1374. The first lazaret was founded by Venice in 1403, on a small island adjoining the city; in 1467 Genova followed the example of Venice; and in 1476 the old leper hospital of Marseille was converted into a plague hospital. The great lazaret of that city, perhaps the most complete of its kind, having been founded in 1526 on the island of Pomgue. The practice at all the Mediterranean lazarets was not different from the English procedure in the Levantine and North African trade. On the approach of cholera in 1831 some new lazarets were set up at western ports, notably a very extensive establishment near Bordeaux, afterwards turned to another use.
The plague had disappeared from England, never to return, for more than thirty years before the practice of quarantine against it was definitely established by an act of British Parliament of Queen Anne's reign (1710). The first act was called for, owing to an alarm, lest plague should be imported from Poland and the Baltics; the second act of 1721 was due to the disastrous prevalence of plague at Marseille and other places in Provence; it was renewed in 1733 owing to a fresh outbreak of the malady on the continent of Europe, and again in 1743, owing to the disastrous epidemic at Messina. In 1752 a rigorous quarantine clause was introduced into an act regulating the Levantine trade; and various arbitrary orders were issued during the next twenty years to meet the supposed danger of infection from the Baltics. Although no plague cases ever came to England all those years, the restrictions on traffic became more and more stringent (following the movements of medical dogma), and in 1788 a very oppressive Quarantine Act was passed, with provisions affecting cargoes in particular. The first year of the 19th century marked the turning-point in quarantine legislation; a parliamentary committee sat on the practice, and a more reasonable act arose on their report. In 1805 there was another new act, and in 1823-24 again an elaborate inquiry followed by an act making the quarantine only at discretion of the privy council, and at the same time recognizing yellow fever or other highly infectious disorder as calling for quarantine measures along with plague. The steady approach of cholera in 1831 was the last occasion in England of a thoroughgoing resort to quarantine restrictions. The pestilence invaded every country of Europe despite all efforts to keep it out. In England the experiment of hermetically sealing the ports was not seriously tried when cholera returned in 1849, 1853 and 1865-66. In 1847 the privy council ordered all arrivals with clean bills from the Black Sea and the Levant to be admitted to free pratique, provided there had been no case of plague during the voyage; and therewith the last remnant of the once formidable quarantine practice against plague may be said to have disappeared.
For a number of years after the passing of the first Quarantine Act (1710) the protective practices in England were of the most haphazard and arbitrary kind. In 1721 two vessels laden with cotton goods from Cyprus, then a seat of plague, were ordered to be burned with their cargoes, the owners receiving 23,935 as indemnity. By the clause in the Levant Trade Act of 1752 vessels for the United Kingdom with a foul bill (i.e. coming from a country where plague existed) had to repair to the lazarets of Malta, Venice, Messina, Leghorn, Genoa or Marseille, to perform their quarantine or to have their cargoes sufficiently opened and aired. Since 1741 Stangate Creek (on the Medway) had been made the quarantine station at home; but it would appear from the above clause that it was available only for vessels with clean bills. In 1755 lazarets in the form of floating hulks were established in England for the first time, the cleansing of cargo (particularly by exposure to dews) having been done previously on the ships deck. There was no medical inspection employed, but the whole routine left to the officers of customs and quarantine. In 1780, when plague was in Poland, even vessels with grain from the Baltic had to lie forty days in quarantine, and unpack and air the sacks; but owing to remonstrances, which came chiefly from Edinburgh and Leith, grain was from that date declared to be a nonsusceptible article. About 1788 an order of the council required every ship liable to quarantine, in case of meeting any vessel at sea, or within four leagues of the coast of Great Britain or Ireland, to hoist a yellow flag in the daytime and show a light at the main topmast head at night, under a penalty of 200 pounds. After 1800, ships from plague-countries (or with foul bills) were enabled to perform their quarantine on arrival in the Medway instead of taking a Mediterranean port on the way for that purpose; and about the same time an extensive lazaret was built on Chetney Hill near Chatham at an expense of 170,000 ponds, which was almost at once condemned owing to its marshy foundations, and the materials sold for 15,000 pounds. The use of floating hulks as lazarets continued as before. In 1800 two ships with hides from Mogador (Morocco) were ordered to be sunk with their cargoes at the Nore, the owners receiving 15,000 pounds. About this period it was merchandise that was chiefly suspected: there was a long schedule of susceptible articles, and these were first exposed on the ships deck for twenty-one days or less (six days for each instalment of the cargo), and then transported to the lazaret, where they were opened and aired forty days more. The whole detention of the vessel was from sixty to sixty-five days, including the time for reshipment of her cargo. Pilots had to pass fifteen days on board a convalescent ship. The expenses may be estimated from one or two examples. In 1820 the Asia, 763 tons, arrived in the Medway with a foul bill from Alexandria, laden with linseed; her freight was 1475 and her quarantine dues 610. The same year the Pilato, 495 tons, making the same voyage, paid 200 quarantine dues on a freight of 1060. In 1823 the expenses of the quarantine service (at various ports) were 26,090, and the dues paid by shipping (nearly all with clean bills) 22,000. A return for the United Kingdom and colonies in 1849 showed, among other details, that the expenses of the lazaret at Malta for ten years from 1839 to 1848 had been 53,553. From 1846 onwards the establishments in the United Kingdom were gradually reduced, while the last vestige of the British quarantine law was removed by the Public Health Act of 1896, which repealed the Quarantine Act of 1825 (with dependent clauses of other acts), and transferred from the privy council to the Local Government Board the powers to deal with ships arriving infected with yellow fever or plague, the powers to deal with cholera ships having been already transferred by the Public Health Act of 1875.
The British regulations of 9th November 1896 applied to yellow fever, plague and cholera. Officers of the Customs, as well as of Coast Guard and Board of Trade (for signalling), were empowered to take the initial steps. They certified in writing the master of a supposed infected ship, and detained the vessel provisionally for not more than twelve hours, giving notice meanwhile to the port sanitary authority. The medical officer of the port boarded the ship and examined every person in it. Every person found infected was certified of the fact, removed to a hospital provided (if his condition allow), and kept under the orders of the medical officer. If the sick could be removed, the vessel remained under his orders. Every person suspected (owing to his or her immediate attendance on the sick) could be detained on board for 48 hours or removed to the hospital for a similar period. All others were free to land on giving the addresses of their destinations to be sent to the respective local authorities, so that the dispersed passengers and crew could be kept individually under observation for a few days. The ship was then disinfected, dead bodies buried at sea, infected clothing, bedding, etc., destroyed or disinfected, and bilge-water and water-ballast (subject to exceptions) pumped out at a suitable distance before the ship entered a dock or basin. Mails were subject to no detention. A stricken ship within 3 miles of the shore had to fly at the main mast a yellow and black flag borne quarterly from sunrise to sunset.
## International Conventions
Since 1852 several conferences have been held between delegates of the European powers, with a view to uniform action in keeping out infection from the East and preventing its spread within Europe; all but that of 1897 were occupied with cholera. No result came of those at Paris (1852), Constantinople (1866), Vienna (1874), and Rome (1885), but each of the subsequent ones has been followed by an international convention on the part of nearly one-half of the governments represented. The general effect has been an abandonment of the high quarantine doctrine of constructive infection of a ship as coming from a scheduled port, and an approximation to the principles advocated by Great Britain for many years. The principal countries which retained the old system at the time were Spain, Portugal, Turkey, Greece and Russia (the British possessions at the time, Gibraltar, Malta and Cyprus, being under the same influence). The aim of each international sanitary convention had been to bind the governments to a uniform minimum of preventive action, with further restrictions permissible to individual countries. The minimum specified by international conventions were very nearly the same as the British practice, which had been in turn adapted to continental opinion in the matter of the importation of rags.
The Venice convention of 1892 was on cholera by the Suez Canal route; that of Dresden, 1893, on cholera within European countries; that of Paris, 1894, on cholera by the pilgrim traffic; and that of Venice, in 1897, was in connection with the outbreak of plague in the East, and the conference met to settle on an international basis the steps to be taken to prevent, if possible, its spread into Europe.
One of the first points to be dealt with in 1897 was to settle the incubation period for this disease, and the period to be adopted for administrative purposes. It was admitted that the incubation period was, as a rule, a comparatively short one, namely, of some three or four days. After much discussion ten days was accepted by a very large majority. The principle of disease notification was unanimously adopted. Each government had to notify to other governments on the existence of plague within their several jurisdictions, and at the same time state the measures of prevention which are being carried out to prevent its diffusion. The area deemed to be infected was limited to the actual district or village where the disease prevailed, and no locality was deemed to be infected merely because of the importation into it of a few cases of plague while there has been no diffusion of the malady. As regards the precautions to be taken on land frontiers, it was decided that during the prevalence of plague every country had the inherent right to close its land frontiers against traffic. As regards the Red Sea, it was decided after discussion that a healthy vessel could pass through the Suez Canal, and continue its voyage in the Mediterranean during the period of incubation of the disease the prevention of which is in question. It was also agreed that vessels passing through the Canal in quarantine might, subject to the use of the electric light, coal in quarantine at Port Said by night as well as by day, and that passengers might embark in quarantine at that port. Infected vessels, if these carry a doctor and are provided with a disinfecting stove, have a right to navigate the Canal, in quarantine, subject only to the landing of those who were suffering from plague.
## 1900s
The United States had isolation facilities at every port of entry in the 1950s and 60s. The last federal order of involuntary quarantine, prior to the 2007 tuberculosis scare, was issued in 1963.
Template:Sect-stub
# Other uses
U.S. President John F. Kennedy euphemistically referred to the U.S. Navy's interdiction of shipping en route to Cuba during the Cuban missile crisis as a "quarantine" rather than a blockade, because a quarantine is a legal act in peacetime, whereas a blockade is defined as an act of aggression under the U.N. Charter.
In computer science, it describes putting files infected by computer viruses into a special directory, so as to eliminate the threat they pose, without irreversibly deleting them.
# Notable quarantines
- Eyam was a village in Britain that chose to isolate itself to stop the spread of the Plague northward in 1665. They were hindered in this by the time's limited knowledge of the disease: what caused it, what forms infection took, what animal vectors carried it, how it spread.
- Mary Mallon AKA "Typhoid Mary" was quarantined in New York in the early 20th Century. She was an asymptomatic Typhoid carrier and was considered a public health hazard.
- The 1972 outbreak of smallpox in Yugoslavia was the final outbreak of smallpox in Europe. The WHO fought the outbreak with extensive quarantine, and the government instituted martial law.
- Ted DeVita had severe aplastic anemia and lived in a sterile hospital environment for 8 years due to his compromised immune system.
- David Vetter suffered from a rare genetic disorder and lived his entire life in an isolated sterile environment.
- The astronauts on Apollo 11 were put into quarantine for a couple of days in the Lunar Receiving Laboratory to make sure that they didn't carry any unknown diseases from the moon.
- Robert Daniels was quarantined for having the deadliest form of Tuberculosis in an Arizona hospital, partly for not wearing a mask during his time in the outside world when he was diagnosed with the disease. [2]
- During World-war II (1942) the British forces tested out their biological weapons programme on Gruinard Island and infected it with Anthrax. The quarantine was lifted in 1990 when the island was declared safe and a flock of sheep were released onto the island.
- Andrew Speaker was placed under U.S. Federal quarantine in 2007 after flying to Europe while knowing he had tuberculosis, then flying back after learning it was an extensively drug resistant strain. He is the first person since 1963 to be under Federal quarantine.
# Notes
- ↑ David W. Tschanz, MSPH, PhD (August 2003). "Arab Roots of European Medicine", Heart Views 4 (2).
- ↑ NPR.org | https://www.wikidoc.org/index.php/Quarantine | |
3d007cdff8c491e624ec89ea2a7bf8861f74620d | wikidoc | Quetiapine | Quetiapine
# Disclaimer
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# Black Box Warning
# Overview
Quetiapine is an atypical antipsychotic that is FDA approved for the treatment of schizophrenia, bipolar I disorder, manic or mixed episodes, bipolar disorder, depressive episodes, major depressive disorder, adjunctive therapy with antidepressants. There is a Black Box Warning for this drug as shown here. Common adverse reactions include somnolence, dry mouth, constipation, dizziness, increased appetite, dyspepsia, weight gain, fatigue, dysarthria, nasal congestion, nausea, vomiting, and tachycardia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Important Administration Instructions
- Quetiapine tablets should be swallowed whole and not split, chewed or crushed.
- It is recommended that Quetiapine be taken without food or with a light meal (approximately 300 calories).
- Quetiapine should be administered once daily, preferably in the evening.
- Recommended Dosing
- The recommended initial dose, titration, dose range and maximum Quetiapine dose for each approved indication is displayed in Table 1 below. After initial dosing, adjustments can be made upwards or downwards, if necessary, depending upon the clinical response and tolerability of the patient
- Maintenance Treatment for Schizophrenia and Bipolar I Disorder
- Maintenance Treatment
Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment.
- Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment.
- Dose Modifications in Elderly Patients
- Consideration should be given to a slower rate of dose titration and a lower target dose in the elderly and in patients who are debilitated or who have a predisposition to hypotensive reactions. When indicated, dose escalation should be performed with caution in these patients.
- Elderly patients should be started on Quetiapine 50 mg/day and the dose can be increased in increments of 50 mg/day depending on the clinical response and tolerability of the individual patient.
- Dose Modifications in Hepatically Impaired Patients
- Patients with hepatic impairment should be started on Quetiapine 50 mg/day. The dose can be increased daily in increments of 50 mg/day to an effective dose, depending on the clinical response and tolerability of the patient.
- Dose Modifications when used with CYP3A4 Inhibitors
- Quetiapine dose should be reduced to one sixth of original dose when co-medicated with a potent CYP3A4 inhibitor (e.g., ketoconazole, itraconazole, indinavir, ritonavir, nefazodone, etc.). When the CYP3A4 inhibitor is discontinued, the dose of Quetiapine should be increased by 6 fold.
- Dose Modifications when used with CYP3A4 Inducers
- Quetiapine dose should be increased up to 5 fold of the original dose when used in combination with a chronic treatment (e.g., greater than 7-14 days) of a potent CYP3A4 inducer (e.g., phenytoin, carbamazepine, rifampin, avasimibe, St. John’s wort etc.). The dose should be titrated based on the clinical response and tolerance of the individual patient. When the CYP3A4 inducer is discontinued, the dose of Quetiapine should be reduced to the original level within 7-14 days.
- Reinitiation of Treatment in Patients Previously Discontinued
- Although there are no data to specifically address re-initiation of treatment, it is recommended that when restarting therapy of patients who have been off Quetiapine for more than one week, the initial dosing schedule should be followed. When restarting patients who have been off Quetiapine for less than one week, gradual dose escalation may not be required and the maintenance dose may be reinitiated.
- Switching Patients from SEROQUEL Tablets to Quetiapine Tablets
- Patients who are currently being treated with SEROQUEL (immediate release formulation) may be switched to Quetiapine at the equivalent total daily dose taken once daily. Individual dosage adjustments may be necessary.
- Switching from Antipsychotics
- There are no systematically collected data to specifically address switching patients from other antipsychotics to Quetiapine, or concerning concomitant administration with other antipsychotics. While immediate discontinuation of the previous antipsychotic treatment may be acceptable for some patients, more gradual discontinuation may be most appropriate for others. In all cases, the period of overlapping antipsychotic administration should be minimized. When switching patients from depot antipsychotics, if medically appropriate, initiate Quetiapine therapy in place of the next scheduled injection. The need for continuing existing extrapyramidal syndrome medication should be re-evaluated periodically.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Quetiapine in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- Quetiapine 300 to 800 mg/day
- Dosing Information
- Doses of 50, 150, or 300 mg/day
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Recommended Dose: 400-600 mg/day.
- Maximum Dose: 600 mg/day.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Quetiapine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Quetiapine in pediatric patients.
# Contraindications
- Hypersensitivity to quetiapine or to any excipients in the Quetiapine formulation. Anaphylactic reactions have been reported in patients treated with Quetiapine.
# Warnings
### Precautions
- Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analysis of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. Quetiapine is not approved for the treatment of patients with dementia-related psychosis.
- Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.
- The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 2.
- No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.
- It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.
- All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.
- The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.
- Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.
- Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for Quetiapine should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.
- A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, including Quetiapine, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression.
- In placebo-controlled trials with risperidone, aripiprazole, and olanzapine in elderly subjects with dementia, there was a higher incidence of cerebrovascular adverse reactions (cerebrovascular accidents and transient ischemic attacks), including fatalities, compared to placebo-treated subjects. Quetiapine is not approved for the treatment of patients with dementia-related psychosis.
- A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs, including quetiapine. Rare cases of NMS have been reported with quetiapine. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis) and acute renal failure.
- The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to exclude cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology.
- The management of NMS should include: 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; 2) intensive symptomatic treatment and medical monitoring; and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for NMS.
- If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored since recurrences of NMS have been reported.
- Atypical antipsychotic drugs have been associated with metabolic changes that include hyperglycemia/diabetes mellitus, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile. In some patients, a worsening of more than one of the metabolic parameters of weight, blood glucose, and lipids was observed in clinical studies. Changes in these metabolic profiles should be managed as clinically appropriate.
- Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics, including quetiapine. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse reactions is not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics. Precise risk estimates for hyperglycemia-related adverse reactions in patients treated with atypical antipsychotics are not available.
- Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug.
- Adults:
- In a 24-week trial (active-controlled, 115 patients treated with SEROQUEL) designed to evaluate glycemic status with oral glucose tolerance testing of all patients, at week 24 the incidence of a treatment-emergent post-glucose challenge glucose level ≥ 200 mg/dL was 1.7% and the incidence of a fasting treatment-emergent blood glucose level ≥ 126 mg/dL was 2.6%. The mean change in fasting glucose from baseline was 3.2 mg/dL and mean change in 2 hour glucose from baseline was -1.8 mg/dL for quetiapine.
- In 2 long-term placebo-controlled randomized withdrawal clinical trials for bipolar I disorder maintenance, mean exposure of 213 days for SEROQUEL (646 patients) and 152 days for placebo (680 patients), the mean change in glucose from baseline was +5.0 mg/dL for quetiapine and –0.05 mg/dL for placebo. The exposure-adjusted rate of any increased blood glucose level (≥ 126 mg/dL) for patients more than 8 hours since a meal (however, some patients may not have been precluded from calorie intake from fluids during fasting period) was 18.0 per 100 patient years for SEROQUEL (10.7% of patients; n=556) and 9.5 for placebo per 100 patient years (4.6% of patients; n=581).
- Table 4 shows the percentage of patients with shifts in blood glucose to ≥ 126 mg/dL from normal baseline in MDD adjunct therapy trials by dose.
- Children and Adolescents: Safety and effectiveness of Quetiapine is supported from studies of SEROQUEL in children and adolescent patients 10 to 17 years of age. In a placebo-controlled Quetiapine monotherapy study (8 weeks duration) of children and adolescent patients (10 – 17 years of age) with bipolar depression, in which efficacy was not established, the mean change in fasting glucose levels for Quetiapine (n = 60) compared to placebo (n = 62) was 1.8 mg/dL versus 1.6 mg/dL. In this study, there were no patients in the Quetiapine or placebo-treated groups with a baseline normal fasting glucose level ( 126 mg/dL compared to zero patients in the placebo group.
- In a placebo-controlled SEROQUEL monotherapy study of adolescent patients (13–17 years of age) with schizophrenia (6 weeks duration), the mean change in fasting glucose levels for SEROQUEL (n=138) compared to placebo (n=67) was –0.75 mg/dL versus –1.70 mg/dL. In a placebo-controlled SEROQUEL monotherapy study of children and adolescent patients (10–17 years of age) with bipolar mania (3 weeks duration), the mean change in fasting glucose level for SEROQUEL (n=170) compared to placebo (n=81) was 3.62 mg/dL versus –1.17 mg/dL. No patient in either study with a baseline normal fasting glucose level (<100 mg/dL) or a baseline borderline fasting glucose level (≥100 mg/dL and <126 mg/dL) had a treatment-emergent blood glucose level of ≥126 mg/dL.
- Dyslipidemia
- Adults:
- Table 5 shows the percentage of patients with changes in cholesterol and triglycerides from baseline by indication in clinical trials with Quetiapine.
- In SEROQUEL clinical trials for schizophrenia, the percentage of patients with shifts in cholesterol and triglycerides from baseline to clinically significant levels were 18% (placebo: 7%) and 22% (placebo: 16%). HDL-cholesterol and LDL-cholesterol parameters were not measured in these studies. In SEROQUEL clinical trials for bipolar depression, the following percentage of patients had shifts from baseline to clinically significant levels for the four lipid parameters measured: total cholesterol 9% (placebo: 6%); triglycerides 14% (placebo: 9%); LDL-cholesterol 6% (placebo: 5%) and HDL-cholesterol 14% (placebo: 14%). Lipid parameters were not measured in the bipolar mania studies.
- Table 6 shows the percentage of patients in MDD adjunctive therapy trials with clinically significant shifts in total-cholesterol, triglycerides, LDL-cholesterol and HDL-cholesterol from baseline by dose.
- Children and Adolescents:
- Safety and effectiveness of Quetiapine is supported by studies of SEROQUEL in children and adolescent patients 10 to 17 years of age.
- In a placebo-controlled Quetiapine monotherapy study (8 weeks duration) of children and adolescent patients (10-17 years of age) with bipolar depression, in which efficacy was not established, the percentage of children and adolescents with shifts in total cholesterol (≥200 mg/dL), triglycerides (≥150 mg/dL), LDL-cholesterol (≥ 130 mg/dL) and HDL-cholesterol (≤40 mg/dL) from baseline to clinically significant levels were: total cholesterol 8% (7/83) for Quetiapine vs. 6% (5/84) for placebo; triglycerides 28% (22/80) for Quetiapine vs. 9% (7/82) for placebo; LDL-cholesterol 2% (2/86) for Quetiapine vs. 4% (3/85) for placebo and HDL-cholesterol 20% (13/65) for Quetiapine vs 15% (11/74) for placebo.
- Table 7 shows the percentage of children and adolescents with shifts in total cholesterol, triglycerides, LDL-cholesterol and HDL-cholesterol from baseline to clinically significant levels by indication in clinical trials with SEROQUEL in adolescents (13–17 years) with schizophrenia and in children and adolescents (10-17 years) with bipolar mania.
- Weight Gain
- Increases in weight have been observed in clinical trials. Patients receiving quetiapine should receive regular monitoring of weight.
- Adults: Table 8 shows the percentage of adult patients with weight gain of ≥7% of body weight by indication.
- In schizophrenia trials, the proportions of patients meeting a weight gain criterion of ≥7% of body weight were compared in a pool of four 3- to 6-week placebo-controlled clinical trials, revealing a statistically significant greater incidence of weight gain for SEROQUEL (23%) compared to placebo (6%).
- Table 9 shows the percentage of adult patients with weight gain of ≥7% of body weight for MDD by dose.
- Children and Adolescents: Safety and effectiveness of Quetiapine is supported by studies of SEROQUEL in children and adolescent patients 10 to 17 years of age. In a clinical trial for Quetiapine in children and adolescents (10-17 years of age) with bipolar depression, in which efficacy was not established, the percentage of patients with weight gain ≥7% of body weight at any time was 15% (14/92) for Quetiapine vs. 10% (10/100) for placebo. The mean change in body weight was 1.4 kg in the Quetiapine group vs. 0.6 kg in the placebo group.
- Weight gain was greater in patients 10-12 years of age compared to patients 13-17 years of age. The percentage of patients 10-12 years of age with weight gain ≥7% at any time was 28% (7/25) for Quetiapine vs. 0% (0/28) for placebo. The percentage of patients 13-17 years of age with weight gain ≥7% at any time was 10.4% (7/67) for Quetiapine vs. 13.9% (10/72) for placebo.
- Table 10 shows the percentage of children and adolescents with weight gain ≥7% of body weight in clinical trials with SEROQUEL in adolescents (13 – 17 years) with schizophrenia and in children and adolescents (10 – 17 years) with bipolar mania.
- The mean change in body weight in the schizophrenia trial was 2.0 kg in the SEROQUEL group and -0.4 kg in the placebo group and in the bipolar mania trial it was 1.7 kg in the SEROQUEL group and 0.4 kg in the placebo group.
- In an open-label study that enrolled patients from the above two pediatric trials, 63% of patients (241/380) completed 26 weeks of therapy with SEROQUEL. After 26 weeks of treatment, the mean increase in body weight was 4.4 kg. Forty-five percent of the patients gained ≥ 7% of their body weight, not adjusted for normal growth. In order to adjust for normal growth over 26 weeks, an increase of at least 0.5 standard deviation from baseline in BMI was used as a measure of a clinically significant change; 18.3% of patients on SEROQUEL met this criterion after 26 weeks of treatment.
- When treating pediatric patients with SEROQUEL for any indication, weight gain should be assessed against that expected for normal growth.
- A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs including quetiapine. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.
- The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses or may even arise after discontinuation of treatment.
- There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.
- Given these considerations, Quetiapine should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who appear to suffer from a chronic illness that (1) is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.
- If signs and symptoms of tardive dyskinesia appear in a patient on Quetiapine, drug discontinuation should be considered. However, some patients may require treatment with quetiapine despite the presence of the syndrome.
- Quetiapine may induce orthostatic hypotension associated with dizziness, tachycardia and, in some patients, syncope, especially during the initial dose-titration period, probably reflecting its ά1-adrenergic antagonist properties. Syncope was reported in 0.3% (5/1866) of the patients treated with Quetiapine across all indications, compared with 0.2% (2/928) on placebo. Syncope was reported in 1% (28/3265) of the patients treated with SEROQUEL, compared with 0.2% (2/954) on placebo. Orthostatic hypotension, dizziness, and syncope may lead to falls.
- Quetiapine should be used with particular caution in patients with known cardiovascular disease (history of myocardial infarction or ischemic heart disease, heart failure or conduction abnormalities), cerebrovascular disease or conditions which would predispose patients to hypotension (dehydration, hypovolemia and treatment with antihypertensive medications). If hypotension occurs during titration to the target dose, a return to the previous dose in the titration schedule is appropriate.
- Safety and effectiveness of Quetiapine is supported by studies of SEROQUEL in children and adolescent patients 10 to 17 years of age.
- In a placebo-controlled Quetiapine clinical trial (8 weeks duration) in children and adolescents (10-17 years of age) with bipolar depression, in which efficacy was not established, the incidence of increases at any time in systolic blood pressure (≥20 mmHg) was 6.5% (6/92) for Quetiapine and 6.0% (6/100) for placebo; the incidence of increases at any time in diastolic blood pressure (≥10 mmHg) was 46.7% (43/92) for Quetiapine and 36.0% (36/100) for placebo.
- In placebo-controlled trials in children and adolescents with schizophrenia (13-17 years old, 6-week duration) or bipolar mania (10-17 years old, 3-week duration), the incidence of increases at any time in systolic blood pressure (≥20 mmHg) was 15.2% (51/335) for SEROQUEL and 5.5% (9/163) for placebo; the incidence of increases at any time in diastolic blood pressure (≥10 mmHg) was 40.6% (136/335) for SEROQUEL and 24.5% (40/163) for placebo. In the 26-week open-label clinical trial, one child with a reported history of hypertension experienced a hypertensive crisis. Blood pressure in children and adolescents should be measured at the beginning of, and periodically during treatment.
- In clinical trials and postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to atypical antipsychotic agents, including quetiapine fumarate. Agranulocytosis (including fatal cases) has also been reported.
- Possible risk factors for leukopenia/neutropenia include pre-existing low white cell count (WBC) and history of drug induced leukopenia/neutropenia. Patients with a pre-existing low WBC or a history of drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and should discontinue Quetiapine at the first sign of a decline in WBC in absence of other causative factors.
- Patients with neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1000/mm3) should discontinue Quetiapine and have their WBC followed until recovery.
- The development of cataracts was observed in association with quetiapine treatment in chronic dog studies. Lens changes have also been observed in adults, children, and adolescents during long-term quetiapine treatment but a causal relationship to quetiapine use has not been established. Nevertheless, the possibility of lenticular changes cannot be excluded at this time. Therefore, examination of the lens by methods adequate to detect cataract formation, such as slit lamp exam or other appropriately sensitive methods, is recommended at initiation of treatment or shortly thereafter, and at 6-month intervals during chronic treatment.
- In clinical trials quetiapine was not associated with a persistent increase in QT intervals. However, the QT effect was not systematically evaluated in a thorough QT study. In post marketing experience there were cases reported of QT prolongation in patients who overdosed on quetiapine, in patients with concomitant illness, and in patients taking medicines known to cause electrolyte imbalance or increase QT interval.
- The use of quetiapine should be avoided in combination with other drugs that are known to prolong QTc including Class 1A antiarrythmics (e.g., quinidine, procainamide) or Class III antiarrythmics (e.g., amiodarone, sotalol), antipsychotic medications (e.g., ziprasidone, chlorpromazine, thioridazine), antibiotics (e.g., gatifloxacin, moxifloxacin), or any other class of medications known to prolong the QTc interval (e.g., pentamidine, levomethadyl acetate, methadone).
- Quetiapine should also be avoided in circumstances that may increase the risk of occurrence of torsade de pointes and/or sudden death including (1) a history of cardiac arrhythmias such as bradycardia; (2) hypokalemia or hypomagnesemia; (3) concomitant use of other drugs that prolong the QTc interval; and (4) presence of congenital prolongation of the QT interval.
- Caution should also be exercised when quetiapine is prescribed in patients with increased risk of QT prolongation (e.g., cardiovascular disease, family history of QT prolongation, the elderly, congestive heart failure and heart hypertrophy).
- During short-term clinical trials with Quetiapine, seizures occurred in 0.05% (1/1866) of patients treated with Quetiapine across all indications compared to 0.3% (3/928) on placebo. During clinical trials with SEROQUEL, seizures occurred in 0.5% (20/3490) of patients treated with SEROQUEL compared to 0.2% (2/954) on placebo. As with other antipsychotics, quetiapine fumarate should be used cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold, e.g., Alzheimer’s dementia. Conditions that lower the seizure threshold may be more prevalent in a population of 65 years or older.
- Adults: Clinical trials with quetiapine demonstrated dose-related decreases in thyroid hormone levels. The reduction in total and free thyroxine (T4) of approximately 20% at the higher end of the therapeutic dose range was maximal in the first six weeks of treatment and maintained without adaptation or progression during more chronic therapy. In nearly all cases, cessation of quetiapine treatment was associated with a reversal of the effects on total and free T4, irrespective of the duration of treatment. The mechanism by which quetiapine effects the thyroid axis is unclear. If there is an effect on the hypothalamic-pituitary axis, measurement of TSH alone may not accurately reflect a patient’s thyroid status. Therefore, both TSH and free T4, in addition to clinical assessment, should be measured at baseline and at follow-up.
- In Quetiapine clinical trials across all indications 1.8% (24/1336) of patients on Quetiapine versus 0.6% (3/530) on placebo experienced decreased free thyroxine (<0.8 LLN) and 1.6% (21/1346) on Quetiapine versus 3.4% (18/534) on placebo experienced increased thyroid stimulating hormone (TSH). About 0.7% (26/3489) of SEROQUEL patients did experience TSH increases in monotherapy studies. Some patients with TSH increases needed replacement thyroid treatment.
- In all quetiapine trials, the incidence of shifts in thyroid hormones and TSH were1: decrease in free T4 (<0.8 LLN), 2.0% (357/17513); decrease in total T4, 4.0% (75/1861); decrease in free T3, 0.4% (53/13766); decrease in total T3, 2.0% (26/1312), and increase in TSH, 4.9% (956/19412). In eight patients, where TBG was measured, levels of TBG were unchanged.
- Table 11 shows the incidence of these shifts in short term placebo-controlled clinical trials.
- In short-term placebo-controlled monotherapy trials, the incidence of reciprocal shifts in T3 and TSH was 0.0 % for both quetiapine (1/4800) and placebo (0/2190) and for T4 and TSH the shifts were 0.1% (7/6154) for quetiapine versus 0.0 % (1/3007) for placebo.
- Children and Adolescents: Safety and effectiveness of Quetiapine is supported by studies of SEROQUEL in children and adolescent patients 10 to 17 years of age.
- In acute placebo-controlled trials in children and adolescent patients with schizophrenia (6-week duration) or bipolar mania (3-week duration), the incidence of shifts at any time for SEROQUEL treated patients and placebo-treated patients for elevated TSH was 2.9% (8/280) vs. 0.7% (1/138), respectively and for decreased total thyroxine was 2.8% (8/289) vs. 0% (0/145), respectively. Of the SEROQUEL treated patients with elevated TSH levels, 1 had simultaneous low free T4 level at end of treatment.
- Based on shifts from normal baseline to potentially clinically important value at anytime post-baseline. Shifts in total T4, free T4, total T3 and free T3 are defined as 5 mIU/L at any time.
- Based on shifts from normal baseline to potentially clinically important value at anytime post-baseline. Shifts in total T4, free T4, total T3 and free T3 are defined as 5 mIU/L at any time.
- Includes SEROQUEL and Quetiapine data.
- Adults: During clinical trials with quetiapine across all indications, the incidence of shifts in prolactin levels to a clinically significant value occurred in 3.6% (158/4416) of patients treated with quetiapine compared to 2.6% (51/1968) on placebo.
- Children and Adolescents: Safety and effectiveness of Quetiapine is supported by studies of SEROQUEL in children and adolescent patients 10 to 17 years of age. In acute placebo-controlled trials in children and adolescent patients with bipolar mania (3-week duration) or schizophrenia (6-week duration), the incidence of shifts in prolactin levels to a value (>20 µg/L males; > 26 µg/L females at any time) was 13.4% (18/134) for SEROQUEL compared to 4% (3/75) for placebo in males and 8.7% (9/104) for SEROQUEL compared to 0% (0/39) for placebo in females.
- Like other drugs that antagonize dopamine D2 receptors, Quetiapine elevates prolactin levels in some patients and the elevation may persist during chronic administration. Hyperprolactinemia, regardless of etiology, may suppress hypothalamic GnRH, resulting in reduced ] secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male subjects.
- Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is considered in a patient with previously detected breast cancer. As is common with compounds which increase prolactin release, mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary and pancreatic adenomas) was observed in carcinogenicity studies conducted in mice and rats. Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans, but the available evidence is too limited to be conclusive.
- Somnolence was a commonly reported adverse reaction reported in patients treated with quetiapine especially during the 3-day period of initial dose titration. In schizophrenia trials, somnolence was reported in 24.7% (235/951) of patients on Quetiapine compared to 10.3% (33/319) of placebo patients. In a bipolar depression clinical trial, somnolence was reported in 51.8% (71/137) of patients on Quetiapine compared to 12.9% (18/140) of placebo patients. In a clinical trial for bipolar mania, somnolence was reported in 50.3% (76/151) of patients on Quetiapine compared to 11.9% (19/160) of placebo patients. Since quetiapine has the potential to impair judgment, thinking, or motor skills, patients should be cautioned about performing activities requiring mental alertness, such as operating a motor vehicle (including automobiles) or operating hazardous machinery until they are reasonably certain that quetiapine therapy does not affect them adversely. Somnolence may lead to falls.
- In short-term adjunctive therapy trials for MDD, somnolence was reported in 40% (252/627) of patients on Quetiapine respectively compared to 9% (27/309) of placebo patients. Somnolence was dose-related in these trials (37% (117/315) and 43% (135/312) for the 150 mg and 300 mg groups, respectively).
- Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing Quetiapine for patients who will be experiencing conditions which may contribute to an elevation in core body temperature, eg, exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration.
- Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in elderly patients, in particular those with advanced Alzheimer's dementia. Quetiapine and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.
- Acute withdrawal symptoms, such as insomnia, nausea and vomiting have been described after abrupt cessation of atypical antipsychotic drugs, including quetiapine fumarate. In short-term placebo-controlled, monotherapy clinical trials with Quetiapine that included a discontinuation phase which evaluated discontinuation symptoms, the aggregated incidence of patients experiencing one or more discontinuation symptoms after abrupt cessation was 12.1% (241/1993) for Quetiapine and 6.7% (71/1065) for placebo. The incidence of the individual adverse reactions (i.e., insomnia, nausea, headache, diarrhea, vomiting, dizziness and irritability) did not exceed 5.3% in any treatment group and usually resolved after 1 week post-discontinuation. Gradual dose reduction is advised.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- Adults
- The information below is derived from a clinical trial database for Quetiapine consisting of approximately 3400 patients exposed to Quetiapine for the treatment of Schizophrenia, Bipolar Disorder, and Major Depressive Disorder in placebo-controlled trials. This experience corresponds to approximately 1020.1 patient-years. Adverse reactions were assessed by collecting adverse reactions, results of physical examinations, vital signs, body weights, laboratory analyses and ECG results.
- The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at least once, an adverse reaction of the type listed.
- Adverse Reactions Associated with Discontinuation of Treatment in Short-Term, Placebo-Controlled Trials
- Schizophrenia: There were no adverse reactions leading to discontinuation that occurred at an incidence of ≥ 2% for Quetiapine in schizophrenia trials.
- Bipolar I Disorder, Manic or Mixed Episodes:
- There were no adverse reactions leading to discontinuation that occurred at an incidence of ≥ 2% for Quetiapine in the bipolar mania trial.
- Bipolar Disorder, Depressive Episode: In a single clinical trial in patients with bipolar depression, 14% (19/137) of patients on Quetiapine discontinued due to an adverse reaction compared to 4% (5/140) on placebo. Somnolence4 was the only adverse reaction leading to discontinuation that occurred at an incidence of ≥ 2% in Quetiapine in the bipolar depression trial.
- MDD, Adjunctive Therapy: In adjunctive therapy clinical trials in patients with MDD, 12.1% (76/627) of patients on Quetiapine discontinued due to adverse reaction compared to 1.9% (6/309) on placebo. Somnolence4 was the only adverse reaction leading to discontinuation that occurred at an incidence of ≥ 2% in Quetiapine in MDD trials.
- Commonly Observed Adverse Reactions in Short-Term, Placebo-Controlled Trials:
- In short-term placebo-controlled studies for schizophrenia the most commonly observed adverse reactions associated with the use of Quetiapine (incidence of 5% or greater) and observed at a rate on Quetiapine at least twice that of placebo were somnolence (25%), dry mouth (12%), dizziness (10%), and dyspepsia (5%).
- Adverse Reactions Occurring at an Incidence of 2% or More Among Quetiapine Treated Patients in Short-Term, Placebo-Controlled Trials
- Table 12 enumerates the incidence, rounded to the nearest percent, of adverse reactions that occurred during acute therapy of schizophrenia (up to 6 weeks) in 2% or more in patients treated with Quetiapine (doses ranging from 300 to 800 mg/day) where the incidence in patients treated with Quetiapine was greater than the incidence in placebo-treated patients.
- In a 3-week, placebo-controlled study in bipolar mania the most commonly observed adverse reactions associated with the use of Quetiapine (incidence of 5% or greater) and observed at a rate on Quetiapine at least twice that of placebo were somnolence (50%), dry mouth (34%), dizziness (10%), constipation (10%), weight gain (7%), dysarthria (5%), and nasal congestion (5%).
- Table 13 enumerates the incidence, rounded to the nearest percent, of adverse reactions that occurred during acute therapy of bipolar mania (up to 3 weeks) in 2% or more of patients treated with Quetiapine (doses ranging from 400 to 800 mg/day) where the incidence in patients treated with Quetiapine was greater than the incidence in placebo-treated patients.
- In the 8-week placebo-controlled bipolar depression study in adults, the most commonly observed adverse reactions associated with the use of Quetiapine (incidence of 5% or greater) and observed at a rate on Quetiapine at least twice that of placebo were somnolence (52%), dry mouth (37%), increased appetite (12%), weight gain (7%), dyspepsia (7%), and fatigue (6%).
- Table 14 enumerates the incidence, rounded to the nearest percent, of adverse reactions that occurred during acute therapy of bipolar depression (up to 8 weeks) in 2% or more of adult patients treated with Quetiapine 300 mg/day where the incidence in patients treated with Quetiapine was greater than the incidence in placebo-treated patients.
- In the 6-week placebo-controlled fixed dose adjunctive therapy clinical trials, for MDD, the most commonly observed adverse reactions associated with the use of Quetiapine (incidence of 5% or greater and observed at a rate on Quetiapine and at least twice that of placebo) were somnolence (150 mg: 37%; 300 mg: 43%), dry mouth (150 mg: 27%; 300 mg: 40%), fatigue (150 mg: 14%; 300 mg: 11%), constipation 300 mg only: 11%) and weight increased (300 mg only: 5%).
- Table 15 enumerates the incidence, rounded to the nearest percent, of adverse reactions that occurred during short-term adjunctive therapy of MDD (up to 6 weeks) in 2% or more of patients treated with Quetiapine (at doses of either 150 mg or 300 mg/day) where the incidence in patients treated with Quetiapine was greater than the incidence in placebo-treated patients.
- Adverse Reactions in clinical trials with quetiapine and not listed elsewhere in the label:
- Pyrexia, nightmares, peripheral edema, dyspnea, palpitations, rhinitis, eosinophilia, hypersensitivity, elevations in gamma-GT levels, and elevations in serum creatine phosphokinase (not associated with NMS), somnambulism (and other related events), hypothermia, decreased platelets, galactorrhea, bradycardia (which may occur at or near initiation of treatment and be associated with hypotension and/ or syncope), and priapism.
- Extrapyramidal Symptoms (EPS):
- Dystonia
Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.
- Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.
- Four methods were used to measure EPS: (1) Simpson-Angus total score (mean change from baseline) which evaluates Parkinsonism and akathisia, (2) Barnes Akathisia Rating Scale (BARS) Global Assessment Score, (3) incidence of spontaneous complaints of EPS (akathisia, akinesia, cogwheel rigidity, extrapyramidal syndrome, hypertonia, hypokinesia, neck rigidity, and tremor), and (4) use of anticholinergic medications to treat emergent EPS.
- Adults: In placebo-controlled clinical trials with quetiapine, utilizing doses up to 800 mg per day, the incidence of any adverse reactions related to EPS ranged from 8% to 11% for quetiapine and 4% to 11% for placebo.
- In three-arm placebo-controlled clinical trials for the treatment of schizophrenia, utilizing doses between 300 mg and 800 mg of Quetiapine, the incidence of any adverse reactions related to EPS was 8% for Quetiapine and 8% for SEROQUEL (without evidence of being dose related), and 5% in the placebo group. In these studies, the incidence of the individual adverse reactions (akathisia, extrapyramidal disorder, tremor, dyskinesia, dystonia, restlessness, and muscle rigidity) was generally low and did not exceed 3% for any treatment group.
- At the end of treatment, the mean change from baseline in SAS total score and BARS Global Assessment score was similar across the treatment groups. The use of concomitant anticholinergic medications was infrequent and similar across the treatment groups. The incidence of extrapyramidal symptoms was consistent with that seen with the profile of SEROQUEL in schizophrenia patients.
- In Tables 16-19, dystonic event included nuchal rigidity, hypertonia, dystonia, muscle rigidity, oculogyration; parkinsonism included cogwheel rigidity, tremor, drooling, hypokinesia; akathisia included akathisia, psychomotor agitation; dyskinetic event included tardive dyskinesia, dyskinesia, choreoathetosis; and other extrapyramidal event included restlessness, extrapyramidal disorder, movement disorder.
- In a placebo-controlled clinical trial for the treatment of bipolar mania, utilizing the dose range of 400-800 mg/day of Quetiapine, the incidence of any adverse reactions related to EPS was 6.6% for Quetiapine and 3.8% in the placebo group. In this study, the incidence of the individual adverse reactions (akathisia, extrapyramidal disorder, tremor, dystonia, restlessness, and cogwheel rigidity) did not exceed 2.0% for any adverse reaction.
- In a placebo-controlled clinical trial for the treatment of bipolar depression utilizing 300 mg of Quetiapine, the incidence of any adverse reactions related to EPS was 4.4% for Quetiapine and 0.7% in the placebo group. In this study, the incidence of the individual adverse reactions (akathisia, extrapyramidal disorder, tremor, dystonia, hypertonia) did not exceed 1.5% for any individual adverse reaction.
- In two placebo-controlled short-term adjunctive therapy clinical trials for the treatment of MDD utilizing between 150 mg and 300 mg of Quetiapine, the incidence of any adverse reactions related to EPS was 5.1% for Quetiapine and 4.2% for the placebo group.
- Table 19 shows the percentage of patients experiencing adverse reactions associated with EPS in adjunct clinical trials for MDD by dose:
- Children and Adolescents
- The information below is derived from a clinical trial database for SEROQUEL consisting of over 1000 pediatric patients. This database includes 677 adolescents (13 – 17 years old) exposed to SEROQUEL for the treatment of schizophrenia and 393 children and adolescents (10 – 17 years old) exposed to SEROQUEL for the treatment of acute bipolar mania.
- Adverse Reactions Associated with Discontinuation of Treatment in Short-Term, Placebo-Controlled Trials
- Schizophrenia: The incidence of discontinuation due to adverse reactions for quetiapine-treated and placebo-treated patients was 8.2% and 2.7%, respectively. The adverse reaction leading to discontinuation in 2% or more of patients on quetiapine and at a greater incidence than placebo was somnolence (2.7% and 0% for placebo).
- Bipolar I Mania: The incidence of discontinuation due to adverse reactions for quetiapine-treated and placebo-treated patients was 11.4% and 4.4%, respectively. The adverse reactions leading to discontinuation in 2% or more of patients on SEROQUEL and at a greater incidence than placebo were somnolence (4.1% vs. 1.1%) and fatigue (2.1% vs. 0).
- In an acute (8-week) Quetiapine trial in children and adolescents (10-17 years of age) with bipolar depression, in which efficacy was not established, the most commonly observed adverse reactions associated with the use of Quetiapine (incidence of 5% or greater and at least twice that for placebo) were: dizziness (7%), diarrhea (5%), fatigue (5%) and nausea (5%).
- In therapy for schizophrenia (up to 6 weeks), the most commonly observed adverse reactions associated with the use of quetiapine in adolescents (incidence of 5% or greater and quetiapine incidence at least twice that for placebo) were somnolence (34%), dizziness (12%), dry mouth (7%), tachycardia (7%).
- In bipolar mania therapy (up to 3 weeks) the most commonly observed adverse reactions associated with the use of quetiapine in children and adolescents (incidence of 5% or greater and quetiapine incidence at least twice that for placebo) were somnolence (53%), dizziness (18%), fatigue (11%), increased appetite (9%), nausea (8%), vomiting (8%), tachycardia (7%), dry mouth (7%), and weight increased (6%).
- Adverse Reactions Occurring at an Incidence of ≥ 2% Among Seroquel Treated Patients in Short-Term, Placebo-Controlled Trials
- Schizophrenia (Adolescents, 13 – 17 years old)
- The following findings were based on a 6-week placebo-controlled trial in which quetiapine was administered in either doses of 400 or 800 mg/day.
- Table 20 enumerates the incidence, rounded to the nearest percent, of adverse reactions that occurred during therapy (up to 6 weeks) of schizophrenia in 2% or more of patients treated with SEROQUEL (doses of 400 or 800 mg/day) where the incidence in patients treated with SEROQUEL was greater than the incidence in placebo-treated patients.
- Adverse reactions that were potentially dose-related with higher frequency in the 800 mg group compared to the 400 mg group included dizziness (8% vs. 15%), dry mouth (4% vs. 10%), and tachycardia (6% vs. 11%).
- Bipolar I Mania (Children and Adolescents 10 to 17 years old)
- The following findings were based on a 3-week placebo-controlled trial in which quetiapine was administered in either doses of 400 or 600 mg/day.
- Table 21 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse reactions that occurred during therapy (up to 3 weeks) of bipolar mania in 2% or more of patients treated with SEROQUEL (doses of 400 or 600 mg/day) where the incidence in patients treated with SEROQUEL was greater than the incidence in placebo-treated patients.
- Adverse reactions that were potentially dose-related with higher frequency in the 600 mg group compared to the 400 mg group included somnolence (50% vs. 57%), nausea (6% vs. 10%) and tachycardia (6% vs. 9%).
- Extrapyramidal Symptoms:
- Safety and effectiveness of Quetiapine is supported by studies of SEROQUEL in children and adolescent patients 10 to 17 years of age.
- In a short-term placebo-controlled Quetiapine monotherapy trial in children and adolescent patients (10-17 years of age) with bipolar depression (8-week duration), in which efficacy was not established, the aggregated incidence of extrapyramidal symptoms was 1.1% (1/92) for Quetiapine and 0% (0/100) for placebo.
- In a short-term placebo-controlled SEROQUEL monotherapy trial in adolescent patients (13-17 years of age) with schizophrenia (6-week duration), the aggregated incidence of extrapyramidal symptoms was 12.9% (19/147) for SEROQUEL and 5.3% (4/75) for placebo, though the incidence of the individual adverse reactions (e.g., akathisia, tremor, extrapyramidal disorder, hypokinesia, restlessness, psychomotor hyperactivity, muscle rigidity, dyskinesia) did not exceed 4.1% in any treatment group. In a short-term placebo-controlled SEROQUEL monotherapy trial in children and adolescent patients (10-17 years of age) with bipolar mania (3-week duration), the aggregated incidence of extrapyramidal symptoms was 3.6% (7/193) for SEROQUEL and 1.1% (1/90) for placebo.
- In Tables 22 and 23, dystonic events included nuchal rigidity, hypertonia, dystonia, and muscle rigidity; parkinsonism included cogwheel rigidity and tremor; akathisia included akathisia only; dyskinetic event included tardive dyskinesia, dyskinesia and choreoathetosis; and other extrapyramidal event included restlessness and extrapyramidal disorder.
- Table 22 below presents a listing of patients with adverse reactions associated with EPS in the short-term placebo-controlled SEROQUEL monotherapy trial in adolescent patients with schizophrenia (6-week duration).
- Table 23 below presents a listing of patients with adverse reactions associated with EPS in a short-term placebo-controlled monotherapy trial in children and adolescent patients with bipolar mania (3-week duration).
- Laboratory Changes:
- Neutrophil Counts
- Adults: In three-arm Quetiapine placebo-controlled monotherapy clinical trials, among patients with a baseline neutrophil count ≥ 1.5 x 109/L, the incidence of at least one occurrence of neutrophil count <1.5 x 109/L was 1.5% in patients treated with Quetiapine and 1.5% for SEROQUEL, compared to 0.8% in placebo-treated patients.
- In placebo-controlled monotherapy clinical trials involving 3368 patients on quetiapine fumarate and 1515 on placebo, the incidence of at least one occurrence of neutrophil count <1.0 x 109/L among patients with a normal baseline neutrophil count and at least one available follow up laboratory measurement was 0.3% (10/2967) in patients treated with quetiapine, compared to 0.1% (2/1349) in patients treated with placebo.
- Transaminase Elevations
- Adults: Asymptomatic, transient and reversible elevations in serum transaminases (primarily ALT) have been reported. The proportions of adult patients with transaminase elevations of >3 times the upper limits of the normal reference range in a pool of placebo-controlled trials ranged between 1% and 2% for Quetiapine compared to 2% for placebo. In schizophrenia trials in adults, the proportions of patients with transaminase elevations of >3 times the upper limits of the normal reference range in a pool of 3- to 6-week placebo-controlled trials were approximately 6% (29/483) for SEROQUEL compared to 1% (3/194) for placebo. These hepatic enzyme elevations usually occurred within the first 3 weeks of drug treatment and promptly returned to pre-study levels with ongoing treatment with quetiapine.
- Decreased Hemoglobin
- Adults: In short-term placebo-controlled trials, decreases in hemoglobin to ≤ 13 g/dL males, ≤ 12 g/dL females on at least one occasion occurred in 8.3% (594/7155) of quetiapine-treated patients compared to 6.2% (219/3536) of patients treated with placebo. In a database of controlled and uncontrolled clinical trials, decreases in hemoglobin to ≤ 13 g/dL males, ≤ 12 g/dL females on at least one occasion occurred in 11% (2277/20729) of quetiapine-treated patients.
- Interference with Urine Drug Screens
- There have been literature reports suggesting false positive results in urine enzyme immunoassays for methadone and tricyclic antidepressants in patients who have taken quetiapine. Caution should be exercised in the interpretation of positive urine drug screen results for these drugs, and confirmation by alternative analytical technique (e.g., chromatographic methods) should be considered.
- ECG Changes:
- Adults: 2.5% of Quetiapine patients, and 2.3% of placebo patients, had tachycardia (>120 bpm) at any time during the trials. Quetiapine was associated with a mean increase in heart rate, assessed by ECG, of 6.3 beats per minute compared to a mean increase of 0.4 beats per minute for placebo. This is consistent with the rates for SEROQUEL. The incidence of adverse reactions of tachycardia was 1.9% for Quetiapine compared to 0.5% for placebo. SEROQUEL use was associated with a mean increase in heart rate, assessed by ECG, of 7 beats per minute compared to a mean increase of 1 beat per minute among placebo patients. The slight tendency for tachycardia may be related to quetiapine’s potential for inducing orthostatic changes.
- Children and Adolescents: Safety and effectiveness of Quetiapine is supported by studies of SEROQUEL in children and adolescent patients 10 to 17 years of age.
- In an acute (8-week) Quetiapine trial in children and adolescents (10-17 years of age) with bipolar depression, in which efficacy was not established, increases in heart rate (> 110 bpm 10-12 years and 13-17 years) occurred in 0% of patients receiving Quetiapine and 1.2% of patients receiving placebo. Mean increases in heart rate were 3.4 bpm for Quetiapine, compared to 0.3 bpm in the placebo group.
- In the acute (6-week) SEROQUEL schizophrenia trial in adolescents (13-17 years of age), increases in heart rate (> 110 bpm) occurred in 5.2% of patients receiving SEROQUEL 400 mg and 8.5% of patients receiving SEROQUEL 800 mg compared to 0% of patients receiving placebo. Mean increases in heart rate were 3.8 bpm and 11.2 bpm for SEROQUEL 400 mg and 800 mg groups, respectively, compared to a decrease of 3.3 bpm in the placebo group.
- In the acute (3-week) SEROQUEL bipolar mania trial in children and adolescents (10-17 years of age), increases in heart rate (> 110 bpm) occurred in 1.1% of patients receiving SEROQUEL 400 mg and 4.7% of patients receiving SEROQUEL 600 mg compared to 0% of patients receiving placebo. Mean increases in heart rate were 12.8 bpm and 13.4 bpm for SEROQUEL 400 mg and 600 mg groups, respectively, compared to a decrease of 1.7 bpm in the placebo group.
## Postmarketing Experience
- The following adverse reactions were identified during post approval use of SEROQUEL. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- Adverse reactions reported since market introduction which were temporally related to quetiapine therapy include anaphylactic reaction, cardiomyopathy, hyponatremia, myocarditis, nocturnal enuresis, pancreatitis, retrograde amnesia, rhabdomyolysis, syndrome of inappropriate antidiuretic hormone secretion (SIADH), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN).
# Drug Interactions
- The risks of using Quetiapine in combination with other drugs have not been extensively evaluated in systematic studies. Given the primary CNS effects of Quetiapine, caution should be used when it is taken in combination with other centrally acting drugs. Quetiapine potentiated the cognitive and motor effects of alcohol in a clinical trial in subjects with selected psychotic disorders, and alcoholic beverages should be limited while taking quetiapine.
- Quetiapine exposure is increased by the prototype CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, indinavir, ritonavir, nefazodone, etc.) and decreased by the prototype of CYP3A4 inducers (e.g, phenytoin, carbamazepine, rifampin, avasimibe, St. John’s wort etc.) Dose adjustment of quetiapine will be necessary if it is co-administered with potent CYP3A4 inducers or inhibitors.
- CYP3A4 inhibitors:
- Coadministration of ketoconazole, a potent inhibitor of cytochrome CYP3A4, resulted in significant increase in quetiapine exposure. The dose should be reduced to one sixth of the original dose in patients coadministered with a strong CYP3A4 inhibitor.
- CYP3A4 inducers:
- Coadministration of quetiapine and phenytoin, a CYP3A4 inducer increased the mean oral clearance of quetiapine by 5-fold. Increased doses of Quetiapine up to 5 fold may be required to maintain control of symptoms of schizophrenia in patients receiving quetiapine and phenytoin, or other known potent CYP3A4 inducers. When the CYP3A4 inducer is discontinued, the dose of Quetiapine should be reduced to the original level within 7-14 days.
- The potential effects of several concomitant medications on quetiapine pharmacokinetics were studied.
- Because of its potential for inducing hypotension, Quetiapine may enhance the effects of certain antihypertensive agents.
- Quetiapine may antagonize the effects of levodopa and dopamine agonists.
- There are no clinically relevant pharmacokinetic interactions of Seroquel on other drugs based on the CYP pathway. Seroquel and its metabolites are non-inhibitors of major metabolizing CYPs (1A2, 2C9, 2C19, 2D6 and 3A4).
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- There are no adequate and well-controlled studies of Quetiapine use in pregnant women. In limited published literature, there were no major malformations associated with quetiapine exposure during pregnancy. In animal studies, embryo-fetal toxicity occurred. Quetiapine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Human Data
- There are limited published data on the use of quetiapine for treatment of schizophrenia and other psychiatric disorders during pregnancy. In a prospective observational study, 21 women exposed to quetiapine and other psychoactive medications during pregnancy delivered infants with no major malformations. Among 42 other infants born to pregnant women who used quetiapine during pregnancy, there were no major malformations reported (one study of 36 women, 6 case reports). Due to the limited number of exposed pregnancies, these postmarketing data do not reliably estimate the frequency or absence of adverse outcomes. Neonates exposed to antipsychotic drugs (including Quetiapine), during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization.
- Animal Data
- When pregnant rats and rabbits were exposed to quetiapine during organogenesis, there was no teratogenic effect in fetuses at doses up to 2.4 times the maximum recommended human dose (MRHD), for schizophrenia of 800 mg/day based on mg/m2 body surface area. However, there was evidence of embryo-fetal toxicity. These included delays in skeletal ossification occurred at approximately 1 and 2 times the MRHD of 800 mg/day and in both rats and rabbits and an increased incidence of carpal/tarsal flexure (minor soft tissue anomaly) in rabbit fetuses at approximately 2 times the MRHD. In addition, fetal weights were decreased in both species. Maternal toxicity observed as decreased body weights and/or death occurred at 2 times the MRHD in rats and at approximately 1-2 times the MRHD (all doses) in rabbits.
- In a peri/postnatal reproductive study in rats, no drug-related effects were observed when pregnant dams were treated with quetiapine at doses 0.01, 0.1, and 0.2 times the MRHD of 800 mg/day on mg/m2 body surface area. However, in a preliminary peri/postnatal study, there were increases in fetal and pup death, and decreases in mean litter weight at 3 times the MRHD.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Quetiapine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Quetiapine during labor and delivery.
### Nursing Mothers
- Quetiapine was excreted into human milk. Because of the potential for serious adverse reactions in nursing infants from Quetiapine, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother’s health.
- In published case reports, the level of quetiapine in breast milk ranged from undetectable to 170 μg/L. The estimated infant dose ranged from 0.09% to 0.43% of the weight-adjusted maternal dose. Based on a limited number (N=8) of mother/infant pairs, calculated infant daily doses range from less than 0.01 mg/kg (at a maternal daily dose up to 100 mg quetiapine) to 0.1 mg/kg (at a maternal daily dose of 400 mg).
### Pediatric Use
- Safety and effectiveness of Quetiapine is supported by studies of SEROQUEL for schizophrenia in adolescent patients 13 to 17 years of age and in bipolar mania in children and adolescent patients 10 to 17 years of age.
- In general, the adverse reactions observed in children and adolescents during the clinical trials with SEROQUEL were similar to those in the adult population with few exceptions. Increases in systolic and diastolic blood pressure occurred in children and adolescents and did not occur in adults. Orthostatic hypotension occurred more frequently in adults (4-7%) compared to children and adolescents (< 1%)
- Bipolar Depression
- The effectiveness of Quetiapine for the treatment of bipolar depression in patients under the age of 18 years has not been established. One 8-week trial was conducted to evaluate the safety and efficacy of Quetiapine in the treatment of bipolar depression in pediatric patients 10 to 17 years of age. The primary objective of the study was to evaluate whether Quetiapine at a dose of 150 to 300 mg/day demonstrated superior efficacy (as measured by change in CDRS-R total score from baseline to end of 8 weeks) compared to placebo in children and adolescents 10 to 17 years of age with bipolar depression. A total of 193 patients with bipolar depression were randomized to placebo or Quetiapine. The primary results of this study did not show a difference between Quetiapine and placebo in decreasing depression symptoms in children and adolescents with bipolar disorder. In this study, patients treated with Quetiapine exhibited metabolic changes, weight gain, increases in blood pressure and increases in heart rate.
- Some differences in the pharmacokinetics of quetiapine were noted between children/adolescents (10 to 17 years of age) and adults. When adjusted for weight, the AUC and Cmax of quetiapine were 41% and 39% lower, respectively, in children and adolescents compared to adults. The pharmacokinetics of the active metabolite, norquetiapine, were similar between children/adolescents and adults after adjusting for weight.
- Schizophrenia
- The efficacy and safety of Quetiapine in the treatment of schizophrenia in adolescents aged 13 to 17 years is supported by one 6-week, double-blind, placebo-controlled trial with SEROQUEL.
- Safety and effectiveness of Quetiapine in pediatric patients less than 13 years of age with schizophrenia have not been established.
- The safety and effectiveness of Quetiapine in the maintenance treatment of schizophrenia has not been established in patients less than 18 years of age.
- Bipolar Mania
- The efficacy and safety of Quetiapine in the treatment of bipolar mania in children and adolescents ages 10 to 17 years is supported by one 3-week, double-blind, placebo-controlled trial with SEROQUEL.
- Safety and effectiveness of Quetiapine in pediatric patients less than 10 years of age with bipolar mania have not been established.
- The safety and effectiveness of Quetiapine in the maintenance treatment of bipolar disorder has not been established in patients less than 18 years of age.
### Geriatic Use
- Sixty-eight patients in clinical studies with Quetiapine were 65 years of age or over. In general, there was no indication of any different tolerability of Quetiapine in the elderly compared to younger adults. Nevertheless, the presence of factors that might decrease pharmacokinetic clearance, increase the pharmacodynamic response to Quetiapine, or cause poorer tolerance or orthostasis, should lead to consideration of a lower starting dose, slower titration, and careful monitoring during the initial dosing period in the elderly. The mean plasma clearance of quetiapine was reduced by 30% to 50% in elderly patients when compared to younger patients.
### Gender
There is no FDA guidance on the use of Quetiapine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Quetiapine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Quetiapine in patients with renal impairment.
### Hepatic Impairment
- Since quetiapine is extensively metabolized by the liver, higher plasma levels are expected in patients with hepatic impairment. In this population, a low starting dose of 50 mg/day is recommended and the dose may be increased in increments of 50 mg/day.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Quetiapine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Quetiapine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- Patients receiving quetiapine should receive regular monitoring of weight.
# IV Compatibility
There is limited information regarding IV Compatibility of Quetiapine in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- In clinical trials, survival has been reported in acute overdoses of up to 30 grams of quetiapine. Most patients who overdosed experienced no adverse reactions or recovered fully from the reported events. Death has been reported in a clinical trial following an overdose of 13.6 grams of quetiapine alone. In general, reported signs and symptoms were those resulting from an exaggeration of the drug’s known pharmacological effects, ie, drowsiness and sedation, tachycardia and hypotension. Patients with pre-existing severe cardiovascular disease may be at an increased risk of the effects of overdose. One case, involving an estimated overdose of 9600 mg, was associated with hypokalemia and first degree heart block. In post-marketing experience, there were cases reported of QT prolongation with overdose. There were also very rare reports of overdose of SEROQUEL alone resulting in death or coma.
### Management
- In case of acute overdosage, establish and maintain an airway and ensure adequate oxygenation and ventilation. Gastric lavage (after intubation, if patient is unconscious) and administration of activated charcoal together with a laxative should be considered. The possibility of obtundation, seizure or dystonic reaction of the head and neck following overdose may create a risk of aspiration with induced emesis. Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias. If antiarrhythmic therapy is administered, disopyramide, procainamide and quinidine carry a theoretical hazard of additive QT-prolonging effects when administered in patients with acute overdosage of Quetiapine. Similarly it is reasonable to expect that the α-adrenergic-blocking properties of bretylium might be additive to those of quetiapine, resulting in problematic hypotension.
- There is no specific antidote to Quetiapine. Therefore, appropriate supportive measures should be instituted. The possibility of multiple drug involvement should be considered. Hypotension and circulatory collapse should be treated with appropriate measures such as intravenous fluids and/or sympathomimetic agents (epinephrine and dopamine should not be used, since β stimulation may worsen hypotension in the setting of quetiapine-induced α blockade). In cases of severe extrapyramidal symptoms, anticholinergic medication should be administered. Close medical supervision and monitoring should continue until the patient recovers.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Quetiapine in the drug label.
# Pharmacology
## Mechanism of Action
- The mechanism of action of Quetiapine in the treatment of schizophrenia, bipolar disorder and major depressive disorder (MDD), is unknown. However, its efficacy in schizophrenia could be mediated through a combination of dopamine type 2 (D2) and serotonin type 2A (5HT2A) antagonism. The active metabolite, N-desalkyl quetiapine (norquetiapine), has similar activity at D2, but greater activity at 5HT2A receptors, than the parent drug (quetiapine). Quetiapine’s efficacy in bipolar depression and MDD may partly be explained by the high affinity and potent inhibitory effects that norquetiapine exhibits for the norepinephrine transporter.
- Antagonism at receptors other than dopamine and serotonin with similar or greater affinities may explain some of the other effects of quetiapine and norquetiapine: antagonism at histamine H1 receptors may explain the somnolence, antagonism at adrenergic α1b receptors may explain the orthostatic hypotension, and antagonism at muscarinic M1 receptors may explain the anticholinergic effects.
## Structure
- Quetiapine (quetiapine fumarate) is an atypical antipsychotic belonging to a chemical class, the dibenzothiazepine derivatives. The chemical designation is 2- thiazepin-11-yl-1-piperazinyl)ethoxy]-ethanol fumarate (2:1) (salt). It is present in tablets as the fumarate salt. All doses and tablet strengths are expressed as milligrams of base, not as fumarate salt. Its molecular formula is C42H50N6O4S2C4H4O4 and it has a molecular weight of 883.11 (fumarate salt). The structural formula is:
- Quetiapine fumarate is a white to off-white crystalline powder which is moderately soluble in water.
- Quetiapine is supplied for oral administration as 50 mg (peach), 150 mg (white), 200 mg (yellow), 300 mg (pale yellow), and 400 mg (white). All tablets are capsule shaped and film coated.
- Inactive ingredients for Quetiapine are lactose monohydrate, microcrystalline cellulose, sodium citrate, hypromellose, and magnesium stearate. The film coating for all Quetiapine tablets contain hypromellose, polyethylene glycol 400 and titanium dioxide. In addition, yellow iron oxide (50, 200 and 300 mg tablets) and red iron oxide (50 mg tablets) are included in the film coating of specific strengths.
- Each 50 mg tablet contains 58 mg of quetiapine fumarate equivalent to 50 mg quetiapine. Each 150 mg tablet contains 173 mg of quetiapine fumarate equivalent to 150 mg quetiapine. Each 200 mg tablet contains 230 mg of quetiapine fumarate equivalent to 200 mg quetiapine. Each 300 mg tablet contains 345 mg of quetiapine fumarate equivalent to 300 mg quetiapine. Each 400 mg tablet contains 461 mg of quetiapine fumarate equivalent to 400 mg quetiapine.
## Pharmacodynamics
- Quetiapine and norquetiapine have affinity for multiple neurotransmitter receptors including dopamine D1 and D2, serotonin 5HT1A and 5HT2A, histamine H1, muscarinic M1, and adrenergic α1b and α2 receptors. Quetiapine differs from norquetiapine in having no appreciable affinity for muscarinic M1 receptors whereas norquetiapine has high affinity. Quetiapine and norquetiapine lack appreciable affinity for benzodiazepine receptors.
- Effect on QT Interval
- In clinical trials quetiapine was not associated with a persistent increase in QT intervals. However, the QT effect was not systematically evaluated in a thorough QT study. In post marketing experience there were cases reported of QT prolongation in patients who overdosed on quetiapine, in patients with concomitant illness, and in patients taking medicines known to cause electrolyte imbalance or increase QT interval.
## Pharmacokinetics
- Adults
- Following multiple dosing of quetiapine up to a total daily dose of 800 mg, administered in divided doses, the plasma concentration of quetiapine and norquetiapine, the major active metabolite of quetiapine, were proportional to the total daily dose. Accumulation is predictable upon multiple dosing. Steady-state mean Cmax and AUC of norquetiapine are about 21-27% and 46-56%, respectively of that observed for quetiapine. Elimination of quetiapine is mainly via hepatic metabolism. The mean-terminal half-life is approximately 7 hours for quetiapine and approximately 12 hours for norquetiapine within the clinical dose range. Steady-state concentrations are expected to be achieved within two days of dosing. Quetiapine is unlikely to interfere with the metabolism of drugs metabolized by cytochrome P450 enzymes.
- Children and Adolescents
- At steady-state the pharmacokinetics of the parent compound, in children and adolescents (10-17 years of age), were similar to adults. However, when adjusted for dose and weight, AUC and Cmax of the parent compound were 41% and 39% lower, respectively, in children and adolescents than in adults. For the active metabolite, norquetiapine, AUC and Cmax were 45% and 31% higher, respectively, in children and adolescents than in adults. When adjusted for dose and weight, the pharmacokinetics of the metabolite, norquetiapine, was similar between children and adolescents and adults.
- Absorption
- Quetiapine fumarate reaches peak plasma concentrations approximately 6 hours following administration. Quetiapine dosed once daily at steady-state has comparable bioavailability to an equivalent total daily dose of SEROQUEL administered in divided doses, twice daily. A high-fat meal (approximately 800 to 1000 calories) was found to produce statistically significant increases in the Quetiapine Cmax and AUC of 44% to 52% and 20% to 22%, respectively, for the 50 mg and 300 mg tablets. In comparison, a light meal (approximately 300 calories) had no significant effect on the Cmax or AUC of quetiapine. It is recommended that Quetiapine be taken without food or with a light meal.
- Distribution
- Quetiapine is widely distributed throughout the body with an apparent volume of distribution of 10±4 L/kg. It is 83% bound to plasma proteins at therapeutic concentrations. In vitro, quetiapine did not affect the binding of warfarin or diazepam to human serum albumin. In turn, neither warfarin nor diazepam altered the binding of quetiapine.
- Metabolism and Elimination
- Following a single oral dose of 14C-quetiapine, less than 1% of the administered dose was excreted as unchanged drug, indicating that quetiapine is highly metabolized. Approximately 73% and 20% of the dose was recovered in the urine and feces, respectively. The average dose fraction of free quetiapine and its major active metabolite is <5% excreted in the urine.
- Quetiapine is extensively metabolized by the liver. The major metabolic pathways are sulfoxidation to the sulfoxide metabolite and oxidation to the parent acid metabolite; both metabolites are pharmacologically inactive. In vitro studies using human liver microsomes revealed that the cytochrome P450 3A4 isoenzyme is involved in the metabolism of quetiapine to its major, but inactive, sulfoxide metabolite and in the metabolism of its active metabolite norquetiapine.
- Age
- Oral clearance of quetiapine was reduced by 40% in elderly patients (≥ 65 years, n = 9) compared to young patients (n = 12), and dosing adjustment may be necessary.
- Gender
- There is no gender effect on the pharmacokinetics of quetiapine.
- Race
- There is no race effect on the pharmacokinetics of quetiapine.
- Smoking
- Smoking has no effect on the oral clearance of quetiapine.
- Renal Insufficiency
- Patients with severe renal impairment (CLcr=10-30 mL/min/1.73m2, n=8) had a 25% lower mean oral clearance than normal subjects (CLcr>80 mL/min/1.73m2, n=8), but plasma quetiapine concentrations in the subjects with renal insufficiency were within the range of concentrations seen in normal subjects receiving the same dose. Dosage adjustment is therefore not needed in these patients.
- Hepatic Insufficiency
- Hepatically impaired patients (n=8) had a 30% lower mean oral clearance of quetiapine than normal subjects. In 2 of the 8 hepatically impaired patients, AUC and Cmax were 3 times higher than those observed typically in healthy subjects. Since quetiapine is extensively metabolized by the liver, higher plasma levels are expected in the hepatically impaired population, and dosage adjustment may be needed.
- Drug-Drug Interaction Studies
- The in vivo assessments of effect of other drugs on the pharmacokinetics of quetiapine are summarized in Table 25.
- In vitro enzyme inhibition data suggest that quetiapine and 9 of its metabolites would have little inhibitory effect on in vivo metabolism mediated by cytochromes CYP 1A2, 2C9, 2C19, 2D6 and 3A4. Quetiapine at doses of 750 mg/day did not affect the single dose pharmacokinetics of antipyrine, lithium or lorazepam (Table 26).
## Nonclinical Toxicology
- Carcinogenicity studies were conducted in C57BL mice and Wistar rats. Quetiapine was administered in the diet to mice at doses of 20, 75, 250, and 750 mg/kg and to rats by gavage at doses of 25, 75, and 250 mg/kg for two years. These doses are equivalent to 0.1, 0.5, 1.5, and 4.5 times the maximum human dose (MRHD) of 800 mg/day based on mg/m2 body surface area (mice) or 0.3, 1, and 3 times the MRHD based on mg/m2 body surface area (rats). There were statistically significant increases in thyroid gland follicular adenomas in male mice at doses 1.5 and 4.5 times the MRHD on mg/m2 body surface area and in male rats at a dose of 3 times the MRHD on mg/m2 body surface area. Mammary gland adenocarcinomas were statistically significantly increased in female rats at all doses tested (0.3, 1, and 3 times the MRHD on mg/m2 body surface area).
- Thyroid follicular cell adenomas may have resulted from chronic stimulation of the thyroid gland by thyroid stimulating hormone (TSH) resulting from enhanced metabolism and clearance of thyroxine by rodent liver. Changes in TSH, thyroxine, and thyroxine clearance consistent with this mechanism were observed in subchronic toxicity studies in rat and mouse and in a 1-year toxicity study in rat; however, the results of these studies were not definitive. The relevance of the increases in thyroid follicular cell adenomas to human risk, through whatever mechanism, is unknown.
- Antipsychotic drugs have been shown to chronically elevate prolactin levels in rodents. Serum measurements in a 1-year toxicity study showed that quetiapine increased median serum prolactin levels a maximum of 32- and 13-fold in male and female rats, respectively. Increases in mammary neoplasms have been found in rodents after chronic administration of other antipsychotic drugs and are considered to be prolactin-mediated. The relevance of this increased incidence of prolactin-mediated mammary gland tumors in rats to human risk is unknown.
- The mutagenic potential of quetiapine was tested in the in vitro Ames bacterial gene mutation assay and in the in vitro mammalian gene mutation assay in Chinese Hamster Ovary cells. The clastogenic potential of quetiapine was tested in the in vitro chromosomal aberration assay in cultured human lymphocytes and in the in vivo bone marrow micronucleus assay in rats up to 500 mg/kg which is 6 times the maximum recommended human dose on mg/m2 body surface area. Based on weight of evidence quetiapine was not mutagenic or clastogenic in these tests.
- Quetiapine decreased mating and fertility in male Sprague-Dawley rats at oral doses of 50 and 150 mg/kg or approximately 1 and 3 times the maximum human dose (MRHD) of 800 mg/day on mg/m2 body surface area. Drug-related effects included increases in interval to mate and in the number of matings required for successful impregnation. These effects continued to be observed at 3 times the MRHD even after a two-week period without treatment. The no-effect dose for impaired mating and fertility in male rats was 25 mg/kg, or 0.3 times the MRHD dose on mg/m2 body surface area. Quetiapine adversely affected mating and fertility in female Sprague-Dawley rats at an oral dose approximately 1 times the MRHD of 800 mg/day on mg/m2 body surface area. Drug-related effects included decreases in matings and in matings resulting in pregnancy, and an increase in the interval to mate. An increase in irregular estrus cycles was observed at doses of 10 and 50 mg/kg, or approximately 0.1 and 1 times the MRHD of 800 mg/day on mg/m2 body surface area. The no-effect dose in female rats was 1 mg/kg, or 0.01 times the MRHD of 800 mg/day on mg/m2 body surface area.
- Quetiapine caused a dose-related increase in pigment deposition in thyroid gland in rat toxicity studies which were 4 weeks in duration or longer and in a mouse 2-year carcinogenicity study. Doses were 10 to 250 mg/kg in rats and 75 to 750 mg/kg in mice; these doses are 0.1-3, and 0.1-4.5 times the maximum recommended human dose (MRHD) of 800 mg/day on mg/m2 body surface area, respectively. Pigment deposition was shown to be irreversible in rats. The identity of the pigment could not be determined, but was found to be co-localized with quetiapine in thyroid gland follicular epithelial cells. The functional effects and the relevance of this finding to human risk are unknown.
- In dogs receiving quetiapine for 6 or 12 months, but not for 1 month, focal triangular cataracts occurred at the junction of posterior sutures in the outer cortex of the lens at a dose of 100 mg/kg, or 4 times the MRHD of 800 mg/day on mg/m2 body surface area. This finding may be due to inhibition of cholesterol biosynthesis by quetiapine. Quetiapine caused a dose-related reduction in plasma cholesterol levels in repeat-dose dog and monkey studies; however, there was no correlation between plasma cholesterol and the presence of cataracts in individual dogs. The appearance of delta 8 cholestanol in plasma is consistent with inhibition of a late stage in cholesterol biosynthesis in these species. There also was a 25% reduction in cholesterol content of the outer cortex of the lens observed in a special study in quetiapine treated female dogs. Drug-related cataracts have not been seen in any other species; however, in a 1-year study in monkeys, a striated appearance of the anterior lens surface was detected in 2/7 females at a dose of 225 mg/kg or 5.5 times the MRHD of 800 mg/day on mg/m2 body surface area.
# Clinical Studies
- The efficacy of Quetiapine in the treatment of schizophrenia was demonstrated in 1 short-term, 6-week, fixed-dose, placebo-controlled trial of inpatients and outpatients with schizophrenia (n=573) who met DSM-IV criteria for schizophrenia. Quetiapine (once daily) was administered as 300 mg on Day 1, and the dose was increased to either 400 mg or 600 mg by Day 2, or 800 mg by Day 3. The primary endpoint was the change from baseline of the Positive and Negative Syndrome Scale (PANSS) total score at the end of treatment (Day 42). Quetiapine doses of 400 mg, 600 mg and 800 mg once daily were superior to placebo in the PANSS total score at Day 42 (study 1 in Table 27).
- The efficacy of Quetiapine in the treatment of schizophrenia in adolescents (13–17 years of age) was supported by a 6-week, double-blind, placebo-controlled trial. Patients who met DSM-IV diagnostic criteria for schizophrenia were randomized into one of three treatment groups: SEROQUEL 400 mg/day (n = 73), SEROQUEL 800 mg/day (n = 74), or placebo (n = 75). Study medication was initiated at 50 mg/day and on day 2 increased to 100 mg/per day (divided and given two or three times per day). Subsequently, the dose was titrated to the target dose of 400 mg/day or 800 mg/day using increments of 100 mg/day, divided and given two or three times daily. The primary efficacy variable was the mean change from baseline in total Positive and Negative Syndrome Scale (PANSS). SEROQUEL at 400 mg/day and 800 mg/day was superior to placebo in the reduction of PANSS total score (study 2 in Table 27).
- In a longer-term trial (study 3), clinically stable adult outpatients (n=171) meeting DSM-IV criteria for schizophrenia who remained stable following 16 weeks of open-label treatment with flexible doses of Quetiapine (400 mg/day-800 mg/day) were randomized to placebo or to continue on their current Quetiapine (400 mg/day-800 mg/day) for observation for possible relapse during the double-blind continuation (maintenance) phase. Stabilization during the open-label phase was defined as receiving a stable dose of Quetiapine and having a CGI-S≤4 and a PANSS score ≤60 from beginning to end of this open-label phase (with no increase of ≥10 points in PANSS total score). Relapse during the double-blind phase was defined in terms of a ≥30% increase in the PANSS Total score, or CGI-Improvement score of ≥6, or hospitalization due to worsening of schizophrenia, or need for any other antipsychotic medication. Patients on Quetiapine experienced a statistically significant longer time to relapse than did patients on placebo (Figure 1).
- PLA Placebo. QTP Quetiapine. XR Extended-release.
- Note: Results are from the interim analysis.
- Bipolar I Disorder, manic or mixed episodes
- Adults
- The efficacy of Quetiapine in the acute treatment of manic episodes was established in one 3-week, placebo-controlled trial (Study 1 in Table 28) in patients who met DSM-IV criteria for bipolar I disorder with manic or mixed episodes with or without psychotic features (N=316). Patients were hospitalized for a minimum of 4 days at randomization. Patients randomized to Quetiapine received 300 mg on Day 1 and 600 mg on Day 2. Afterwards, the dose could be adjusted between 400 mg and 800 mg per day.
- The primary rating instrument used for assessing manic symptoms in these trials was the Young Mania Rating Scale (YMRS), an 11-item clinician-rated scale traditionally used to assess the degree of manic symptoms in a range from 0 (no manic features) to 60 (maximum score). Quetiapine was superior to placebo in the reduction of the YMRS total score at week 3.
- The efficacy of SEROQUEL in the treatment of acute manic episodes was also established in 3 placebo-controlled trials in patients who met DSM-IV criteria for bipolar I disorder with manic episodes. These trials included patients with or without psychotic features and excluded patients with rapid cycling and mixed episodes. Of these trials, 2 were monotherapy (12 weeks) and 1 was adjunct therapy (3 weeks) to either lithium or divalproex. Key outcomes in these trials were change from baseline in the YMRS score at 3 and 12 weeks for monotherapy and at 3 weeks for adjunct therapy. Adjunct therapy is defined as the simultaneous initiation or subsequent administration of SEROQUEL with lithium or divalproex.
- The results of the trials follow:
- Monotherapy
In two 12-week trials (n=300, n=299) comparing SEROQUEL to placebo, SEROQUEL was superior to placebo in the reduction of the YMRS total score at weeks 3 and 12. The majority of patients in these trials taking SEROQUEL were dosed in a range between 400 mg/day and 800 mg/ day (Studies 2 and 3 in Table 28).
- In two 12-week trials (n=300, n=299) comparing SEROQUEL to placebo, SEROQUEL was superior to placebo in the reduction of the YMRS total score at weeks 3 and 12. The majority of patients in these trials taking SEROQUEL were dosed in a range between 400 mg/day and 800 mg/ day (Studies 2 and 3 in Table 28).
- Adjunct Therapy
In a 3-week placebo-controlled trial, 170 patients with bipolar mania (YMRS ≥ 20) were randomized to receive SEROQUEL or placebo as adjunct treatment to lithium or divalproex. Patients may or may not have received an adequate treatment course of lithium or divalproex prior to randomization. SEROQUEL was superior to placebo when added to lithium or divalproex alone in the reduction of YMRS total score. The majority of patients in this trial taking SEROQUEL were dosed in a range between 400 mg/day and 800 mg/day (study 4 in Table 28).
- In a 3-week placebo-controlled trial, 170 patients with bipolar mania (YMRS ≥ 20) were randomized to receive SEROQUEL or placebo as adjunct treatment to lithium or divalproex. Patients may or may not have received an adequate treatment course of lithium or divalproex prior to randomization. SEROQUEL was superior to placebo when added to lithium or divalproex alone in the reduction of YMRS total score. The majority of patients in this trial taking SEROQUEL were dosed in a range between 400 mg/day and 800 mg/day (study 4 in Table 28).
- Children and Adolescents (ages 10-17)
- The efficacy of Quetiapine in the acute treatment of manic episodes associated with bipolar I disorder in children and adolescents (10 to 17 years of age) was extrapolated from a 3-week, double-blind, placebo-controlled, multicenter trial. Patients who met DSM-IV diagnostic criteria for a manic episode were randomized into one of three treatment groups: SEROQUEL 400 mg/day (n = 95), SEROQUEL 600 mg/day (n = 98), or placebo (n = 91). Study medication was initiated at 50 mg/day and on day 2 increased to 100 mg/day (divided doses given two or three times daily). Subsequently, the dose was titrated to a target dose of 400 mg/day or 600 mg/day using increments of 100 mg/day, given in divided doses two or three times daily. The primary efficacy variable was the mean change from baseline in total YMRS score. SEROQUEL 400 mg/day and 600 mg/day were superior to placebo in the reduction of YMRS total score (study 5 in Table 28).
- Bipolar Disorder, Depressive Episodes
- Adults
- The efficacy of Quetiapine for the acute treatment of depressive episodes associated with bipolar disorder in patients who met DSM-IV criteria for bipolar disorder was established in one 8-week, randomized, double-blind, placebo-controlled study (N=280 outpatients). This study included patients with bipolar I and II disorder, and those with and without a rapid cycling course. Patients randomized to Quetiapine were administered 50 mg on Day 1, 100 mg on Day 2, 200 mg on Day 3, and 300 mg on Day 4 and after.
- The primary rating instrument used to assess depressive symptoms was the Montgomery-Asberg Depression Rating Scale (MADRS), a 10-item clinician-rated scale with scores ranging from 0 (no depressive features) to 60 (maximum score). The primary endpoint was the change from baseline in MADRS score at week 8. Quetiapine was superior to placebo in reduction of MADRS score at week 8 (study 6 in Table 29).
- The efficacy of SEROQUEL for the treatment of depressive episodes associated with bipolar disorder was established in 2 identical 8-week, randomized, double-blind, placebo-controlled studies (N=1045). These studies included patients with either bipolar I or II disorder and those with or without a rapid cycling course. Patients randomized to SEROQUEL were administered fixed doses of either 300 mg or 600 mg once daily.
- The primary rating instrument used to assess depressive symptoms in these studies was the MADRS. The primary endpoint in both studies was the change from baseline in MADRS score at week 8. In both studies, SEROQUEL was superior to placebo in reduction of MADRS score at week 8 (Studies 7 and 8 in Table 29). In these studies, no additional benefit was seen with the 600 mg dose. For the 300 mg dose group, statistically significant improvements over placebo were seen in overall quality of life and satisfaction related to various areas of functioning, as measured using the Q-LES-Q(SF).
- Maintenance Treatment as an Adjunct to Lithium or Divalproex
- The efficacy of SEROQUEL in the maintenance treatment of bipolar I disorder was established in 2 placebo-controlled trials in patients (n=1326) who met DSM-IV criteria for bipolar I disorder (studies 9 and 10). The trials included patients whose most recent episode was manic, depressed, or mixed, with or without psychotic features. In the open-label phase, patients were required to be stable on SEROQUEL plus lithium or divalproex for at least 12 weeks in order to be randomized. On average, patients were stabilized for 15 weeks. In the randomization phase, patients continued treatment with lithium or divalproex and were randomized to receive either SEROQUEL (administered twice daily totaling 400 mg/day to 800 mg/day or placebo. Approximately 50% of the patients had discontinued from the SEROQUEL group by day 280 and 50% of the placebo group had discontinued by day 117 of double-blind treatment. The primary endpoint in these studies was time to recurrence of a mood event (manic, mixed or depressed episode). A mood event was defined as medication initiation or hospitalization for a mood episode; YMRS score ≥ 20 or MADRS score ≥ 20 at 2 consecutive assessments; or study discontinuation due to a mood event.
- In both studies, SEROQUEL was superior to placebo in increasing the time to recurrence of any mood event (Figure 2 and Figure 3). The treatment effect was present for increasing time to recurrence of both manic and depressed episodes. The effect of SEROQUEL was independent of any specific subgroup (assigned mood stabilizer, sex, age, race, most recent bipolar episode, or rapid cycling course).
- The efficacy of Quetiapine as adjunctive therapy to antidepressants in the treatment of MDD was demonstrated in two 6-week placebo-controlled, fixed-dose trials (n=936). Quetiapine 150 mg/day or 300 mg/day was given as adjunctive therapy to existing antidepressant therapy in patients who had previously shown an inadequate response to at least one antidepressant. Quetiapine was administered as 50 mg/day on Days 1 and 2, and increased to 150 mg/day on Day 3 for both dose groups. On Day 5, the dose was increased to 300 mg/day in the 300 mg/day fixed-dose group. Inadequate response was defined as having continued depressive symptoms for the current episode despite using an antidepressant for 6 weeks at or above the minimally effective labelled dose. The mean HAM-D total score at entry was 24, and 17% of patients scored 28 or greater. Patients were on various antidepressants prior to study entry including SSRI’s (paroxetine, fluoxetine, sertraline, escitalopram, or citalopram), SNRI’s, (duloxetine and venlafaxine,) TCA (amitriptyline) and other (bupropion).
- The primary endpoint in these trials was change from baseline to week 6 in the Montgomery-Asberg Depression Rating Scale (MADRS.), Quetiapine 300 mg once daily as adjunctive treatment to other antidepressant therapy was superior to antidepressant alone in reduction of MADRS total score in both trials. Quetiapine 150 mg once daily as adjunctive treatment was superior to antidepressant therapy alone in reduction of MADRS total score in one trial (studies 1 and 2 in Table 30).
# How Supplied
- 50 mg Tablets (NDC 0310-0280) peach, film coated, capsule-shaped, biconvex, intagliated tablet with “XR 50” on one side and plain on the other are supplied in bottles of 60 tablets and hospital unit dose packages of 100 tablets.
- 150 mg Tablets (NDC 0310-0281) white, film-coated, capsule-shaped, biconvex, intagliated tablet with ‘XR 150’ on one side and plain on the other are supplied in bottles of 60 tablets and hospital unit dose packages of 100 tablets.
- 200 mg Tablets (NDC 0310-0282) yellow, film coated, capsule-shaped, biconvex, intagliated tablet with “XR 200” on one side and plain on the other are supplied in bottles of 60 tablets and hospital unit dose packages of 100 tablets.
- 300 mg Tablets (NDC 0310-0283) pale yellow, film coated, capsule-shaped, biconvex, intagliated tablet with “XR 300” on one side and plain on the other are supplied in bottles of 60 tablets and hospital unit dose packages of 100 tablets.
- 400 mg Tablets (NDC 0310-0284) white, film coated, capsule-shaped, biconvex, intagliated tablet with “XR 400” on one side and plain on the other are supplied in bottles of 60 tablets and hospital unit dose packages of 100 tablets.
- Store Quetiapine at 25ºC (77ºF); excursions permitted to 15-30ºC (59-86ºF).
## Storage
There is limited information regarding Quetiapine Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with Quetiapine and should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions” is available for Quetiapine. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document.
- Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking Quetiapine.
- Increased Mortality in Elderly Patients with Dementia-Related Psychosis
- Patients and caregivers should be advised that elderly patients with dementia-related psychoses treated with atypical antipsychotic drugs are at increased risk of death compared with placebo. Quetiapine is not approved for elderly patients with dementia-related psychosis.
- Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.
- Patients should be advised to report to their physician any signs or symptoms that may be related to NMS. These may include muscle stiffness and high fever.
- Patients should be aware of the symptoms of hyperglycemia (high blood sugar) and diabetes mellitus. Patients who are diagnosed with diabetes, those with risk factors for diabetes, or those that develop these symptoms during treatment should have their blood glucose monitored at the beginning of and periodically during treatment.
- Patients should be advised that elevations in total cholesterol, LDL-cholesterol and triglycerides and decreases in HDL-cholesterol may occur. Patients should have their lipid profile monitored at the beginning of and periodically during treatment.
- Patients should be advised that they may experience weight gain. Patients should have their weight monitored regularly.
- Patients should be advised of the risk of orthostatic hypotension (symptoms include feeling dizzy or lightheaded upon standing, which may lead to falls) especially during the period of initial dose titration, and also at times of re-initiating treatment or increases in dose.
- Increased Blood Pressure in Children and Adolescents
- Children and adolescent patients should have their blood pressure measured at the beginning of, and periodically during, treatment.
- Patients with a pre-existing low WBC or a history of drug induced leukopenia/neutropenia should be advised that they should have their CBC monitored while taking Quetiapine.
- Interference with Cognitive and Motor Performance
- Patients should be advised of the risk of somnolence or sedation (which may lead to falls), especially during the period of initial dose titration. Patients should be cautioned about performing any activity requiring mental alertness, such as operating a motor vehicle (including automobiles) or operating machinery, until they are reasonably certain quetiapine therapy does not affect them adversely..
- Patients should be advised regarding appropriate care in avoiding overheating and dehydration.
- As with other medications, patients should be advised to notify their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs.
- Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy with Quetiapine.
- Quetiapine is indicated as an integral part of a total treatment program for adolescents with schizophrenia and pediatric bipolar disorder that may include other measures (psychological, educational, and social). Effectiveness and safety of Quetiapine have not been established in pediatric patients less than 13 years of age for schizophrenia or less than 10 years of age for bipolar mania. Appropriate educational placement is essential and psychosocial intervention is often helpful. The decision to prescribe atypical antipsychotic medication will depend upon the physician’s assessment of the chronicity and severity of the patient’s symptoms.
- Read this Medication Guide before you start taking Quetiapine and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or treatment.
- What is the most important information I should know about Quetiapine?
- Quetiapine may cause serious side effects, including:
- risk of death in the elderly with dementia: Medicines like Quetiapine can increase the risk of death in elderly people who have memory loss (dementia). Quetiapine is not for treating psychosis in the elderly with dementia.
- risk of suicidal thoughts or actions (antidepressant medicines, depression and other serious mental illnesses, and suicidal thoughts or actions).
- Talk to your, or your family member’s, healthcare provider about:
- all risks and benefits of treatment with antidepressant medicines
- all treatment choices for depression or other serious mental illness
- Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment.
- Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have a particularly high risk of having suicidal thoughts or actions. These include people who have (or have a family history of) depression, bipolar illness (also called manic-depressive illness), or suicidal thoughts or actions.
- How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member?
- Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. This is very important when an antidepressant medicine is started or when the dose is changed.
- Call the healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings.
- Keep all follow-up visits with the healthcare provider as scheduled. Call the healthcare provider between visits as needed, especially if you have concerns about symptoms.
- Call a healthcare provider right away if you or your family member has any of the following symptoms, especially if they are new, worse, or worry you:
- thoughts about suicide or dying
- attempts to commit suicide
- new or worse depression
- new or worse anxiety
- feeling very agitated or restless
- panic attacks
- trouble sleeping (insomnia)
- new or worse irritability
- acting aggressive, being angry, or violent
- acting on dangerous impulses
- an extreme increase in activity and talking (mania)
- other unusual changes in behavior or mood
- What else do I need to know about antidepressant medicines?
- Never stop an antidepressant medicine without first talking to your healthcare provider. Stopping an antidepressant medicine suddenly can cause other symptoms.
- Antidepressants are medicines used to treat depression and other illnesses. It is important to discuss all the risks of treating depression and also the risks of not treating it. Patients and their families or other caregivers should discuss all treatment choices with the healthcare provider, not just the use of antidepressants.
- Antidepressant medicines have other side effects. Talk to the healthcare provider about the side effects of the medicine prescribed for you or your family member.
- Antidepressant medicines can interact with other medicines. Know all of the medicines that you or your family member take. Keep a list of all medicines to show the healthcare provider. Do not start new medicines without first checking with your healthcare provider.
- Not all antidepressant medicines prescribed for children are FDA approved for use in children. Talk to your child’s healthcare provider for more information.
- What is Quetiapine?
- Quetiapine is a prescription medicine used to treat:
- schizophrenia in people 13 years of age or older
- bipolar disorder in adults, including:
depressive episodes associated with bipolar disorder
manic episodes associated with bipolar I disorder alone or with lithium or divalproex
long-term treatment of bipolar I disorder with lithium or divalproex
manic episodes associated with bipolar I disorder in children ages 10 to 17 years old.
major depressive disorder as add-on treatment with antidepressant medicines when your healthcare provider determines that 1 antidepressant alone is not enough to treat your depression.
- depressive episodes associated with bipolar disorder
- manic episodes associated with bipolar I disorder alone or with lithium or divalproex
- long-term treatment of bipolar I disorder with lithium or divalproex
- manic episodes associated with bipolar I disorder in children ages 10 to 17 years old.
- major depressive disorder as add-on treatment with antidepressant medicines when your healthcare provider determines that 1 antidepressant alone is not enough to treat your depression.
- It is not known if Quetiapine is safe and effective in children under 10 years of age.
- Who should not take Quetiapine?
- Do not take Quetiapine if you are allergic to quetiapine fumarate or any of the ingredients in Quetiapine.
- What should I tell my healthcare provider before taking Quetiapine?
- Before you take Quetiapine, tell your healthcare provider if you have or have had:
- diabetes or high blood sugar in you or your family. Your healthcare provider should check your blood sugar before you start Quetiapine and also during therapy.
high levels of total cholesterol, triglycerides or LDL-cholesterol or low levels of HDL-cholesterol
low or high blood pressure
low white blood cell count
cataracts
seizures
abnormal thyroid tests
high prolactin levels
heart problems
liver problems
any other medical condition
pregnancy or plans to become pregnant. It is not known if Quetiapine will harm your unborn baby
breast-feeding or plans to breast-feed. Quetiapine can pass into your breast milk. You and your healthcare provider should decide if you will take Quetiapine or breast-feed. You should not do both.
- diabetes or high blood sugar in you or your family. Your healthcare provider should check your blood sugar before you start Quetiapine and also during therapy.
- high levels of total cholesterol, triglycerides or LDL-cholesterol or low levels of HDL-cholesterol
- low or high blood pressure
- low white blood cell count
- cataracts
- seizures
- abnormal thyroid tests
- high prolactin levels
- heart problems
- liver problems
- any other medical condition
- pregnancy or plans to become pregnant. It is not known if Quetiapine will harm your unborn baby
- breast-feeding or plans to breast-feed. Quetiapine can pass into your breast milk. You and your healthcare provider should decide if you will take Quetiapine or breast-feed. You should not do both.
- Tell the healthcare provider about all the medicines that you take or recently have taken including prescription medicines, over-the-counter medicines, herbal supplements and vitamins.
- Quetiapine and other medicines may affect each other causing serious side effects. Quetiapine may affect the way other medicines work, and other medicines may affect how Quetiapine works.
- Tell your healthcare provider if you are having a urine drug screen because Quetiapine may affect your test results. Tell those giving the test that you are taking Quetiapine.
- How should I take Quetiapine?
- Take Quetiapine exactly as your healthcare provider tells you to take it. Do not change the dose yourself.
- Take Quetiapine by mouth, with a light meal or without food.
- Quetiapine should be swallowed whole and not split, chewed or crushed.
- If you feel you need to stop Quetiapine, talk with your healthcare provider first. If you suddenly stop taking Quetiapine, you may have side effects such as trouble sleeping or trouble staying asleep (insomnia), nausea, and vomiting.
- If you miss a dose of Quetiapine, take it as soon as you remember. If you are close to your next dose, skip the missed dose. Just take the next dose at your regular time. Do not take 2 doses at the same time unless your healthcare provider tells you to. If you are not sure about your dosing, call your healthcare provider.
- What should I avoid while taking Quetiapine?
- Do not drive, operate machinery, or do other dangerous activities until you know how Quetiapine affects you. Quetiapine may make you drowsy.
- Avoid getting overheated or dehydrated.
- Do not over-exercise.
- In hot weather, stay inside in a cool place if possible.
- Stay out of the sun. Do not wear too much or heavy clothing.
- Drink plenty of water.
- Do not drink alcohol while taking Quetiapine. It may make some side effects of Quetiapine worse.
- What are possible side effects of Quetiapine?
- Quetiapine can cause serious side effects, including:
See “What is the most important information I should know about Quetiapine?”
stroke that can lead to death can happen in elderly people with dementia who take medicines like SEROQUEL
neuroleptic malignant syndrome (NMS). NMS is a rare but very serious condition that can happen in people who take antipsychotic medicines, including Quetiapine. NMS can cause death and must be treated in a hospital. Call your healthcare provider right away if you become severely ill and have some or all of these symptoms:
high fever
excessive sweating
rigid muscles
confusion
changes in your breathing, heartbeat, and blood pressure
high blood sugar (hyperglycemia). High blood sugar can happen if you have diabetes already or if you have never had diabetes.
- See “What is the most important information I should know about Quetiapine?”
- stroke that can lead to death can happen in elderly people with dementia who take medicines like SEROQUEL
- neuroleptic malignant syndrome (NMS). NMS is a rare but very serious condition that can happen in people who take antipsychotic medicines, including Quetiapine. NMS can cause death and must be treated in a hospital. Call your healthcare provider right away if you become severely ill and have some or all of these symptoms:
high fever
excessive sweating
rigid muscles
confusion
changes in your breathing, heartbeat, and blood pressure
high blood sugar (hyperglycemia). High blood sugar can happen if you have diabetes already or if you have never had diabetes.
- high fever
- excessive sweating
- rigid muscles
- confusion
- changes in your breathing, heartbeat, and blood pressure
- high blood sugar (hyperglycemia). High blood sugar can happen if you have diabetes already or if you have never had diabetes.
- High blood sugar could lead to:
- build up of acid in your blood due to ketones (ketoacidosis)
- coma
- death
- Increases in blood sugar can happen in some people who take Quetiapine. Extremely high blood sugar can lead to coma or death. If you have diabetes or risk factors for diabetes (such as being overweight or a family history of diabetes) your healthcare provider should check your blood sugar before you start Quetiapine and during therapy.
- Call your healthcare provider if you have any of these symptoms of high blood sugar (hyperglycemia) while taking Quetiapine:
- feel very thirsty
- need to urinate more than usual
- feel very hungry
- feel weak or tired
- feel sick to your stomach
- feel confused, or your breath smells fruity
- High fat levels in your blood (increased cholesterol and triglycerides). High fat levels may happen in people treated with Quetiapine. You may not have any symptoms, so your healthcare provider may decide to check your cholesterol and triglycerides during your treatment with Quetiapine.
- Increase in weight (weight gain). Weight gain is common in people who take Quetiapine so you and your healthcare provider should check your weight regularly. Talk to your healthcare provider about ways to control weight gain, such as eating a healthy, balanced diet, and exercising.
- Movements you cannot control in your face, tongue, or other body parts (tardive dyskinesia). These may be signs of a serious condition. Tardive dyskinesia may not go away, even if you stop taking Quetiapine. Tardive dyskinesia may also start after you stop taking Quetiapine.
- Decreased blood pressure (orthostatic hypotension), including lightheadedness or fainting caused by a sudden change in heart rate and blood pressure when rising too quickly from a sitting or lying position.
- Increases in blood pressure in children and teenagers. Your healthcare provider should check blood pressure in children and adolescents before starting Quetiapine and during therapy. Quetiapine is not approved for patients under 10 years of age.
- Low white blood cell count
- Cataracts
- Seizures
- Abnormal thyroid tests: Your healthcare provider may do blood tests to check your thyroid hormone level.
- Increases in prolactin levels: Your healthcare provider may do blood tests to check your prolactin levels.
- Sleepiness, drowsiness, feeling tired, difficulty thinking and doing normal activities
- Increased body temperature
- Difficulty swallowing
- Trouble sleeping or trouble staying asleep (insomnia), nausea, or vomiting if you suddenly stop taking Quetiapine. These symptoms usually get better 1 week after you start having them.
- The most common side effects of Quetiapine include:
- dry mouth
- constipation
- dizziness
- increased appetite
- upset stomach
- fatigue
- stuffy nose
- difficulty moving
- These are not all the possible side effects of Quetiapine. For more information, ask your healthcare provider or pharmacist.
- Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
- How should I store Quetiapine?
- Store Quetiapine at room temperature, between 68°F to 77°F (20°C to 25°C).
- Keep Quetiapine and all medicines out of the reach of children.
- General information about the safe and effective use of Quetiapine.
- Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Quetiapine for a condition for which it was not prescribed. Do not give Quetiapine to other people, even if they have the same symptoms you have. It may harm them.
- This Medication Guide summarizes the most important information about Quetiapine. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about Quetiapine that is written for health professionals.
- For more information, go to www.SEROQUELXR.com, or call 1-800-236-9933.
- What are the ingredients in Quetiapine?
- Active ingredient: quetiapine fumarate
- Inactive ingredients: lactose monohydrate, microcrystalline cellulose, sodium citrate, hypromellose, and magnesium stearate. The film coating for all Quetiapine tablets contain hypromellose, polyethylene glycol 400 and titanium dioxide. In addition, yellow iron oxide (50, 200 and 300 mg tablets) and red iron oxide (50 mg tablets) are included in the film coating of specific strengths.
- This Medication Guide has been approved by the U.S. Food and Drug Administration.
# Precautions with Alcohol
- Do not drink alcohol while taking Quetiapine. It may make some side effects of Quetiapine worse.
# Brand Names
- SEROQUEL XR®
# Look-Alike Drug Names
- QUEtiapine® — OLANZapine®
- Seroquel® — Quetiapine®
- SEROquel® — Serzone®
- SEROquel® — SINEquan®
# Drug Shortage Status
# Price | Quetiapine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Black Box Warning
# Overview
Quetiapine is an atypical antipsychotic that is FDA approved for the treatment of schizophrenia, bipolar I disorder, manic or mixed episodes, bipolar disorder, depressive episodes, major depressive disorder, adjunctive therapy with antidepressants. There is a Black Box Warning for this drug as shown here. Common adverse reactions include somnolence, dry mouth, constipation, dizziness, increased appetite, dyspepsia, weight gain, fatigue, dysarthria, nasal congestion, nausea, vomiting, and tachycardia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Important Administration Instructions
- Quetiapine tablets should be swallowed whole and not split, chewed or crushed.
- It is recommended that Quetiapine be taken without food or with a light meal (approximately 300 calories).
- Quetiapine should be administered once daily, preferably in the evening.
- Recommended Dosing
- The recommended initial dose, titration, dose range and maximum Quetiapine dose for each approved indication is displayed in Table 1 below. After initial dosing, adjustments can be made upwards or downwards, if necessary, depending upon the clinical response and tolerability of the patient
- Maintenance Treatment for Schizophrenia and Bipolar I Disorder
- Maintenance Treatment
Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment.
- Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment.
- Dose Modifications in Elderly Patients
- Consideration should be given to a slower rate of dose titration and a lower target dose in the elderly and in patients who are debilitated or who have a predisposition to hypotensive reactions. When indicated, dose escalation should be performed with caution in these patients.
- Elderly patients should be started on Quetiapine 50 mg/day and the dose can be increased in increments of 50 mg/day depending on the clinical response and tolerability of the individual patient.
- Dose Modifications in Hepatically Impaired Patients
- Patients with hepatic impairment should be started on Quetiapine 50 mg/day. The dose can be increased daily in increments of 50 mg/day to an effective dose, depending on the clinical response and tolerability of the patient.
- Dose Modifications when used with CYP3A4 Inhibitors
- Quetiapine dose should be reduced to one sixth of original dose when co-medicated with a potent CYP3A4 inhibitor (e.g., ketoconazole, itraconazole, indinavir, ritonavir, nefazodone, etc.). When the CYP3A4 inhibitor is discontinued, the dose of Quetiapine should be increased by 6 fold.
- Dose Modifications when used with CYP3A4 Inducers
- Quetiapine dose should be increased up to 5 fold of the original dose when used in combination with a chronic treatment (e.g., greater than 7-14 days) of a potent CYP3A4 inducer (e.g., phenytoin, carbamazepine, rifampin, avasimibe, St. John’s wort etc.). The dose should be titrated based on the clinical response and tolerance of the individual patient. When the CYP3A4 inducer is discontinued, the dose of Quetiapine should be reduced to the original level within 7-14 days.
- Reinitiation of Treatment in Patients Previously Discontinued
- Although there are no data to specifically address re-initiation of treatment, it is recommended that when restarting therapy of patients who have been off Quetiapine for more than one week, the initial dosing schedule should be followed. When restarting patients who have been off Quetiapine for less than one week, gradual dose escalation may not be required and the maintenance dose may be reinitiated.
- Switching Patients from SEROQUEL Tablets to Quetiapine Tablets
- Patients who are currently being treated with SEROQUEL (immediate release formulation) may be switched to Quetiapine at the equivalent total daily dose taken once daily. Individual dosage adjustments may be necessary.
- Switching from Antipsychotics
- There are no systematically collected data to specifically address switching patients from other antipsychotics to Quetiapine, or concerning concomitant administration with other antipsychotics. While immediate discontinuation of the previous antipsychotic treatment may be acceptable for some patients, more gradual discontinuation may be most appropriate for others. In all cases, the period of overlapping antipsychotic administration should be minimized. When switching patients from depot antipsychotics, if medically appropriate, initiate Quetiapine therapy in place of the next scheduled injection. The need for continuing existing extrapyramidal syndrome medication should be re-evaluated periodically.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Quetiapine in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- Quetiapine 300 to 800 mg/day[1]
- Dosing Information
- Doses of 50, 150, or 300 mg/day[2]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Recommended Dose: 400-600 mg/day.
- Maximum Dose: 600 mg/day.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Quetiapine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Quetiapine in pediatric patients.
# Contraindications
- Hypersensitivity to quetiapine or to any excipients in the Quetiapine formulation. Anaphylactic reactions have been reported in patients treated with Quetiapine.
# Warnings
### Precautions
- Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analysis of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. Quetiapine is not approved for the treatment of patients with dementia-related psychosis.
- Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.
- The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 2.
- No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.
- It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.
- All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.
- The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.
- Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.
- Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for Quetiapine should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.
- A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, including Quetiapine, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression.
- In placebo-controlled trials with risperidone, aripiprazole, and olanzapine in elderly subjects with dementia, there was a higher incidence of cerebrovascular adverse reactions (cerebrovascular accidents and transient ischemic attacks), including fatalities, compared to placebo-treated subjects. Quetiapine is not approved for the treatment of patients with dementia-related psychosis.
- A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs, including quetiapine. Rare cases of NMS have been reported with quetiapine. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis) and acute renal failure.
- The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to exclude cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology.
- The management of NMS should include: 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; 2) intensive symptomatic treatment and medical monitoring; and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for NMS.
- If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored since recurrences of NMS have been reported.
- Atypical antipsychotic drugs have been associated with metabolic changes that include hyperglycemia/diabetes mellitus, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile. In some patients, a worsening of more than one of the metabolic parameters of weight, blood glucose, and lipids was observed in clinical studies. Changes in these metabolic profiles should be managed as clinically appropriate.
- Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics, including quetiapine. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse reactions is not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics. Precise risk estimates for hyperglycemia-related adverse reactions in patients treated with atypical antipsychotics are not available.
- Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug.
- Adults:
- In a 24-week trial (active-controlled, 115 patients treated with SEROQUEL) designed to evaluate glycemic status with oral glucose tolerance testing of all patients, at week 24 the incidence of a treatment-emergent post-glucose challenge glucose level ≥ 200 mg/dL was 1.7% and the incidence of a fasting treatment-emergent blood glucose level ≥ 126 mg/dL was 2.6%. The mean change in fasting glucose from baseline was 3.2 mg/dL and mean change in 2 hour glucose from baseline was -1.8 mg/dL for quetiapine.
- In 2 long-term placebo-controlled randomized withdrawal clinical trials for bipolar I disorder maintenance, mean exposure of 213 days for SEROQUEL (646 patients) and 152 days for placebo (680 patients), the mean change in glucose from baseline was +5.0 mg/dL for quetiapine and –0.05 mg/dL for placebo. The exposure-adjusted rate of any increased blood glucose level (≥ 126 mg/dL) for patients more than 8 hours since a meal (however, some patients may not have been precluded from calorie intake from fluids during fasting period) was 18.0 per 100 patient years for SEROQUEL (10.7% of patients; n=556) and 9.5 for placebo per 100 patient years (4.6% of patients; n=581).
- Table 4 shows the percentage of patients with shifts in blood glucose to ≥ 126 mg/dL from normal baseline in MDD adjunct therapy trials by dose.
- Children and Adolescents: Safety and effectiveness of Quetiapine is supported from studies of SEROQUEL in children and adolescent patients 10 to 17 years of age. In a placebo-controlled Quetiapine monotherapy study (8 weeks duration) of children and adolescent patients (10 – 17 years of age) with bipolar depression, in which efficacy was not established, the mean change in fasting glucose levels for Quetiapine (n = 60) compared to placebo (n = 62) was 1.8 mg/dL versus 1.6 mg/dL. In this study, there were no patients in the Quetiapine or placebo-treated groups with a baseline normal fasting glucose level (< 100 mg/dL) that had an increase in blood glucose level ≥ 126 mg/dL. There was one patient in the Quetiapine group with a baseline borderline fasting glucose level (≥ 100 mg/dL) and < 126 mg/dL) who had an increase in blood glucose level of > 126 mg/dL compared to zero patients in the placebo group.
- In a placebo-controlled SEROQUEL monotherapy study of adolescent patients (13–17 years of age) with schizophrenia (6 weeks duration), the mean change in fasting glucose levels for SEROQUEL (n=138) compared to placebo (n=67) was –0.75 mg/dL versus –1.70 mg/dL. In a placebo-controlled SEROQUEL monotherapy study of children and adolescent patients (10–17 years of age) with bipolar mania (3 weeks duration), the mean change in fasting glucose level for SEROQUEL (n=170) compared to placebo (n=81) was 3.62 mg/dL versus –1.17 mg/dL. No patient in either study with a baseline normal fasting glucose level (<100 mg/dL) or a baseline borderline fasting glucose level (≥100 mg/dL and <126 mg/dL) had a treatment-emergent blood glucose level of ≥126 mg/dL.
- Dyslipidemia
- Adults:
- Table 5 shows the percentage of patients with changes in cholesterol and triglycerides from baseline by indication in clinical trials with Quetiapine.
- In SEROQUEL clinical trials for schizophrenia, the percentage of patients with shifts in cholesterol and triglycerides from baseline to clinically significant levels were 18% (placebo: 7%) and 22% (placebo: 16%). HDL-cholesterol and LDL-cholesterol parameters were not measured in these studies. In SEROQUEL clinical trials for bipolar depression, the following percentage of patients had shifts from baseline to clinically significant levels for the four lipid parameters measured: total cholesterol 9% (placebo: 6%); triglycerides 14% (placebo: 9%); LDL-cholesterol 6% (placebo: 5%) and HDL-cholesterol 14% (placebo: 14%). Lipid parameters were not measured in the bipolar mania studies.
- Table 6 shows the percentage of patients in MDD adjunctive therapy trials with clinically significant shifts in total-cholesterol, triglycerides, LDL-cholesterol and HDL-cholesterol from baseline by dose.
- Children and Adolescents:
- Safety and effectiveness of Quetiapine is supported by studies of SEROQUEL in children and adolescent patients 10 to 17 years of age.
- In a placebo-controlled Quetiapine monotherapy study (8 weeks duration) of children and adolescent patients (10-17 years of age) with bipolar depression, in which efficacy was not established, the percentage of children and adolescents with shifts in total cholesterol (≥200 mg/dL), triglycerides (≥150 mg/dL), LDL-cholesterol (≥ 130 mg/dL) and HDL-cholesterol (≤40 mg/dL) from baseline to clinically significant levels were: total cholesterol 8% (7/83) for Quetiapine vs. 6% (5/84) for placebo; triglycerides 28% (22/80) for Quetiapine vs. 9% (7/82) for placebo; LDL-cholesterol 2% (2/86) for Quetiapine vs. 4% (3/85) for placebo and HDL-cholesterol 20% (13/65) for Quetiapine vs 15% (11/74) for placebo.
- Table 7 shows the percentage of children and adolescents with shifts in total cholesterol, triglycerides, LDL-cholesterol and HDL-cholesterol from baseline to clinically significant levels by indication in clinical trials with SEROQUEL in adolescents (13–17 years) with schizophrenia and in children and adolescents (10-17 years) with bipolar mania.
- Weight Gain
- Increases in weight have been observed in clinical trials. Patients receiving quetiapine should receive regular monitoring of weight.
- Adults: Table 8 shows the percentage of adult patients with weight gain of ≥7% of body weight by indication.
- In schizophrenia trials, the proportions of patients meeting a weight gain criterion of ≥7% of body weight were compared in a pool of four 3- to 6-week placebo-controlled clinical trials, revealing a statistically significant greater incidence of weight gain for SEROQUEL (23%) compared to placebo (6%).
- Table 9 shows the percentage of adult patients with weight gain of ≥7% of body weight for MDD by dose.
- Children and Adolescents: Safety and effectiveness of Quetiapine is supported by studies of SEROQUEL in children and adolescent patients 10 to 17 years of age. In a clinical trial for Quetiapine in children and adolescents (10-17 years of age) with bipolar depression, in which efficacy was not established, the percentage of patients with weight gain ≥7% of body weight at any time was 15% (14/92) for Quetiapine vs. 10% (10/100) for placebo. The mean change in body weight was 1.4 kg in the Quetiapine group vs. 0.6 kg in the placebo group.
- Weight gain was greater in patients 10-12 years of age compared to patients 13-17 years of age. The percentage of patients 10-12 years of age with weight gain ≥7% at any time was 28% (7/25) for Quetiapine vs. 0% (0/28) for placebo. The percentage of patients 13-17 years of age with weight gain ≥7% at any time was 10.4% (7/67) for Quetiapine vs. 13.9% (10/72) for placebo.
- Table 10 shows the percentage of children and adolescents with weight gain ≥7% of body weight in clinical trials with SEROQUEL in adolescents (13 – 17 years) with schizophrenia and in children and adolescents (10 – 17 years) with bipolar mania.
- The mean change in body weight in the schizophrenia trial was 2.0 kg in the SEROQUEL group and -0.4 kg in the placebo group and in the bipolar mania trial it was 1.7 kg in the SEROQUEL group and 0.4 kg in the placebo group.
- In an open-label study that enrolled patients from the above two pediatric trials, 63% of patients (241/380) completed 26 weeks of therapy with SEROQUEL. After 26 weeks of treatment, the mean increase in body weight was 4.4 kg. Forty-five percent of the patients gained ≥ 7% of their body weight, not adjusted for normal growth. In order to adjust for normal growth over 26 weeks, an increase of at least 0.5 standard deviation from baseline in BMI was used as a measure of a clinically significant change; 18.3% of patients on SEROQUEL met this criterion after 26 weeks of treatment.
- When treating pediatric patients with SEROQUEL for any indication, weight gain should be assessed against that expected for normal growth.
- A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs including quetiapine. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.
- The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses or may even arise after discontinuation of treatment.
- There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.
- Given these considerations, Quetiapine should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who appear to suffer from a chronic illness that (1) is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.
- If signs and symptoms of tardive dyskinesia appear in a patient on Quetiapine, drug discontinuation should be considered. However, some patients may require treatment with quetiapine despite the presence of the syndrome.
- Quetiapine may induce orthostatic hypotension associated with dizziness, tachycardia and, in some patients, syncope, especially during the initial dose-titration period, probably reflecting its ά1-adrenergic antagonist properties. Syncope was reported in 0.3% (5/1866) of the patients treated with Quetiapine across all indications, compared with 0.2% (2/928) on placebo. Syncope was reported in 1% (28/3265) of the patients treated with SEROQUEL, compared with 0.2% (2/954) on placebo. Orthostatic hypotension, dizziness, and syncope may lead to falls.
- Quetiapine should be used with particular caution in patients with known cardiovascular disease (history of myocardial infarction or ischemic heart disease, heart failure or conduction abnormalities), cerebrovascular disease or conditions which would predispose patients to hypotension (dehydration, hypovolemia and treatment with antihypertensive medications). If hypotension occurs during titration to the target dose, a return to the previous dose in the titration schedule is appropriate.
- Safety and effectiveness of Quetiapine is supported by studies of SEROQUEL in children and adolescent patients 10 to 17 years of age.
- In a placebo-controlled Quetiapine clinical trial (8 weeks duration) in children and adolescents (10-17 years of age) with bipolar depression, in which efficacy was not established, the incidence of increases at any time in systolic blood pressure (≥20 mmHg) was 6.5% (6/92) for Quetiapine and 6.0% (6/100) for placebo; the incidence of increases at any time in diastolic blood pressure (≥10 mmHg) was 46.7% (43/92) for Quetiapine and 36.0% (36/100) for placebo.
- In placebo-controlled trials in children and adolescents with schizophrenia (13-17 years old, 6-week duration) or bipolar mania (10-17 years old, 3-week duration), the incidence of increases at any time in systolic blood pressure (≥20 mmHg) was 15.2% (51/335) for SEROQUEL and 5.5% (9/163) for placebo; the incidence of increases at any time in diastolic blood pressure (≥10 mmHg) was 40.6% (136/335) for SEROQUEL and 24.5% (40/163) for placebo. In the 26-week open-label clinical trial, one child with a reported history of hypertension experienced a hypertensive crisis. Blood pressure in children and adolescents should be measured at the beginning of, and periodically during treatment.
- In clinical trials and postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to atypical antipsychotic agents, including quetiapine fumarate. Agranulocytosis (including fatal cases) has also been reported.
- Possible risk factors for leukopenia/neutropenia include pre-existing low white cell count (WBC) and history of drug induced leukopenia/neutropenia. Patients with a pre-existing low WBC or a history of drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and should discontinue Quetiapine at the first sign of a decline in WBC in absence of other causative factors.
- Patients with neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1000/mm3) should discontinue Quetiapine and have their WBC followed until recovery.
- The development of cataracts was observed in association with quetiapine treatment in chronic dog studies. Lens changes have also been observed in adults, children, and adolescents during long-term quetiapine treatment but a causal relationship to quetiapine use has not been established. Nevertheless, the possibility of lenticular changes cannot be excluded at this time. Therefore, examination of the lens by methods adequate to detect cataract formation, such as slit lamp exam or other appropriately sensitive methods, is recommended at initiation of treatment or shortly thereafter, and at 6-month intervals during chronic treatment.
- In clinical trials quetiapine was not associated with a persistent increase in QT intervals. However, the QT effect was not systematically evaluated in a thorough QT study. In post marketing experience there were cases reported of QT prolongation in patients who overdosed on quetiapine, in patients with concomitant illness, and in patients taking medicines known to cause electrolyte imbalance or increase QT interval.
- The use of quetiapine should be avoided in combination with other drugs that are known to prolong QTc including Class 1A antiarrythmics (e.g., quinidine, procainamide) or Class III antiarrythmics (e.g., amiodarone, sotalol), antipsychotic medications (e.g., ziprasidone, chlorpromazine, thioridazine), antibiotics (e.g., gatifloxacin, moxifloxacin), or any other class of medications known to prolong the QTc interval (e.g., pentamidine, levomethadyl acetate, methadone).
- Quetiapine should also be avoided in circumstances that may increase the risk of occurrence of torsade de pointes and/or sudden death including (1) a history of cardiac arrhythmias such as bradycardia; (2) hypokalemia or hypomagnesemia; (3) concomitant use of other drugs that prolong the QTc interval; and (4) presence of congenital prolongation of the QT interval.
- Caution should also be exercised when quetiapine is prescribed in patients with increased risk of QT prolongation (e.g., cardiovascular disease, family history of QT prolongation, the elderly, congestive heart failure and heart hypertrophy).
- During short-term clinical trials with Quetiapine, seizures occurred in 0.05% (1/1866) of patients treated with Quetiapine across all indications compared to 0.3% (3/928) on placebo. During clinical trials with SEROQUEL, seizures occurred in 0.5% (20/3490) of patients treated with SEROQUEL compared to 0.2% (2/954) on placebo. As with other antipsychotics, quetiapine fumarate should be used cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold, e.g., Alzheimer’s dementia. Conditions that lower the seizure threshold may be more prevalent in a population of 65 years or older.
- Adults: Clinical trials with quetiapine demonstrated dose-related decreases in thyroid hormone levels. The reduction in total and free thyroxine (T4) of approximately 20% at the higher end of the therapeutic dose range was maximal in the first six weeks of treatment and maintained without adaptation or progression during more chronic therapy. In nearly all cases, cessation of quetiapine treatment was associated with a reversal of the effects on total and free T4, irrespective of the duration of treatment. The mechanism by which quetiapine effects the thyroid axis is unclear. If there is an effect on the hypothalamic-pituitary axis, measurement of TSH alone may not accurately reflect a patient’s thyroid status. Therefore, both TSH and free T4, in addition to clinical assessment, should be measured at baseline and at follow-up.
- In Quetiapine clinical trials across all indications 1.8% (24/1336) of patients on Quetiapine versus 0.6% (3/530) on placebo experienced decreased free thyroxine (<0.8 LLN) and 1.6% (21/1346) on Quetiapine versus 3.4% (18/534) on placebo experienced increased thyroid stimulating hormone (TSH). About 0.7% (26/3489) of SEROQUEL patients did experience TSH increases in monotherapy studies. Some patients with TSH increases needed replacement thyroid treatment.
- In all quetiapine trials, the incidence of shifts in thyroid hormones and TSH were1: decrease in free T4 (<0.8 LLN), 2.0% (357/17513); decrease in total T4, 4.0% (75/1861); decrease in free T3, 0.4% (53/13766); decrease in total T3, 2.0% (26/1312), and increase in TSH, 4.9% (956/19412). In eight patients, where TBG was measured, levels of TBG were unchanged.
- Table 11 shows the incidence of these shifts in short term placebo-controlled clinical trials.
- In short-term placebo-controlled monotherapy trials, the incidence of reciprocal shifts in T3 and TSH was 0.0 % for both quetiapine (1/4800) and placebo (0/2190) and for T4 and TSH the shifts were 0.1% (7/6154) for quetiapine versus 0.0 % (1/3007) for placebo.
- Children and Adolescents: Safety and effectiveness of Quetiapine is supported by studies of SEROQUEL in children and adolescent patients 10 to 17 years of age.
- In acute placebo-controlled trials in children and adolescent patients with schizophrenia (6-week duration) or bipolar mania (3-week duration), the incidence of shifts at any time for SEROQUEL treated patients and placebo-treated patients for elevated TSH was 2.9% (8/280) vs. 0.7% (1/138), respectively and for decreased total thyroxine was 2.8% (8/289) vs. 0% (0/145), respectively. Of the SEROQUEL treated patients with elevated TSH levels, 1 had simultaneous low free T4 level at end of treatment.
- Based on shifts from normal baseline to potentially clinically important value at anytime post-baseline. Shifts in total T4, free T4, total T3 and free T3 are defined as <0.8 x LLN (pmol/L) and shift in TSH is > 5 mIU/L at any time.
- Based on shifts from normal baseline to potentially clinically important value at anytime post-baseline. Shifts in total T4, free T4, total T3 and free T3 are defined as <0.8 x LLN (pmol/L) and shift in TSH is >5 mIU/L at any time.
- Includes SEROQUEL and Quetiapine data.
- Adults: During clinical trials with quetiapine across all indications, the incidence of shifts in prolactin levels to a clinically significant value occurred in 3.6% (158/4416) of patients treated with quetiapine compared to 2.6% (51/1968) on placebo.
- Children and Adolescents: Safety and effectiveness of Quetiapine is supported by studies of SEROQUEL in children and adolescent patients 10 to 17 years of age. In acute placebo-controlled trials in children and adolescent patients with bipolar mania (3-week duration) or schizophrenia (6-week duration), the incidence of shifts in prolactin levels to a value (>20 µg/L males; > 26 µg/L females at any time) was 13.4% (18/134) for SEROQUEL compared to 4% (3/75) for placebo in males and 8.7% (9/104) for SEROQUEL compared to 0% (0/39) for placebo in females.
- Like other drugs that antagonize dopamine D2 receptors, Quetiapine elevates prolactin levels in some patients and the elevation may persist during chronic administration. Hyperprolactinemia, regardless of etiology, may suppress hypothalamic GnRH, resulting in reduced [[pituitary gonadotrophin]] secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male subjects.
- Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is considered in a patient with previously detected breast cancer. As is common with compounds which increase prolactin release, mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary and pancreatic adenomas) was observed in carcinogenicity studies conducted in mice and rats. Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans, but the available evidence is too limited to be conclusive.
- Somnolence was a commonly reported adverse reaction reported in patients treated with quetiapine especially during the 3-day period of initial dose titration. In schizophrenia trials, somnolence was reported in 24.7% (235/951) of patients on Quetiapine compared to 10.3% (33/319) of placebo patients. In a bipolar depression clinical trial, somnolence was reported in 51.8% (71/137) of patients on Quetiapine compared to 12.9% (18/140) of placebo patients. In a clinical trial for bipolar mania, somnolence was reported in 50.3% (76/151) of patients on Quetiapine compared to 11.9% (19/160) of placebo patients. Since quetiapine has the potential to impair judgment, thinking, or motor skills, patients should be cautioned about performing activities requiring mental alertness, such as operating a motor vehicle (including automobiles) or operating hazardous machinery until they are reasonably certain that quetiapine therapy does not affect them adversely. Somnolence may lead to falls.
- In short-term adjunctive therapy trials for MDD, somnolence was reported in 40% (252/627) of patients on Quetiapine respectively compared to 9% (27/309) of placebo patients. Somnolence was dose-related in these trials (37% (117/315) and 43% (135/312) for the 150 mg and 300 mg groups, respectively).
- Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing Quetiapine for patients who will be experiencing conditions which may contribute to an elevation in core body temperature, eg, exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration.
- Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in elderly patients, in particular those with advanced Alzheimer's dementia. Quetiapine and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.
- Acute withdrawal symptoms, such as insomnia, nausea and vomiting have been described after abrupt cessation of atypical antipsychotic drugs, including quetiapine fumarate. In short-term placebo-controlled, monotherapy clinical trials with Quetiapine that included a discontinuation phase which evaluated discontinuation symptoms, the aggregated incidence of patients experiencing one or more discontinuation symptoms after abrupt cessation was 12.1% (241/1993) for Quetiapine and 6.7% (71/1065) for placebo. The incidence of the individual adverse reactions (i.e., insomnia, nausea, headache, diarrhea, vomiting, dizziness and irritability) did not exceed 5.3% in any treatment group and usually resolved after 1 week post-discontinuation. Gradual dose reduction is advised.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- Adults
- The information below is derived from a clinical trial database for Quetiapine consisting of approximately 3400 patients exposed to Quetiapine for the treatment of Schizophrenia, Bipolar Disorder, and Major Depressive Disorder in placebo-controlled trials. This experience corresponds to approximately 1020.1 patient-years. Adverse reactions were assessed by collecting adverse reactions, results of physical examinations, vital signs, body weights, laboratory analyses and ECG results.
- The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at least once, an adverse reaction of the type listed.
- Adverse Reactions Associated with Discontinuation of Treatment in Short-Term, Placebo-Controlled Trials
- Schizophrenia: There were no adverse reactions leading to discontinuation that occurred at an incidence of ≥ 2% for Quetiapine in schizophrenia trials.
- Bipolar I Disorder, Manic or Mixed Episodes:
- There were no adverse reactions leading to discontinuation that occurred at an incidence of ≥ 2% for Quetiapine in the bipolar mania trial.
- Bipolar Disorder, Depressive Episode: In a single clinical trial in patients with bipolar depression, 14% (19/137) of patients on Quetiapine discontinued due to an adverse reaction compared to 4% (5/140) on placebo. Somnolence4 was the only adverse reaction leading to discontinuation that occurred at an incidence of ≥ 2% in Quetiapine in the bipolar depression trial.
- MDD, Adjunctive Therapy: In adjunctive therapy clinical trials in patients with MDD, 12.1% (76/627) of patients on Quetiapine discontinued due to adverse reaction compared to 1.9% (6/309) on placebo. Somnolence4 was the only adverse reaction leading to discontinuation that occurred at an incidence of ≥ 2% in Quetiapine in MDD trials.
- Commonly Observed Adverse Reactions in Short-Term, Placebo-Controlled Trials:
- In short-term placebo-controlled studies for schizophrenia the most commonly observed adverse reactions associated with the use of Quetiapine (incidence of 5% or greater) and observed at a rate on Quetiapine at least twice that of placebo were somnolence (25%), dry mouth (12%), dizziness (10%), and dyspepsia (5%).
- Adverse Reactions Occurring at an Incidence of 2% or More Among Quetiapine Treated Patients in Short-Term, Placebo-Controlled Trials
- Table 12 enumerates the incidence, rounded to the nearest percent, of adverse reactions that occurred during acute therapy of schizophrenia (up to 6 weeks) in 2% or more in patients treated with Quetiapine (doses ranging from 300 to 800 mg/day) where the incidence in patients treated with Quetiapine was greater than the incidence in placebo-treated patients.
- In a 3-week, placebo-controlled study in bipolar mania the most commonly observed adverse reactions associated with the use of Quetiapine (incidence of 5% or greater) and observed at a rate on Quetiapine at least twice that of placebo were somnolence (50%), dry mouth (34%), dizziness (10%), constipation (10%), weight gain (7%), dysarthria (5%), and nasal congestion (5%).
- Table 13 enumerates the incidence, rounded to the nearest percent, of adverse reactions that occurred during acute therapy of bipolar mania (up to 3 weeks) in 2% or more of patients treated with Quetiapine (doses ranging from 400 to 800 mg/day) where the incidence in patients treated with Quetiapine was greater than the incidence in placebo-treated patients.
- In the 8-week placebo-controlled bipolar depression study in adults, the most commonly observed adverse reactions associated with the use of Quetiapine (incidence of 5% or greater) and observed at a rate on Quetiapine at least twice that of placebo were somnolence (52%), dry mouth (37%), increased appetite (12%), weight gain (7%), dyspepsia (7%), and fatigue (6%).
- Table 14 enumerates the incidence, rounded to the nearest percent, of adverse reactions that occurred during acute therapy of bipolar depression (up to 8 weeks) in 2% or more of adult patients treated with Quetiapine 300 mg/day where the incidence in patients treated with Quetiapine was greater than the incidence in placebo-treated patients.
- In the 6-week placebo-controlled fixed dose adjunctive therapy clinical trials, for MDD, the most commonly observed adverse reactions associated with the use of Quetiapine (incidence of 5% or greater and observed at a rate on Quetiapine and at least twice that of placebo) were somnolence (150 mg: 37%; 300 mg: 43%), dry mouth (150 mg: 27%; 300 mg: 40%), fatigue (150 mg: 14%; 300 mg: 11%), constipation 300 mg only: 11%) and weight increased (300 mg only: 5%).
- Table 15 enumerates the incidence, rounded to the nearest percent, of adverse reactions that occurred during short-term adjunctive therapy of MDD (up to 6 weeks) in 2% or more of patients treated with Quetiapine (at doses of either 150 mg or 300 mg/day) where the incidence in patients treated with Quetiapine was greater than the incidence in placebo-treated patients.
- Adverse Reactions in clinical trials with quetiapine and not listed elsewhere in the label:
- Pyrexia, nightmares, peripheral edema, dyspnea, palpitations, rhinitis, eosinophilia, hypersensitivity, elevations in gamma-GT levels, and elevations in serum creatine phosphokinase (not associated with NMS), somnambulism (and other related events), hypothermia, decreased platelets, galactorrhea, bradycardia (which may occur at or near initiation of treatment and be associated with hypotension and/ or syncope), and priapism.
- Extrapyramidal Symptoms (EPS):
- Dystonia
Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.
- Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.
- Four methods were used to measure EPS: (1) Simpson-Angus total score (mean change from baseline) which evaluates Parkinsonism and akathisia, (2) Barnes Akathisia Rating Scale (BARS) Global Assessment Score, (3) incidence of spontaneous complaints of EPS (akathisia, akinesia, cogwheel rigidity, extrapyramidal syndrome, hypertonia, hypokinesia, neck rigidity, and tremor), and (4) use of anticholinergic medications to treat emergent EPS.
- Adults: In placebo-controlled clinical trials with quetiapine, utilizing doses up to 800 mg per day, the incidence of any adverse reactions related to EPS ranged from 8% to 11% for quetiapine and 4% to 11% for placebo.
- In three-arm placebo-controlled clinical trials for the treatment of schizophrenia, utilizing doses between 300 mg and 800 mg of Quetiapine, the incidence of any adverse reactions related to EPS was 8% for Quetiapine and 8% for SEROQUEL (without evidence of being dose related), and 5% in the placebo group. In these studies, the incidence of the individual adverse reactions (akathisia, extrapyramidal disorder, tremor, dyskinesia, dystonia, restlessness, and muscle rigidity) was generally low and did not exceed 3% for any treatment group.
- At the end of treatment, the mean change from baseline in SAS total score and BARS Global Assessment score was similar across the treatment groups. The use of concomitant anticholinergic medications was infrequent and similar across the treatment groups. The incidence of extrapyramidal symptoms was consistent with that seen with the profile of SEROQUEL in schizophrenia patients.
- In Tables 16-19, dystonic event included nuchal rigidity, hypertonia, dystonia, muscle rigidity, oculogyration; parkinsonism included cogwheel rigidity, tremor, drooling, hypokinesia; akathisia included akathisia, psychomotor agitation; dyskinetic event included tardive dyskinesia, dyskinesia, choreoathetosis; and other extrapyramidal event included restlessness, extrapyramidal disorder, movement disorder.
- In a placebo-controlled clinical trial for the treatment of bipolar mania, utilizing the dose range of 400-800 mg/day of Quetiapine, the incidence of any adverse reactions related to EPS was 6.6% for Quetiapine and 3.8% in the placebo group. In this study, the incidence of the individual adverse reactions (akathisia, extrapyramidal disorder, tremor, dystonia, restlessness, and cogwheel rigidity) did not exceed 2.0% for any adverse reaction.
- In a placebo-controlled clinical trial for the treatment of bipolar depression utilizing 300 mg of Quetiapine, the incidence of any adverse reactions related to EPS was 4.4% for Quetiapine and 0.7% in the placebo group. In this study, the incidence of the individual adverse reactions (akathisia, extrapyramidal disorder, tremor, dystonia, hypertonia) did not exceed 1.5% for any individual adverse reaction.
- In two placebo-controlled short-term adjunctive therapy clinical trials for the treatment of MDD utilizing between 150 mg and 300 mg of Quetiapine, the incidence of any adverse reactions related to EPS was 5.1% for Quetiapine and 4.2% for the placebo group.
- Table 19 shows the percentage of patients experiencing adverse reactions associated with EPS in adjunct clinical trials for MDD by dose:
- Children and Adolescents
- The information below is derived from a clinical trial database for SEROQUEL consisting of over 1000 pediatric patients. This database includes 677 adolescents (13 – 17 years old) exposed to SEROQUEL for the treatment of schizophrenia and 393 children and adolescents (10 – 17 years old) exposed to SEROQUEL for the treatment of acute bipolar mania.
- Adverse Reactions Associated with Discontinuation of Treatment in Short-Term, Placebo-Controlled Trials
- Schizophrenia: The incidence of discontinuation due to adverse reactions for quetiapine-treated and placebo-treated patients was 8.2% and 2.7%, respectively. The adverse reaction leading to discontinuation in 2% or more of patients on quetiapine and at a greater incidence than placebo was somnolence (2.7% and 0% for placebo).
- Bipolar I Mania: The incidence of discontinuation due to adverse reactions for quetiapine-treated and placebo-treated patients was 11.4% and 4.4%, respectively. The adverse reactions leading to discontinuation in 2% or more of patients on SEROQUEL and at a greater incidence than placebo were somnolence (4.1% vs. 1.1%) and fatigue (2.1% vs. 0).
- In an acute (8-week) Quetiapine trial in children and adolescents (10-17 years of age) with bipolar depression, in which efficacy was not established, the most commonly observed adverse reactions associated with the use of Quetiapine (incidence of 5% or greater and at least twice that for placebo) were: dizziness (7%), diarrhea (5%), fatigue (5%) and nausea (5%).
- In therapy for schizophrenia (up to 6 weeks), the most commonly observed adverse reactions associated with the use of quetiapine in adolescents (incidence of 5% or greater and quetiapine incidence at least twice that for placebo) were somnolence (34%), dizziness (12%), dry mouth (7%), tachycardia (7%).
- In bipolar mania therapy (up to 3 weeks) the most commonly observed adverse reactions associated with the use of quetiapine in children and adolescents (incidence of 5% or greater and quetiapine incidence at least twice that for placebo) were somnolence (53%), dizziness (18%), fatigue (11%), increased appetite (9%), nausea (8%), vomiting (8%), tachycardia (7%), dry mouth (7%), and weight increased (6%).
- Adverse Reactions Occurring at an Incidence of ≥ 2% Among Seroquel Treated Patients in Short-Term, Placebo-Controlled Trials
- Schizophrenia (Adolescents, 13 – 17 years old)
- The following findings were based on a 6-week placebo-controlled trial in which quetiapine was administered in either doses of 400 or 800 mg/day.
- Table 20 enumerates the incidence, rounded to the nearest percent, of adverse reactions that occurred during therapy (up to 6 weeks) of schizophrenia in 2% or more of patients treated with SEROQUEL (doses of 400 or 800 mg/day) where the incidence in patients treated with SEROQUEL was greater than the incidence in placebo-treated patients.
- Adverse reactions that were potentially dose-related with higher frequency in the 800 mg group compared to the 400 mg group included dizziness (8% vs. 15%), dry mouth (4% vs. 10%), and tachycardia (6% vs. 11%).
- Bipolar I Mania (Children and Adolescents 10 to 17 years old)
- The following findings were based on a 3-week placebo-controlled trial in which quetiapine was administered in either doses of 400 or 600 mg/day.
- Table 21 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse reactions that occurred during therapy (up to 3 weeks) of bipolar mania in 2% or more of patients treated with SEROQUEL (doses of 400 or 600 mg/day) where the incidence in patients treated with SEROQUEL was greater than the incidence in placebo-treated patients.
- Adverse reactions that were potentially dose-related with higher frequency in the 600 mg group compared to the 400 mg group included somnolence (50% vs. 57%), nausea (6% vs. 10%) and tachycardia (6% vs. 9%).
- Extrapyramidal Symptoms:
- Safety and effectiveness of Quetiapine is supported by studies of SEROQUEL in children and adolescent patients 10 to 17 years of age.
- In a short-term placebo-controlled Quetiapine monotherapy trial in children and adolescent patients (10-17 years of age) with bipolar depression (8-week duration), in which efficacy was not established, the aggregated incidence of extrapyramidal symptoms was 1.1% (1/92) for Quetiapine and 0% (0/100) for placebo.
- In a short-term placebo-controlled SEROQUEL monotherapy trial in adolescent patients (13-17 years of age) with schizophrenia (6-week duration), the aggregated incidence of extrapyramidal symptoms was 12.9% (19/147) for SEROQUEL and 5.3% (4/75) for placebo, though the incidence of the individual adverse reactions (e.g., akathisia, tremor, extrapyramidal disorder, hypokinesia, restlessness, psychomotor hyperactivity, muscle rigidity, dyskinesia) did not exceed 4.1% in any treatment group. In a short-term placebo-controlled SEROQUEL monotherapy trial in children and adolescent patients (10-17 years of age) with bipolar mania (3-week duration), the aggregated incidence of extrapyramidal symptoms was 3.6% (7/193) for SEROQUEL and 1.1% (1/90) for placebo.
- In Tables 22 and 23, dystonic events included nuchal rigidity, hypertonia, dystonia, and muscle rigidity; parkinsonism included cogwheel rigidity and tremor; akathisia included akathisia only; dyskinetic event included tardive dyskinesia, dyskinesia and choreoathetosis; and other extrapyramidal event included restlessness and extrapyramidal disorder.
- Table 22 below presents a listing of patients with adverse reactions associated with EPS in the short-term placebo-controlled SEROQUEL monotherapy trial in adolescent patients with schizophrenia (6-week duration).
- Table 23 below presents a listing of patients with adverse reactions associated with EPS in a short-term placebo-controlled monotherapy trial in children and adolescent patients with bipolar mania (3-week duration).
- Laboratory Changes:
- Neutrophil Counts
- Adults: In three-arm Quetiapine placebo-controlled monotherapy clinical trials, among patients with a baseline neutrophil count ≥ 1.5 x 109/L, the incidence of at least one occurrence of neutrophil count <1.5 x 109/L was 1.5% in patients treated with Quetiapine and 1.5% for SEROQUEL, compared to 0.8% in placebo-treated patients.
- In placebo-controlled monotherapy clinical trials involving 3368 patients on quetiapine fumarate and 1515 on placebo, the incidence of at least one occurrence of neutrophil count <1.0 x 109/L among patients with a normal baseline neutrophil count and at least one available follow up laboratory measurement was 0.3% (10/2967) in patients treated with quetiapine, compared to 0.1% (2/1349) in patients treated with placebo.
- Transaminase Elevations
- Adults: Asymptomatic, transient and reversible elevations in serum transaminases (primarily ALT) have been reported. The proportions of adult patients with transaminase elevations of >3 times the upper limits of the normal reference range in a pool of placebo-controlled trials ranged between 1% and 2% for Quetiapine compared to 2% for placebo. In schizophrenia trials in adults, the proportions of patients with transaminase elevations of >3 times the upper limits of the normal reference range in a pool of 3- to 6-week placebo-controlled trials were approximately 6% (29/483) for SEROQUEL compared to 1% (3/194) for placebo. These hepatic enzyme elevations usually occurred within the first 3 weeks of drug treatment and promptly returned to pre-study levels with ongoing treatment with quetiapine.
- Decreased Hemoglobin
- Adults: In short-term placebo-controlled trials, decreases in hemoglobin to ≤ 13 g/dL males, ≤ 12 g/dL females on at least one occasion occurred in 8.3% (594/7155) of quetiapine-treated patients compared to 6.2% (219/3536) of patients treated with placebo. In a database of controlled and uncontrolled clinical trials, decreases in hemoglobin to ≤ 13 g/dL males, ≤ 12 g/dL females on at least one occasion occurred in 11% (2277/20729) of quetiapine-treated patients.
- Interference with Urine Drug Screens
- There have been literature reports suggesting false positive results in urine enzyme immunoassays for methadone and tricyclic antidepressants in patients who have taken quetiapine. Caution should be exercised in the interpretation of positive urine drug screen results for these drugs, and confirmation by alternative analytical technique (e.g., chromatographic methods) should be considered.
- ECG Changes:
- Adults: 2.5% of Quetiapine patients, and 2.3% of placebo patients, had tachycardia (>120 bpm) at any time during the trials. Quetiapine was associated with a mean increase in heart rate, assessed by ECG, of 6.3 beats per minute compared to a mean increase of 0.4 beats per minute for placebo. This is consistent with the rates for SEROQUEL. The incidence of adverse reactions of tachycardia was 1.9% for Quetiapine compared to 0.5% for placebo. SEROQUEL use was associated with a mean increase in heart rate, assessed by ECG, of 7 beats per minute compared to a mean increase of 1 beat per minute among placebo patients. The slight tendency for tachycardia may be related to quetiapine’s potential for inducing orthostatic changes.
- Children and Adolescents: Safety and effectiveness of Quetiapine is supported by studies of SEROQUEL in children and adolescent patients 10 to 17 years of age.
- In an acute (8-week) Quetiapine trial in children and adolescents (10-17 years of age) with bipolar depression, in which efficacy was not established, increases in heart rate (> 110 bpm 10-12 years and 13-17 years) occurred in 0% of patients receiving Quetiapine and 1.2% of patients receiving placebo. Mean increases in heart rate were 3.4 bpm for Quetiapine, compared to 0.3 bpm in the placebo group.
- In the acute (6-week) SEROQUEL schizophrenia trial in adolescents (13-17 years of age), increases in heart rate (> 110 bpm) occurred in 5.2% of patients receiving SEROQUEL 400 mg and 8.5% of patients receiving SEROQUEL 800 mg compared to 0% of patients receiving placebo. Mean increases in heart rate were 3.8 bpm and 11.2 bpm for SEROQUEL 400 mg and 800 mg groups, respectively, compared to a decrease of 3.3 bpm in the placebo group.
- In the acute (3-week) SEROQUEL bipolar mania trial in children and adolescents (10-17 years of age), increases in heart rate (> 110 bpm) occurred in 1.1% of patients receiving SEROQUEL 400 mg and 4.7% of patients receiving SEROQUEL 600 mg compared to 0% of patients receiving placebo. Mean increases in heart rate were 12.8 bpm and 13.4 bpm for SEROQUEL 400 mg and 600 mg groups, respectively, compared to a decrease of 1.7 bpm in the placebo group.
## Postmarketing Experience
- The following adverse reactions were identified during post approval use of SEROQUEL. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- Adverse reactions reported since market introduction which were temporally related to quetiapine therapy include anaphylactic reaction, cardiomyopathy, hyponatremia, myocarditis, nocturnal enuresis, pancreatitis, retrograde amnesia, rhabdomyolysis, syndrome of inappropriate antidiuretic hormone secretion (SIADH), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN).
# Drug Interactions
- The risks of using Quetiapine in combination with other drugs have not been extensively evaluated in systematic studies. Given the primary CNS effects of Quetiapine, caution should be used when it is taken in combination with other centrally acting drugs. Quetiapine potentiated the cognitive and motor effects of alcohol in a clinical trial in subjects with selected psychotic disorders, and alcoholic beverages should be limited while taking quetiapine.
- Quetiapine exposure is increased by the prototype CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, indinavir, ritonavir, nefazodone, etc.) and decreased by the prototype of CYP3A4 inducers (e.g, phenytoin, carbamazepine, rifampin, avasimibe, St. John’s wort etc.) Dose adjustment of quetiapine will be necessary if it is co-administered with potent CYP3A4 inducers or inhibitors.
- CYP3A4 inhibitors:
- Coadministration of ketoconazole, a potent inhibitor of cytochrome CYP3A4, resulted in significant increase in quetiapine exposure. The dose should be reduced to one sixth of the original dose in patients coadministered with a strong CYP3A4 inhibitor.
- CYP3A4 inducers:
- Coadministration of quetiapine and phenytoin, a CYP3A4 inducer increased the mean oral clearance of quetiapine by 5-fold. Increased doses of Quetiapine up to 5 fold may be required to maintain control of symptoms of schizophrenia in patients receiving quetiapine and phenytoin, or other known potent CYP3A4 inducers. When the CYP3A4 inducer is discontinued, the dose of Quetiapine should be reduced to the original level within 7-14 days.
- The potential effects of several concomitant medications on quetiapine pharmacokinetics were studied.
- Because of its potential for inducing hypotension, Quetiapine may enhance the effects of certain antihypertensive agents.
- Quetiapine may antagonize the effects of levodopa and dopamine agonists.
- There are no clinically relevant pharmacokinetic interactions of Seroquel on other drugs based on the CYP pathway. Seroquel and its metabolites are non-inhibitors of major metabolizing CYPs (1A2, 2C9, 2C19, 2D6 and 3A4).
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- There are no adequate and well-controlled studies of Quetiapine use in pregnant women. In limited published literature, there were no major malformations associated with quetiapine exposure during pregnancy. In animal studies, embryo-fetal toxicity occurred. Quetiapine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Human Data
- There are limited published data on the use of quetiapine for treatment of schizophrenia and other psychiatric disorders during pregnancy. In a prospective observational study, 21 women exposed to quetiapine and other psychoactive medications during pregnancy delivered infants with no major malformations. Among 42 other infants born to pregnant women who used quetiapine during pregnancy, there were no major malformations reported (one study of 36 women, 6 case reports). Due to the limited number of exposed pregnancies, these postmarketing data do not reliably estimate the frequency or absence of adverse outcomes. Neonates exposed to antipsychotic drugs (including Quetiapine), during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization.
- Animal Data
- When pregnant rats and rabbits were exposed to quetiapine during organogenesis, there was no teratogenic effect in fetuses at doses up to 2.4 times the maximum recommended human dose (MRHD), for schizophrenia of 800 mg/day based on mg/m2 body surface area. However, there was evidence of embryo-fetal toxicity. These included delays in skeletal ossification occurred at approximately 1 and 2 times the MRHD of 800 mg/day and in both rats and rabbits and an increased incidence of carpal/tarsal flexure (minor soft tissue anomaly) in rabbit fetuses at approximately 2 times the MRHD. In addition, fetal weights were decreased in both species. Maternal toxicity observed as decreased body weights and/or death occurred at 2 times the MRHD in rats and at approximately 1-2 times the MRHD (all doses) in rabbits.
- In a peri/postnatal reproductive study in rats, no drug-related effects were observed when pregnant dams were treated with quetiapine at doses 0.01, 0.1, and 0.2 times the MRHD of 800 mg/day on mg/m2 body surface area. However, in a preliminary peri/postnatal study, there were increases in fetal and pup death, and decreases in mean litter weight at 3 times the MRHD.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Quetiapine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Quetiapine during labor and delivery.
### Nursing Mothers
- Quetiapine was excreted into human milk. Because of the potential for serious adverse reactions in nursing infants from Quetiapine, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother’s health.
- In published case reports, the level of quetiapine in breast milk ranged from undetectable to 170 μg/L. The estimated infant dose ranged from 0.09% to 0.43% of the weight-adjusted maternal dose. Based on a limited number (N=8) of mother/infant pairs, calculated infant daily doses range from less than 0.01 mg/kg (at a maternal daily dose up to 100 mg quetiapine) to 0.1 mg/kg (at a maternal daily dose of 400 mg).
### Pediatric Use
- Safety and effectiveness of Quetiapine is supported by studies of SEROQUEL for schizophrenia in adolescent patients 13 to 17 years of age and in bipolar mania in children and adolescent patients 10 to 17 years of age.
- In general, the adverse reactions observed in children and adolescents during the clinical trials with SEROQUEL were similar to those in the adult population with few exceptions. Increases in systolic and diastolic blood pressure occurred in children and adolescents and did not occur in adults. Orthostatic hypotension occurred more frequently in adults (4-7%) compared to children and adolescents (< 1%)
- Bipolar Depression
- The effectiveness of Quetiapine for the treatment of bipolar depression in patients under the age of 18 years has not been established. One 8-week trial was conducted to evaluate the safety and efficacy of Quetiapine in the treatment of bipolar depression in pediatric patients 10 to 17 years of age. The primary objective of the study was to evaluate whether Quetiapine at a dose of 150 to 300 mg/day demonstrated superior efficacy (as measured by change in CDRS-R total score from baseline to end of 8 weeks) compared to placebo in children and adolescents 10 to 17 years of age with bipolar depression. A total of 193 patients with bipolar depression were randomized to placebo or Quetiapine. The primary results of this study did not show a difference between Quetiapine and placebo in decreasing depression symptoms in children and adolescents with bipolar disorder. In this study, patients treated with Quetiapine exhibited metabolic changes, weight gain, increases in blood pressure and increases in heart rate.
- Some differences in the pharmacokinetics of quetiapine were noted between children/adolescents (10 to 17 years of age) and adults. When adjusted for weight, the AUC and Cmax of quetiapine were 41% and 39% lower, respectively, in children and adolescents compared to adults. The pharmacokinetics of the active metabolite, norquetiapine, were similar between children/adolescents and adults after adjusting for weight.
- Schizophrenia
- The efficacy and safety of Quetiapine in the treatment of schizophrenia in adolescents aged 13 to 17 years is supported by one 6-week, double-blind, placebo-controlled trial with SEROQUEL.
- Safety and effectiveness of Quetiapine in pediatric patients less than 13 years of age with schizophrenia have not been established.
- The safety and effectiveness of Quetiapine in the maintenance treatment of schizophrenia has not been established in patients less than 18 years of age.
- Bipolar Mania
- The efficacy and safety of Quetiapine in the treatment of bipolar mania in children and adolescents ages 10 to 17 years is supported by one 3-week, double-blind, placebo-controlled trial with SEROQUEL.
- Safety and effectiveness of Quetiapine in pediatric patients less than 10 years of age with bipolar mania have not been established.
- The safety and effectiveness of Quetiapine in the maintenance treatment of bipolar disorder has not been established in patients less than 18 years of age.
### Geriatic Use
- Sixty-eight patients in clinical studies with Quetiapine were 65 years of age or over. In general, there was no indication of any different tolerability of Quetiapine in the elderly compared to younger adults. Nevertheless, the presence of factors that might decrease pharmacokinetic clearance, increase the pharmacodynamic response to Quetiapine, or cause poorer tolerance or orthostasis, should lead to consideration of a lower starting dose, slower titration, and careful monitoring during the initial dosing period in the elderly. The mean plasma clearance of quetiapine was reduced by 30% to 50% in elderly patients when compared to younger patients.
### Gender
There is no FDA guidance on the use of Quetiapine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Quetiapine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Quetiapine in patients with renal impairment.
### Hepatic Impairment
- Since quetiapine is extensively metabolized by the liver, higher plasma levels are expected in patients with hepatic impairment. In this population, a low starting dose of 50 mg/day is recommended and the dose may be increased in increments of 50 mg/day.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Quetiapine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Quetiapine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- Patients receiving quetiapine should receive regular monitoring of weight.
# IV Compatibility
There is limited information regarding IV Compatibility of Quetiapine in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- In clinical trials, survival has been reported in acute overdoses of up to 30 grams of quetiapine. Most patients who overdosed experienced no adverse reactions or recovered fully from the reported events. Death has been reported in a clinical trial following an overdose of 13.6 grams of quetiapine alone. In general, reported signs and symptoms were those resulting from an exaggeration of the drug’s known pharmacological effects, ie, drowsiness and sedation, tachycardia and hypotension. Patients with pre-existing severe cardiovascular disease may be at an increased risk of the effects of overdose. One case, involving an estimated overdose of 9600 mg, was associated with hypokalemia and first degree heart block. In post-marketing experience, there were cases reported of QT prolongation with overdose. There were also very rare reports of overdose of SEROQUEL alone resulting in death or coma.
### Management
- In case of acute overdosage, establish and maintain an airway and ensure adequate oxygenation and ventilation. Gastric lavage (after intubation, if patient is unconscious) and administration of activated charcoal together with a laxative should be considered. The possibility of obtundation, seizure or dystonic reaction of the head and neck following overdose may create a risk of aspiration with induced emesis. Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias. If antiarrhythmic therapy is administered, disopyramide, procainamide and quinidine carry a theoretical hazard of additive QT-prolonging effects when administered in patients with acute overdosage of Quetiapine. Similarly it is reasonable to expect that the α-adrenergic-blocking properties of bretylium might be additive to those of quetiapine, resulting in problematic hypotension.
- There is no specific antidote to Quetiapine. Therefore, appropriate supportive measures should be instituted. The possibility of multiple drug involvement should be considered. Hypotension and circulatory collapse should be treated with appropriate measures such as intravenous fluids and/or sympathomimetic agents (epinephrine and dopamine should not be used, since β stimulation may worsen hypotension in the setting of quetiapine-induced α blockade). In cases of severe extrapyramidal symptoms, anticholinergic medication should be administered. Close medical supervision and monitoring should continue until the patient recovers.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Quetiapine in the drug label.
# Pharmacology
## Mechanism of Action
- The mechanism of action of Quetiapine in the treatment of schizophrenia, bipolar disorder and major depressive disorder (MDD), is unknown. However, its efficacy in schizophrenia could be mediated through a combination of dopamine type 2 (D2) and serotonin type 2A (5HT2A) antagonism. The active metabolite, N-desalkyl quetiapine (norquetiapine), has similar activity at D2, but greater activity at 5HT2A receptors, than the parent drug (quetiapine). Quetiapine’s efficacy in bipolar depression and MDD may partly be explained by the high affinity and potent inhibitory effects that norquetiapine exhibits for the norepinephrine transporter.
- Antagonism at receptors other than dopamine and serotonin with similar or greater affinities may explain some of the other effects of quetiapine and norquetiapine: antagonism at histamine H1 receptors may explain the somnolence, antagonism at adrenergic α1b receptors may explain the orthostatic hypotension, and antagonism at muscarinic M1 receptors may explain the anticholinergic effects.
## Structure
- Quetiapine (quetiapine fumarate) is an atypical antipsychotic belonging to a chemical class, the dibenzothiazepine derivatives. The chemical designation is 2-[2-(4-dibenzo [b,f ] [1,4] thiazepin-11-yl-1-piperazinyl)ethoxy]-ethanol fumarate (2:1) (salt). It is present in tablets as the fumarate salt. All doses and tablet strengths are expressed as milligrams of base, not as fumarate salt. Its molecular formula is C42H50N6O4S2•C4H4O4 and it has a molecular weight of 883.11 (fumarate salt). The structural formula is:
- Quetiapine fumarate is a white to off-white crystalline powder which is moderately soluble in water.
- Quetiapine is supplied for oral administration as 50 mg (peach), 150 mg (white), 200 mg (yellow), 300 mg (pale yellow), and 400 mg (white). All tablets are capsule shaped and film coated.
- Inactive ingredients for Quetiapine are lactose monohydrate, microcrystalline cellulose, sodium citrate, hypromellose, and magnesium stearate. The film coating for all Quetiapine tablets contain hypromellose, polyethylene glycol 400 and titanium dioxide. In addition, yellow iron oxide (50, 200 and 300 mg tablets) and red iron oxide (50 mg tablets) are included in the film coating of specific strengths.
- Each 50 mg tablet contains 58 mg of quetiapine fumarate equivalent to 50 mg quetiapine. Each 150 mg tablet contains 173 mg of quetiapine fumarate equivalent to 150 mg quetiapine. Each 200 mg tablet contains 230 mg of quetiapine fumarate equivalent to 200 mg quetiapine. Each 300 mg tablet contains 345 mg of quetiapine fumarate equivalent to 300 mg quetiapine. Each 400 mg tablet contains 461 mg of quetiapine fumarate equivalent to 400 mg quetiapine.
## Pharmacodynamics
- Quetiapine and norquetiapine have affinity for multiple neurotransmitter receptors including dopamine D1 and D2, serotonin 5HT1A and 5HT2A, histamine H1, muscarinic M1, and adrenergic α1b and α2 receptors. Quetiapine differs from norquetiapine in having no appreciable affinity for muscarinic M1 receptors whereas norquetiapine has high affinity. Quetiapine and norquetiapine lack appreciable affinity for benzodiazepine receptors.
- Effect on QT Interval
- In clinical trials quetiapine was not associated with a persistent increase in QT intervals. However, the QT effect was not systematically evaluated in a thorough QT study. In post marketing experience there were cases reported of QT prolongation in patients who overdosed on quetiapine, in patients with concomitant illness, and in patients taking medicines known to cause electrolyte imbalance or increase QT interval.
## Pharmacokinetics
- Adults
- Following multiple dosing of quetiapine up to a total daily dose of 800 mg, administered in divided doses, the plasma concentration of quetiapine and norquetiapine, the major active metabolite of quetiapine, were proportional to the total daily dose. Accumulation is predictable upon multiple dosing. Steady-state mean Cmax and AUC of norquetiapine are about 21-27% and 46-56%, respectively of that observed for quetiapine. Elimination of quetiapine is mainly via hepatic metabolism. The mean-terminal half-life is approximately 7 hours for quetiapine and approximately 12 hours for norquetiapine within the clinical dose range. Steady-state concentrations are expected to be achieved within two days of dosing. Quetiapine is unlikely to interfere with the metabolism of drugs metabolized by cytochrome P450 enzymes.
- Children and Adolescents
- At steady-state the pharmacokinetics of the parent compound, in children and adolescents (10-17 years of age), were similar to adults. However, when adjusted for dose and weight, AUC and Cmax of the parent compound were 41% and 39% lower, respectively, in children and adolescents than in adults. For the active metabolite, norquetiapine, AUC and Cmax were 45% and 31% higher, respectively, in children and adolescents than in adults. When adjusted for dose and weight, the pharmacokinetics of the metabolite, norquetiapine, was similar between children and adolescents and adults.
- Absorption
- Quetiapine fumarate reaches peak plasma concentrations approximately 6 hours following administration. Quetiapine dosed once daily at steady-state has comparable bioavailability to an equivalent total daily dose of SEROQUEL administered in divided doses, twice daily. A high-fat meal (approximately 800 to 1000 calories) was found to produce statistically significant increases in the Quetiapine Cmax and AUC of 44% to 52% and 20% to 22%, respectively, for the 50 mg and 300 mg tablets. In comparison, a light meal (approximately 300 calories) had no significant effect on the Cmax or AUC of quetiapine. It is recommended that Quetiapine be taken without food or with a light meal.
- Distribution
- Quetiapine is widely distributed throughout the body with an apparent volume of distribution of 10±4 L/kg. It is 83% bound to plasma proteins at therapeutic concentrations. In vitro, quetiapine did not affect the binding of warfarin or diazepam to human serum albumin. In turn, neither warfarin nor diazepam altered the binding of quetiapine.
- Metabolism and Elimination
- Following a single oral dose of 14C-quetiapine, less than 1% of the administered dose was excreted as unchanged drug, indicating that quetiapine is highly metabolized. Approximately 73% and 20% of the dose was recovered in the urine and feces, respectively. The average dose fraction of free quetiapine and its major active metabolite is <5% excreted in the urine.
- Quetiapine is extensively metabolized by the liver. The major metabolic pathways are sulfoxidation to the sulfoxide metabolite and oxidation to the parent acid metabolite; both metabolites are pharmacologically inactive. In vitro studies using human liver microsomes revealed that the cytochrome P450 3A4 isoenzyme is involved in the metabolism of quetiapine to its major, but inactive, sulfoxide metabolite and in the metabolism of its active metabolite norquetiapine.
- Age
- Oral clearance of quetiapine was reduced by 40% in elderly patients (≥ 65 years, n = 9) compared to young patients (n = 12), and dosing adjustment may be necessary.
- Gender
- There is no gender effect on the pharmacokinetics of quetiapine.
- Race
- There is no race effect on the pharmacokinetics of quetiapine.
- Smoking
- Smoking has no effect on the oral clearance of quetiapine.
- Renal Insufficiency
- Patients with severe renal impairment (CLcr=10-30 mL/min/1.73m2, n=8) had a 25% lower mean oral clearance than normal subjects (CLcr>80 mL/min/1.73m2, n=8), but plasma quetiapine concentrations in the subjects with renal insufficiency were within the range of concentrations seen in normal subjects receiving the same dose. Dosage adjustment is therefore not needed in these patients.
- Hepatic Insufficiency
- Hepatically impaired patients (n=8) had a 30% lower mean oral clearance of quetiapine than normal subjects. In 2 of the 8 hepatically impaired patients, AUC and Cmax were 3 times higher than those observed typically in healthy subjects. Since quetiapine is extensively metabolized by the liver, higher plasma levels are expected in the hepatically impaired population, and dosage adjustment may be needed.
- Drug-Drug Interaction Studies
- The in vivo assessments of effect of other drugs on the pharmacokinetics of quetiapine are summarized in Table 25.
- In vitro enzyme inhibition data suggest that quetiapine and 9 of its metabolites would have little inhibitory effect on in vivo metabolism mediated by cytochromes CYP 1A2, 2C9, 2C19, 2D6 and 3A4. Quetiapine at doses of 750 mg/day did not affect the single dose pharmacokinetics of antipyrine, lithium or lorazepam (Table 26).
## Nonclinical Toxicology
- Carcinogenicity studies were conducted in C57BL mice and Wistar rats. Quetiapine was administered in the diet to mice at doses of 20, 75, 250, and 750 mg/kg and to rats by gavage at doses of 25, 75, and 250 mg/kg for two years. These doses are equivalent to 0.1, 0.5, 1.5, and 4.5 times the maximum human dose (MRHD) of 800 mg/day based on mg/m2 body surface area (mice) or 0.3, 1, and 3 times the MRHD based on mg/m2 body surface area (rats). There were statistically significant increases in thyroid gland follicular adenomas in male mice at doses 1.5 and 4.5 times the MRHD on mg/m2 body surface area and in male rats at a dose of 3 times the MRHD on mg/m2 body surface area. Mammary gland adenocarcinomas were statistically significantly increased in female rats at all doses tested (0.3, 1, and 3 times the MRHD on mg/m2 body surface area).
- Thyroid follicular cell adenomas may have resulted from chronic stimulation of the thyroid gland by thyroid stimulating hormone (TSH) resulting from enhanced metabolism and clearance of thyroxine by rodent liver. Changes in TSH, thyroxine, and thyroxine clearance consistent with this mechanism were observed in subchronic toxicity studies in rat and mouse and in a 1-year toxicity study in rat; however, the results of these studies were not definitive. The relevance of the increases in thyroid follicular cell adenomas to human risk, through whatever mechanism, is unknown.
- Antipsychotic drugs have been shown to chronically elevate prolactin levels in rodents. Serum measurements in a 1-year toxicity study showed that quetiapine increased median serum prolactin levels a maximum of 32- and 13-fold in male and female rats, respectively. Increases in mammary neoplasms have been found in rodents after chronic administration of other antipsychotic drugs and are considered to be prolactin-mediated. The relevance of this increased incidence of prolactin-mediated mammary gland tumors in rats to human risk is unknown.
- The mutagenic potential of quetiapine was tested in the in vitro Ames bacterial gene mutation assay and in the in vitro mammalian gene mutation assay in Chinese Hamster Ovary cells. The clastogenic potential of quetiapine was tested in the in vitro chromosomal aberration assay in cultured human lymphocytes and in the in vivo bone marrow micronucleus assay in rats up to 500 mg/kg which is 6 times the maximum recommended human dose on mg/m2 body surface area. Based on weight of evidence quetiapine was not mutagenic or clastogenic in these tests.
- Quetiapine decreased mating and fertility in male Sprague-Dawley rats at oral doses of 50 and 150 mg/kg or approximately 1 and 3 times the maximum human dose (MRHD) of 800 mg/day on mg/m2 body surface area. Drug-related effects included increases in interval to mate and in the number of matings required for successful impregnation. These effects continued to be observed at 3 times the MRHD even after a two-week period without treatment. The no-effect dose for impaired mating and fertility in male rats was 25 mg/kg, or 0.3 times the MRHD dose on mg/m2 body surface area. Quetiapine adversely affected mating and fertility in female Sprague-Dawley rats at an oral dose approximately 1 times the MRHD of 800 mg/day on mg/m2 body surface area. Drug-related effects included decreases in matings and in matings resulting in pregnancy, and an increase in the interval to mate. An increase in irregular estrus cycles was observed at doses of 10 and 50 mg/kg, or approximately 0.1 and 1 times the MRHD of 800 mg/day on mg/m2 body surface area. The no-effect dose in female rats was 1 mg/kg, or 0.01 times the MRHD of 800 mg/day on mg/m2 body surface area.
- Quetiapine caused a dose-related increase in pigment deposition in thyroid gland in rat toxicity studies which were 4 weeks in duration or longer and in a mouse 2-year carcinogenicity study. Doses were 10 to 250 mg/kg in rats and 75 to 750 mg/kg in mice; these doses are 0.1-3, and 0.1-4.5 times the maximum recommended human dose (MRHD) of 800 mg/day on mg/m2 body surface area, respectively. Pigment deposition was shown to be irreversible in rats. The identity of the pigment could not be determined, but was found to be co-localized with quetiapine in thyroid gland follicular epithelial cells. The functional effects and the relevance of this finding to human risk are unknown.
- In dogs receiving quetiapine for 6 or 12 months, but not for 1 month, focal triangular cataracts occurred at the junction of posterior sutures in the outer cortex of the lens at a dose of 100 mg/kg, or 4 times the MRHD of 800 mg/day on mg/m2 body surface area. This finding may be due to inhibition of cholesterol biosynthesis by quetiapine. Quetiapine caused a dose-related reduction in plasma cholesterol levels in repeat-dose dog and monkey studies; however, there was no correlation between plasma cholesterol and the presence of cataracts in individual dogs. The appearance of delta 8 cholestanol in plasma is consistent with inhibition of a late stage in cholesterol biosynthesis in these species. There also was a 25% reduction in cholesterol content of the outer cortex of the lens observed in a special study in quetiapine treated female dogs. Drug-related cataracts have not been seen in any other species; however, in a 1-year study in monkeys, a striated appearance of the anterior lens surface was detected in 2/7 females at a dose of 225 mg/kg or 5.5 times the MRHD of 800 mg/day on mg/m2 body surface area.
# Clinical Studies
- The efficacy of Quetiapine in the treatment of schizophrenia was demonstrated in 1 short-term, 6-week, fixed-dose, placebo-controlled trial of inpatients and outpatients with schizophrenia (n=573) who met DSM-IV criteria for schizophrenia. Quetiapine (once daily) was administered as 300 mg on Day 1, and the dose was increased to either 400 mg or 600 mg by Day 2, or 800 mg by Day 3. The primary endpoint was the change from baseline of the Positive and Negative Syndrome Scale (PANSS) total score at the end of treatment (Day 42). Quetiapine doses of 400 mg, 600 mg and 800 mg once daily were superior to placebo in the PANSS total score at Day 42 (study 1 in Table 27).
- The efficacy of Quetiapine in the treatment of schizophrenia in adolescents (13–17 years of age) was supported by a 6-week, double-blind, placebo-controlled trial. Patients who met DSM-IV diagnostic criteria for schizophrenia were randomized into one of three treatment groups: SEROQUEL 400 mg/day (n = 73), SEROQUEL 800 mg/day (n = 74), or placebo (n = 75). Study medication was initiated at 50 mg/day and on day 2 increased to 100 mg/per day (divided and given two or three times per day). Subsequently, the dose was titrated to the target dose of 400 mg/day or 800 mg/day using increments of 100 mg/day, divided and given two or three times daily. The primary efficacy variable was the mean change from baseline in total Positive and Negative Syndrome Scale (PANSS). SEROQUEL at 400 mg/day and 800 mg/day was superior to placebo in the reduction of PANSS total score (study 2 in Table 27).
- In a longer-term trial (study 3), clinically stable adult outpatients (n=171) meeting DSM-IV criteria for schizophrenia who remained stable following 16 weeks of open-label treatment with flexible doses of Quetiapine (400 mg/day-800 mg/day) were randomized to placebo or to continue on their current Quetiapine (400 mg/day-800 mg/day) for observation for possible relapse during the double-blind continuation (maintenance) phase. Stabilization during the open-label phase was defined as receiving a stable dose of Quetiapine and having a CGI-S≤4 and a PANSS score ≤60 from beginning to end of this open-label phase (with no increase of ≥10 points in PANSS total score). Relapse during the double-blind phase was defined in terms of a ≥30% increase in the PANSS Total score, or CGI-Improvement score of ≥6, or hospitalization due to worsening of schizophrenia, or need for any other antipsychotic medication. Patients on Quetiapine experienced a statistically significant longer time to relapse than did patients on placebo (Figure 1).
- PLA Placebo. QTP Quetiapine. XR Extended-release.
- Note: Results are from the interim analysis.
- Bipolar I Disorder, manic or mixed episodes
- Adults
- The efficacy of Quetiapine in the acute treatment of manic episodes was established in one 3-week, placebo-controlled trial (Study 1 in Table 28) in patients who met DSM-IV criteria for bipolar I disorder with manic or mixed episodes with or without psychotic features (N=316). Patients were hospitalized for a minimum of 4 days at randomization. Patients randomized to Quetiapine received 300 mg on Day 1 and 600 mg on Day 2. Afterwards, the dose could be adjusted between 400 mg and 800 mg per day.
- The primary rating instrument used for assessing manic symptoms in these trials was the Young Mania Rating Scale (YMRS), an 11-item clinician-rated scale traditionally used to assess the degree of manic symptoms in a range from 0 (no manic features) to 60 (maximum score). Quetiapine was superior to placebo in the reduction of the YMRS total score at week 3.
- The efficacy of SEROQUEL in the treatment of acute manic episodes was also established in 3 placebo-controlled trials in patients who met DSM-IV criteria for bipolar I disorder with manic episodes. These trials included patients with or without psychotic features and excluded patients with rapid cycling and mixed episodes. Of these trials, 2 were monotherapy (12 weeks) and 1 was adjunct therapy (3 weeks) to either lithium or divalproex. Key outcomes in these trials were change from baseline in the YMRS score at 3 and 12 weeks for monotherapy and at 3 weeks for adjunct therapy. Adjunct therapy is defined as the simultaneous initiation or subsequent administration of SEROQUEL with lithium or divalproex.
- The results of the trials follow:
- Monotherapy
In two 12-week trials (n=300, n=299) comparing SEROQUEL to placebo, SEROQUEL was superior to placebo in the reduction of the YMRS total score at weeks 3 and 12. The majority of patients in these trials taking SEROQUEL were dosed in a range between 400 mg/day and 800 mg/ day (Studies 2 and 3 in Table 28).
- In two 12-week trials (n=300, n=299) comparing SEROQUEL to placebo, SEROQUEL was superior to placebo in the reduction of the YMRS total score at weeks 3 and 12. The majority of patients in these trials taking SEROQUEL were dosed in a range between 400 mg/day and 800 mg/ day (Studies 2 and 3 in Table 28).
- Adjunct Therapy
In a 3-week placebo-controlled trial, 170 patients with bipolar mania (YMRS ≥ 20) were randomized to receive SEROQUEL or placebo as adjunct treatment to lithium or divalproex. Patients may or may not have received an adequate treatment course of lithium or divalproex prior to randomization. SEROQUEL was superior to placebo when added to lithium or divalproex alone in the reduction of YMRS total score. The majority of patients in this trial taking SEROQUEL were dosed in a range between 400 mg/day and 800 mg/day (study 4 in Table 28).
- In a 3-week placebo-controlled trial, 170 patients with bipolar mania (YMRS ≥ 20) were randomized to receive SEROQUEL or placebo as adjunct treatment to lithium or divalproex. Patients may or may not have received an adequate treatment course of lithium or divalproex prior to randomization. SEROQUEL was superior to placebo when added to lithium or divalproex alone in the reduction of YMRS total score. The majority of patients in this trial taking SEROQUEL were dosed in a range between 400 mg/day and 800 mg/day (study 4 in Table 28).
- Children and Adolescents (ages 10-17)
- The efficacy of Quetiapine in the acute treatment of manic episodes associated with bipolar I disorder in children and adolescents (10 to 17 years of age) was extrapolated from a 3-week, double-blind, placebo-controlled, multicenter trial. Patients who met DSM-IV diagnostic criteria for a manic episode were randomized into one of three treatment groups: SEROQUEL 400 mg/day (n = 95), SEROQUEL 600 mg/day (n = 98), or placebo (n = 91). Study medication was initiated at 50 mg/day and on day 2 increased to 100 mg/day (divided doses given two or three times daily). Subsequently, the dose was titrated to a target dose of 400 mg/day or 600 mg/day using increments of 100 mg/day, given in divided doses two or three times daily. The primary efficacy variable was the mean change from baseline in total YMRS score. SEROQUEL 400 mg/day and 600 mg/day were superior to placebo in the reduction of YMRS total score (study 5 in Table 28).
- Bipolar Disorder, Depressive Episodes
- Adults
- The efficacy of Quetiapine for the acute treatment of depressive episodes associated with bipolar disorder in patients who met DSM-IV criteria for bipolar disorder was established in one 8-week, randomized, double-blind, placebo-controlled study (N=280 outpatients). This study included patients with bipolar I and II disorder, and those with and without a rapid cycling course. Patients randomized to Quetiapine were administered 50 mg on Day 1, 100 mg on Day 2, 200 mg on Day 3, and 300 mg on Day 4 and after.
- The primary rating instrument used to assess depressive symptoms was the Montgomery-Asberg Depression Rating Scale (MADRS), a 10-item clinician-rated scale with scores ranging from 0 (no depressive features) to 60 (maximum score). The primary endpoint was the change from baseline in MADRS score at week 8. Quetiapine was superior to placebo in reduction of MADRS score at week 8 (study 6 in Table 29).
- The efficacy of SEROQUEL for the treatment of depressive episodes associated with bipolar disorder was established in 2 identical 8-week, randomized, double-blind, placebo-controlled studies (N=1045). These studies included patients with either bipolar I or II disorder and those with or without a rapid cycling course. Patients randomized to SEROQUEL were administered fixed doses of either 300 mg or 600 mg once daily.
- The primary rating instrument used to assess depressive symptoms in these studies was the MADRS. The primary endpoint in both studies was the change from baseline in MADRS score at week 8. In both studies, SEROQUEL was superior to placebo in reduction of MADRS score at week 8 (Studies 7 and 8 in Table 29). In these studies, no additional benefit was seen with the 600 mg dose. For the 300 mg dose group, statistically significant improvements over placebo were seen in overall quality of life and satisfaction related to various areas of functioning, as measured using the Q-LES-Q(SF).
- Maintenance Treatment as an Adjunct to Lithium or Divalproex
- The efficacy of SEROQUEL in the maintenance treatment of bipolar I disorder was established in 2 placebo-controlled trials in patients (n=1326) who met DSM-IV criteria for bipolar I disorder (studies 9 and 10). The trials included patients whose most recent episode was manic, depressed, or mixed, with or without psychotic features. In the open-label phase, patients were required to be stable on SEROQUEL plus lithium or divalproex for at least 12 weeks in order to be randomized. On average, patients were stabilized for 15 weeks. In the randomization phase, patients continued treatment with lithium or divalproex and were randomized to receive either SEROQUEL (administered twice daily totaling 400 mg/day to 800 mg/day or placebo. Approximately 50% of the patients had discontinued from the SEROQUEL group by day 280 and 50% of the placebo group had discontinued by day 117 of double-blind treatment. The primary endpoint in these studies was time to recurrence of a mood event (manic, mixed or depressed episode). A mood event was defined as medication initiation or hospitalization for a mood episode; YMRS score ≥ 20 or MADRS score ≥ 20 at 2 consecutive assessments; or study discontinuation due to a mood event.
- In both studies, SEROQUEL was superior to placebo in increasing the time to recurrence of any mood event (Figure 2 and Figure 3). The treatment effect was present for increasing time to recurrence of both manic and depressed episodes. The effect of SEROQUEL was independent of any specific subgroup (assigned mood stabilizer, sex, age, race, most recent bipolar episode, or rapid cycling course).
- The efficacy of Quetiapine as adjunctive therapy to antidepressants in the treatment of MDD was demonstrated in two 6-week placebo-controlled, fixed-dose trials (n=936). Quetiapine 150 mg/day or 300 mg/day was given as adjunctive therapy to existing antidepressant therapy in patients who had previously shown an inadequate response to at least one antidepressant. Quetiapine was administered as 50 mg/day on Days 1 and 2, and increased to 150 mg/day on Day 3 for both dose groups. On Day 5, the dose was increased to 300 mg/day in the 300 mg/day fixed-dose group. Inadequate response was defined as having continued depressive symptoms for the current episode [Hamilton Depression Rating Scale (HAM-D) total score of ≥ 20] despite using an antidepressant for 6 weeks at or above the minimally effective labelled dose. The mean HAM-D total score at entry was 24, and 17% of patients scored 28 or greater. Patients were on various antidepressants prior to study entry including SSRI’s (paroxetine, fluoxetine, sertraline, escitalopram, or citalopram), SNRI’s, (duloxetine and venlafaxine,) TCA (amitriptyline) and other (bupropion).
- The primary endpoint in these trials was change from baseline to week 6 in the Montgomery-Asberg Depression Rating Scale (MADRS.), Quetiapine 300 mg once daily as adjunctive treatment to other antidepressant therapy was superior to antidepressant alone in reduction of MADRS total score in both trials. Quetiapine 150 mg once daily as adjunctive treatment was superior to antidepressant therapy alone in reduction of MADRS total score in one trial (studies 1 and 2 in Table 30).
# How Supplied
- 50 mg Tablets (NDC 0310-0280) peach, film coated, capsule-shaped, biconvex, intagliated tablet with “XR 50” on one side and plain on the other are supplied in bottles of 60 tablets and hospital unit dose packages of 100 tablets.
- 150 mg Tablets (NDC 0310-0281) white, film-coated, capsule-shaped, biconvex, intagliated tablet with ‘XR 150’ on one side and plain on the other are supplied in bottles of 60 tablets and hospital unit dose packages of 100 tablets.
- 200 mg Tablets (NDC 0310-0282) yellow, film coated, capsule-shaped, biconvex, intagliated tablet with “XR 200” on one side and plain on the other are supplied in bottles of 60 tablets and hospital unit dose packages of 100 tablets.
- 300 mg Tablets (NDC 0310-0283) pale yellow, film coated, capsule-shaped, biconvex, intagliated tablet with “XR 300” on one side and plain on the other are supplied in bottles of 60 tablets and hospital unit dose packages of 100 tablets.
- 400 mg Tablets (NDC 0310-0284) white, film coated, capsule-shaped, biconvex, intagliated tablet with “XR 400” on one side and plain on the other are supplied in bottles of 60 tablets and hospital unit dose packages of 100 tablets.
- Store Quetiapine at 25ºC (77ºF); excursions permitted to 15-30ºC (59-86ºF).
## Storage
There is limited information regarding Quetiapine Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with Quetiapine and should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions” is available for Quetiapine. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document.
- Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking Quetiapine.
- Increased Mortality in Elderly Patients with Dementia-Related Psychosis
- Patients and caregivers should be advised that elderly patients with dementia-related psychoses treated with atypical antipsychotic drugs are at increased risk of death compared with placebo. Quetiapine is not approved for elderly patients with dementia-related psychosis.
- Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.
- Patients should be advised to report to their physician any signs or symptoms that may be related to NMS. These may include muscle stiffness and high fever.
- Patients should be aware of the symptoms of hyperglycemia (high blood sugar) and diabetes mellitus. Patients who are diagnosed with diabetes, those with risk factors for diabetes, or those that develop these symptoms during treatment should have their blood glucose monitored at the beginning of and periodically during treatment.
- Patients should be advised that elevations in total cholesterol, LDL-cholesterol and triglycerides and decreases in HDL-cholesterol may occur. Patients should have their lipid profile monitored at the beginning of and periodically during treatment.
- Patients should be advised that they may experience weight gain. Patients should have their weight monitored regularly.
- Patients should be advised of the risk of orthostatic hypotension (symptoms include feeling dizzy or lightheaded upon standing, which may lead to falls) especially during the period of initial dose titration, and also at times of re-initiating treatment or increases in dose.
- Increased Blood Pressure in Children and Adolescents
- Children and adolescent patients should have their blood pressure measured at the beginning of, and periodically during, treatment.
- Patients with a pre-existing low WBC or a history of drug induced leukopenia/neutropenia should be advised that they should have their CBC monitored while taking Quetiapine.
- Interference with Cognitive and Motor Performance
- Patients should be advised of the risk of somnolence or sedation (which may lead to falls), especially during the period of initial dose titration. Patients should be cautioned about performing any activity requiring mental alertness, such as operating a motor vehicle (including automobiles) or operating machinery, until they are reasonably certain quetiapine therapy does not affect them adversely..
- Patients should be advised regarding appropriate care in avoiding overheating and dehydration.
- As with other medications, patients should be advised to notify their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs.
- Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy with Quetiapine.
- Quetiapine is indicated as an integral part of a total treatment program for adolescents with schizophrenia and pediatric bipolar disorder that may include other measures (psychological, educational, and social). Effectiveness and safety of Quetiapine have not been established in pediatric patients less than 13 years of age for schizophrenia or less than 10 years of age for bipolar mania. Appropriate educational placement is essential and psychosocial intervention is often helpful. The decision to prescribe atypical antipsychotic medication will depend upon the physician’s assessment of the chronicity and severity of the patient’s symptoms.
- Read this Medication Guide before you start taking Quetiapine and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or treatment.
- What is the most important information I should know about Quetiapine?
- Quetiapine may cause serious side effects, including:
- risk of death in the elderly with dementia: Medicines like Quetiapine can increase the risk of death in elderly people who have memory loss (dementia). Quetiapine is not for treating psychosis in the elderly with dementia.
- risk of suicidal thoughts or actions (antidepressant medicines, depression and other serious mental illnesses, and suicidal thoughts or actions).
- Talk to your, or your family member’s, healthcare provider about:
- all risks and benefits of treatment with antidepressant medicines
- all treatment choices for depression or other serious mental illness
- Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment.
- Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have a particularly high risk of having suicidal thoughts or actions. These include people who have (or have a family history of) depression, bipolar illness (also called manic-depressive illness), or suicidal thoughts or actions.
- How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member?
- Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. This is very important when an antidepressant medicine is started or when the dose is changed.
- Call the healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings.
- Keep all follow-up visits with the healthcare provider as scheduled. Call the healthcare provider between visits as needed, especially if you have concerns about symptoms.
- Call a healthcare provider right away if you or your family member has any of the following symptoms, especially if they are new, worse, or worry you:
- thoughts about suicide or dying
- attempts to commit suicide
- new or worse depression
- new or worse anxiety
- feeling very agitated or restless
- panic attacks
- trouble sleeping (insomnia)
- new or worse irritability
- acting aggressive, being angry, or violent
- acting on dangerous impulses
- an extreme increase in activity and talking (mania)
- other unusual changes in behavior or mood
- What else do I need to know about antidepressant medicines?
- Never stop an antidepressant medicine without first talking to your healthcare provider. Stopping an antidepressant medicine suddenly can cause other symptoms.
- Antidepressants are medicines used to treat depression and other illnesses. It is important to discuss all the risks of treating depression and also the risks of not treating it. Patients and their families or other caregivers should discuss all treatment choices with the healthcare provider, not just the use of antidepressants.
- Antidepressant medicines have other side effects. Talk to the healthcare provider about the side effects of the medicine prescribed for you or your family member.
- Antidepressant medicines can interact with other medicines. Know all of the medicines that you or your family member take. Keep a list of all medicines to show the healthcare provider. Do not start new medicines without first checking with your healthcare provider.
- Not all antidepressant medicines prescribed for children are FDA approved for use in children. Talk to your child’s healthcare provider for more information.
- What is Quetiapine?
- Quetiapine is a prescription medicine used to treat:
- schizophrenia in people 13 years of age or older
- bipolar disorder in adults, including:
depressive episodes associated with bipolar disorder
manic episodes associated with bipolar I disorder alone or with lithium or divalproex
long-term treatment of bipolar I disorder with lithium or divalproex
manic episodes associated with bipolar I disorder in children ages 10 to 17 years old.
major depressive disorder as add-on treatment with antidepressant medicines when your healthcare provider determines that 1 antidepressant alone is not enough to treat your depression.
- depressive episodes associated with bipolar disorder
- manic episodes associated with bipolar I disorder alone or with lithium or divalproex
- long-term treatment of bipolar I disorder with lithium or divalproex
- manic episodes associated with bipolar I disorder in children ages 10 to 17 years old.
- major depressive disorder as add-on treatment with antidepressant medicines when your healthcare provider determines that 1 antidepressant alone is not enough to treat your depression.
- It is not known if Quetiapine is safe and effective in children under 10 years of age.
- Who should not take Quetiapine?
- Do not take Quetiapine if you are allergic to quetiapine fumarate or any of the ingredients in Quetiapine.
- What should I tell my healthcare provider before taking Quetiapine?
- Before you take Quetiapine, tell your healthcare provider if you have or have had:
- diabetes or high blood sugar in you or your family. Your healthcare provider should check your blood sugar before you start Quetiapine and also during therapy.
high levels of total cholesterol, triglycerides or LDL-cholesterol or low levels of HDL-cholesterol
low or high blood pressure
low white blood cell count
cataracts
seizures
abnormal thyroid tests
high prolactin levels
heart problems
liver problems
any other medical condition
pregnancy or plans to become pregnant. It is not known if Quetiapine will harm your unborn baby
breast-feeding or plans to breast-feed. Quetiapine can pass into your breast milk. You and your healthcare provider should decide if you will take Quetiapine or breast-feed. You should not do both.
- diabetes or high blood sugar in you or your family. Your healthcare provider should check your blood sugar before you start Quetiapine and also during therapy.
- high levels of total cholesterol, triglycerides or LDL-cholesterol or low levels of HDL-cholesterol
- low or high blood pressure
- low white blood cell count
- cataracts
- seizures
- abnormal thyroid tests
- high prolactin levels
- heart problems
- liver problems
- any other medical condition
- pregnancy or plans to become pregnant. It is not known if Quetiapine will harm your unborn baby
- breast-feeding or plans to breast-feed. Quetiapine can pass into your breast milk. You and your healthcare provider should decide if you will take Quetiapine or breast-feed. You should not do both.
- Tell the healthcare provider about all the medicines that you take or recently have taken including prescription medicines, over-the-counter medicines, herbal supplements and vitamins.
- Quetiapine and other medicines may affect each other causing serious side effects. Quetiapine may affect the way other medicines work, and other medicines may affect how Quetiapine works.
- Tell your healthcare provider if you are having a urine drug screen because Quetiapine may affect your test results. Tell those giving the test that you are taking Quetiapine.
- How should I take Quetiapine?
- Take Quetiapine exactly as your healthcare provider tells you to take it. Do not change the dose yourself.
- Take Quetiapine by mouth, with a light meal or without food.
- Quetiapine should be swallowed whole and not split, chewed or crushed.
- If you feel you need to stop Quetiapine, talk with your healthcare provider first. If you suddenly stop taking Quetiapine, you may have side effects such as trouble sleeping or trouble staying asleep (insomnia), nausea, and vomiting.
- If you miss a dose of Quetiapine, take it as soon as you remember. If you are close to your next dose, skip the missed dose. Just take the next dose at your regular time. Do not take 2 doses at the same time unless your healthcare provider tells you to. If you are not sure about your dosing, call your healthcare provider.
- What should I avoid while taking Quetiapine?
- Do not drive, operate machinery, or do other dangerous activities until you know how Quetiapine affects you. Quetiapine may make you drowsy.
- Avoid getting overheated or dehydrated.
- Do not over-exercise.
- In hot weather, stay inside in a cool place if possible.
- Stay out of the sun. Do not wear too much or heavy clothing.
- Drink plenty of water.
- Do not drink alcohol while taking Quetiapine. It may make some side effects of Quetiapine worse.
- What are possible side effects of Quetiapine?
- Quetiapine can cause serious side effects, including:
See “What is the most important information I should know about Quetiapine?”
stroke that can lead to death can happen in elderly people with dementia who take medicines like SEROQUEL
neuroleptic malignant syndrome (NMS). NMS is a rare but very serious condition that can happen in people who take antipsychotic medicines, including Quetiapine. NMS can cause death and must be treated in a hospital. Call your healthcare provider right away if you become severely ill and have some or all of these symptoms:
high fever
excessive sweating
rigid muscles
confusion
changes in your breathing, heartbeat, and blood pressure
high blood sugar (hyperglycemia). High blood sugar can happen if you have diabetes already or if you have never had diabetes.
- See “What is the most important information I should know about Quetiapine?”
- stroke that can lead to death can happen in elderly people with dementia who take medicines like SEROQUEL
- neuroleptic malignant syndrome (NMS). NMS is a rare but very serious condition that can happen in people who take antipsychotic medicines, including Quetiapine. NMS can cause death and must be treated in a hospital. Call your healthcare provider right away if you become severely ill and have some or all of these symptoms:
high fever
excessive sweating
rigid muscles
confusion
changes in your breathing, heartbeat, and blood pressure
high blood sugar (hyperglycemia). High blood sugar can happen if you have diabetes already or if you have never had diabetes.
- high fever
- excessive sweating
- rigid muscles
- confusion
- changes in your breathing, heartbeat, and blood pressure
- high blood sugar (hyperglycemia). High blood sugar can happen if you have diabetes already or if you have never had diabetes.
- High blood sugar could lead to:
- build up of acid in your blood due to ketones (ketoacidosis)
- coma
- death
- Increases in blood sugar can happen in some people who take Quetiapine. Extremely high blood sugar can lead to coma or death. If you have diabetes or risk factors for diabetes (such as being overweight or a family history of diabetes) your healthcare provider should check your blood sugar before you start Quetiapine and during therapy.
- Call your healthcare provider if you have any of these symptoms of high blood sugar (hyperglycemia) while taking Quetiapine:
- feel very thirsty
- need to urinate more than usual
- feel very hungry
- feel weak or tired
- feel sick to your stomach
- feel confused, or your breath smells fruity
- High fat levels in your blood (increased cholesterol and triglycerides). High fat levels may happen in people treated with Quetiapine. You may not have any symptoms, so your healthcare provider may decide to check your cholesterol and triglycerides during your treatment with Quetiapine.
- Increase in weight (weight gain). Weight gain is common in people who take Quetiapine so you and your healthcare provider should check your weight regularly. Talk to your healthcare provider about ways to control weight gain, such as eating a healthy, balanced diet, and exercising.
- Movements you cannot control in your face, tongue, or other body parts (tardive dyskinesia). These may be signs of a serious condition. Tardive dyskinesia may not go away, even if you stop taking Quetiapine. Tardive dyskinesia may also start after you stop taking Quetiapine.
- Decreased blood pressure (orthostatic hypotension), including lightheadedness or fainting caused by a sudden change in heart rate and blood pressure when rising too quickly from a sitting or lying position.
- Increases in blood pressure in children and teenagers. Your healthcare provider should check blood pressure in children and adolescents before starting Quetiapine and during therapy. Quetiapine is not approved for patients under 10 years of age.
- Low white blood cell count
- Cataracts
- Seizures
- Abnormal thyroid tests: Your healthcare provider may do blood tests to check your thyroid hormone level.
- Increases in prolactin levels: Your healthcare provider may do blood tests to check your prolactin levels.
- Sleepiness, drowsiness, feeling tired, difficulty thinking and doing normal activities
- Increased body temperature
- Difficulty swallowing
- Trouble sleeping or trouble staying asleep (insomnia), nausea, or vomiting if you suddenly stop taking Quetiapine. These symptoms usually get better 1 week after you start having them.
- The most common side effects of Quetiapine include:
- dry mouth
- constipation
- dizziness
- increased appetite
- upset stomach
- fatigue
- stuffy nose
- difficulty moving
- These are not all the possible side effects of Quetiapine. For more information, ask your healthcare provider or pharmacist.
- Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
- How should I store Quetiapine?
- Store Quetiapine at room temperature, between 68°F to 77°F (20°C to 25°C).
- Keep Quetiapine and all medicines out of the reach of children.
- General information about the safe and effective use of Quetiapine.
- Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Quetiapine for a condition for which it was not prescribed. Do not give Quetiapine to other people, even if they have the same symptoms you have. It may harm them.
- This Medication Guide summarizes the most important information about Quetiapine. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about Quetiapine that is written for health professionals.
- For more information, go to www.SEROQUELXR.com, or call 1-800-236-9933.
- What are the ingredients in Quetiapine?
- Active ingredient: quetiapine fumarate
- Inactive ingredients: lactose monohydrate, microcrystalline cellulose, sodium citrate, hypromellose, and magnesium stearate. The film coating for all Quetiapine tablets contain hypromellose, polyethylene glycol 400 and titanium dioxide. In addition, yellow iron oxide (50, 200 and 300 mg tablets) and red iron oxide (50 mg tablets) are included in the film coating of specific strengths.
- This Medication Guide has been approved by the U.S. Food and Drug Administration.
# Precautions with Alcohol
- Do not drink alcohol while taking Quetiapine. It may make some side effects of Quetiapine worse.
# Brand Names
- SEROQUEL XR®[8]
# Look-Alike Drug Names
- QUEtiapine® — OLANZapine®
- Seroquel® — Quetiapine®
- SEROquel® — Serzone®
- SEROquel® — SINEquan®
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Quetiapine | |
27f7489e5c7aec09001e261fc8d29c7f84761ceb | wikidoc | Quickening | Quickening
# Overview
In pregnancy terms, the moment of quickening refers to the initial motion of the fetus in the uterus as it is perceived or felt by the pregnant woman. According to the Oxford English Dictionary, to "quicken" means "to reach the stage of pregnancy at which the child shows signs of life." In the twentieth century, ultrasound technology made it possible to see that a fetus is in motion even if the pregnant woman does not yet feel it. This technological development made the concept of "quickening" a bit more complex.
# Medical facts
The first natural sensation of quickening may feel like a light tapping, or the fluttering of a butterfly. These sensations eventually become stronger and more regular as the pregnancy progresses. Sometimes, the first movements are misattributed to gas or hunger pangs.
A woman’s uterine muscles, rather than her abdominal muscles, are first to sense fetal motion. Therefore, a woman’s body weight usually does not have a substantial effect on when movements are initially perceived. Women who have already given birth have more relaxed uterine muscles that are consequently more sensitive to fetal motion, and for them fetal motion can sometimes be felt as early as 14 weeks.
Usually, quickening occurs naturally at about the middle of a pregnancy. A woman pregnant for the first time (i.e. a primiparous woman) typically feels fetal movements at about 20-21 weeks, whereas a woman who has already given birth at least two times (i.e. a multiparous woman) will typically feel movements around 18 weeks.
# Legal history
Historically, quickening has sometimes been considered to be the beginning of the possession of "individual life" by the fetus. British legal scholar William Blackstone explained the subject of quickening in the eighteenth century, relative to feticide and abortion:
Nevertheless, quickening was only one of several standards that were used historically to determine when the right to life attaches to a fetus. According to the "ancient law" mentioned by Blackstone, another standard was formation of the fetus, which occurs weeks before quickening. Henry Bracton explained the ancient law, about five hundred years before Blackstone:
The rule that a fetus was considered alive upon formation dates back at least another millennium. In the Septuagint text of the Old Testament, formation of the fetus was emphasized instead of quickening, according to the Book of Exodus:
Thus, in the earliest history of Judeo-Christian tradition, the highest value for life was thought to accrue when the fetus is formed. Later in history, the moment of quickening became the predominant standard for a right to life. Ultimately, the moment of fetal viability became more significant, although the moment of conception has also been used as a standard for when the right to life legally attaches to a human being. | Quickening
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
In pregnancy terms, the moment of quickening refers to the initial motion of the fetus in the uterus as it is perceived or felt by the pregnant woman. According to the Oxford English Dictionary, to "quicken" means "to reach the stage of pregnancy at which the child shows signs of life."[1] In the twentieth century, ultrasound technology made it possible to see that a fetus is in motion even if the pregnant woman does not yet feel it. This technological development made the concept of "quickening" a bit more complex.
# Medical facts
The first natural sensation of quickening may feel like a light tapping, or the fluttering of a butterfly. These sensations eventually become stronger and more regular as the pregnancy progresses. Sometimes, the first movements are misattributed to gas or hunger pangs.[2]
A woman’s uterine muscles, rather than her abdominal muscles, are first to sense fetal motion. Therefore, a woman’s body weight usually does not have a substantial effect on when movements are initially perceived. Women who have already given birth have more relaxed uterine muscles that are consequently more sensitive to fetal motion, and for them fetal motion can sometimes be felt as early as 14 weeks.[3]
Usually, quickening occurs naturally at about the middle of a pregnancy. A woman pregnant for the first time (i.e. a primiparous woman) typically feels fetal movements at about 20-21 weeks, whereas a woman who has already given birth at least two times (i.e. a multiparous woman) will typically feel movements around 18 weeks.[4]
# Legal history
Historically, quickening has sometimes been considered to be the beginning of the possession of "individual life" by the fetus. British legal scholar William Blackstone explained the subject of quickening in the eighteenth century, relative to feticide and abortion:
Nevertheless, quickening was only one of several standards that were used historically to determine when the right to life attaches to a fetus. According to the "ancient law" mentioned by Blackstone, another standard was formation of the fetus, which occurs weeks before quickening. Henry Bracton explained the ancient law, about five hundred years before Blackstone:
The rule that a fetus was considered alive upon formation dates back at least another millennium. In the Septuagint text of the Old Testament, formation of the fetus was emphasized instead of quickening, according to the Book of Exodus:
Thus, in the earliest history of Judeo-Christian tradition, the highest value for life was thought to accrue when the fetus is formed. Later in history, the moment of quickening became the predominant standard for a right to life. Ultimately, the moment of fetal viability became more significant, although the moment of conception has also been used as a standard for when the right to life legally attaches to a human being. | https://www.wikidoc.org/index.php/Quickening | |
79606d33c47a23d919a38707db11cd0ddcbb0866 | wikidoc | Quinacrine | Quinacrine
Quinacrine (trade name: Atabrine) is a drug with a number of different medical applications being initially used in the 1930s as an antimalarial drug. It has also been used as an antibiotic in the treatment of Giardiasis (an intestinal parasite), and in research as an inhibitor of phospholipase A2. It has also been proposed for use in systemic lupus erythematosus.
# History and licensed uses
Scientists at Bayer in Germany first synthesised Quinacrine in 1931 and subsequently marketed as Mepacrine or Atebrin. The product was one of the first synthetic substitutes for quinine although later superseded by chloroquine.
Its mechanism of action against giardia is uncertain, but it is thought to act against the bacteria cell wall. In addition it has been used for treating cutaneous leishmaniasis.
# Quinacrine Sterilization (QS)
Controversially, Quinacrine has been used as a method of non-surgical sterlisation. This method , was developed by Zipper et al who reported a first year failure rate of 3.1%. Pellets of quinacrine and an anti-inflammatory drug ibuprofen are inserted through the cervix into a woman's uterine cavity using a preloaded inserter device, similar in manner to IUCD insertion. The proceedure is undertaken twice, first in the proliferative phase 6th to 14th of the menstrual cycle and again one month later. The sclerosing effects of the drugs at the utero-tubal junctions (where the Fallopian tubes enter the uterus) results in scar tissue forming over a over a six week interval to close off the tubes permanently.
In over 30,000 cases of quinacrine pellet sterilizations in Vietnam, 10,000 cases in India and 5000 cases in other regions not a single death has been reported; which compares to the fatality rates of surgical sterilizations of 21 per 100,000 in India, and in the US & UK of respectively 10 & 2 per 100,000.
## Controversy About Quinacrine Sterilization
Use of quinacrine for sterilization is highly controversial. The two leading promoters of quinacrine sterilization are Dr. Elton Kessel and Stephen Mumford, who both previously worked for the Family Health International (FHI), a non-profit agency that funded quinacrine research in Chile during the 1970s. Subsequent funding from the conservative Leland Fikes Foundation and the Scaife Family Foundation made it possible for Mumford and Kessel to provide quinacrine free of charge to researchers, clinicians, and government health agencies worldwide. Mumford and Kessel's gifts of quinacrine were made possible not only through family foundations, but also through the financial support of individuals such as Sarah G. Epstein and Donald Collins, both board members of the Federation for American Immigration Reform (FAIR), an organization advocating reduced immigration.
Risks of quinacrine sterilization include cancer, development of abnormal lesions in the uterus, severe pain, ectopic pregnancy and fetal exposure. The pellets have already been banned in India and Chile (Wall Street Journal, 10/19/98).
Quinacrine has never been approved by the FDA for sterilization. Despite this fact, Kessel and Mumford have solicited abortion providers in the United States to perform quinacrine sterilization. According to Kessel, official government approval through the FDA would have been "desirable but not necessary" because the FDA permits approved drugs to be used "off-label." The FDA, however, disagreed and in October 1998, it ordered Kessel and Mumford to destroy their existing supply of quinacrine tablets and to immediately stop all export and distribution of the drug. The FDA stated that quinacrine used for sterilizations was an "unapproved new drug and a misbranded drug in violation of the Federal Food, Drug, and Cosmetic Act." and was an "unsafe use of this drug product.", with the FDA being "very concerned about the safety risks associated with the use of this drug and its effects on women and the fetus if a woman is or becomes pregnant." In addition to forbidding the marketing of quinacrine in the United States for sterilization purposes, the Warning Letter forbade the import of the drug into the United States or its exporting to another country.
From September 1998 until December 1999, little was written about Mumford and Kessel's quinacrine plans. The future of quinacrine sterilizations laid in abeyance until Warren Buffett revived quinacrine research by donating two million dollars to FHI, who will resume animal testing and begin human testing of quinacrine sterilizations in preparation for FDA approval. Planned Parenthood Federation of America, the largest reproductive health-care organization in the United States, has defended quinacrine sterilizations, indicating that they are willing to test quinacrine on their patients. In the meantime, Jack Lippes, Population Council consultant and inventor of the discontinued Lippes Loop IUD, has received approval from the Children's Hospital of Buffalo to conduct quinacrine sterilization on ten women.
### Concerns about consent
Field tests carried out in India and Vietnam led to notable concern over the lack of disclosure to test subjects regarding the permanent effects of the procedure, or that they were given quinacrine at all. In Vietnam, more than a hundred women were given quinacrine during routine pelvic exams, without their knowledge or consent, as "testing." These acts, along with a lack of knowledge about the long-term effects of Quinacrine Sterilization has led to a ban by the World Health Organization on further human testing.
# Quinacrine and Creutzfeldt-Jakob disease
Quinacrine has been shown to bind to the prion protein and prevent the formation of prion aggregates in vitro,
and full clinical trials of its use as a treatment for Creutzfeldt-Jakob disease are under way in the United Kingdom and the United States. Small trials in Japan have reported improvement in the condition of patients with the disease,
although other reports have shown no significant effect,
and treatment of scrapie in mice and sheep has also shown no effect. | Quinacrine
Template:Cleanup
Quinacrine (trade name: Atabrine) is a drug with a number of different medical applications being initially used in the 1930s as an antimalarial drug. It has also been used as an antibiotic in the treatment of Giardiasis (an intestinal parasite)[1], and in research as an inhibitor of phospholipase A2. It has also been proposed for use in systemic lupus erythematosus.[2]
# History and licensed uses
Scientists at Bayer in Germany first synthesised Quinacrine in 1931 and subsequently marketed as Mepacrine or Atebrin. The product was one of the first synthetic substitutes for quinine although later superseded by chloroquine.
Its mechanism of action against giardia is uncertain, but it is thought to act against the bacteria cell wall. In addition it has been used for treating cutaneous leishmaniasis.
# Quinacrine Sterilization (QS)
Controversially, Quinacrine has been used as a method of non-surgical sterlisation. This method [3], was developed by Zipper et al who reported a first year failure rate of 3.1%.[4] Pellets of quinacrine and an anti-inflammatory drug ibuprofen are inserted through the cervix into a woman's uterine cavity using a preloaded inserter device, similar in manner to IUCD insertion. The proceedure is undertaken twice, first in the proliferative phase 6th to 14th of the menstrual cycle and again one month later. The sclerosing effects of the drugs at the utero-tubal junctions (where the Fallopian tubes enter the uterus) results in scar tissue forming over a over a six week interval to close off the tubes permanently.
In over 30,000 cases of quinacrine pellet sterilizations in Vietnam, 10,000 cases in India and 5000 cases in other regions not a single death has been reported;[5] which compares to the fatality rates of surgical sterilizations of 21 per 100,000 in India,[6] and in the US & UK of respectively 10 & 2 per 100,000.[7]
## Controversy About Quinacrine Sterilization
Use of quinacrine for sterilization is highly controversial. The two leading promoters of quinacrine sterilization are Dr. Elton Kessel and Stephen Mumford, who both previously worked for the Family Health International (FHI), a non-profit agency that funded quinacrine research in Chile during the 1970s. Subsequent funding from the conservative Leland Fikes Foundation and the Scaife Family Foundation made it possible for Mumford and Kessel to provide quinacrine free of charge to researchers, clinicians, and government health agencies worldwide. Mumford and Kessel's gifts of quinacrine were made possible not only through family foundations, but also through the financial support of individuals such as Sarah G. Epstein and Donald Collins, both board members of the Federation for American Immigration Reform (FAIR), an organization advocating reduced immigration.
Risks of quinacrine sterilization include cancer, development of abnormal lesions in the uterus, severe pain, ectopic pregnancy and fetal exposure.[citation needed] The pellets have already been banned in India and Chile (Wall Street Journal, 10/19/98).
Quinacrine has never been approved by the FDA for sterilization. Despite this fact, Kessel and Mumford have solicited abortion providers in the United States to perform quinacrine sterilization. According to Kessel, official government approval through the FDA would have been "desirable but not necessary" because the FDA permits approved drugs to be used "off-label." The FDA, however, disagreed and in October 1998, it ordered Kessel and Mumford to destroy their existing supply of quinacrine tablets and to immediately stop all export and distribution of the drug. The FDA stated that quinacrine used for sterilizations was an "unapproved new drug and a misbranded drug in violation of the Federal Food, Drug, and Cosmetic Act." and was an "unsafe use of this drug product.", with the FDA being "very concerned about the safety risks associated with the use of this drug and its effects on women and the fetus if a woman is or becomes pregnant." In addition to forbidding the marketing of quinacrine in the United States for sterilization purposes, the Warning Letter forbade the import of the drug into the United States or its exporting to another country.
From September 1998 until December 1999, little was written about Mumford and Kessel's quinacrine plans. The future of quinacrine sterilizations laid in abeyance until Warren Buffett revived quinacrine research by donating two million dollars to FHI, who will resume animal testing and begin human testing of quinacrine sterilizations in preparation for FDA approval.[citation needed] Planned Parenthood Federation of America, the largest reproductive health-care organization in the United States, has defended quinacrine sterilizations, indicating that they are willing to test quinacrine on their patients. In the meantime, Jack Lippes, Population Council consultant and inventor of the discontinued Lippes Loop IUD, has received approval from the Children's Hospital of Buffalo to conduct quinacrine sterilization on ten women.[8][9]
### Concerns about consent
Field tests carried out in India and Vietnam led to notable concern over the lack of disclosure to test subjects regarding the permanent effects of the procedure, or that they were given quinacrine at all. In Vietnam, more than a hundred women were given quinacrine during routine pelvic exams, without their knowledge or consent, as "testing." These acts, along with a lack of knowledge about the long-term effects of Quinacrine Sterilization has led to a ban by the World Health Organization on further human testing.[10]
# Quinacrine and Creutzfeldt-Jakob disease
Quinacrine has been shown to bind to the prion protein and prevent the formation of prion aggregates in vitro,[11]
and full clinical trials of its use as a treatment for Creutzfeldt-Jakob disease are under way in the United Kingdom and the United States. Small trials in Japan have reported improvement in the condition of patients with the disease,[12]
although other reports have shown no significant effect,[13]
and treatment of scrapie in mice and sheep has also shown no effect.[14][15] | https://www.wikidoc.org/index.php/Quinacrine | |
27c6fe7fb856344fc2fa7f2fbe2a0fb668951e2f | wikidoc | RADIANCE 1 | RADIANCE 1
# Official Title
Phase 3 Multi-Center, Double-Blind, Randomized, Parallel Group, Carotid B-Mode Ultrasound Evaluation of the Anti-Atherosclerotic Efficacy, Safety and Tolerability of Fixed Combination CP-529,414/Atorvastatin, Administered Orally, Once Daily (QD) for 24 Months, Compared With Maximally Tolerated Atorvastatin Therapy Alone, in Subjects With Heterozygous Familial Hypercholesterolemia.
# Objective
The objective of this study is to look at ultrasound images taken in the carotid arteries and to look at various lipids in the blood of people with heterozygous familial hypercholesterolemia.
The Torcetrapib project was terminated on December 2, 2006 due to safety findings.
# Sponsor
Pfizer
# Timeline
The previous information was derived from ClinicalTrials.gov on 08/18/2014 using the identification number NCT00136981.
# Study Description
The previous information was derived from ClinicalTrials.gov on 09/19/2013 using the identification number NCT00136981.
# Eligibility Criteria
## Inclusion Criteria
- Diagnosis of heterozygous familial hypercholesterolemia
- At least 18 years of age
## Exclusion Criteria
- Women who are pregnant or lactating, or planning to become pregnant.
- Subjects with a clinically indicated need for statin (HMG-CoA reductase inhibitor) therapy other than atorvastatin or other concomitant therapy with known lipid altering effects on LDL-C and HDL-C including fibrates and nicotinic acid (high doses)
- Subjects taking any drugs known to be associated with an increased risk of myositis in combination with HMG-CoA reductase inhibitors
- Subjects with any other medical condition or laboratory abnormality which could affect subject safety, preclude evaluation of response, or render unlikely that the subject would complete the study
# Outcomes
## Primary Outcomes
- Change in intima media thickness as measures by carotid ultrasound
## Secondary Outcomes
- Changes in levels of lipids and other biomarkers
# Publications
The administration of torcetrapib with atorvastatin among patients with familial hypercholesterolemia did not lead to decrease in the progression of atherosclerosis as compared with atorvastatin alone. | RADIANCE 1
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rim Halaby, M.D. [2]
# Official Title
Phase 3 Multi-Center, Double-Blind, Randomized, Parallel Group, Carotid B-Mode Ultrasound Evaluation of the Anti-Atherosclerotic Efficacy, Safety and Tolerability of Fixed Combination CP-529,414/Atorvastatin, Administered Orally, Once Daily (QD) for 24 Months, Compared With Maximally Tolerated Atorvastatin Therapy Alone, in Subjects With Heterozygous Familial Hypercholesterolemia.
# Objective
The objective of this study is to look at ultrasound images taken in the carotid arteries and to look at various lipids in the blood of people with heterozygous familial hypercholesterolemia.
The Torcetrapib project was terminated on December 2, 2006 due to safety findings.
# Sponsor
Pfizer
# Timeline
The previous information was derived from ClinicalTrials.gov on 08/18/2014 using the identification number NCT00136981.
# Study Description
The previous information was derived from ClinicalTrials.gov on 09/19/2013 using the identification number NCT00136981.
# Eligibility Criteria
## Inclusion Criteria
- Diagnosis of heterozygous familial hypercholesterolemia
- At least 18 years of age
## Exclusion Criteria
- Women who are pregnant or lactating, or planning to become pregnant.
- Subjects with a clinically indicated need for statin (HMG-CoA reductase inhibitor) therapy other than atorvastatin or other concomitant therapy with known lipid altering effects on LDL-C and HDL-C including fibrates and nicotinic acid (high doses)
- Subjects taking any drugs known to be associated with an increased risk of myositis in combination with HMG-CoA reductase inhibitors
- Subjects with any other medical condition or laboratory abnormality which could affect subject safety, preclude evaluation of response, or render unlikely that the subject would complete the study
# Outcomes
## Primary Outcomes
- Change in intima media thickness as measures by carotid ultrasound
## Secondary Outcomes
- Changes in levels of lipids and other biomarkers
# Publications
The administration of torcetrapib with atorvastatin among patients with familial hypercholesterolemia did not lead to decrease in the progression of atherosclerosis as compared with atorvastatin alone.[1] | https://www.wikidoc.org/index.php/RADIANCE_1 | |
fe4a8c6565c3651cea7c34fa6090fed05cd8211c | wikidoc | RADIANCE 2 | RADIANCE 2
# Official Title
Phase 3 Multi-Center, Double-Blind, Randomized, Parallel Group, Carotid B-mode Ultrasound Evaluation of the Anti-Atherosclerotic Efficacy, Safety, and Tolerability of Fixed Combination CP-529,414/Atorvastatin, Administered Orally, Once Daily (QD) for 24 Months, Compared With Atorvastatin Alone, in Subjects With Mixed Hyperlipidemia
# Objective
The objective of this study is to look at ultrasound images taken in the carotid arteries and to look at various lipids in the blood of people with mixed hyperlipidemia.
# Sponsor
Pfizer
# Timeline
The previous information was derived from ClinicalTrials.gov on 08/18/2014 using the identification number NCT00134238.
# Study Description
The previous information was derived from ClinicalTrials.gov on 09/19/2013 using the identification number NCT00134238.
# Eligibility Criteria
## Inclusion Criteria
- Diagnosis of mixed hyperlipidemia
- At least 18 years of age
## Exclusion Criteria
- Women who are pregnant or lactating, or planning to become pregnant.
- Subjects with a clinically indicated need for statin (HMG-CoA reductase inhibitor) therapy other than atorvastatin or other concomitant therapy with known lipid altering effects on LDL-C and HDL-C including fibrates and nicotinic acid (high doses)
- Subjects taking any drugs known to be associated with an increased risk of myositis in combination with HMG-CoA reductase inhibitors
- Subjects with any other medical condition or laboratory abnormality which could affect subject safety, preclude evaluation of response, or render unlikely that the subject would complete the study
# Outcomes
## Primary Outcomes
Change in intima media thickness as measured by carotid ultrasound
## Secondary Outcomes
Changes in levels of lipids and other biomarkers
# Publications
## Conclusion
There is no clinical benefit with the administration of torcetrapib. Torcetrapib did not lead to a decrease in the thickness of the intima and media of carotid segments. Torcetrapib led to an increase in HDL and decrement in LDL; however, these findings were accompanied by an increase in systolic blood pressure. | RADIANCE 2
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rim Halaby, M.D. [2]
# Official Title
Phase 3 Multi-Center, Double-Blind, Randomized, Parallel Group, Carotid B-mode Ultrasound Evaluation of the Anti-Atherosclerotic Efficacy, Safety, and Tolerability of Fixed Combination CP-529,414/Atorvastatin, Administered Orally, Once Daily (QD) for 24 Months, Compared With Atorvastatin Alone, in Subjects With Mixed Hyperlipidemia
# Objective
The objective of this study is to look at ultrasound images taken in the carotid arteries and to look at various lipids in the blood of people with mixed hyperlipidemia.
# Sponsor
Pfizer
# Timeline
The previous information was derived from ClinicalTrials.gov on 08/18/2014 using the identification number NCT00134238.
# Study Description
The previous information was derived from ClinicalTrials.gov on 09/19/2013 using the identification number NCT00134238.
# Eligibility Criteria
## Inclusion Criteria
- Diagnosis of mixed hyperlipidemia
- At least 18 years of age
## Exclusion Criteria
- Women who are pregnant or lactating, or planning to become pregnant.
- Subjects with a clinically indicated need for statin (HMG-CoA reductase inhibitor) therapy other than atorvastatin or other concomitant therapy with known lipid altering effects on LDL-C and HDL-C including fibrates and nicotinic acid (high doses)
- Subjects taking any drugs known to be associated with an increased risk of myositis in combination with HMG-CoA reductase inhibitors
- Subjects with any other medical condition or laboratory abnormality which could affect subject safety, preclude evaluation of response, or render unlikely that the subject would complete the study
# Outcomes
## Primary Outcomes
Change in intima media thickness as measured by carotid ultrasound
## Secondary Outcomes
Changes in levels of lipids and other biomarkers
# Publications
## Conclusion
There is no clinical benefit with the administration of torcetrapib. Torcetrapib did not lead to a decrease in the thickness of the intima and media of carotid segments. Torcetrapib led to an increase in HDL and decrement in LDL; however, these findings were accompanied by an increase in systolic blood pressure.[1] | https://www.wikidoc.org/index.php/RADIANCE_2 | |
519ca8166fb007209d21038971ed67048e003618 | wikidoc | RHD (gene) | RHD (gene)
Rh blood group, D antigen also known as Rh polypeptide 1 (RhPI) or cluster of differentiation 240D (CD240D) is a protein that in humans is encoded by the RHD gene.
The RHD gene codes for the RhD erythrocyte membrane protein that is the Rh factor antigen of the Rh blood group system. RHD has sequence similarity to RHCE, RhAG, RhBG, and RhCG and these five genes constitute the Rh family. It was proposed that the erythrocyte Rh complex is a heterotrimer of RhAG, RhD, and RhCE protein subunits. RhAG is a functional ammonia transporter and is required for normal cell surface expression of RhD and RhCE. Patients who lack RhD/RhCE/RhAG on the surface of their erythrocytes have hemolytic anemia . Antibodies to the RhD protein can cause Rh disease.
# Model organisms
Model organisms have been used in the study of RHD function. A conditional knockout mouse line, called Rhdtm1a(EUCOMM)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty five tests were carried out on mutant mice and one significant abnormality was observed: homozygous mutant males had a decrease in mean corpuscular hemoglobin. | RHD (gene)
Rh blood group, D antigen also known as Rh polypeptide 1 (RhPI) or cluster of differentiation 240D (CD240D) is a protein that in humans is encoded by the RHD gene.[1]
The RHD gene codes for the RhD erythrocyte membrane protein that is the Rh factor antigen of the Rh blood group system.[2] RHD has sequence similarity to RHCE, RhAG, RhBG, and RhCG and these five genes constitute the Rh family. It was proposed that the erythrocyte Rh complex is a heterotrimer of RhAG, RhD, and RhCE protein subunits.[3] RhAG is a functional ammonia transporter and is required for normal cell surface expression of RhD and RhCE. Patients who lack RhD/RhCE/RhAG on the surface of their erythrocytes have hemolytic anemia . Antibodies to the RhD protein can cause Rh disease.
# Model organisms
Model organisms have been used in the study of RHD function. A conditional knockout mouse line, called Rhdtm1a(EUCOMM)Wtsi[8][9] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[10][11][12]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[6][13] Twenty five tests were carried out on mutant mice and one significant abnormality was observed: homozygous mutant males had a decrease in mean corpuscular hemoglobin.[6] | https://www.wikidoc.org/index.php/RHD_(gene) | |
819e774458922d2c3e05f13d3fed6e51d0b465d6 | wikidoc | Rabi cycle | Rabi cycle
# Overview
[In physics, the Rabi cycle is the cyclic behaviour of a two-state quantum system in the presence of an oscillatory driving field. A two-state system has two possible states, and if they are not degenerate energy levels the system can become "excited" when it absorbs a quantum of energy.
The effect is important in quantum optics, nuclear magnetic resonance and quantum computing. The term is named in honour of Isidor Isaac Rabi.
When an atom (or some other two-level system) is illuminated by a coherent beam of photons, it will cyclically absorb photons and re-emit them by stimulated emission. One such cycle is called a Rabi cycle and the inverse of its duration the Rabi frequency of the photon beam.
This mechanism is fundamental to quantum optics. It can be modelled using the Jaynes-Cummings model and the Bloch vector formalism.
For example, in a two-state atom (an atom in which an electron can either be in the excited or ground state), the probability of finding the atom in the excited state is found from the Bloch equations to be: |c_b(t)|^2=\cos(\omega t)^2 where \omega is the Rabi frequency.
More generally, one can consider a system where the two levels under consideration are not energy eigenstates. Therefore if the system is initialized in one of these levels, time evolution will make the population of each of the levels oscillate with some characteristic frequency, whose angular frequency is also known as the Rabi frequency.
# Links
- A Java applet that visualizes Rabi Cycles of two-state systems (laser driven).
- extended version of the applet. Includes electron phonon interaction.
# Notes
- ↑ Encyclopedia of Laser Physics and Technology - Rabi oscillations, Rabi frequency, stimulated emission | Rabi cycle
# Overview
[In physics, the Rabi cycle is the cyclic behaviour of a two-state quantum system in the presence of an oscillatory driving field. A two-state system has two possible states, and if they are not degenerate energy levels the system can become "excited" when it absorbs a quantum of energy.
The effect is important in quantum optics, nuclear magnetic resonance and quantum computing. The term is named in honour of Isidor Isaac Rabi.
When an atom (or some other two-level system) is illuminated by a coherent beam of photons, it will cyclically absorb photons and re-emit them by stimulated emission. One such cycle is called a Rabi cycle and the inverse of its duration the Rabi frequency of the photon beam.
This mechanism is fundamental to quantum optics. It can be modelled using the Jaynes-Cummings model and the Bloch vector formalism.
For example, in a two-state atom (an atom in which an electron can either be in the excited or ground state), the probability of finding the atom in the excited state is found from the Bloch equations to be: <math>|c_b(t)|^2=\cos(\omega t)^2</math> where <math>\omega</math> is the Rabi frequency.
More generally, one can consider a system where the two levels under consideration are not energy eigenstates. Therefore if the system is initialized in one of these levels, time evolution will make the population of each of the levels oscillate with some characteristic frequency, whose angular frequency[1] is also known as the Rabi frequency.
# Links
- http://www.itp.tu-berlin.de/en/menue/lehre/owl/quantenmechanik/zweiniveau/?H=1 A Java applet that visualizes Rabi Cycles of two-state systems (laser driven).
- http://www.itp.tu-berlin.de/index.php?id=6854&L=1 extended version of the applet. Includes electron phonon interaction.
# Notes
- ↑ Encyclopedia of Laser Physics and Technology - Rabi oscillations, Rabi frequency, stimulated emission | https://www.wikidoc.org/index.php/Rabi_cycle | |
1c6139b11b5c7fd9f5635fb637311dcaf8c023af | wikidoc | Vulvectomy | Vulvectomy
Vulvectomy refers to a gynecological procedure in which the vulva is partly or completely removed. Usually this is performed as a last resort in certain cases of cancer, vulvar dysplasia or Human Papilloma Virus (genital warts). The patient experiences severe pain in the groin area for a couple of weeks after the procedure. Sexual function is generally still possible but limited.
A simple vulvectomy means removal of all external tissue, and a radical vulvectomy is the same but also includes lymph node removal, clitoris, and nearby tissue is also removed. A partial vulvectomy is the least severe, only removing the affected portion of the vulva.
Skinning vulvectomy involves the removal of the top layer of vulvar skin (the external female genital organs,incluiding the clitoris, vaginal lips and the opening of the vagina) where the cancer is found. Skin grafts from other parts of the body may be needed to cover the area. There are 2 types of Skinning Vulvectomy, the Partial skinning vulvectomy and the Total skinning vulvectomy. The objective of the first one is the preservation of the cosmetic and functional integrity of the vulva in younger and sexually active patients in whom a steady increase in the incidence of vulvar intraepithelial neoplasia has been observed in the last decade meanwhile the objective of the Total skinning vulvectomy is to remove the entire vulva with total skin graft replacement in patients with an entire vulva cancer involvement.
Modified radical vulvectomy involves the removal of vulva containing cancer and some of the normal tissue around it. | Vulvectomy
Vulvectomy refers to a gynecological procedure in which the vulva is partly or completely removed. Usually this is performed as a last resort in certain cases of cancer, vulvar dysplasia or Human Papilloma Virus (genital warts). The patient experiences severe pain in the groin area for a couple of weeks after the procedure. Sexual function is generally still possible but limited.
A simple vulvectomy means removal of all external tissue, and a radical vulvectomy is the same but also includes lymph node removal, clitoris, and nearby tissue is also removed. A partial vulvectomy is the least severe, only removing the affected portion of the vulva.
Skinning vulvectomy involves the removal of the top layer of vulvar skin (the external female genital organs,incluiding the clitoris, vaginal lips and the opening of the vagina) where the cancer is found. Skin grafts from other parts of the body may be needed to cover the area. There are 2 types of Skinning Vulvectomy, the Partial skinning vulvectomy and the Total skinning vulvectomy. The objective of the first one is the preservation of the cosmetic and functional integrity of the vulva in younger and sexually active patients in whom a steady increase in the incidence of vulvar intraepithelial neoplasia has been observed in the last decade meanwhile the objective of the Total skinning vulvectomy is to remove the entire vulva with total skin graft replacement in patients with an entire vulva cancer involvement.
Modified radical vulvectomy involves the removal of vulva containing cancer and some of the normal tissue around it.
Template:Urogenital surgical and other procedures
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Radical_vulvectomy |
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