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4018fd0db0d11b8373bad721f77b3b9e97c8cd2d | wikidoc | Temozolomide | Temozolomide
# 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
Temozolomide is an antineoplastic agent that is FDA approved for the treatment of newly diagnosed glioblastoma multiforme (GBM) and refractory anaplastic astrocytoma. Common adverse reactions include alopecia, fatigue, nausea, vomiting, headache, constipation, anorexia, convulsions, rash, hemiparesis, diarrhea, asthenia, fever, dizziness, incoordination, viral infection, amnesia, and insomnia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Newly Diagnosed Glioblastoma Multiforme
- Temozolomide is indicated for the treatment of adult patients with newly diagnosed glioblastoma multiforme concomitantly with radiotherapy and then as maintenance treatment.
- Dosage:
- 75 mg/m2 for 42 days concomitant with focal radiotherapy followed by initial maintenance dose of 150 mg/m2 once daily for Days 1–5 of a 28-day cycle of temozolomide for 6 cycles.
### Refractory Anaplastic Astrocytoma
- Temozolomide is indicated for the treatment of adult patients with refractory anaplastic astrocytoma.
- Dosage:
- Initial dose 150 mg/m2 once daily for 5 consecutive days per 28-day treatment cycle.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Temozolomide in adult patients.
### Non–Guideline-Supported Use
- Relapsed, refractory, or progressive malignant glioma as monotherapy
- As monotherapy of metastatic malignant melanoma
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Temozolomide 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 Temozolomide in pediatric patients.
### Non–Guideline-Supported Use
- Relapsed, refractory, or progressive malignant glioma as monotherapy
# Contraindications
Temozolomide is contraindicated in patients who have a history of hypersensitivity reaction (such as urticaria, allergic reaction including anaphylaxis, toxic epidermal necrolysis, and Stevens-Johnson syndrome) to any of its components. temozolomide is also contraindicated in patients who have a history of hypersensitivity to dacarbazine (DTIC), since both drugs are metabolized to 5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide (MTIC).
# Warnings
### Myelosuppression
- Patients treated with temozolomide may experience myelosuppression, including prolonged pancytopenia, which may result in aplastic anemia, which in some cases has resulted in a fatal outcome.
- In some cases, exposure to concomitant medications associated with aplastic anemia, including carbamazepine, phenytoin, and sulfamethoxazole/trimethoprim, complicates assessment.
- Prior to dosing, patients must have an absolute neutrophil count (ANC) greater than or equal to 1.5 × 109/L and a platelet count greater than or equal to 100 × 109/L.
- A complete blood count should be obtained on Day 22 (21 days after the first dose) or within 48 hours of that day, and weekly until the ANC is above 1.5 × 109/L and platelet count exceeds 100 × 109/L
- Geriatric patients and women have been shown in clinical trials to have a higher risk of developing myelosuppression.
### Myelodysplastic Syndrome
- Cases of myelodysplastic syndrome and secondary malignancies, including myeloid leukemia, have been observed.
### Pneumocystis Pneumonia
- For treatment of newly diagnosed glioblastoma multiforme: Prophylaxis against Pneumocystis pneumonia (PCP) is required for all patients receiving concomitant temozolomide and radiotherapy for the 42-day regimen.
- There may be a higher occurrence of PCP when temozolomide is administered during a longer dosing regimen. However, all patients receiving temozolomide, particularly patients receiving steroids, should be observed closely for the development of PCP regardless of the regimen.
### Laboratory Tests
- For the concomitant treatment phase with RT, a complete blood count should be obtained prior to initiation of treatment and weekly during treatment.
- For the 28-day treatment cycles, a complete blood count should be obtained prior to treatment on Day 1 and on Day 22 (21 days after the first dose) of each cycle. Blood counts should be performed weekly until recovery if the ANC falls below 1.5 × 109/L and the platelet count falls below 100 × 109/L.
### Hepatotoxicity
- Fatal and severe hepatotoxicity have been reported in patients receiving temozolomide. Perform liver function tests at baseline, midway through the first cycle, prior to each subsequent cycle, and approximately two to four weeks after the last dose of temozolomide.
### Use in Pregnancy
- Temozolomide can cause fetal harm when administered to a pregnant woman. Administration of temozolomide to rats and rabbits during organogenesis at 0.38 and 0.75 times the maximum recommended human dose (75 and 150 mg/m2), respectively, caused numerous fetal malformations of the external organs, soft tissues, and skeleton in both species.
### Infusion Time
- As bioequivalence has been established only when temozolomide for Injection was given over 90 minutes, infusion over a shorter or longer period of time may result in suboptimal dosing. Additionally, the possibility of an increase in infusion-related adverse reactions cannot be ruled out.
# 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.
### Newly Diagnosed Glioblastoma Multiforme
During the concomitant phase (temozolomide+radiotherapy), adverse reactions including thrombocytopenia, nausea, vomiting, anorexia, and constipation were more frequent in the temozolomide+RT arm. The incidence of other adverse reactions was comparable in the two arms. The most common adverse reactions across the cumulative temozolomide experience were alopecia, nausea, vomiting, anorexia, headache, and constipation. Forty-nine percent (49%) of patients treated with temozolomide reported one or more severe or life-threatening reactions, most commonly fatigue (13%), convulsions (6%), headache (5%), and thrombocytopenia (5%). Overall, the pattern of reactions during the maintenance phase was consistent with the known safety profile of temozolomide.
Myelosuppression (neutropenia and thrombocytopenia), which is a known dose-limiting toxicity for most cytotoxic agents, including temozolomide, was observed. When laboratory abnormalities and adverse reactions were combined, Grade 3 or Grade 4 neutrophil abnormalities including neutropenic reactions were observed in 8% of the patients, and Grade 3 or Grade 4 platelet abnormalities, including thrombocytopenic reactions, were observed in 14% of the patients treated with temozolomide.
### Refractory Anaplastic Astrocytoma
TABLES 8 and 9 show the incidence of adverse reactions in the 158 patients in the anaplastic astrocytoma study for whom data are available. In the absence of a control group, it is not clear in many cases whether these reactions should be attributed to temozolomide or the patients' underlying conditions, but nausea, vomiting, fatigue, and hematologic effects appear to be clearly drug-related. The most frequently occurring adverse reactions were nausea, vomiting, headache, and fatigue. The adverse reactions were usually NCI Common Toxicity Criteria (CTC) Grade 1 or 2 (mild to moderate in severity) and were self-limiting, with nausea and vomiting readily controlled with antiemetics. The incidence of severe nausea and vomiting (CTC Grade 3 or 4) was 10% and 6%, respectively. Myelosuppression (thrombocytopenia and neutropenia) was the dose-limiting adverse reaction. It usually occurred within the first few cycles of therapy and was not cumulative.
Myelosuppression occurred late in the treatment cycle and returned to normal, on average, within 14 days of nadir counts. The median nadirs occurred at 26 days for platelets (range: 21–40 days) and 28 days for neutrophils (range: 1–44 days). Only 14% (22/158) of patients had a neutrophil nadir and 20% (32/158) of patients had a platelet nadir, which may have delayed the start of the next cycle. Less than 10% of patients required hospitalization, blood transfusion, or discontinuation of therapy due to myelosuppression.
In clinical trial experience with 110 to 111 women and 169 to 174 men (depending on measurements), there were higher rates of Grade 4 neutropenia (ANC less than 500 cells/µL) and thrombocytopenia (less than 20,000 cells/µL) in women than men in the first cycle of therapy (12% vs. 5% and 9% vs. 3%, respectively).
In the entire safety database for which hematologic data exist (N=932), 7% (4/61) and 9.5% (6/63) of patients over age 70 experienced Grade 4 neutropenia or thrombocytopenia in the first cycle, respectively. For patients less than or equal to age 70, 7% (62/871) and 5.5% (48/879) experienced Grade 4 neutropenia or thrombocytopenia in the first cycle, respectively. Pancytopenia, leukopenia, and anemia have also been reported.
Temozolomide for injection delivers equivalent temozolomide dose and exposure to both temozolomide and 5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide (MTIC) as the corresponding temozolomide capsules. Adverse reactions probably related to treatment that were reported from the 2 studies with the intravenous formulation (n=35) that were not reported in studies using the temozolomide capsules were: pain, irritation, pruritus, warmth, swelling, and erythema at infusion site as well as the following adverse reactions: petechiae and hematoma.
## Postmarketing Experience
The following adverse reactions have been identified during postapproval use of temozolomide. 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 the drug exposure.
- Dermatologic disorders: Toxic epidermal necrolysis and Stevens-Johnson syndrome
- Immune system disorders: Allergic reactions, including anaphylaxis. Erythema multiforme, which resolved after discontinuation of temozolomide and, in some cases, recurred upon rechallenge.
- Hematopoietic disorders: Prolonged pancytopenia, which may result in aplastic anemia and fatal outcomes.
- Hepatobiliary disorders: Fatal and severe hepatotoxicity, elevation of liver enzymes, hyperbilirubinemia, cholestasis, and hepatitis.
- Infections and infestations: Opportunistic infections including Pneumocystis pneumonia (PCP), reactivation of infections such as cytomegalovirus and hepatitis B.
- Pulmonary disorders: Interstitial pneumonitis, pneumonitis, alveolitis, and pulmonary fibrosis.
- Endocrine disorders: Diabetes insipidus
# Drug Interactions
Administration of valproic acid decreases oral clearance of temozolomide by about 5%. The clinical implication of this effect is not known
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
temozolomide can cause fetal harm when administered to a pregnant woman. Five consecutive days of oral temozolomide administration of 0.38 and 0.75 times the highest recommended human dose (75 and 150 mg/m2) in rats and rabbits, respectively, during the period of organogenesis caused numerous malformations of the external and internal soft tissues and skeleton in both species. Doses equivalent to 0.75 times the highest recommended human dose (150 mg/m2) caused embryolethality in rats and rabbits as indicated by increased resorptions. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Women of childbearing potential should be advised to avoid becoming pregnant during therapy with temozolomide.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Temozolomide in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Temozolomide during labor and delivery.
### Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants and tumorigenicity shown for temozolomide in animal studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of temozolomide to the mother.
### Pediatric Use
Safety and effectiveness in pediatric patients have not been established. temozolomide Capsules have been studied in 2 open-label studies in pediatric patients (aged 3–18 years) at a dose of 160 to 200 mg/m2 daily for 5 days every 28 days. In one trial, 29 patients with recurrent brain stem glioma and 34 patients with recurrent high grade astrocytoma were enrolled. All patients had recurrence following surgery and radiation therapy, while 31% also had disease progression following chemotherapy. In a second study conducted by the Children's Oncology Group (COG), 122 patients were enrolled, including patients with medulloblastoma/PNET (29), high grade astrocytoma (23), low grade astrocytoma (22), brain stem glioma (16), ependymoma (14), other CNS tumors (9), and non-CNS tumors (9). The temozolomide toxicity profile in pediatric patients is similar to adults.
### Geriatic Use
Clinical studies of temozolomide did not include sufficient numbers of subjects aged 65 and over to determine whether they responded differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
In the anaplastic astrocytoma study population, patients 70 years of age or older had a higher incidence of Grade 4 neutropenia and Grade 4 thrombocytopenia (2/8; 25%, P=0.31 and 2/10; 20%, P=0.09, respectively) in the first cycle of therapy than patients under 70 years of age.
In newly diagnosed patients with glioblastoma multiforme, the adverse reaction profile was similar in younger patients (<65 years) vs. older (≥65 years).
### Gender
A population pharmacokinetic analysis indicated that women have an approximately 5% lower clearance (adjusted for body surface area) for temozolomide than men.
### Race
The effect of race on the pharmacokinetics of temozolomide has not been studied.
### Renal Impairment
- Caution should be exercised when temozolomide is administered to patients with severe renal impairment.
- A population pharmacokinetic analysis indicated that creatinine clearance over the range of 36 to 130 mL/min/m2 has no effect on the clearance of temozolomide after oral administration. The pharmacokinetics of temozolomide have not been studied in patients with severely impaired renal function (CLcr <36 mL/min/m2). Caution should be exercised when temozolomide is administered to patients with severe renal impairment. Temozolomide has not been studied in patients on dialysis.
### Hepatic Impairment
- Caution should be exercised when temozolomide is administered to patients with severe hepatic impairment.
- A study showed that the pharmacokinetics of temozolomide in patients with mild-to-moderate hepatic impairment (Child-Pugh Class I – II) were similar to those observed in patients with normal hepatic function. Caution should be exercised when temozolomide is administered to patients with severe hepatic impairment
### Females of Reproductive Potential and Males
Temozolomide impairs male fertility. Temozolomide caused syncytial cells/immature sperm formation at 0.25 and 0.63 times the maximum recommended human dose (50 and 125 mg/m2) in rats and dogs, respectively, and testicular atrophy in dogs at 0.63 times the maximum recommended human dose (125 mg/m2).
### Immunocompromised Patients
There is no FDA guidance one the use of Temozolomide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
- Intravenous
### Monitoring
There is limited information regarding Temozolomide Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Temozolomide and IV administrations.
# Overdosage
Doses of 500, 750, 1000, and 1250 mg/m2 (total dose per cycle over 5 days) have been evaluated clinically in patients. Dose-limiting toxicity was hematologic and was reported with any dose but is expected to be more severe at higher doses. An overdose of 2000 mg per day for 5 days was taken by one patient and the adverse reactions reported were pancytopenia, pyrexia, multi-organ failure, and death. There are reports of patients who have taken more than 5 days of treatment (up to 64 days), with adverse reactions reported including bone marrow suppression, which in some cases was severe and prolonged, and infections and resulted in death. In the event of an overdose, hematologic evaluation is needed. Supportive measures should be provided as necessary.
# Pharmacology
## Mechanism of Action
Temozolomide is not directly active but undergoes rapid nonenzymatic conversion at physiologic pH to the reactive compound 5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide (MTIC). The cytotoxicity of MTIC is thought to be primarily due to alkylation of DNA. Alkylation (methylation) occurs mainly at the O6 and N7 positions of guanine.
## Structure
The chemical name of temozolomide is 3,4-dihydro-3-methyl-4-oxoimidazo-as-tetrazine-8-carboxamide. The structural formula is:
## Pharmacodynamics
There is limited information regarding Temozolomide Pharmacodynamics in the drug label.
## Pharmacokinetics
### Absorption
Temozolomide is rapidly and completely absorbed after oral administration with a peak plasma concentration (Cmax) achieved in a median Tmax of 1 hour. Food reduces the rate and extent of temozolomide absorption. Mean peak plasma concentration and AUC decreased by 32% and 9%, respectively, and median Tmax increased by 2-fold (from 1–2.25 hours) when temozolomide was administered after a modified high-fat breakfast.
A pharmacokinetic study comparing oral and intravenous temozolomide in 19 patients with primary CNS malignancies showed that 150 mg/m2 temozolomide for injection administered over 90 minutes is bioequivalent to 150 mg/m2 temozolomide oral capsules with respect to both Cmax and AUC of temozolomide and MTIC. Following a single 90-minute intravenous infusion of 150 mg/m2, the geometric mean Cmax values for temozolomide and MTIC were 7.3 mcg/mL and 276 ng/mL, respectively. Following a single oral dose of 150 mg/m2, the geometric mean Cmax values for temozolomide and MTIC were 7.5 mcg/mL and 282 ng/mL, respectively. Following a single 90-minute intravenous infusion of 150 mg/m2, the geometric mean AUC values for temozolomide and MTIC were 24.6 mcg∙hr/mL and 891 ng∙hr/mL, respectively. Following a single oral dose of 150 mg/m2, the geometric mean AUC values for temozolomide and MTIC were 23.4 mcg∙hr/mL and 864 ng∙hr/mL, respectively.
### Distribution
Temozolomide has a mean apparent volume of distribution of 0.4 L/kg (%CV=13%). It is weakly bound to human plasma proteins; the mean percent bound of drug-related total radioactivity is 15%.
### Metabolism and Elimination
Temozolomide is spontaneously hydrolyzed at physiologic pH to the active species, MTIC and to temozolomide acid metabolite. MTIC is further hydrolyzed to 5-amino-imidazole-4-carboxamide (AIC), which is known to be an intermediate in purine and nucleic acid biosynthesis, and to methylhydrazine, which is believed to be the active alkylating species. Cytochrome P450 enzymes play only a minor role in the metabolism of temozolomide and MTIC. Relative to the AUC of temozolomide, the exposure to MTIC and AIC is 2.4% and 23%, respectively.
### Excretion
About 38% of the administered temozolomide total radioactive dose is recovered over 7 days: 37.7% in urine and 0.8% in feces. The majority of the recovery of radioactivity in urine is unchanged temozolomide (5.6%), AIC (12%), temozolomide acid metabolite (2.3%), and unidentified polar metabolite(s) (17%). Overall clearance of temozolomide is about 5.5 L/hr/m2. Temozolomide is rapidly eliminated, with a mean elimination half-life of 1.8 hours, and exhibits linear kinetics over the therapeutic dosing range of 75 to 250 mg/m2/day.
### Tobacco Use
A population pharmacokinetic analysis indicated that the oral clearance of temozolomide is similar in smokers and nonsmokers.
## Nonclinical Toxicology
### Carcinogenesis and Mutagenesis
Temozolomide is carcinogenic in rats at doses less than the maximum recommended human dose. Temozolomide induced mammary carcinomas in both males and females at doses 0.13 to 0.63 times the maximum human dose (25–125 mg/m2) when administered orally on 5 consecutive days every 28 days for 6 cycles. Temozolomide also induced fibrosarcomas of the heart, eye, seminal vesicles, salivary glands, abdominal cavity, uterus, and prostate, carcinomas of the seminal vesicles, schwannomas of the heart, optic nerve, and harderian gland, and adenomas of the skin, lung, pituitary, and thyroid at doses 0.5 times the maximum daily dose. Mammary tumors were also induced following 3 cycles of temozolomide at the maximum recommended daily dose.
Temozolomide is a mutagen and a clastogen. In a reverse bacterial mutagenesis assay (Ames assay), temozolomide increased revertant frequency in the absence and presence of metabolic activation. Temozolomide was clastogenic in human lymphocytes in the presence and absence of metabolic activation.
### Animal Toxicology and/or Pharmacology
Toxicology studies in rats and dogs identified a low incidence of hemorrhage, degeneration, and necrosis of the retina at temozolomide doses equal to or greater than 0.63 times the maximum recommended human dose (125 mg/m2). These changes were most commonly seen at doses where mortality was observed.
# Clinical Studies
### Newly Diagnosed Glioblastoma Multiforme
Five hundred and seventy-three patients were randomized to receive either temozolomide (TMZ)+Radiotherapy (RT) (n=287) or RT alone (n=286). Patients in the temozolomide+RT arm received concomitant temozolomide (75 mg/m2) once daily, starting the first day of RT until the last day of RT, for 42 days (with a maximum of 49 days). This was followed by 6 cycles of temozolomide alone (150 or 200 mg/m2) on Days 1 to 5 of every 28-day cycle, starting 4 weeks after the end of RT. Patients in the control arm received RT only. In both arms, focal radiation therapy was delivered as 60 Gy/30 fractions. Focal RT includes the tumor bed or resection site with a 2- to 3-cm margin. Pneumocystis pneumonia (PCP) prophylaxis was required during the TMZ+RT, regardless of lymphocyte count, and was to continue until recovery of lymphocyte count to less than or equal to Grade 1.
At the time of disease progression, temozolomide was administered as salvage therapy in 161 patients of the 282 (57%) in the RT alone arm, and 62 patients of the 277 (22%) in the temozolomide+RT arm.
The addition of concomitant and maintenance temozolomide to radiotherapy in the treatment of patients with newly diagnosed GBM showed a statistically significant improvement in overall survival compared to radiotherapy alone. The hazard ratio (HR) for overall survival was 0.63 (95% CI for HR=0.52-0.75) with a log-rank P<0.0001 in favor of the temozolomide arm. The median survival was increased by 2.5 months in the temozolomide arm.
### Refractory Anaplastic Astrocytoma
A single-arm, multicenter study was conducted in 162 patients who had anaplastic astrocytoma at first relapse and who had a baseline Karnofsky performance status of 70 or greater. Patients had previously received radiation therapy and may also have previously received a nitrosourea with or without other chemotherapy. Fifty-four patients had disease progression on prior therapy with both a nitrosourea and procarbazine, and their malignancy was considered refractory to chemotherapy (refractory anaplastic astrocytoma population). Median age of this subgroup of 54 patients was 42 years (19–76). Sixty-five percent were male. Seventy-two percent of patients had a KPS of >80. Sixty-three percent of patients had surgery other than a biopsy at the time of initial diagnosis. Of those patients undergoing resection, 73% underwent a subtotal resection and 27% underwent a gross total resection. Eighteen percent of patients had surgery at the time of first relapse. The median time from initial diagnosis to first relapse was 13.8 months (4.2–75.4).
temozolomide Capsules were given for the first 5 consecutive days of a 28-day cycle at a starting dose of 150 mg/m2/day. If the nadir and day of dosing (Day 29, Day 1 of next cycle) absolute neutrophil count was greater than or equal to 1.5 × 109/L (1500/µL) and the nadir and Day 29, Day 1 of next cycle platelet count was greater than or equal to 100 × 109/L (100,000/µL), the temozolomide dose was increased to 200 mg/m2/day for the first 5 consecutive days of a 28-day cycle.
In the refractory anaplastic astrocytoma population, the overall tumor response rate (CR+PR) was 22% (12/54 patients) and the complete response rate was 9% (5/54 patients). The median duration of all responses was 50 weeks (range: 16–114 weeks) and the median duration of complete responses was 64 weeks (range: 52–114 weeks). In this population, progression-free survival at 6 months was 45% (95% CI: 31%–58%) and progression-free survival at 12 months was 29% (95% CI: 16%–42%). Median progression-free survival was 4.4 months. Overall survival at 6 months was 74% (95% CI: 62%–86%) and 12-month overall survival was 65% (95% CI: 52%–78%). Median overall survival was 15.9 months.
# How Supplied
### Temozolomide Capsules
- Temozolomide Capsules 5 mg
- 5-count – NDC 0085-3004-03
- 14-count – NDC 0085-3004-04
- Temozolomide Capsules 20 mg
- 5-count – NDC 0085-1519-03
- 14-count – NDC 0085-1519-04
- Temozolomide Capsules 100 mg:
- 5-count – NDC 0085-1366-03
- 14-count – NDC 0085-1366-04
- Temozolomide Capsules 140 mg
- 5-count – NDC 0085-1425-03
- 14-count – NDC 0085-1425-04
- Temozolomide Capsules 180 mg
- 5-count – NDC 0085-1430-03
- 14-count – NDC 0085-1430-04
- Temozolomide Capsules 250 mg
- 5-count – NDC 0085-1417-02
### Temozolomide for Injection
- Temozolomide for Injection 100 mg
- NDC 0085-1381-01
## Storage
- Store temozolomidecapsules at 25°C (77°F)
- Store temozolomide for Injection refrigerated at 2–8°C (36–46°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Physicians should discuss the following with their patients:
- Nausea and vomiting are the most frequently occurring adverse reactions. Nausea and vomiting are usually either self-limiting or readily controlled with standard antiemetic therapy.
- Capsules should not be opened. If capsules are accidentally opened or damaged, rigorous precautions should be taken with the capsule contents to avoid inhalation or contact with the skin or mucous membranes.
- The medication should be kept away from children and pets.
# Precautions with Alcohol
Alcohol-Temozolomide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Temodar
# Look-Alike Drug Names
There is limited information regarding Temozolomide Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Temozolomide
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gloria Picoy [2];Aparna Vuppala, M.B.B.S. [3]
# 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
Temozolomide is an antineoplastic agent that is FDA approved for the treatment of newly diagnosed glioblastoma multiforme (GBM) and refractory anaplastic astrocytoma. Common adverse reactions include alopecia, fatigue, nausea, vomiting, headache, constipation, anorexia, convulsions, rash, hemiparesis, diarrhea, asthenia, fever, dizziness, incoordination, viral infection, amnesia, and insomnia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Newly Diagnosed Glioblastoma Multiforme
- Temozolomide is indicated for the treatment of adult patients with newly diagnosed glioblastoma multiforme concomitantly with radiotherapy and then as maintenance treatment.
- Dosage:
- 75 mg/m2 for 42 days concomitant with focal radiotherapy followed by initial maintenance dose of 150 mg/m2 once daily for Days 1–5 of a 28-day cycle of temozolomide for 6 cycles.
### Refractory Anaplastic Astrocytoma
- Temozolomide is indicated for the treatment of adult patients with refractory anaplastic astrocytoma.
- Dosage:
- Initial dose 150 mg/m2 once daily for 5 consecutive days per 28-day treatment cycle.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Temozolomide in adult patients.
### Non–Guideline-Supported Use
- Relapsed, refractory, or progressive malignant glioma as monotherapy
- As monotherapy of metastatic malignant melanoma
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Temozolomide 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 Temozolomide in pediatric patients.
### Non–Guideline-Supported Use
- Relapsed, refractory, or progressive malignant glioma as monotherapy
# Contraindications
Temozolomide is contraindicated in patients who have a history of hypersensitivity reaction (such as urticaria, allergic reaction including anaphylaxis, toxic epidermal necrolysis, and Stevens-Johnson syndrome) to any of its components. temozolomide is also contraindicated in patients who have a history of hypersensitivity to dacarbazine (DTIC), since both drugs are metabolized to 5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide (MTIC).
# Warnings
### Myelosuppression
- Patients treated with temozolomide may experience myelosuppression, including prolonged pancytopenia, which may result in aplastic anemia, which in some cases has resulted in a fatal outcome.
- In some cases, exposure to concomitant medications associated with aplastic anemia, including carbamazepine, phenytoin, and sulfamethoxazole/trimethoprim, complicates assessment.
- Prior to dosing, patients must have an absolute neutrophil count (ANC) greater than or equal to 1.5 × 109/L and a platelet count greater than or equal to 100 × 109/L.
- A complete blood count should be obtained on Day 22 (21 days after the first dose) or within 48 hours of that day, and weekly until the ANC is above 1.5 × 109/L and platelet count exceeds 100 × 109/L
- Geriatric patients and women have been shown in clinical trials to have a higher risk of developing myelosuppression.
### Myelodysplastic Syndrome
- Cases of myelodysplastic syndrome and secondary malignancies, including myeloid leukemia, have been observed.
### Pneumocystis Pneumonia
- For treatment of newly diagnosed glioblastoma multiforme: Prophylaxis against Pneumocystis pneumonia (PCP) is required for all patients receiving concomitant temozolomide and radiotherapy for the 42-day regimen.
- There may be a higher occurrence of PCP when temozolomide is administered during a longer dosing regimen. However, all patients receiving temozolomide, particularly patients receiving steroids, should be observed closely for the development of PCP regardless of the regimen.
### Laboratory Tests
- For the concomitant treatment phase with RT, a complete blood count should be obtained prior to initiation of treatment and weekly during treatment.
- For the 28-day treatment cycles, a complete blood count should be obtained prior to treatment on Day 1 and on Day 22 (21 days after the first dose) of each cycle. Blood counts should be performed weekly until recovery if the ANC falls below 1.5 × 109/L and the platelet count falls below 100 × 109/L.
### Hepatotoxicity
- Fatal and severe hepatotoxicity have been reported in patients receiving temozolomide. Perform liver function tests at baseline, midway through the first cycle, prior to each subsequent cycle, and approximately two to four weeks after the last dose of temozolomide.
### Use in Pregnancy
- Temozolomide can cause fetal harm when administered to a pregnant woman. Administration of temozolomide to rats and rabbits during organogenesis at 0.38 and 0.75 times the maximum recommended human dose (75 and 150 mg/m2), respectively, caused numerous fetal malformations of the external organs, soft tissues, and skeleton in both species.
### Infusion Time
- As bioequivalence has been established only when temozolomide for Injection was given over 90 minutes, infusion over a shorter or longer period of time may result in suboptimal dosing. Additionally, the possibility of an increase in infusion-related adverse reactions cannot be ruled out.
# 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.
### Newly Diagnosed Glioblastoma Multiforme
During the concomitant phase (temozolomide+radiotherapy), adverse reactions including thrombocytopenia, nausea, vomiting, anorexia, and constipation were more frequent in the temozolomide+RT arm. The incidence of other adverse reactions was comparable in the two arms. The most common adverse reactions across the cumulative temozolomide experience were alopecia, nausea, vomiting, anorexia, headache, and constipation. Forty-nine percent (49%) of patients treated with temozolomide reported one or more severe or life-threatening reactions, most commonly fatigue (13%), convulsions (6%), headache (5%), and thrombocytopenia (5%). Overall, the pattern of reactions during the maintenance phase was consistent with the known safety profile of temozolomide.
Myelosuppression (neutropenia and thrombocytopenia), which is a known dose-limiting toxicity for most cytotoxic agents, including temozolomide, was observed. When laboratory abnormalities and adverse reactions were combined, Grade 3 or Grade 4 neutrophil abnormalities including neutropenic reactions were observed in 8% of the patients, and Grade 3 or Grade 4 platelet abnormalities, including thrombocytopenic reactions, were observed in 14% of the patients treated with temozolomide.
### Refractory Anaplastic Astrocytoma
TABLES 8 and 9 show the incidence of adverse reactions in the 158 patients in the anaplastic astrocytoma study for whom data are available. In the absence of a control group, it is not clear in many cases whether these reactions should be attributed to temozolomide or the patients' underlying conditions, but nausea, vomiting, fatigue, and hematologic effects appear to be clearly drug-related. The most frequently occurring adverse reactions were nausea, vomiting, headache, and fatigue. The adverse reactions were usually NCI Common Toxicity Criteria (CTC) Grade 1 or 2 (mild to moderate in severity) and were self-limiting, with nausea and vomiting readily controlled with antiemetics. The incidence of severe nausea and vomiting (CTC Grade 3 or 4) was 10% and 6%, respectively. Myelosuppression (thrombocytopenia and neutropenia) was the dose-limiting adverse reaction. It usually occurred within the first few cycles of therapy and was not cumulative.
Myelosuppression occurred late in the treatment cycle and returned to normal, on average, within 14 days of nadir counts. The median nadirs occurred at 26 days for platelets (range: 21–40 days) and 28 days for neutrophils (range: 1–44 days). Only 14% (22/158) of patients had a neutrophil nadir and 20% (32/158) of patients had a platelet nadir, which may have delayed the start of the next cycle. Less than 10% of patients required hospitalization, blood transfusion, or discontinuation of therapy due to myelosuppression.
In clinical trial experience with 110 to 111 women and 169 to 174 men (depending on measurements), there were higher rates of Grade 4 neutropenia (ANC less than 500 cells/µL) and thrombocytopenia (less than 20,000 cells/µL) in women than men in the first cycle of therapy (12% vs. 5% and 9% vs. 3%, respectively).
In the entire safety database for which hematologic data exist (N=932), 7% (4/61) and 9.5% (6/63) of patients over age 70 experienced Grade 4 neutropenia or thrombocytopenia in the first cycle, respectively. For patients less than or equal to age 70, 7% (62/871) and 5.5% (48/879) experienced Grade 4 neutropenia or thrombocytopenia in the first cycle, respectively. Pancytopenia, leukopenia, and anemia have also been reported.
Temozolomide for injection delivers equivalent temozolomide dose and exposure to both temozolomide and 5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide (MTIC) as the corresponding temozolomide capsules. Adverse reactions probably related to treatment that were reported from the 2 studies with the intravenous formulation (n=35) that were not reported in studies using the temozolomide capsules were: pain, irritation, pruritus, warmth, swelling, and erythema at infusion site as well as the following adverse reactions: petechiae and hematoma.
## Postmarketing Experience
The following adverse reactions have been identified during postapproval use of temozolomide. 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 the drug exposure.
- Dermatologic disorders: Toxic epidermal necrolysis and Stevens-Johnson syndrome
- Immune system disorders: Allergic reactions, including anaphylaxis. Erythema multiforme, which resolved after discontinuation of temozolomide and, in some cases, recurred upon rechallenge.
- Hematopoietic disorders: Prolonged pancytopenia, which may result in aplastic anemia and fatal outcomes.
- Hepatobiliary disorders: Fatal and severe hepatotoxicity, elevation of liver enzymes, hyperbilirubinemia, cholestasis, and hepatitis.
- Infections and infestations: Opportunistic infections including Pneumocystis pneumonia (PCP), reactivation of infections such as cytomegalovirus and hepatitis B.
- Pulmonary disorders: Interstitial pneumonitis, pneumonitis, alveolitis, and pulmonary fibrosis.
- Endocrine disorders: Diabetes insipidus
# Drug Interactions
Administration of valproic acid decreases oral clearance of temozolomide by about 5%. The clinical implication of this effect is not known
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
temozolomide can cause fetal harm when administered to a pregnant woman. Five consecutive days of oral temozolomide administration of 0.38 and 0.75 times the highest recommended human dose (75 and 150 mg/m2) in rats and rabbits, respectively, during the period of organogenesis caused numerous malformations of the external and internal soft tissues and skeleton in both species. Doses equivalent to 0.75 times the highest recommended human dose (150 mg/m2) caused embryolethality in rats and rabbits as indicated by increased resorptions. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Women of childbearing potential should be advised to avoid becoming pregnant during therapy with temozolomide.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Temozolomide in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Temozolomide during labor and delivery.
### Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants and tumorigenicity shown for temozolomide in animal studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of temozolomide to the mother.
### Pediatric Use
Safety and effectiveness in pediatric patients have not been established. temozolomide Capsules have been studied in 2 open-label studies in pediatric patients (aged 3–18 years) at a dose of 160 to 200 mg/m2 daily for 5 days every 28 days. In one trial, 29 patients with recurrent brain stem glioma and 34 patients with recurrent high grade astrocytoma were enrolled. All patients had recurrence following surgery and radiation therapy, while 31% also had disease progression following chemotherapy. In a second study conducted by the Children's Oncology Group (COG), 122 patients were enrolled, including patients with medulloblastoma/PNET (29), high grade astrocytoma (23), low grade astrocytoma (22), brain stem glioma (16), ependymoma (14), other CNS tumors (9), and non-CNS tumors (9). The temozolomide toxicity profile in pediatric patients is similar to adults.
### Geriatic Use
Clinical studies of temozolomide did not include sufficient numbers of subjects aged 65 and over to determine whether they responded differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
In the anaplastic astrocytoma study population, patients 70 years of age or older had a higher incidence of Grade 4 neutropenia and Grade 4 thrombocytopenia (2/8; 25%, P=0.31 and 2/10; 20%, P=0.09, respectively) in the first cycle of therapy than patients under 70 years of age.
In newly diagnosed patients with glioblastoma multiforme, the adverse reaction profile was similar in younger patients (<65 years) vs. older (≥65 years).
### Gender
A population pharmacokinetic analysis indicated that women have an approximately 5% lower clearance (adjusted for body surface area) for temozolomide than men.
### Race
The effect of race on the pharmacokinetics of temozolomide has not been studied.
### Renal Impairment
- Caution should be exercised when temozolomide is administered to patients with severe renal impairment.
- A population pharmacokinetic analysis indicated that creatinine clearance over the range of 36 to 130 mL/min/m2 has no effect on the clearance of temozolomide after oral administration. The pharmacokinetics of temozolomide have not been studied in patients with severely impaired renal function (CLcr <36 mL/min/m2). Caution should be exercised when temozolomide is administered to patients with severe renal impairment. Temozolomide has not been studied in patients on dialysis.
### Hepatic Impairment
- Caution should be exercised when temozolomide is administered to patients with severe hepatic impairment.
- A study showed that the pharmacokinetics of temozolomide in patients with mild-to-moderate hepatic impairment (Child-Pugh Class I – II) were similar to those observed in patients with normal hepatic function. Caution should be exercised when temozolomide is administered to patients with severe hepatic impairment
### Females of Reproductive Potential and Males
Temozolomide impairs male fertility. Temozolomide caused syncytial cells/immature sperm formation at 0.25 and 0.63 times the maximum recommended human dose (50 and 125 mg/m2) in rats and dogs, respectively, and testicular atrophy in dogs at 0.63 times the maximum recommended human dose (125 mg/m2).
### Immunocompromised Patients
There is no FDA guidance one the use of Temozolomide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
- Intravenous
### Monitoring
There is limited information regarding Temozolomide Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Temozolomide and IV administrations.
# Overdosage
Doses of 500, 750, 1000, and 1250 mg/m2 (total dose per cycle over 5 days) have been evaluated clinically in patients. Dose-limiting toxicity was hematologic and was reported with any dose but is expected to be more severe at higher doses. An overdose of 2000 mg per day for 5 days was taken by one patient and the adverse reactions reported were pancytopenia, pyrexia, multi-organ failure, and death. There are reports of patients who have taken more than 5 days of treatment (up to 64 days), with adverse reactions reported including bone marrow suppression, which in some cases was severe and prolonged, and infections and resulted in death. In the event of an overdose, hematologic evaluation is needed. Supportive measures should be provided as necessary.
# Pharmacology
## Mechanism of Action
Temozolomide is not directly active but undergoes rapid nonenzymatic conversion at physiologic pH to the reactive compound 5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide (MTIC). The cytotoxicity of MTIC is thought to be primarily due to alkylation of DNA. Alkylation (methylation) occurs mainly at the O6 and N7 positions of guanine.
## Structure
The chemical name of temozolomide is 3,4-dihydro-3-methyl-4-oxoimidazo[5,1-d]-as-tetrazine-8-carboxamide. The structural formula is:
## Pharmacodynamics
There is limited information regarding Temozolomide Pharmacodynamics in the drug label.
## Pharmacokinetics
### Absorption
Temozolomide is rapidly and completely absorbed after oral administration with a peak plasma concentration (Cmax) achieved in a median Tmax of 1 hour. Food reduces the rate and extent of temozolomide absorption. Mean peak plasma concentration and AUC decreased by 32% and 9%, respectively, and median Tmax increased by 2-fold (from 1–2.25 hours) when temozolomide was administered after a modified high-fat breakfast.
A pharmacokinetic study comparing oral and intravenous temozolomide in 19 patients with primary CNS malignancies showed that 150 mg/m2 temozolomide for injection administered over 90 minutes is bioequivalent to 150 mg/m2 temozolomide oral capsules with respect to both Cmax and AUC of temozolomide and MTIC. Following a single 90-minute intravenous infusion of 150 mg/m2, the geometric mean Cmax values for temozolomide and MTIC were 7.3 mcg/mL and 276 ng/mL, respectively. Following a single oral dose of 150 mg/m2, the geometric mean Cmax values for temozolomide and MTIC were 7.5 mcg/mL and 282 ng/mL, respectively. Following a single 90-minute intravenous infusion of 150 mg/m2, the geometric mean AUC values for temozolomide and MTIC were 24.6 mcg∙hr/mL and 891 ng∙hr/mL, respectively. Following a single oral dose of 150 mg/m2, the geometric mean AUC values for temozolomide and MTIC were 23.4 mcg∙hr/mL and 864 ng∙hr/mL, respectively.
### Distribution
Temozolomide has a mean apparent volume of distribution of 0.4 L/kg (%CV=13%). It is weakly bound to human plasma proteins; the mean percent bound of drug-related total radioactivity is 15%.
### Metabolism and Elimination
Temozolomide is spontaneously hydrolyzed at physiologic pH to the active species, MTIC and to temozolomide acid metabolite. MTIC is further hydrolyzed to 5-amino-imidazole-4-carboxamide (AIC), which is known to be an intermediate in purine and nucleic acid biosynthesis, and to methylhydrazine, which is believed to be the active alkylating species. Cytochrome P450 enzymes play only a minor role in the metabolism of temozolomide and MTIC. Relative to the AUC of temozolomide, the exposure to MTIC and AIC is 2.4% and 23%, respectively.
### Excretion
About 38% of the administered temozolomide total radioactive dose is recovered over 7 days: 37.7% in urine and 0.8% in feces. The majority of the recovery of radioactivity in urine is unchanged temozolomide (5.6%), AIC (12%), temozolomide acid metabolite (2.3%), and unidentified polar metabolite(s) (17%). Overall clearance of temozolomide is about 5.5 L/hr/m2. Temozolomide is rapidly eliminated, with a mean elimination half-life of 1.8 hours, and exhibits linear kinetics over the therapeutic dosing range of 75 to 250 mg/m2/day.
### Tobacco Use
A population pharmacokinetic analysis indicated that the oral clearance of temozolomide is similar in smokers and nonsmokers.
## Nonclinical Toxicology
### Carcinogenesis and Mutagenesis
Temozolomide is carcinogenic in rats at doses less than the maximum recommended human dose. Temozolomide induced mammary carcinomas in both males and females at doses 0.13 to 0.63 times the maximum human dose (25–125 mg/m2) when administered orally on 5 consecutive days every 28 days for 6 cycles. Temozolomide also induced fibrosarcomas of the heart, eye, seminal vesicles, salivary glands, abdominal cavity, uterus, and prostate, carcinomas of the seminal vesicles, schwannomas of the heart, optic nerve, and harderian gland, and adenomas of the skin, lung, pituitary, and thyroid at doses 0.5 times the maximum daily dose. Mammary tumors were also induced following 3 cycles of temozolomide at the maximum recommended daily dose.
Temozolomide is a mutagen and a clastogen. In a reverse bacterial mutagenesis assay (Ames assay), temozolomide increased revertant frequency in the absence and presence of metabolic activation. Temozolomide was clastogenic in human lymphocytes in the presence and absence of metabolic activation.
### Animal Toxicology and/or Pharmacology
Toxicology studies in rats and dogs identified a low incidence of hemorrhage, degeneration, and necrosis of the retina at temozolomide doses equal to or greater than 0.63 times the maximum recommended human dose (125 mg/m2). These changes were most commonly seen at doses where mortality was observed.
# Clinical Studies
### Newly Diagnosed Glioblastoma Multiforme
Five hundred and seventy-three patients were randomized to receive either temozolomide (TMZ)+Radiotherapy (RT) (n=287) or RT alone (n=286). Patients in the temozolomide+RT arm received concomitant temozolomide (75 mg/m2) once daily, starting the first day of RT until the last day of RT, for 42 days (with a maximum of 49 days). This was followed by 6 cycles of temozolomide alone (150 or 200 mg/m2) on Days 1 to 5 of every 28-day cycle, starting 4 weeks after the end of RT. Patients in the control arm received RT only. In both arms, focal radiation therapy was delivered as 60 Gy/30 fractions. Focal RT includes the tumor bed or resection site with a 2- to 3-cm margin. Pneumocystis pneumonia (PCP) prophylaxis was required during the TMZ+RT, regardless of lymphocyte count, and was to continue until recovery of lymphocyte count to less than or equal to Grade 1.
At the time of disease progression, temozolomide was administered as salvage therapy in 161 patients of the 282 (57%) in the RT alone arm, and 62 patients of the 277 (22%) in the temozolomide+RT arm.
The addition of concomitant and maintenance temozolomide to radiotherapy in the treatment of patients with newly diagnosed GBM showed a statistically significant improvement in overall survival compared to radiotherapy alone. The hazard ratio (HR) for overall survival was 0.63 (95% CI for HR=0.52-0.75) with a log-rank P<0.0001 in favor of the temozolomide arm. The median survival was increased by 2.5 months in the temozolomide arm.
### Refractory Anaplastic Astrocytoma
A single-arm, multicenter study was conducted in 162 patients who had anaplastic astrocytoma at first relapse and who had a baseline Karnofsky performance status of 70 or greater. Patients had previously received radiation therapy and may also have previously received a nitrosourea with or without other chemotherapy. Fifty-four patients had disease progression on prior therapy with both a nitrosourea and procarbazine, and their malignancy was considered refractory to chemotherapy (refractory anaplastic astrocytoma population). Median age of this subgroup of 54 patients was 42 years (19–76). Sixty-five percent were male. Seventy-two percent of patients had a KPS of >80. Sixty-three percent of patients had surgery other than a biopsy at the time of initial diagnosis. Of those patients undergoing resection, 73% underwent a subtotal resection and 27% underwent a gross total resection. Eighteen percent of patients had surgery at the time of first relapse. The median time from initial diagnosis to first relapse was 13.8 months (4.2–75.4).
temozolomide Capsules were given for the first 5 consecutive days of a 28-day cycle at a starting dose of 150 mg/m2/day. If the nadir and day of dosing (Day 29, Day 1 of next cycle) absolute neutrophil count was greater than or equal to 1.5 × 109/L (1500/µL) and the nadir and Day 29, Day 1 of next cycle platelet count was greater than or equal to 100 × 109/L (100,000/µL), the temozolomide dose was increased to 200 mg/m2/day for the first 5 consecutive days of a 28-day cycle.
In the refractory anaplastic astrocytoma population, the overall tumor response rate (CR+PR) was 22% (12/54 patients) and the complete response rate was 9% (5/54 patients). The median duration of all responses was 50 weeks (range: 16–114 weeks) and the median duration of complete responses was 64 weeks (range: 52–114 weeks). In this population, progression-free survival at 6 months was 45% (95% CI: 31%–58%) and progression-free survival at 12 months was 29% (95% CI: 16%–42%). Median progression-free survival was 4.4 months. Overall survival at 6 months was 74% (95% CI: 62%–86%) and 12-month overall survival was 65% (95% CI: 52%–78%). Median overall survival was 15.9 months.
# How Supplied
### Temozolomide Capsules
- Temozolomide Capsules 5 mg
- 5-count – NDC 0085-3004-03
- 14-count – NDC 0085-3004-04
- Temozolomide Capsules 20 mg
- 5-count – NDC 0085-1519-03
- 14-count – NDC 0085-1519-04
- Temozolomide Capsules 100 mg:
- 5-count – NDC 0085-1366-03
- 14-count – NDC 0085-1366-04
- Temozolomide Capsules 140 mg
- 5-count – NDC 0085-1425-03
- 14-count – NDC 0085-1425-04
- Temozolomide Capsules 180 mg
- 5-count – NDC 0085-1430-03
- 14-count – NDC 0085-1430-04
- Temozolomide Capsules 250 mg
- 5-count – NDC 0085-1417-02
### Temozolomide for Injection
- Temozolomide for Injection 100 mg
- NDC 0085-1381-01
## Storage
- Store temozolomidecapsules at 25°C (77°F)
- Store temozolomide for Injection refrigerated at 2–8°C (36–46°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Physicians should discuss the following with their patients:
- Nausea and vomiting are the most frequently occurring adverse reactions. Nausea and vomiting are usually either self-limiting or readily controlled with standard antiemetic therapy.
- Capsules should not be opened. If capsules are accidentally opened or damaged, rigorous precautions should be taken with the capsule contents to avoid inhalation or contact with the skin or mucous membranes.
- The medication should be kept away from children and pets.
# Precautions with Alcohol
Alcohol-Temozolomide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Temodar [1]
# Look-Alike Drug Names
There is limited information regarding Temozolomide Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Temodal | |
4f5ffa3747115be599360ca9e938d483115311db | wikidoc | Temsirolimus | Temsirolimus
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# Overview
Temsirolimus is an antineoplastic agent that is FDA approved for the treatment of advanced renal cell carcinoma. Common adverse reactions include edema, rash, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypophosphatemia, inflammatory disease of mucous membrane, loss of appetite, nausea, decreased hemoglobin, decreased lymphocyte count, decreased platelet count, leukopenia, neutropenia, alkaline phosphatase raised, AST/SGOT level raised, asthenia, serum creatinine raised.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Temsirolimus is indicated for the treatment of advanced renal cell carcinoma.
- The recommended dose of Temsirolimus for advanced renal cell carcinoma is 25 mg infused over a 30 – 60 minute period once a week.
- Treatment should continue until disease progression or unacceptable toxicity occurs.
- Patients should receive prophylactic intravenous diphenhydramine 25 to 50 mg (or similar antihistamine) approximately 30 minutes before the start of each dose of Temsirolimus.
- Temsirolimus should be held for absolute neutrophil count (ANC) <1,000/mm3, platelet count <75,000/mm3, or NCI CTCAE grade 3 or greater adverse reactions. Once toxicities have resolved to grade 2 or less, Temsirolimus may be restarted with the dose reduced by 5 mg/week to a dose no lower than 15 mg/week.
- Hepatic Impairment
- Use caution when treating patients with hepatic impairment. If Temsirolimus must be given in patients with mild hepatic impairment (bilirubin >1 – 1.5×ULN or AST >ULN but bilirubin ≤ULN), reduce the dose of Temsirolimus to 15 mg/week. Temsirolimus is contraindicated in patients with bilirubin >1.5×ULN.
- Concomitant Strong CYP3A4 Inhibitors
- The concomitant use of strong CYP3A4 inhibitors should be avoided (e.g. ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole). Grapefruit juice may also increase plasma concentrations of sirolimus (a major metabolite of temsirolimus) and should be avoided. If patients must be co-administered a strong CYP3A4 inhibitor, based on pharmacokinetic studies, a Temsirolimus dose reduction to 12.5 mg/week should be considered. This dose of Temsirolimus is predicted to adjust the AUC to the range observed without inhibitors. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inhibitors. If the strong inhibitor is discontinued, a washout period of approximately 1 week should be allowed before the Temsirolimus dose is adjusted back to the dose used prior to initiation of the strong CYP3A4 inhibitor.
- Concomitant Strong CYP3A4 Inducers
- The use of concomitant strong CYP3A4 inducers should be avoided (e.g. dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifampicin, phenobarbital). If patients must be co-administered a strong CYP3A4 inducer, based on pharmacokinetic studies, a Temsirolimus dose increase from 25 mg/week up to 50 mg/week should be considered. This dose of Temsirolimus is predicted to adjust the AUC to the range observed without inducers. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inducers. If the strong inducer is discontinued the temsirolimus dose should be returned to the dose used prior to initiation of the strong CYP3A4 inducer.
- Temsirolimus must be stored under refrigeration at 2°–8°C (36°–46°F) and protected from light. During handling and preparation of admixtures, Temsirolimus should be protected from excessive room light and sunlight. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
- In order to minimize the patient exposure to the plasticizer DEHP (di-2-ethylhexyl phthalate), which may be leached from PVC infusion bags or sets, the final Temsirolimus dilution for infusion should be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined administration sets.
- Temsirolimus 25 mg/mL injection must be diluted with the supplied diluent before further dilution in 0.9% Sodium Chloride Injection, USP.
- Please note that both the Temsirolimus injection and diluent vials contain an overfill to ensure the recommended volume can be withdrawn.
- Follow this two-step dilution process in an aseptic manner.
- Step 1
- DILUTION OF Temsirolimus INJECTION 25 MG/ML WITH SUPPLIED DILUENT
- Each Vial of Temsirolimus (temsirolimus) must first be mixed with 1.8 mL of the enclosed diluent. The resultant solution contains 30 mg/3 mL (10 mg/mL).
- Mix well by inversion of the vial. Allow sufficient time for the air bubbles to subside. The solution should be clear to slightly turbid, colorless to light-yellow solution, essentially free from visual particulates.
- The concentrate-diluent mixture is stable below 25°C for up to 24 hours.
- Step 2
- DILUTION OF CONCENTRATE-DILUENT MIXTURE WITH 0.9% SODIUM CHLORIDE INJECTION, USP
- Withdraw precisely the required amount of concentrate-diluent mixture containing temsirolimus 10 mg/mL as prepared in Step 1 from the vial (i.e., 2.5 mL for a temsirolimus dose of 25 mg) and further dilute into an infusion bag containing 250 mL of 0.9% Sodium Chloride Injection, USP.
Mix by inversion of the bag or bottle, avoiding excessive shaking, as this may cause foaming.
- The resulting solution should be inspected visually for particulate matter and discoloration prior to administration. The admixture of Temsirolimus in 0.9% Sodium Chloride Injection, USP should be protected from excessive room light and sunlight.
- Administration of the final diluted solution should be completed within six hours from the time that Temsirolimus is first added to 0.9% Solution Chloride Injection, USP.
- Temsirolimus is infused over a 30- to 60-minute period once weekly. The use of an infusion pump is the preferred method of administration to ensure accurate delivery of the product.
- Appropriate administration materials should be composed of glass, polyolefin, or polyethylene to avoid excessive loss of product and diethylhexylpthalate (DEHP) extraction. The administration materials should consist of non-DEHP, non-polyvinylchloride (PVC) tubing with appropriate filter. In the case when a PVC administration set has to be used, it should not contain DEHP. An in-line polyethersulfone filter with a pore size of not greater than 5 microns is recommended for administration to avoid the possibility of particles bigger than 5 microns being infused.
- If the administration set available does not have an in-line filter incorporated, a polyethersulfone filter should be added at the set (i.e., an end-filter) before the admixture reaches the vein of the patient. Different end-filters can be used, ranging in filter pore size from 0.2 microns up to 5 microns. The use of both an in-line and end-filter is not recommended.
- Temsirolimus, when diluted, contains polysorbate 80, which is known to increase the rate of DEHP extraction from PVC. This should be considered during the preparation and administration of Temsirolimus, including storage time elapsed when in direct contact with PVC following constitution.
- Undiluted Temsirolimus injection should not be added directly to aqueous infusion solutions. Direct addition of Temsirolimus injection to aqueous solutions will result in precipitation of drug. Always combine Temsirolimus injection with DILUENT for Temsirolimus before adding to infusion solutions.
- It is recommended that Temsirolimus be administered in 0.9% Sodium Chloride Injection after combining with diluent. The stability of Temsirolimus in other infusion solutions has not been evaluated. Addition of other drugs or nutritional agents to admixtures of Temsirolimus in 0.9% Sodium Chloride Injection has not been evaluated and should be avoided. Temsirolimus is degraded by both acids and bases, and thus combinations of temsirolimus with agents capable of modifying solution pH should be avoided.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Temsirolimus in adult patients.
### Non–Guideline-Supported Use
- Mantle cell lymphoma, Relapsed or refractory
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Temsirolimus 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 Temsirolimus in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Temsirolimus in pediatric patients.
# Contraindications
- Temsirolimus is contraindicated in patients with bilirubin >1.5×ULN
# Warnings
- Hypersensitivity/infusion reactions, including but not limited to flushing, chest pain, dyspnea, hypotension, apnea, loss of consciousness, hypersensitivity and anaphylaxis, have been associated with the administration of temsirolimus.
- These reactions can occur very early in the first infusion, but may also occur with subsequent infusions. Patients should be monitored throughout the infusion and appropriate supportive care should be available. Temsirolimus infusion should be interrupted in all patients with severe infusion reactions and appropriate medical therapy administered.
- Temsirolimus should be used with caution in persons with known hypersensitivity to temsirolimus or its metabolites (including sirolimus), polysorbate 80, or to any other component (including the excipients) of Temsirolimus.
- An H1 antihistamine should be administered to patients before the start of the intravenous temsirolimus infusion. Temsirolimus should be used with caution in patients with known hypersensitivity to an antihistamine, or patients who cannot receive an antihistamine for other medical reasons.
- If a patient develops a hypersensitivity reactions during the Temsirolimus infusion, the infusion should be stopped and the patient should be observed for at least 30 to 60 minutes (depending on the severity of the reaction). At the discretion of the physician, treatment may be resumed with the administration of an H1-receptor antagonist (such as diphenhydramine), if not previously administered, and/or an H2-receptor antagonist (such as intravenous famotidine 20 mg or intravenous ranitidine 50 mg) approximately 30 minutes before restarting the Temsirolimus infusion. The infusion may then be resumed at a slower rate (up to 60 minutes).
- A benefit-risk assessment should be done prior to the continuation of temsirolimus therapy in patients with severe or life-threatening reactions.
- The safety and pharmacokinetics of Temsirolimus were evaluated in a dose escalation phase 1 study in 110 patients with normal or varying degrees of hepatic impairment. Patients with baseline bilirubin >1.5×ULN experienced greater toxicity than patients with baseline bilirubin ≤1.5×ULN when treated with Temsirolimus. The overall frequency of ≥ grade 3 adverse reactions and deaths, including deaths due to progressive disease, were greater in patients with baseline bilirubin >1.5×ULN due to increased risk of death.
- Use caution when treating patients with mild hepatic impairment. Concentrations of temsirolimus and its metabolite sirolimus were increased in patients with elevated AST or bilirubin levels. If Temsirolimus must be given in patients with mild hepatic impairment (bilirubin >1 – 1.5×ULN or AST >ULN but bilirubin ≤ULN), reduce the dose of Temsirolimus to 15 mg/week.
- The use of Temsirolimus is likely to result in increases in serum glucose. In the phase 3 trial, 89% of patients receiving Temsirolimus had at least one elevated serum glucose while on treatment, and 26% of patients reported hyperglycemia as an adverse event. This may result in the need for an increase in the dose of, or initiation of, insulin and/or oral hypoglycemic agent therapy. Serum glucose should be tested before and during treatment with Temsirolimus. Patients should be advised to report excessive thirst or any increase in the volume or frequency of urination.
- The use of Temsirolimus may result in immunosuppression. Patients should be carefully observed for the occurrence of infections, including opportunistic infections.
- Pneumocystis jiroveci pneumonia (PJP), including fatalities, has been reported in patients who received temsirolimus. This may be associated with concomitant use of corticosteroids or other immunosuppressive agents. Prophylaxis of PJP should be considered when concomitant use of corticosteroids or other immunosuppressive agents are required.
- Cases of interstitial lung disease, some resulting in death, occurred in patients who received Temsirolimus. Some patients were asymptomatic, or had minimal symptoms, with infiltrates detected on computed tomography scan or chest radiograph. Others presented with symptoms such as dyspnea, cough, hypoxia, and fever. Some patients required discontinuation of Temsirolimus and/or treatment with corticosteroids and/or antibiotics, while some patients continued treatment without additional intervention. Patients should be advised to report promptly any new or worsening respiratory symptoms.
- It is recommended that patients undergo baseline radiographic assessment by lung computed tomography scan or chest radiograph prior to the initiation of Temsirolimus therapy. Follow such assessments periodically, even in the absence of clinical respiratory symptoms.
- It is recommended that patients be followed closely for occurrence of clinical respiratory symptoms. If clinically significant respiratory symptoms develop, consider withholding Temsirolimus administration until after recovery of symptoms and improvement of radiographic findings related to pneumonitis. Empiric treatment with corticosteroids and/or antibiotics may be considered. Opportunistic infections such as PJP should be considered in the differential diagnosis. For patients who require use of corticosteroids, prophylaxis of PJP may be considered.
- The use of Temsirolimus is likely to result in increases in serum triglycerides and cholesterol. In the phase 3 trial, 87% of patients receiving Temsirolimus had at least one elevated serum cholesterol value and 83% had at least one elevated serum triglyceride value. This may require initiation, or increase in the dose, of lipid-lowering agents. Serum cholesterol and triglycerides should be tested before and during treatment with Temsirolimus.
- Cases of fatal bowel perforation occurred in patients who received Temsirolimus. - These patients presented with fever, abdominal pain, metabolic acidosis, bloody stools, diarrhea, and/or acute abdomen. Patients should be advised to report promptly any new or worsening abdominal pain or blood in their stools.
- Cases of rapidly progressive and sometimes fatal acute renal failure not clearly related to disease progression occurred in patients who received Temsirolimus. Some of these cases were not responsive to dialysis.
- Use of Temsirolimus has been associated with abnormal wound healing. Therefore, caution should be exercised with the use of Temsirolimus in the perioperative period.
- Patients with central nervous system tumors (primary CNS tumor or metastases) and/or receiving anticoagulation therapy may be at an increased risk of developing intracerebral bleeding (including fatal outcomes) while receiving Temsirolimus.
- Agents Inducing CYP3A Metabolism
- Strong inducers of CYP3A4/5 such as dexamethasone, carbamazepine, phenytoin, phenobarbital, rifampin, rifabutin, and rifampicin may decrease exposure of the active metabolite, sirolimus. If alternative treatment cannot be administered, a dose adjustment should be considered. St. John's Wort may decrease Temsirolimus plasma concentrations unpredictably. Patients receiving Temsirolimus should not take St. John's Wort concomitantly.
- Agents Inhibiting CYP3A Metabolism
- Strong CYP3A4 inhibitors such as atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin may increase blood concentrations of the active metabolite sirolimus. If alternative treatments cannot be administered, a dose adjustment should be considered.
- The combination of Temsirolimus and sunitinib resulted in dose-limiting toxicity. Dose-limiting toxicities (Grade 3/4 erythematous maculopapular rash, and gout/cellulitis requiring hospitalization) were observed in two out of three patients treated in the first cohort of a phase 1 study at doses of Temsirolimus 15 mg IV per week and sunitinib 25 mg oral per day (Days 1–28 followed by a 2-week rest).
- The use of live vaccines and close contact with those who have received live vaccines should be avoided during treatment with Temsirolimus. Examples of live vaccines are: intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines.
- There are no adequate and well-controlled studies of Temsirolimus in pregnant women. However, based on its mechanism of action, Temsirolimus may cause fetal harm when administered to a pregnant woman. Temsirolimus administered daily as an oral formulation caused embryo-fetal and intrauterine toxicities in rats and rabbits at human sub-therapeutic exposures.
- If this drug is used during pregnancy or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant throughout treatment and for 3 months after Temsirolimus therapy has stopped.
- Men should be counseled regarding the effects of Temsirolimus on the fetus and sperm prior to starting treatment. Men with partners of childbearing potential should use reliable contraception throughout treatment and are recommended to continue this for 3 months after the last dose of Temsirolimus.
- Based on the results of a phase 3 study, elderly patients may be more likely to experience certain adverse reactions including diarrhea, edema, and pneumonia.
- In the randomized, phase 3 trial, complete blood counts (CBCs) were checked weekly, and chemistry panels were checked every two weeks. Laboratory monitoring for patients receiving Temsirolimus may need to be performed more or less frequently at the physician's discretion.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice.
- In the phase 3 randomized, open-label study of interferon alfa (IFN-α) alone, Temsirolimus alone, and Temsirolimus and IFN-α, a total of 616 patients were treated. Two hundred patients received IFN-α weekly, 208 received Temsirolimus 25 mg weekly, and 208 patients received a combination of Temsirolimus and IFN-α weekly.
- Treatment with the combination of Temsirolimus 15 mg and IFN-α was associated with an increased incidence of multiple adverse reactions and did not result in a significant increase in overall survival when compared with IFN-α alone.
- Table 1 shows the percentage of patients experiencing treatment emergent adverse reactions. Reactions reported in at least 10% of patients who received Temsirolimus 25 mg alone or IFN-α alone are listed. Table 2 shows the percentage of patients experiencing selected laboratory abnormalities. Data for the same adverse reactions and laboratory abnormalities in the IFN-α alone arm are shown for comparison:
- Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice.
- In the phase 3 randomized, open-label study of interferon alfa (IFN-α) alone, Temsirolimus alone, and Temsirolimus and IFN-α, a total of 616 patients were treated. Two hundred patients received IFN-α weekly, 208 received Temsirolimus 25 mg weekly, and 208 patients received a combination of Temsirolimus and IFN-α weekly.
- Treatment with the combination of Temsirolimus 15 mg and IFN-α was associated with an increased incidence of multiple adverse reactions and did not result in a significant increase in overall survival when compared with IFN-α alone.
- Table 1 shows the percentage of patients experiencing treatment emergent adverse reactions. Reactions reported in at least 10% of patients who received Temsirolimus 25 mg alone or IFN-α alone are listed. Table 2 shows the percentage of patients experiencing selected laboratory abnormalities. Data for the same adverse reactions and laboratory abnormalities in the IFN-α alone arm are shown for comparison:
## Postmarketing Experience
- The following adverse reactions have been identified during post approval use of Temsirolimus. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to readily estimate their frequency or establish a causal relationship to drug exposure.
- The following adverse reactions have been observed in patients receiving temsirolimus: rhabdomyolysis, Stevens-Johnson Syndrome, and complex regional pain syndrome (reflex sympathetic dystrophy).
- There are also post-marketing reports of temsirolimus extravasations resulting in swelling, pain, warmth, and erythema.
# Drug Interactions
- Co-administration of Temsirolimus with rifampin, a potent CYP3A4/5 inducer, had no significant effect on temsirolimus Cmax (maximum concentration) and AUC (area under the concentration versus the time curve) after intravenous administration, but decreased sirolimus Cmax by 65% and AUC by 56% compared to Temsirolimus treatment alone. If alternative treatment cannot be administered, a dose adjustment should be considered.
- Co-administration of Temsirolimus with ketoconazole, a potent CYP3A4 inhibitor, had no significant effect on temsirolimus Cmax or AUC; however, sirolimus AUC increased 3.1-fold, and Cmax increased 2.2-fold compared to Temsirolimus alone. If alternative treatment cannot be administered, a dose adjustment should be considered.
- The concentration of desipramine, a CYP2D6 substrate, was unaffected when 25 mg of Temsirolimus was co-administered. No clinically significant effect is anticipated when temsirolimus is co-administered with agents that are metabolized by CYP2D6 or CYP3A4.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
- Women of childbearing potential should be advised to avoid becoming pregnant throughout treatment and for 3 months after Temsirolimus therapy has stopped.
- Temsirolimus can cause fetal harm when administered to a pregnant woman. If this drug 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.
- Temsirolimus administered daily as an oral formulation caused embryo-fetal and intrauterine toxicities in rats and rabbits at human sub-therapeutic exposures. Embryo-fetal adverse effects in rats consisted of reduced fetal weight and reduced ossifications, and in rabbits included reduced fetal weight, omphalocele, bifurcated sternabrae, notched ribs, and incomplete ossifications.
- In rats, the intrauterine and embryo-fetal adverse effects were observed at the oral dose of 2.7 mg/m2/day (approximately 0.04-fold the AUC in patients with cancer at the human recommended dose). In rabbits, the intrauterine and embryo-fetal adverse effects were observed at the oral dose of ≥7.2 mg/m2/day (approximately 0.12-fold the AUC in patients with cancer at the recommended human dose).
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Temsirolimus in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Temsirolimus during labor and delivery.
### Nursing Mothers
- It is not known whether Temsirolimus is excreted into human milk, and due to the potential for tumorigenicity shown for sirolimus (active metabolite of Temsirolimus) in animal studies, a decision should be made whether to discontinue nursing or discontinue Temsirolimus, taking into account the importance of the drug to the mother.
### Pediatric Use
- Limited data are available on the use of temsirolimus in pediatric patients. The effectiveness of temsirolimus in pediatric patients with advanced recurrent/refractory solid tumors has not been established.
- Temsirolimus was studied in 71 patients (59 patients ages 1 to 17 years and 12 patients ages 18 to 21 years) with relapsed/refractory solid tumors in a phase 1–2 safety and exploratory pharmacodynamic study.
- In phase 1, 19 pediatric patients with advanced recurrent/refractory solid tumors received Temsirolimus at doses ranging from 10 mg/m2 to 150 mg/m2 as a 60-minute intravenous infusion once weekly in three-week cycles.
- In phase 2, 52 pediatric patients with recurrent/relapsed neuroblastoma, rhabdomyosarcoma, or high grade glioma received Temsirolimus at a weekly dose of 75 mg/m2. One of 19 patients with neuroblastoma achieved a partial response. There were no objective responses in pediatric patients with recurrent/relapsed rhabdomyosarcoma or high grade glioma.
- Adverse reactions associated with Temsirolimus were similar to those observed in adults. The most common adverse reactions (≥20%) in pediatric patients receiving the 75 mg/m2 dose included thrombocytopenia, infections, asthenia/fatigue, fever, pain, leukopenia, rash, anemia, hyperlipidemia, increased cough, stomatitis, anorexia, increased plasma levels of alanine aminotransferase and aspartate aminotransferase, hypercholesterolemia, hyperglycemia, abdominal pain, headache, arthralgia, upper respiratory infection, nausea and vomiting, neutropenia, hypokalemia, and hypophosphatemia.
- Pharmacokinetics
- In phase 1 of the above mentioned pediatric trial, the single dose and multiple dose total systemic exposure (AUC) of temsirolimus and sirolimus were less than dose-proportional over the dose range of 10 to 150 mg/m2.
- In the phase 2 portion, the multiple dose (Day 1, Cycle 2) pharmacokinetics of Temsirolimus 75 mg/m2 were characterized in an additional 35 patients ages 28 days to 21 years (median age of 8 years). The geometric mean body surface adjusted clearance of temsirolimus and sirolimus was 9.45 L/h/m2 and 9.26 L/h/m2, respectively. The mean elimination half-life of temsirolimus and sirolimus was 31 hours and 44 hours, respectively.
- The exposure (AUCss) to temsirolimus and sirolimus was approximately 6-fold and 2-fold higher, respectively than the exposure in adult patients receiving a 25 mg intravenous infusion.
### Geriatic Use
- Clinical studies of Temsirolimus did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. Based on the results of a phase 3 study, elderly patients may be more likely to experience certain adverse reactions including diarrhea, edema, and pneumonia.
### Gender
There is no FDA guidance on the use of Temsirolimus with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Temsirolimus with respect to specific racial populations.
### Renal Impairment
- No clinical studies were conducted with Temsirolimus in patients with decreased renal function. Less than 5% of total radioactivity was excreted in the urine following a 25 mg intravenous dose of -labeled temsirolimus in healthy subjects. Renal impairment is not expected to markedly influence drug exposure, and no dosage adjustment of Temsirolimus is recommended in patients with renal impairment.
- Temsirolimus has not been studied in patients undergoing hemodialysis.
### Hepatic Impairment
- Temsirolimus was evaluated in a dose escalation phase 1 study in 110 patients with normal or varying degrees of hepatic impairment as defined by AST and bilirubin levels and patients with liver transplant (Table 3). Patients with moderate and severe hepatic impairment had increased rates of adverse reactions and deaths, including deaths due to progressive disease, during the study (Table 3).
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Temsirolimus in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Temsirolimus in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
- Intravenous
### Monitoring
- Monitor for symptoms or radiographic changes of interstitial lung disease (ILD). If ILD is suspected, discontinue Temsirolimus, and consider use of corticosteroids and/or antibiotics.
- Monitor renal function at baseline and while on Temsirolimus.
- In the randomized, phase 3 trial, complete blood counts (CBCs) were checked weekly, and chemistry panels were checked every two weeks. Laboratory monitoring for patients receiving Temsirolimus may need to be performed more or less frequently at the physician's discretion.
# IV Compatibility
There is limited information regarding IV Compatibility of Temsirolimus in the drug label.
# Overdosage
- There is no specific treatment for Temsirolimus intravenous overdose. Temsirolimus has been administered to patients with cancer in phase 1 and 2 trials with repeated intravenous doses as high as 220 mg/m2. The risk of several serious adverse events, including thrombosis, bowel perforation, interstitial lung disease (ILD), seizure, and psychosis, is increased with doses of Temsirolimus greater than 25 mg.
# Pharmacology
## Mechanism of Action
- Temsirolimus is an inhibitor of mTOR (mammalian target of rapamycin). Temsirolimus binds to an intracellular protein (FKBP-12), and the protein-drug complex inhibits the activity of mTOR that controls cell division. Inhibition of mTOR activity resulted in a G1 growth arrest in treated tumor cells. When mTOR was inhibited, its ability to phosphorylate p70S6k and S6 ribosomal protein, which are downstream of mTOR in the PI3 kinase/AKT pathway was blocked.
- In in vitro studies using renal cell carcinoma cell lines, temsirolimus inhibited the activity of mTOR and resulted in reduced levels of the hypoxia-inducible factors HIF-1 and HIF-2 alpha, and the vascular endothelial growth factor.
## Structure
- Temsirolimus, an inhibitor of mTOR, is an antineoplastic agent.
- Temsirolimus is a white to off-white powder with a molecular formula of C56H87NO16 and a molecular weight of 1030.30. It is non-hygroscopic. Temsirolimus is practically insoluble in water and soluble in alcohol. It has no ionizable functional groups, and its solubility is independent of pH.
- The chemical name of temsirolimus is (3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-Hexadecahydro-9,27-dihydroxy-3--1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23, 27-epoxy-3H-pyridooxaazacyclohentriacontine-1,5,11,28,29(4H,6H,31H)-pentone 4'-; or Rapamycin, 42-.
- Temsirolimus (temsirolimus) injection, 25 mg/mL, is a clear, colorless to light yellow, non-aqueous, ethanolic, sterile solution. Temsirolimus (temsirolimus) injection requires two dilutions prior to intravenous infusion. Temsirolimus (temsirolimus) injection should be diluted only with the supplied DILUENT for Temsirolimus®.
- DILUENT for Temsirolimus® is a sterile, non-aqueous solution that is supplied with Temsirolimus injection, as a kit.
- Temsirolimus (temsirolimus) injection, 25 mg/mL:
- Active ingredient: temsirolimus (25 mg/mL)
- Inactive ingredients: dehydrated alcohol (39.5% w/v), dl-alpha-tocopherol (0.075% w/v), propylene glycol (50.3% w/v), and anhydrous citric acid (0.0025% w/v).
- Inactive ingredients
- Polysorbate 80 (40.0% w/v), polyethylene glycol 400 (42.8% w/v) and dehydrated alcohol (19.9% w/v).
- After the Temsirolimus (temsirolimus) injection vial has been diluted with DILUENT for Temsirolimus®, in accordance with the instructions in section 2.5, the solution contains 35.2% alcohol.
- Temsirolimus (temsirolimus) injection and DILUENT for Temsirolimus® are filled in clear glass vials with butyl rubber stoppers.
## Pharmacodynamics
- Effects on Electrocardiogram: There were no clinically relevant QT changes observed at the recommended dose for Temsirolimus. In a randomized, single-blinded, crossover study, 58 healthy subjects received Temsirolimus 25 mg, placebo, and a single oral dose of moxifloxacin 400 mg.
- A supratherapeutic Temsirolimus dose was not studied in this randomized QT trial. The largest difference between the upper bound 2-sided 90% CI for the mean difference between Temsirolimus and placebo-corrected QT interval was less than 10 ms. In a different trial in 69 patients with a hematologic malignancy, Temsirolimus doses up to 175 mg were studied. No patient with a normal QTcF at baseline had an increase in QTcF >60 ms. Additionally, there were no patients with a QTcF interval greater than 500 ms.
## Pharmacokinetics
- Effects on Electrocardiogram: There were no clinically relevant QT changes observed at the recommended dose for Temsirolimus. In a randomized, single-blinded, crossover study, 58 healthy subjects received Temsirolimus 25 mg, placebo, and a single oral dose of moxifloxacin 400 mg.
- A supratherapeutic Temsirolimus dose was not studied in this randomized QT trial. The largest difference between the upper bound 2-sided 90% CI for the mean difference between Temsirolimus and placebo-corrected QT interval was less than 10 ms. In a different trial in 69 patients with a hematologic malignancy, Temsirolimus doses up to 175 mg were studied. No patient with a normal QTcF at baseline had an increase in QTcF >60 ms. Additionally, there were no patients with a QTcF interval greater than 500 ms.
## Nonclinical Toxicology
- Effects on Electrocardiogram: There were no clinically relevant QT changes observed at the recommended dose for Temsirolimus. In a randomized, single-blinded, crossover study, 58 healthy subjects received Temsirolimus 25 mg, placebo, and a single oral dose of moxifloxacin 400 mg. A supratherapeutic Temsirolimus dose was not studied in this randomized QT trial.
- The largest difference between the upper bound 2-sided 90% CI for the mean difference between Temsirolimus and placebo-corrected QT interval was less than 10 ms. In a different trial in 69 patients with a hematologic malignancy, Temsirolimus doses up to 175 mg were studied. No patient with a normal QTcF at baseline had an increase in QTcF >60 ms. Additionally, there were no patients with a QTcF interval greater than 500 ms.
# Clinical Studies
- A phase 3, multi-center, three-arm, randomized, open-label study was conducted in previously untreated patients with advanced renal cell carcinoma (clear cell and non-clear cell histologies). The objectives were to compare Overall Survival (OS), Progression-Free Survival (PFS), Objective Response Rate (ORR), and safety in patients receiving IFN-α to those receiving Temsirolimus or Temsirolimus plus IFN-α.
- Patients in this study had 3 or more of 6 pre-selected prognostic risk factors (less than one year from time of initial renal cell carcinoma diagnosis to randomization, Karnofsky performance status of 60 or 70, hemoglobin less than the lower limit of normal, corrected calcium of greater than 10 mg/dL, lactate dehydrogenase >1.5 times the upper limit of normal, more than one metastatic organ site). Patients were stratified for prior nephrectomy status within three geographic regions and were randomly assigned (1:1:1) to receive IFN-α alone (n = 207), Temsirolimus alone (25 mg weekly; n = 209), or the combination arm (n = 210).
- The ITT population for this interim analysis included 626 patients. Demographics were comparable between the three treatment arms with regard to age, gender, and race. The mean age of all groups was 59 years (range 23–86). Sixty-nine percent were male and 31% were female. The racial distribution for all groups was 91% White, 4% Black, 2% Asian, and 3% other. Sixty-seven percent of patients had a history of prior nephrectomy.
- The median duration of treatment in the Temsirolimus arm was 17 weeks (range 1–126 weeks). The median duration of treatment on the IFN arm was 8 weeks (range 1–124 weeks).
- There was a statistically significant improvement in OS (time from randomization to death) in the Temsirolimus 25 mg arm compared to IFN-α. The combination of Temsirolimus 15 mg and IFN-α did not result in a significant increase in OS when compared with IFN-α alone. Figure 1 is a Kaplan-Meier plot of OS in this study. The evaluations of PFS (time from randomization to disease progression or death) and ORR, were based on blinded independent radiologic assessment of tumor response. Efficacy results are summarized in Table 4.
# How Supplied
- NDC 0008-1179-01 Temsirolimus® (temsirolimus) injection, 25 mg/mL.
## Storage
- Each kit is supplied in a single carton containing one single-use vial of 25 mg/mL of temsirolimus and one DILUENT vial which includes a deliverable volume of 1.8 mL, and must be stored at 2°–8° C (36°–46° F). Protect from light.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Each kit is supplied in a single carton containing one single-use vial of 25 mg/mL of temsirolimus and one DILUENT vial which includes a deliverable volume of 1.8 mL, and must be stored at 2°–8° C (36°–46° F). Protect from light.
# Precautions with Alcohol
- Alcohol-Temsirolimus interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Temsirolimus ®
# Look-Alike Drug Names
There is limited information regarding Temsirolimus Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Temsirolimus
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2]
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# Overview
Temsirolimus is an antineoplastic agent that is FDA approved for the treatment of advanced renal cell carcinoma. Common adverse reactions include edema, rash, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypophosphatemia, inflammatory disease of mucous membrane, loss of appetite, nausea, decreased hemoglobin, decreased lymphocyte count, decreased platelet count, leukopenia, neutropenia, alkaline phosphatase raised, AST/SGOT level raised, asthenia, serum creatinine raised.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Temsirolimus is indicated for the treatment of advanced renal cell carcinoma.
- The recommended dose of Temsirolimus for advanced renal cell carcinoma is 25 mg infused over a 30 – 60 minute period once a week.
- Treatment should continue until disease progression or unacceptable toxicity occurs.
- Patients should receive prophylactic intravenous diphenhydramine 25 to 50 mg (or similar antihistamine) approximately 30 minutes before the start of each dose of Temsirolimus.
- Temsirolimus should be held for absolute neutrophil count (ANC) <1,000/mm3, platelet count <75,000/mm3, or NCI CTCAE grade 3 or greater adverse reactions. Once toxicities have resolved to grade 2 or less, Temsirolimus may be restarted with the dose reduced by 5 mg/week to a dose no lower than 15 mg/week.
- Hepatic Impairment
- Use caution when treating patients with hepatic impairment. If Temsirolimus must be given in patients with mild hepatic impairment (bilirubin >1 – 1.5×ULN or AST >ULN but bilirubin ≤ULN), reduce the dose of Temsirolimus to 15 mg/week. Temsirolimus is contraindicated in patients with bilirubin >1.5×ULN.
- Concomitant Strong CYP3A4 Inhibitors
- The concomitant use of strong CYP3A4 inhibitors should be avoided (e.g. ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole). Grapefruit juice may also increase plasma concentrations of sirolimus (a major metabolite of temsirolimus) and should be avoided. If patients must be co-administered a strong CYP3A4 inhibitor, based on pharmacokinetic studies, a Temsirolimus dose reduction to 12.5 mg/week should be considered. This dose of Temsirolimus is predicted to adjust the AUC to the range observed without inhibitors. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inhibitors. If the strong inhibitor is discontinued, a washout period of approximately 1 week should be allowed before the Temsirolimus dose is adjusted back to the dose used prior to initiation of the strong CYP3A4 inhibitor.
- Concomitant Strong CYP3A4 Inducers
- The use of concomitant strong CYP3A4 inducers should be avoided (e.g. dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifampicin, phenobarbital). If patients must be co-administered a strong CYP3A4 inducer, based on pharmacokinetic studies, a Temsirolimus dose increase from 25 mg/week up to 50 mg/week should be considered. This dose of Temsirolimus is predicted to adjust the AUC to the range observed without inducers. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inducers. If the strong inducer is discontinued the temsirolimus dose should be returned to the dose used prior to initiation of the strong CYP3A4 inducer.
- Temsirolimus must be stored under refrigeration at 2°–8°C (36°–46°F) and protected from light. During handling and preparation of admixtures, Temsirolimus should be protected from excessive room light and sunlight. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
- In order to minimize the patient exposure to the plasticizer DEHP (di-2-ethylhexyl phthalate), which may be leached from PVC infusion bags or sets, the final Temsirolimus dilution for infusion should be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined administration sets.
- Temsirolimus 25 mg/mL injection must be diluted with the supplied diluent before further dilution in 0.9% Sodium Chloride Injection, USP.
- Please note that both the Temsirolimus injection and diluent vials contain an overfill to ensure the recommended volume can be withdrawn.
- Follow this two-step dilution process in an aseptic manner.
- Step 1
- DILUTION OF Temsirolimus INJECTION 25 MG/ML WITH SUPPLIED DILUENT
- Each Vial of Temsirolimus (temsirolimus) must first be mixed with 1.8 mL of the enclosed diluent. The resultant solution contains 30 mg/3 mL (10 mg/mL).
- Mix well by inversion of the vial. Allow sufficient time for the air bubbles to subside. The solution should be clear to slightly turbid, colorless to light-yellow solution, essentially free from visual particulates.
- The concentrate-diluent mixture is stable below 25°C for up to 24 hours.
- Step 2
- DILUTION OF CONCENTRATE-DILUENT MIXTURE WITH 0.9% SODIUM CHLORIDE INJECTION, USP
- Withdraw precisely the required amount of concentrate-diluent mixture containing temsirolimus 10 mg/mL as prepared in Step 1 from the vial (i.e., 2.5 mL for a temsirolimus dose of 25 mg) and further dilute into an infusion bag containing 250 mL of 0.9% Sodium Chloride Injection, USP.
Mix by inversion of the bag or bottle, avoiding excessive shaking, as this may cause foaming.
- The resulting solution should be inspected visually for particulate matter and discoloration prior to administration. The admixture of Temsirolimus in 0.9% Sodium Chloride Injection, USP should be protected from excessive room light and sunlight.
- Administration of the final diluted solution should be completed within six hours from the time that Temsirolimus is first added to 0.9% Solution Chloride Injection, USP.
- Temsirolimus is infused over a 30- to 60-minute period once weekly. The use of an infusion pump is the preferred method of administration to ensure accurate delivery of the product.
- Appropriate administration materials should be composed of glass, polyolefin, or polyethylene to avoid excessive loss of product and diethylhexylpthalate (DEHP) extraction. The administration materials should consist of non-DEHP, non-polyvinylchloride (PVC) tubing with appropriate filter. In the case when a PVC administration set has to be used, it should not contain DEHP. An in-line polyethersulfone filter with a pore size of not greater than 5 microns is recommended for administration to avoid the possibility of particles bigger than 5 microns being infused.
- If the administration set available does not have an in-line filter incorporated, a polyethersulfone filter should be added at the set (i.e., an end-filter) before the admixture reaches the vein of the patient. Different end-filters can be used, ranging in filter pore size from 0.2 microns up to 5 microns. The use of both an in-line and end-filter is not recommended.
- Temsirolimus, when diluted, contains polysorbate 80, which is known to increase the rate of DEHP extraction from PVC. This should be considered during the preparation and administration of Temsirolimus, including storage time elapsed when in direct contact with PVC following constitution.
- Undiluted Temsirolimus injection should not be added directly to aqueous infusion solutions. Direct addition of Temsirolimus injection to aqueous solutions will result in precipitation of drug. Always combine Temsirolimus injection with DILUENT for Temsirolimus before adding to infusion solutions.
- It is recommended that Temsirolimus be administered in 0.9% Sodium Chloride Injection after combining with diluent. The stability of Temsirolimus in other infusion solutions has not been evaluated. Addition of other drugs or nutritional agents to admixtures of Temsirolimus in 0.9% Sodium Chloride Injection has not been evaluated and should be avoided. Temsirolimus is degraded by both acids and bases, and thus combinations of temsirolimus with agents capable of modifying solution pH should be avoided.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Temsirolimus in adult patients.
### Non–Guideline-Supported Use
- Mantle cell lymphoma, Relapsed or refractory [1]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Temsirolimus 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 Temsirolimus in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Temsirolimus in pediatric patients.
# Contraindications
- Temsirolimus is contraindicated in patients with bilirubin >1.5×ULN
# Warnings
- Hypersensitivity/infusion reactions, including but not limited to flushing, chest pain, dyspnea, hypotension, apnea, loss of consciousness, hypersensitivity and anaphylaxis, have been associated with the administration of temsirolimus.
- These reactions can occur very early in the first infusion, but may also occur with subsequent infusions. Patients should be monitored throughout the infusion and appropriate supportive care should be available. Temsirolimus infusion should be interrupted in all patients with severe infusion reactions and appropriate medical therapy administered.
- Temsirolimus should be used with caution in persons with known hypersensitivity to temsirolimus or its metabolites (including sirolimus), polysorbate 80, or to any other component (including the excipients) of Temsirolimus.
- An H1 antihistamine should be administered to patients before the start of the intravenous temsirolimus infusion. Temsirolimus should be used with caution in patients with known hypersensitivity to an antihistamine, or patients who cannot receive an antihistamine for other medical reasons.
- If a patient develops a hypersensitivity reactions during the Temsirolimus infusion, the infusion should be stopped and the patient should be observed for at least 30 to 60 minutes (depending on the severity of the reaction). At the discretion of the physician, treatment may be resumed with the administration of an H1-receptor antagonist (such as diphenhydramine), if not previously administered, and/or an H2-receptor antagonist (such as intravenous famotidine 20 mg or intravenous ranitidine 50 mg) approximately 30 minutes before restarting the Temsirolimus infusion. The infusion may then be resumed at a slower rate (up to 60 minutes).
- A benefit-risk assessment should be done prior to the continuation of temsirolimus therapy in patients with severe or life-threatening reactions.
- The safety and pharmacokinetics of Temsirolimus were evaluated in a dose escalation phase 1 study in 110 patients with normal or varying degrees of hepatic impairment. Patients with baseline bilirubin >1.5×ULN experienced greater toxicity than patients with baseline bilirubin ≤1.5×ULN when treated with Temsirolimus. The overall frequency of ≥ grade 3 adverse reactions and deaths, including deaths due to progressive disease, were greater in patients with baseline bilirubin >1.5×ULN due to increased risk of death.
- Use caution when treating patients with mild hepatic impairment. Concentrations of temsirolimus and its metabolite sirolimus were increased in patients with elevated AST or bilirubin levels. If Temsirolimus must be given in patients with mild hepatic impairment (bilirubin >1 – 1.5×ULN or AST >ULN but bilirubin ≤ULN), reduce the dose of Temsirolimus to 15 mg/week.
- The use of Temsirolimus is likely to result in increases in serum glucose. In the phase 3 trial, 89% of patients receiving Temsirolimus had at least one elevated serum glucose while on treatment, and 26% of patients reported hyperglycemia as an adverse event. This may result in the need for an increase in the dose of, or initiation of, insulin and/or oral hypoglycemic agent therapy. Serum glucose should be tested before and during treatment with Temsirolimus. Patients should be advised to report excessive thirst or any increase in the volume or frequency of urination.
- The use of Temsirolimus may result in immunosuppression. Patients should be carefully observed for the occurrence of infections, including opportunistic infections.
- Pneumocystis jiroveci pneumonia (PJP), including fatalities, has been reported in patients who received temsirolimus. This may be associated with concomitant use of corticosteroids or other immunosuppressive agents. Prophylaxis of PJP should be considered when concomitant use of corticosteroids or other immunosuppressive agents are required.
- Cases of interstitial lung disease, some resulting in death, occurred in patients who received Temsirolimus. Some patients were asymptomatic, or had minimal symptoms, with infiltrates detected on computed tomography scan or chest radiograph. Others presented with symptoms such as dyspnea, cough, hypoxia, and fever. Some patients required discontinuation of Temsirolimus and/or treatment with corticosteroids and/or antibiotics, while some patients continued treatment without additional intervention. Patients should be advised to report promptly any new or worsening respiratory symptoms.
- It is recommended that patients undergo baseline radiographic assessment by lung computed tomography scan or chest radiograph prior to the initiation of Temsirolimus therapy. Follow such assessments periodically, even in the absence of clinical respiratory symptoms.
- It is recommended that patients be followed closely for occurrence of clinical respiratory symptoms. If clinically significant respiratory symptoms develop, consider withholding Temsirolimus administration until after recovery of symptoms and improvement of radiographic findings related to pneumonitis. Empiric treatment with corticosteroids and/or antibiotics may be considered. Opportunistic infections such as PJP should be considered in the differential diagnosis. For patients who require use of corticosteroids, prophylaxis of PJP may be considered.
- The use of Temsirolimus is likely to result in increases in serum triglycerides and cholesterol. In the phase 3 trial, 87% of patients receiving Temsirolimus had at least one elevated serum cholesterol value and 83% had at least one elevated serum triglyceride value. This may require initiation, or increase in the dose, of lipid-lowering agents. Serum cholesterol and triglycerides should be tested before and during treatment with Temsirolimus.
- Cases of fatal bowel perforation occurred in patients who received Temsirolimus. * These patients presented with fever, abdominal pain, metabolic acidosis, bloody stools, diarrhea, and/or acute abdomen. Patients should be advised to report promptly any new or worsening abdominal pain or blood in their stools.
- Cases of rapidly progressive and sometimes fatal acute renal failure not clearly related to disease progression occurred in patients who received Temsirolimus. Some of these cases were not responsive to dialysis.
- Use of Temsirolimus has been associated with abnormal wound healing. Therefore, caution should be exercised with the use of Temsirolimus in the perioperative period.
- Patients with central nervous system tumors (primary CNS tumor or metastases) and/or receiving anticoagulation therapy may be at an increased risk of developing intracerebral bleeding (including fatal outcomes) while receiving Temsirolimus.
- Agents Inducing CYP3A Metabolism
- Strong inducers of CYP3A4/5 such as dexamethasone, carbamazepine, phenytoin, phenobarbital, rifampin, rifabutin, and rifampicin may decrease exposure of the active metabolite, sirolimus. If alternative treatment cannot be administered, a dose adjustment should be considered. St. John's Wort may decrease Temsirolimus plasma concentrations unpredictably. Patients receiving Temsirolimus should not take St. John's Wort concomitantly.
- Agents Inhibiting CYP3A Metabolism
- Strong CYP3A4 inhibitors such as atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin may increase blood concentrations of the active metabolite sirolimus. If alternative treatments cannot be administered, a dose adjustment should be considered.
- The combination of Temsirolimus and sunitinib resulted in dose-limiting toxicity. Dose-limiting toxicities (Grade 3/4 erythematous maculopapular rash, and gout/cellulitis requiring hospitalization) were observed in two out of three patients treated in the first cohort of a phase 1 study at doses of Temsirolimus 15 mg IV per week and sunitinib 25 mg oral per day (Days 1–28 followed by a 2-week rest).
- The use of live vaccines and close contact with those who have received live vaccines should be avoided during treatment with Temsirolimus. Examples of live vaccines are: intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines.
- There are no adequate and well-controlled studies of Temsirolimus in pregnant women. However, based on its mechanism of action, Temsirolimus may cause fetal harm when administered to a pregnant woman. Temsirolimus administered daily as an oral formulation caused embryo-fetal and intrauterine toxicities in rats and rabbits at human sub-therapeutic exposures.
- If this drug is used during pregnancy or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant throughout treatment and for 3 months after Temsirolimus therapy has stopped.
- Men should be counseled regarding the effects of Temsirolimus on the fetus and sperm prior to starting treatment. Men with partners of childbearing potential should use reliable contraception throughout treatment and are recommended to continue this for 3 months after the last dose of Temsirolimus.
- Based on the results of a phase 3 study, elderly patients may be more likely to experience certain adverse reactions including diarrhea, edema, and pneumonia.
- In the randomized, phase 3 trial, complete blood counts (CBCs) were checked weekly, and chemistry panels were checked every two weeks. Laboratory monitoring for patients receiving Temsirolimus may need to be performed more or less frequently at the physician's discretion.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice.
- In the phase 3 randomized, open-label study of interferon alfa (IFN-α) alone, Temsirolimus alone, and Temsirolimus and IFN-α, a total of 616 patients were treated. Two hundred patients received IFN-α weekly, 208 received Temsirolimus 25 mg weekly, and 208 patients received a combination of Temsirolimus and IFN-α weekly.
- Treatment with the combination of Temsirolimus 15 mg and IFN-α was associated with an increased incidence of multiple adverse reactions and did not result in a significant increase in overall survival when compared with IFN-α alone.
- Table 1 shows the percentage of patients experiencing treatment emergent adverse reactions. Reactions reported in at least 10% of patients who received Temsirolimus 25 mg alone or IFN-α alone are listed. Table 2 shows the percentage of patients experiencing selected laboratory abnormalities. Data for the same adverse reactions and laboratory abnormalities in the IFN-α alone arm are shown for comparison:
- Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice.
- In the phase 3 randomized, open-label study of interferon alfa (IFN-α) alone, Temsirolimus alone, and Temsirolimus and IFN-α, a total of 616 patients were treated. Two hundred patients received IFN-α weekly, 208 received Temsirolimus 25 mg weekly, and 208 patients received a combination of Temsirolimus and IFN-α weekly.
- Treatment with the combination of Temsirolimus 15 mg and IFN-α was associated with an increased incidence of multiple adverse reactions and did not result in a significant increase in overall survival when compared with IFN-α alone.
- Table 1 shows the percentage of patients experiencing treatment emergent adverse reactions. Reactions reported in at least 10% of patients who received Temsirolimus 25 mg alone or IFN-α alone are listed. Table 2 shows the percentage of patients experiencing selected laboratory abnormalities. Data for the same adverse reactions and laboratory abnormalities in the IFN-α alone arm are shown for comparison:
## Postmarketing Experience
- The following adverse reactions have been identified during post approval use of Temsirolimus. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to readily estimate their frequency or establish a causal relationship to drug exposure.
- The following adverse reactions have been observed in patients receiving temsirolimus: rhabdomyolysis, Stevens-Johnson Syndrome, and complex regional pain syndrome (reflex sympathetic dystrophy).
- There are also post-marketing reports of temsirolimus extravasations resulting in swelling, pain, warmth, and erythema.
# Drug Interactions
- Co-administration of Temsirolimus with rifampin, a potent CYP3A4/5 inducer, had no significant effect on temsirolimus Cmax (maximum concentration) and AUC (area under the concentration versus the time curve) after intravenous administration, but decreased sirolimus Cmax by 65% and AUC by 56% compared to Temsirolimus treatment alone. If alternative treatment cannot be administered, a dose adjustment should be considered.
- Co-administration of Temsirolimus with ketoconazole, a potent CYP3A4 inhibitor, had no significant effect on temsirolimus Cmax or AUC; however, sirolimus AUC increased 3.1-fold, and Cmax increased 2.2-fold compared to Temsirolimus alone. If alternative treatment cannot be administered, a dose adjustment should be considered.
- The concentration of desipramine, a CYP2D6 substrate, was unaffected when 25 mg of Temsirolimus was co-administered. No clinically significant effect is anticipated when temsirolimus is co-administered with agents that are metabolized by CYP2D6 or CYP3A4.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
- Women of childbearing potential should be advised to avoid becoming pregnant throughout treatment and for 3 months after Temsirolimus therapy has stopped.
- Temsirolimus can cause fetal harm when administered to a pregnant woman. If this drug 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.
- Temsirolimus administered daily as an oral formulation caused embryo-fetal and intrauterine toxicities in rats and rabbits at human sub-therapeutic exposures. Embryo-fetal adverse effects in rats consisted of reduced fetal weight and reduced ossifications, and in rabbits included reduced fetal weight, omphalocele, bifurcated sternabrae, notched ribs, and incomplete ossifications.
- In rats, the intrauterine and embryo-fetal adverse effects were observed at the oral dose of 2.7 mg/m2/day (approximately 0.04-fold the AUC in patients with cancer at the human recommended dose). In rabbits, the intrauterine and embryo-fetal adverse effects were observed at the oral dose of ≥7.2 mg/m2/day (approximately 0.12-fold the AUC in patients with cancer at the recommended human dose).
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Temsirolimus in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Temsirolimus during labor and delivery.
### Nursing Mothers
- It is not known whether Temsirolimus is excreted into human milk, and due to the potential for tumorigenicity shown for sirolimus (active metabolite of Temsirolimus) in animal studies, a decision should be made whether to discontinue nursing or discontinue Temsirolimus, taking into account the importance of the drug to the mother.
### Pediatric Use
- Limited data are available on the use of temsirolimus in pediatric patients. The effectiveness of temsirolimus in pediatric patients with advanced recurrent/refractory solid tumors has not been established.
- Temsirolimus was studied in 71 patients (59 patients ages 1 to 17 years and 12 patients ages 18 to 21 years) with relapsed/refractory solid tumors in a phase 1–2 safety and exploratory pharmacodynamic study.
- In phase 1, 19 pediatric patients with advanced recurrent/refractory solid tumors received Temsirolimus at doses ranging from 10 mg/m2 to 150 mg/m2 as a 60-minute intravenous infusion once weekly in three-week cycles.
- In phase 2, 52 pediatric patients with recurrent/relapsed neuroblastoma, rhabdomyosarcoma, or high grade glioma received Temsirolimus at a weekly dose of 75 mg/m2. One of 19 patients with neuroblastoma achieved a partial response. There were no objective responses in pediatric patients with recurrent/relapsed rhabdomyosarcoma or high grade glioma.
- Adverse reactions associated with Temsirolimus were similar to those observed in adults. The most common adverse reactions (≥20%) in pediatric patients receiving the 75 mg/m2 dose included thrombocytopenia, infections, asthenia/fatigue, fever, pain, leukopenia, rash, anemia, hyperlipidemia, increased cough, stomatitis, anorexia, increased plasma levels of alanine aminotransferase and aspartate aminotransferase, hypercholesterolemia, hyperglycemia, abdominal pain, headache, arthralgia, upper respiratory infection, nausea and vomiting, neutropenia, hypokalemia, and hypophosphatemia.
- Pharmacokinetics
- In phase 1 of the above mentioned pediatric trial, the single dose and multiple dose total systemic exposure (AUC) of temsirolimus and sirolimus were less than dose-proportional over the dose range of 10 to 150 mg/m2.
- In the phase 2 portion, the multiple dose (Day 1, Cycle 2) pharmacokinetics of Temsirolimus 75 mg/m2 were characterized in an additional 35 patients ages 28 days to 21 years (median age of 8 years). The geometric mean body surface adjusted clearance of temsirolimus and sirolimus was 9.45 L/h/m2 and 9.26 L/h/m2, respectively. The mean elimination half-life of temsirolimus and sirolimus was 31 hours and 44 hours, respectively.
- The exposure (AUCss) to temsirolimus and sirolimus was approximately 6-fold and 2-fold higher, respectively than the exposure in adult patients receiving a 25 mg intravenous infusion.
### Geriatic Use
- Clinical studies of Temsirolimus did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. Based on the results of a phase 3 study, elderly patients may be more likely to experience certain adverse reactions including diarrhea, edema, and pneumonia.
### Gender
There is no FDA guidance on the use of Temsirolimus with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Temsirolimus with respect to specific racial populations.
### Renal Impairment
- No clinical studies were conducted with Temsirolimus in patients with decreased renal function. Less than 5% of total radioactivity was excreted in the urine following a 25 mg intravenous dose of [14C]-labeled temsirolimus in healthy subjects. Renal impairment is not expected to markedly influence drug exposure, and no dosage adjustment of Temsirolimus is recommended in patients with renal impairment.
- Temsirolimus has not been studied in patients undergoing hemodialysis.
### Hepatic Impairment
- Temsirolimus was evaluated in a dose escalation phase 1 study in 110 patients with normal or varying degrees of hepatic impairment as defined by AST and bilirubin levels and patients with liver transplant (Table 3). Patients with moderate and severe hepatic impairment had increased rates of adverse reactions and deaths, including deaths due to progressive disease, during the study (Table 3).
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Temsirolimus in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Temsirolimus in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
- Intravenous
### Monitoring
- Monitor for symptoms or radiographic changes of interstitial lung disease (ILD). If ILD is suspected, discontinue Temsirolimus, and consider use of corticosteroids and/or antibiotics.
- Monitor renal function at baseline and while on Temsirolimus.
- In the randomized, phase 3 trial, complete blood counts (CBCs) were checked weekly, and chemistry panels were checked every two weeks. Laboratory monitoring for patients receiving Temsirolimus may need to be performed more or less frequently at the physician's discretion.
# IV Compatibility
There is limited information regarding IV Compatibility of Temsirolimus in the drug label.
# Overdosage
- There is no specific treatment for Temsirolimus intravenous overdose. Temsirolimus has been administered to patients with cancer in phase 1 and 2 trials with repeated intravenous doses as high as 220 mg/m2. The risk of several serious adverse events, including thrombosis, bowel perforation, interstitial lung disease (ILD), seizure, and psychosis, is increased with doses of Temsirolimus greater than 25 mg.
# Pharmacology
## Mechanism of Action
- Temsirolimus is an inhibitor of mTOR (mammalian target of rapamycin). Temsirolimus binds to an intracellular protein (FKBP-12), and the protein-drug complex inhibits the activity of mTOR that controls cell division. Inhibition of mTOR activity resulted in a G1 growth arrest in treated tumor cells. When mTOR was inhibited, its ability to phosphorylate p70S6k and S6 ribosomal protein, which are downstream of mTOR in the PI3 kinase/AKT pathway was blocked.
- In in vitro studies using renal cell carcinoma cell lines, temsirolimus inhibited the activity of mTOR and resulted in reduced levels of the hypoxia-inducible factors HIF-1 and HIF-2 alpha, and the vascular endothelial growth factor.
## Structure
- Temsirolimus, an inhibitor of mTOR, is an antineoplastic agent.
- Temsirolimus is a white to off-white powder with a molecular formula of C56H87NO16 and a molecular weight of 1030.30. It is non-hygroscopic. Temsirolimus is practically insoluble in water and soluble in alcohol. It has no ionizable functional groups, and its solubility is independent of pH.
- The chemical name of temsirolimus is (3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-Hexadecahydro-9,27-dihydroxy-3-[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23, 27-epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclohentriacontine-1,5,11,28,29(4H,6H,31H)-pentone 4'-[2,2-bis(hydroxymethyl)propionate]; or Rapamycin, 42-[3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate].
- Temsirolimus (temsirolimus) injection, 25 mg/mL, is a clear, colorless to light yellow, non-aqueous, ethanolic, sterile solution. Temsirolimus (temsirolimus) injection requires two dilutions prior to intravenous infusion. Temsirolimus (temsirolimus) injection should be diluted only with the supplied DILUENT for Temsirolimus®.
- DILUENT for Temsirolimus® is a sterile, non-aqueous solution that is supplied with Temsirolimus injection, as a kit.
- Temsirolimus (temsirolimus) injection, 25 mg/mL:
- Active ingredient: temsirolimus (25 mg/mL)
- Inactive ingredients: dehydrated alcohol (39.5% w/v), dl-alpha-tocopherol (0.075% w/v), propylene glycol (50.3% w/v), and anhydrous citric acid (0.0025% w/v).
- Inactive ingredients
- Polysorbate 80 (40.0% w/v), polyethylene glycol 400 (42.8% w/v) and dehydrated alcohol (19.9% w/v).
- After the Temsirolimus (temsirolimus) injection vial has been diluted with DILUENT for Temsirolimus®, in accordance with the instructions in section 2.5, the solution contains 35.2% alcohol.
- Temsirolimus (temsirolimus) injection and DILUENT for Temsirolimus® are filled in clear glass vials with butyl rubber stoppers.
## Pharmacodynamics
- Effects on Electrocardiogram: There were no clinically relevant QT changes observed at the recommended dose for Temsirolimus. In a randomized, single-blinded, crossover study, 58 healthy subjects received Temsirolimus 25 mg, placebo, and a single oral dose of moxifloxacin 400 mg.
- A supratherapeutic Temsirolimus dose was not studied in this randomized QT trial. The largest difference between the upper bound 2-sided 90% CI for the mean difference between Temsirolimus and placebo-corrected QT interval was less than 10 ms. In a different trial in 69 patients with a hematologic malignancy, Temsirolimus doses up to 175 mg were studied. No patient with a normal QTcF at baseline had an increase in QTcF >60 ms. Additionally, there were no patients with a QTcF interval greater than 500 ms.
## Pharmacokinetics
- Effects on Electrocardiogram: There were no clinically relevant QT changes observed at the recommended dose for Temsirolimus. In a randomized, single-blinded, crossover study, 58 healthy subjects received Temsirolimus 25 mg, placebo, and a single oral dose of moxifloxacin 400 mg.
- A supratherapeutic Temsirolimus dose was not studied in this randomized QT trial. The largest difference between the upper bound 2-sided 90% CI for the mean difference between Temsirolimus and placebo-corrected QT interval was less than 10 ms. In a different trial in 69 patients with a hematologic malignancy, Temsirolimus doses up to 175 mg were studied. No patient with a normal QTcF at baseline had an increase in QTcF >60 ms. Additionally, there were no patients with a QTcF interval greater than 500 ms.
## Nonclinical Toxicology
- Effects on Electrocardiogram: There were no clinically relevant QT changes observed at the recommended dose for Temsirolimus. In a randomized, single-blinded, crossover study, 58 healthy subjects received Temsirolimus 25 mg, placebo, and a single oral dose of moxifloxacin 400 mg. A supratherapeutic Temsirolimus dose was not studied in this randomized QT trial.
- The largest difference between the upper bound 2-sided 90% CI for the mean difference between Temsirolimus and placebo-corrected QT interval was less than 10 ms. In a different trial in 69 patients with a hematologic malignancy, Temsirolimus doses up to 175 mg were studied. No patient with a normal QTcF at baseline had an increase in QTcF >60 ms. Additionally, there were no patients with a QTcF interval greater than 500 ms.
# Clinical Studies
- A phase 3, multi-center, three-arm, randomized, open-label study was conducted in previously untreated patients with advanced renal cell carcinoma (clear cell and non-clear cell histologies). The objectives were to compare Overall Survival (OS), Progression-Free Survival (PFS), Objective Response Rate (ORR), and safety in patients receiving IFN-α to those receiving Temsirolimus or Temsirolimus plus IFN-α.
- Patients in this study had 3 or more of 6 pre-selected prognostic risk factors (less than one year from time of initial renal cell carcinoma diagnosis to randomization, Karnofsky performance status of 60 or 70, hemoglobin less than the lower limit of normal, corrected calcium of greater than 10 mg/dL, lactate dehydrogenase >1.5 times the upper limit of normal, more than one metastatic organ site). Patients were stratified for prior nephrectomy status within three geographic regions and were randomly assigned (1:1:1) to receive IFN-α alone (n = 207), Temsirolimus alone (25 mg weekly; n = 209), or the combination arm (n = 210).
- The ITT population for this interim analysis included 626 patients. Demographics were comparable between the three treatment arms with regard to age, gender, and race. The mean age of all groups was 59 years (range 23–86). Sixty-nine percent were male and 31% were female. The racial distribution for all groups was 91% White, 4% Black, 2% Asian, and 3% other. Sixty-seven percent of patients had a history of prior nephrectomy.
- The median duration of treatment in the Temsirolimus arm was 17 weeks (range 1–126 weeks). The median duration of treatment on the IFN arm was 8 weeks (range 1–124 weeks).
- There was a statistically significant improvement in OS (time from randomization to death) in the Temsirolimus 25 mg arm compared to IFN-α. The combination of Temsirolimus 15 mg and IFN-α did not result in a significant increase in OS when compared with IFN-α alone. Figure 1 is a Kaplan-Meier plot of OS in this study. The evaluations of PFS (time from randomization to disease progression or death) and ORR, were based on blinded independent radiologic assessment of tumor response. Efficacy results are summarized in Table 4.
# How Supplied
- NDC 0008-1179-01 Temsirolimus® (temsirolimus) injection, 25 mg/mL.
## Storage
- Each kit is supplied in a single carton containing one single-use vial of 25 mg/mL of temsirolimus and one DILUENT vial which includes a deliverable volume of 1.8 mL, and must be stored at 2°–8° C (36°–46° F). Protect from light.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Each kit is supplied in a single carton containing one single-use vial of 25 mg/mL of temsirolimus and one DILUENT vial which includes a deliverable volume of 1.8 mL, and must be stored at 2°–8° C (36°–46° F). Protect from light.
# Precautions with Alcohol
- Alcohol-Temsirolimus interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Temsirolimus ®[2]
# Look-Alike Drug Names
There is limited information regarding Temsirolimus Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Temsirolimus | |
466d61edf4c17a907cc10f23ceb2b2397ffb1fab | wikidoc | Tepezcohuite | Tepezcohuite
Tepezcohuite (pronounced Te-pez-Co-wheete) (Mimosa tenuiflorais) a tree bark from Mexico. Also known in Mexico as the "Skin tree", some of the bark’s significant attributed properties are an anti-microbial agent, an analgesic agent, and a cellular regenerator.
An extract of Tepezcohuite contains Flavonoids that diminish the capillary permeability and increases its resistance and protects from skin aging, Tannins which have an astringent action and smooth skin, as well as other micronutrients such as zinc, copper, manganese, iron and magnesium. These play an important role in cellular repair and protection.
Extensive research has been performed in labs in Mexico, Canada and the United Kingdom. They have found that tepezcohuite is a cellular regenerator, an anti-bacterial 300% more effective than streptomycin, and a powerful fungicide.
# Uses for Tepezcohuite
Not all of these uses have been experimentally verfied as useful or safe. Consult a doctor before taking any kind of medication.
Tepezcohuite is considered to be an antiseptic, analgesic and promotor of cellular regeneration. It has also been shown to have a strong effect on peristalsis in animals.
## Burns
Tepezcohuite may protect first and second-degree burns, helping to prevent the loss of fluids. It also may prevent the formation of cheloidal scars and help regenerates hair follicles.
## Traumatology
For traumatic injuries, tepezcohuite is believed to protect exposed bone and help regenerate soft tissue. It is also an antiseptic; however, studies indicate that it is no more effective than current antiseptics, and it may also have toxic effects on the liver.
## Dermatology
Tepezcohuite may prevent wrinkles and acne, as well as treat psoriasis, herpes I and herpes II, and treat chickenpox scars.
## Cosmetology
In addition to the above effects, tepezcohuite may protect and stimulate the generation of collagen and "elastina", as well as protecting flavonoids and hyaluronic acid. | Tepezcohuite
Tepezcohuite (pronounced Te-pez-Co-wheete) (Mimosa tenuiflorais) a tree bark from Mexico. Also known in Mexico as the "Skin tree", some of the bark’s significant attributed properties are an anti-microbial agent, an analgesic agent, and a cellular regenerator.
An extract of Tepezcohuite contains Flavonoids that diminish the capillary permeability and increases its resistance and protects from skin aging, Tannins which have an astringent action and smooth skin, as well as other micronutrients such as zinc, copper, manganese, iron and magnesium. These play an important role in cellular repair and protection.
Extensive research has been performed in labs in Mexico, Canada and the United Kingdom. They have found that tepezcohuite is a cellular regenerator, an anti-bacterial 300% more effective than streptomycin, and a powerful fungicide.[citation needed]
# Uses for Tepezcohuite
Not all of these uses have been experimentally verfied as useful or safe. Consult a doctor before taking any kind of medication.
Tepezcohuite is considered to be an antiseptic, analgesic and promotor of cellular regeneration. It has also been shown to have a strong effect on peristalsis in animals. [1]
## Burns
Tepezcohuite may protect first and second-degree burns, helping to prevent the loss of fluids. It also may prevent the formation of cheloidal scars and help regenerates hair follicles.[citation needed]
## Traumatology
For traumatic injuries, tepezcohuite is believed to protect exposed bone and help regenerate soft tissue. It is also an antiseptic; however, studies indicate that it is no more effective than current antiseptics, and it may also have toxic effects on the liver. [2]
## Dermatology
Tepezcohuite may prevent wrinkles and acne, as well as treat psoriasis, herpes I and herpes II, and treat chickenpox scars.[citation needed]
## Cosmetology
In addition to the above effects, tepezcohuite may protect and stimulate the generation of collagen and "elastina", as well as protecting flavonoids and hyaluronic acid.[citation needed]
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Tepezcohuite | |
1b372e8a59dd8cbbdcbac7f9405d3f4c63f02243 | wikidoc | Terry Chimes | Terry Chimes
Terry Chimes (born 25 January 1955, Stepney, London) was the original drummer of punk rock group The Clash. He originally played with them from July 1976 to November 1976, January 1977 to April 1977, and again from May 1982 to February 1983. He briefly toured with Black Sabbath from November 1987 to December 1987, and again in May 1988.
Since 1994, he has practised as a chiropractor in Essex at his clinic; Chimes Chiropractic.
He also runs chiropractic seminars, with the accompanying website 'chiropractic heaven'.
# The Clash
Terry Chimes was a member of the proto-punk band London SS, which also featured Mick Jones (The Clash) and Paul Simon who, with Chimes, would team up with Joe Strummer and Keith Levene to form The Clash.
Both Chimes and Levene subsequently left, but Chimes was brought back to record the band's self-titled debut album, The Clash (album). On the album sleeve he was credited as Tory Crimes. After the album's release Chimes left the band once again and was replaced by Topper Headon.
In 1982, Headon was forced out of the band and Chimes was asked to rejoin for a U.S. tour supporting The Who and the following UK tour. He also was in the music video for the single (music), "Rock the Casbah".
# Other bands
After leaving The Clash, Chimes drummed in bands including Johnny Thunders and the Heartbreakers briefly in 1977 and 1984, Cowboys International in 1979, Generation X (band) from 1980 to 1981, Hanoi Rocks in 1985, The Cherry Bombz in 1986 (with ex Hanoi Rocks members Andy McCoy and Nasty Suicide and ex Sham 69/Wanderers/The Lords of the New Church (Dave Tregunna) and Black Sabbath on their Eternal Idol Tour in 1987/88.
He also played with Hanoi Rocks for the Razzle tribute show in 1985 that was recorded for YLE Teema finland
# Latterday
In 2003, he was inducted into in the Rock and Roll Hall of Fame as a member of The Clash. He served as the band's spokesman on stage at the induction ceremony, giving an acceptance speech where he praised Topper Headon's work. According to Clash tour manager Johnny Green, Chimes' award "mysteriously broke" on the band's flight back to the United Kingdom. However, he was not included as an inducted member when Black Sabbath was enshrined in 2006.
A May 2008 profile in the Daily Mail newspaper detailed how Chimes, a Teetotaler vegetarian, having been cured of serious arm pain on his first show in 1985 with Black Sabbath by the band's personal chiropractor, eventually turned to that occupation himself.
He was nominated as a Scouting In London Ambassador for the Scout Association Region for Greater London at an Adult Appreciation ceremony in 2008.
# Notes
- ↑ Du Noyer, Paul (1997-09-18). The Clash. Modern Icons. London: Virgin. p. 93. ISBN 1852277157. OCLC 58830766..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}
- ↑ "From the Clash to a chiropractor ... Top complementary therapist tells why he changed his tune". Daily Mail. 2008-05-10. Retrieved 2008-05-11.
- ↑ Scouting In London Ambassador | Terry Chimes
Template:Infobox musical artist
Terry Chimes (born 25 January 1955, Stepney, London[1]) was the original drummer of punk rock group The Clash. He originally played with them from July 1976 to November 1976, January 1977 to April 1977, and again from May 1982 to February 1983. He briefly toured with Black Sabbath from November 1987 to December 1987, and again in May 1988.
Since 1994, he has practised as a chiropractor in Essex at his clinic; Chimes Chiropractic.
He also runs chiropractic seminars, with the accompanying website 'chiropractic heaven'.
# The Clash
Terry Chimes was a member of the proto-punk band London SS, which also featured Mick Jones (The Clash) and Paul Simon who, with Chimes, would team up with Joe Strummer and Keith Levene to form The Clash.
Both Chimes and Levene subsequently left, but Chimes was brought back to record the band's self-titled debut album, The Clash (album). On the album sleeve he was credited as Tory Crimes. After the album's release Chimes left the band once again and was replaced by Topper Headon.
In 1982, Headon was forced out of the band and Chimes was asked to rejoin for a U.S. tour supporting The Who and the following UK tour. He also was in the music video for the single (music), "Rock the Casbah".
# Other bands
After leaving The Clash, Chimes drummed in bands including Johnny Thunders and the Heartbreakers briefly in 1977 and 1984, Cowboys International in 1979, Generation X (band) from 1980 to 1981, Hanoi Rocks in 1985, The Cherry Bombz in 1986 (with ex Hanoi Rocks members Andy McCoy and Nasty Suicide and ex Sham 69/Wanderers/The Lords of the New Church (Dave Tregunna) and Black Sabbath on their Eternal Idol Tour in 1987/88.
He also played with Hanoi Rocks for the Razzle tribute show in 1985 that was recorded for YLE Teema finland
# Latterday
In 2003, he was inducted into in the Rock and Roll Hall of Fame as a member of The Clash. He served as the band's spokesman on stage at the induction ceremony, giving an acceptance speech where he praised Topper Headon's work. According to Clash tour manager Johnny Green, Chimes' award "mysteriously broke" on the band's flight back to the United Kingdom. However, he was not included as an inducted member when Black Sabbath was enshrined in 2006.
A May 2008 profile in the Daily Mail newspaper detailed how Chimes, a Teetotaler vegetarian, having been cured of serious arm pain on his first show in 1985 with Black Sabbath by the band's personal chiropractor, eventually turned to that occupation himself. [2]
He was nominated as a Scouting In London Ambassador for the Scout Association Region for Greater London at an Adult Appreciation ceremony in 2008.[3]
# Notes
- ↑ Du Noyer, Paul (1997-09-18). The Clash. Modern Icons. London: Virgin. p. 93. ISBN 1852277157. OCLC 58830766..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}
- ↑ "From the Clash to a chiropractor ... Top complementary therapist tells why he changed his tune". Daily Mail. 2008-05-10. Retrieved 2008-05-11.
- ↑ Scouting In London Ambassador | https://www.wikidoc.org/index.php/Terry_Chimes | |
d86ffcd564c7b21c2e6ce7a19de19f36483b1031 | wikidoc | tert-Butanol | tert-Butanol
# Overview
tert-Butanol, or 2-methyl-2-propanol, is a tertiary alcohol. It is one of the four isomers of butanol. tert-Butanol is a clear liquid with a camphor-like odor. It is well soluble in water and miscible with ethanol and diethyl ether. It is unique among the isomers of butanol because it tends to be a solid at room temperature, with a melting point slightly above 25 degrees Celsius.
# Applications
tert-Butanol is used as a solvent, as a denaturant for ethanol, as an ingredient in paint removers, as an octane booster for gasoline, as an oxygenate gasoline additive, and as an intermediate in the synthesis of other chemical commodities such as flavors and perfumes.
# Preparation
tert-Butanol can be manufactured industrially by the catalytic hydration of isobutylene.
# Chemistry
As a tertiary alcohol, tert-butanol is more stable to oxidation and less reactive than the other isomers of butanol.
When tert-butanol is deprotonated with a strong base, the product is an alkoxide anion. In this case, it is tert-butoxide. For example, when tert-butanol is deprotonated with sodium hydride, the resultant is sodium tert-butoxide.
The tert-butoxide species is itself useful as a strong, non-nucleophilic base in organic chemistry. It is able to abstract acidic protons from the substrate molecule readily, but its steric bulk inhibits the group from participating in nucleophilic addition, such as in a Williamson ether synthesis or an SN2 reaction.
# Conversion to alkyl halide
tert-Butanol (also tert-butyl alcohol) reacts with hydrogen chloride to form tert-butyl chloride and water via an SN1 mechanism.
Step 1 :(CH_3)_3COH + HCl \overset{fast}\rightarrow (CH_3)_3COH_2^+ + Cl^-
Step 2 :(CH_3)_3COH_2^+ \overset{slow}\rightarrow (CH_3)_3C^+ + H_2O (rate determining)
Step 3 :(CH_3)_3C^+ + Cl^- \overset{fast}\rightarrow (CH_3)_3CCl
The overall reaction, therefore, is:
File:T-butanol-chloride.gif
Because tert-butanol is a tertiary alcohol, the relative stability of the tert-butyl carbocation in the Step 2 allows the SN1 mechanism to be followed. Primary alcohols generally require an SN2 mechanism because the energy barrier to produce a primary carbocation is so high that it will not reasonably happen. The SN2 mechanism allows the carbocation intermediate to be avoided. | tert-Butanol
# Overview
tert-Butanol, or 2-methyl-2-propanol, is a tertiary alcohol. It is one of the four isomers of butanol. tert-Butanol is a clear liquid with a camphor-like odor. It is well soluble in water and miscible with ethanol and diethyl ether. It is unique among the isomers of butanol because it tends to be a solid at room temperature, with a melting point slightly above 25 degrees Celsius.
# Applications
tert-Butanol is used as a solvent, as a denaturant for ethanol, as an ingredient in paint removers, as an octane booster for gasoline, as an oxygenate gasoline additive, and as an intermediate in the synthesis of other chemical commodities such as flavors and perfumes.
# Preparation
tert-Butanol can be manufactured industrially by the catalytic hydration of isobutylene.
# Chemistry
As a tertiary alcohol, tert-butanol is more stable to oxidation and less reactive than the other isomers of butanol.
When tert-butanol is deprotonated with a strong base, the product is an alkoxide anion. In this case, it is tert-butoxide. For example, when tert-butanol is deprotonated with sodium hydride, the resultant is sodium tert-butoxide.
The tert-butoxide species is itself useful as a strong, non-nucleophilic base in organic chemistry. It is able to abstract acidic protons from the substrate molecule readily, but its steric bulk inhibits the group from participating in nucleophilic addition, such as in a Williamson ether synthesis or an SN2 reaction.
# Conversion to alkyl halide
tert-Butanol (also tert-butyl alcohol) reacts with hydrogen chloride to form tert-butyl chloride and water via an SN1 mechanism.
Step 1 :<math>(CH_3)_3COH + HCl \overset{fast}\rightarrow (CH_3)_3COH_2^+ + Cl^-</math>
Step 2 :<math>(CH_3)_3COH_2^+ \overset{slow}\rightarrow (CH_3)_3C^+ + H_2O</math> (rate determining)
Step 3 :<math>(CH_3)_3C^+ + Cl^- \overset{fast}\rightarrow (CH_3)_3CCl</math>
The overall reaction, therefore, is:
File:T-butanol-chloride.gif
Because tert-butanol is a tertiary alcohol, the relative stability of the tert-butyl carbocation in the Step 2 allows the SN1 mechanism to be followed. Primary alcohols generally require an SN2 mechanism because the energy barrier to produce a primary carbocation is so high that it will not reasonably happen. The SN2 mechanism allows the carbocation intermediate to be avoided. | https://www.wikidoc.org/index.php/Tert-Butanol | |
0162b0abafdcebfdfabc782e6e317ef28ba77bb6 | wikidoc | Tesla (unit) | Tesla (unit)
The tesla (symbol T) is the SI derived unit of magnetic field (specifically magnetic flux density). The tesla is equal to one weber per square metre and was defined in 1960 in honor of inventor, scientist and electrical engineer Nikola Tesla.
# Definition
# Conversions
1 tesla is equivalent to:
- 10,000 (or 104) gauss (G), used in CGS system. Thus, 10 G = 1 mT (1 millitesla)
- 1,000,000,000 (or 109) gammas (γ), used in geophysics. Thus, 1 γ = 1 nT (nanotesla)
# Examples | Tesla (unit)
The tesla (symbol T) is the SI derived unit of magnetic field (specifically magnetic flux density). The tesla is equal to one weber per square metre and was defined in 1960[1] in honor of inventor, scientist and electrical engineer Nikola Tesla.
# Definition
Template:SI unit lowercase
# Conversions
1 tesla is equivalent to:
- 10,000 (or 104) gauss (G), used in CGS system. Thus, 10 G = 1 mT (1 millitesla)
- 1,000,000,000 (or 109) gammas (γ), used in geophysics. Thus, 1 γ = 1 nT (nanotesla)
# Examples | https://www.wikidoc.org/index.php/Tesla_(unit) | |
0606bccc93966823365fc11bf730cc7a62e49b69 | wikidoc | Testolactone | Testolactone
# Overview
Testolactone, or Teslac (brand name) is an antineoplastic agent that is a derivative of progesterone and is used to treat advanced stage breast cancer.
# Pharmacology
Testolactone is a synthetic antineoplastic agent that is structurally distinct from the androgen steroid nucleus in possessing a six-membered lactone ring in place of the usual five-membered carbocyclic D-ring. Despite some similarity to testosterone, testolactone has no in vivo androgenic effect. No other hormonal effects have been reported in clinical studies in patients receiving testolactone.
# Mechanism of Action
The principal action of testolactone is reported to be inhibition of steroid aromatase activity and the reduction in estrone synthesis that fallows. Androstenedione, a 19-carbon steroid hormone produced in the adrenal glands and the gonads, is where estrone synthesis originates and is the source of estrogen in postmenopausal women. In vitro studies report that the aromatase inhibition may be noncompetitive and irreversible, and could possibly account for the persistence of this drug's effect on estrogen synthesis after drug withdrawal.
# Uses
This drug is mainly used for treating various types of breast cancer in women who have been through menopause or whose ovaries no longer function. It works by blocking the production of estrogen, which helps prevent the growth of breast cancers that are activated by estrogen. It may also prevent tumor cells from being activated by other hormones.
# Side effects
The most COMMON side effects include:
- Abnormal skin sensations
- Aches of the legs and arms
- General body discomfort
- Hair loss
- Loss of appetite
- Nausea
- Redness of the tongue
- Vomiting | Testolactone
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]
# Overview
Testolactone, or Teslac (brand name) is an antineoplastic agent that is a derivative of progesterone and is used to treat advanced stage breast cancer.[1]
# Pharmacology
Testolactone is a synthetic antineoplastic agent that is structurally distinct from the androgen steroid nucleus in possessing a six-membered lactone ring in place of the usual five-membered carbocyclic D-ring. Despite some similarity to testosterone, testolactone has no in vivo androgenic effect. No other hormonal effects have been reported in clinical studies in patients receiving testolactone.[2]
# Mechanism of Action
The principal action of testolactone is reported to be inhibition of steroid aromatase activity and the reduction in estrone synthesis that fallows. Androstenedione, a 19-carbon steroid hormone produced in the adrenal glands and the gonads, is where estrone synthesis originates and is the source of estrogen in postmenopausal women. In vitro studies report that the aromatase inhibition may be noncompetitive and irreversible, and could possibly account for the persistence of this drug's effect on estrogen synthesis after drug withdrawal.[3]
# Uses
This drug is mainly used for treating various types of breast cancer in women who have been through menopause or whose ovaries no longer function.[4] It works by blocking the production of estrogen, which helps prevent the growth of breast cancers that are activated by estrogen. It may also prevent tumor cells from being activated by other hormones.[5]
# Side effects
The most COMMON side effects include:
- Abnormal skin sensations
- Aches of the legs and arms
- General body discomfort
- Hair loss
- Loss of appetite
- Nausea
- Redness of the tongue
- Vomiting | https://www.wikidoc.org/index.php/Teslac | |
8d9e9edfe1d38f024d888d6ac70e2d0c5e49ad8b | wikidoc | Test05192014 | Test05192014
# 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
Test05192014 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)
Condition 1
- Dosing Information
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
Condition 1
- Developed by: (Organization)
- Class of Recommendation: (Class) (Link)
- Strength of Evidence: (Category A/B/C) (Link)
- Dosing Information/Recommendation
- (Dosage)
### Non–Guideline-Supported Use
Condition 1
- Dosing Information
- There is limited information about Off-Label Non–Guideline-Supported Use of Test05192014 in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Condition 1
- Dosing Information
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
Condition 1
- Developed by: (Organization)
- Class of Recommendation: (Class) (Link)
- Strength of Evidence: (Category A/B/C) (Link)
- Dosing Information/Recommendation
- (Dosage)
### Non–Guideline-Supported Use
Condition 1
- Dosing Information
- There is limited information about Off-Label Non–Guideline-Supported Use of Test05192014 in pediatric patients.
# Contraindications
- Condition 1
- Condition 2
- Condition 3
- Condition 4
- Condition 5
# Warnings
Conidition 1
(Description)
# Adverse Reactions
## Clinical Trials Experience
Central Nervous System
Cardiovascular
Respiratory
Gastrointestinal
Hypersensitive Reactions
Miscellaneous
## Postmarketing Experience
Central Nervous System
Cardiovascular
Respiratory
Gastrointestinal
Hypersensitive Reactions
Miscellaneous
# Drug Interactions
- (Drug 1)
- (Description)
- (Drug 2)
- (Description)
- (Drug 3)
- (Description)
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
There is no FDA guidance on usage of Test05192014 in women who are pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Test05192014 in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Test05192014 during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Test05192014 in women who are nursing.
### Pediatric Use
There is no FDA guidance on the use of Test05192014 in pediatric settings.
### Geriatic Use
There is no FDA guidance on the use of Test05192014 in geriatric settings.
### Gender
There is no FDA guidance on the use of Test05192014 with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Test05192014 with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Test05192014 in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Test05192014 in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Test05192014 in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Test05192014 in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Test05192014 Administration in the drug label.
### Monitoring
There is limited information regarding Test05192014 Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Test05192014 and IV administrations.
# Overdosage
There is limited information regarding Test05192014 overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
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# Overview
Test05192014 is {{{aOrAn}}} {{{drugClass}}} that is FDA approved for the {{{indicationType}}} of {{{indication}}}. Common adverse reactions include {{{adverseReactions}}}.
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a9a6bd610c0afa066bc34241b9026edcc40e112b | wikidoc | Test anxiety | Test anxiety
# Overview
Test anxiety is a psychological condition in which a person experiences distress before, during, or after an examor other assessment to such an extent that this anxiety causes poor performance or interferes with normal learning.
# Test Anxiety
Test anxiety is a combination of perceived physiological over-arousal, feelings of worry and dread, self-depreciating thoughts, tension, and somatic symptoms that occur during test situations. It is a physiological condition in which people experience extreme stress, anxiety, and discomfort during and/or before taking a test. These responses can drastically hinder an individual's ability to perform well and negatively affects their social emotional and behavioural development and feelings about themselves and school. Test anxiety is prevalent amongst the student populations of the world, and has been studied formally since the early 1950s beginning with researchers George Mandler and Seymour Sarason. Sarason's brother, Irwin G. Sarason, then contributed to early investigation of test anxiety, clarifying the relationship between the focused effects of test anxiety, other focused forms of anxiety, and generalized anxiety.
Test anxiety can also be labeled as anticipatory anxiety, situational anxiety or evaluation anxiety. Some anxiety is normal and often helpful to stay mentally and physically alert. When one experiences too much anxiety, however, it can result in emotional or physical distress, difficulty concentrating, and emotional worry. Test anxiety has been shown to have a consistently negative relationship with test performance, and test-anxious students are found to perform about 12 percent below their non-anxious peers. Inferior performance arises not because of intellectual problems or poor academic preparation, but because testing situations create a sense of threat for those experiencing test anxiety; anxiety resulting from the sense of threat then disrupts attention and memory function.
Researchers suggest that between 25 to 40 percent of students experience test anxiety. Students with disabilities and students in gifted educations classes tend to experience high rates of test anxiety. Students who experience test anxiety tend to be easily distracted during a test, experience difficulty with comprehending relatively simple instructions, and have trouble organizing or recalling relevant information.
## Symptoms
- Physical — headaches, nausea or diarrhea, extreme body temperature changes, excessive sweating, shortness or breath, light-headedness or fainting, rapid heart beat, and/or dry mouth.
- Emotional — excessive feelings of fear, disappointment, anger, depression, uncontrollable crying or laughing, feelings of helplessness
- Behavioral — fidgeting, pacing, substance abuse, avoidance
- Cognitive — racing thoughts, 'going blank', difficulty concentrating, negative self-talk, feelings of dread, comparing yourself to others, difficulty organizing your thoughts.
# Clinical Presentation
Researchers believe that feelings of anxiety arise to prepare a person for threats. In humans, anxiety symptoms are distributed along a continuum and different symptom levels of anxiety predict outcomes. Responses consist of increased heart rate, stress hormone secretion, restlessness, vigilance, and fear of a potentially dangerous environment. Anxiety prepares the body physically, cognitively, and behaviourally to detect and deal with threats to survival. As a result, a person’s body begins to hyperventilate to allow more oxygen to enter the bloodstream, divert blood to muscles, and sweat to cool the skin. In individuals, the degree to which an anxiety response is developed is based on the probability of bad things happening in the environment and the individual’s ability to cope with them. In the case of test taking, this might be a failing exam grade that prevents the student from being accepted to a post-secondary institution. A person's beliefs about their own competencies are a form of self-knowledge, which plays an important role in analyzing situations that might be threatening. When a person has feelings of low competence about their abilities they are likely to anticipate negative outcomes such as failure, under uncertain conditions. Thus, evaluative situations including tests and exams, are perceived as more threatening by students who have low competencies.
There is a difference between generalized anxiety disorders (GAD) and test anxiety. GAD is characterized by "trait anxiety" which results in a person experiencing high levels of stress across a wide range of situations. In contrast, people with test anxiety have a "state anxiety" which results in high levels of nervousness specific to testing.
Symptoms of test anxiety can range from moderate to severe. "Students who exhibit moderate symptoms are still able to perform relatively well on exams. Other students with severe anxiety will often experience panic attacks."
Common physical symptoms include: headache, upset stomach, feeling of fear, feeling of dread, shortness of breath, sweating, pacing or fidgeting, crying, racing thoughts and blanking out
During states of excitement or stress, the body releases adrenaline. Adrenaline is known to cause physical symptoms that accompany test anxiety, such as increased heart rate, sweating, and rapid breathing. In many cases having adrenaline is a good thing. It is helpful when dealing with stressful situations, ensuring alertness and preparation. But for some people the symptoms are difficult or impossible to handle, making it impossible to focus on tests.
Test Anxiety consists of:
- Physiological Overarousal — often termed emotionality. Somatic signs include headaches, stomach aches, nausea, diarrhea, excessive sweating, shortness of breath, light-headedness or fainting, rapid heartbeat and dry mouth. Test anxiety can also lead to panic attacks, in which the student may have a sudden intense fear, difficulty breathing, and extreme discomfort.
- Worry & Dread — maladaptive cognitions. This includes catastrophic expectations of gloom and doom, fear of failure, random thoughts, feelings of inadequacy, self-condemnation, negative self-talk, frustration and comparing oneself unfavorably to others.
- Cognitive/Behavioral — poor concentration, "going blank" or "freezing," confusion, and poor organization. The inability to concentrate leads to impaired performance on tests. Fidgeting during or outright avoidance of the test. Students often report "blanking out" even though they have studied sufficiently for the test.
- Emotional — low self-esteem, depression, anger, and a feeling of hopelessness.
# Causes
Test anxiety can develop for a number of reasons. There may be some prior negative experience with test taking that serves as the activating event. Students who have experienced, or have a fear of, blanking out on tests or the inability to perform in testing situations can develop anticipatory anxiety. Worrying about how anxiety will effect you can be as debilitating as the anxiety itself. This kind of anxiety can build as the testing situation approaches, and can interfere with the student's ability to prepare adequately. Lack of preparation is another factor that can contribute to test anxiety. Poor time management, poor study habits, and lack of organization can lead to a student feeling overwhelmed. Student's who are forced to cram at the last minute will feel less confident about the material covered than those who have been able to follow a structured plan for studying. Being able to anticipate what the exam will cover, and knowing all the information has been covered during the study sessions, can help students to enter the testing situation with a more positive attitude. Text anxiety can also develop genetically.
Lack of confidence, fear of failure, and other negative thought processes may also contribute to test anxiety. The pressure to perform well on exams is a great motivator unless it is so extreme that it becomes irrational. Perfectionism and feelings of unworthiness provide unreasonable goals to achieve through testing situations. When a student's self-esteem is too closely tied to the outcome of any one academic task, the results can be devastating. In these situations, students may spend more time focusing on the negative consequences of failure, than preparing to succeed.
Parents are often perceived by students as being a source of pressure, especially when they place a strong emphasis on obtaining high achievement scores on examinations and assessments instead of on the effort made. Research shows that parental pressure is associated with greater worry, test irrelevant thoughts, and stronger bodily symptoms relating to anxiety during a test.
Other causes of test anxiety may include fear of failure, procrastination, and previous poor test performance. As well, characteristics of the test environment such as: nature of the task, difficulty, atmosphere, time constraints, examiner characteristics, mode of administration and physical setting can affect the level of anxiousness felt by the student. Researchers Putwain & Best (2011), examined test performance among elementary children when the teacher put pressure on the students in an attempt to create a more high stress environment. Their findings showed that students performed worse in high threat situations and experienced more test anxiety and worrisome thoughts than when in a low threat environment.
Test anxiety is known to develop into a vicious cycle. After experiencing test anxiety on one test, the student may become so fearful of it happening again they become more anxious and upset than they would normally, or even than they experienced on the previous test. If the cycle continues without acknowledgement, or the student seeking help, the student may begin to feel helpless in the situation.
People who experience test anxiety often have parents or siblings who have test anxiety or other types of anxiety. Anxiety does seem to have some genetic components.
Other variables related to test anxiety are:
- Obsessive compulsive disorder
- Perfectionist tendencies and unrealistic expectations
- Negative self-esteem, self-statements, and criticism
- Poor motivation or lack of confidence
- Stereotype threat
- Inadequate study and test-taking skills
- Poor eating, sleeping and exercising habits.
## Theories
Anxiety is defined as the “psychological mechanism whereby the current intensification of a dangerous drive results in the elicitation of defences.” George Mandler and Seymour Sarason (1952), developed the theory that anxiety present in testing situations is an important determinate of test performance. Individuals that become highly anxious during tests typically perform more poorly on tests than low-test anxious persons, especially when tests are given under stressful evaluative conditions such as a post-secondary exam. The feelings of forgetfulness, or drawing a “blank” are developed because of anxiety-produced interference between relevant responses and irrelevant responses generated from the person’s anxious state. The difference in performance of a high-anxious test taker compared to a low-anxious test taker is largely due to the difference in their ability to focus on the tasks required. A low-anxious test taker is able to focus greater attention on the tasks required of them while taking the test, while a high-anxious test taker is focused on their internal self, and the anxiety they are feeling. Anxious test takers do not perform adequately on the test as their attention is divided between themselves and the test. Therefore, students with high test anxiety are unable to focus their full attention on the test. Furthermore, anxiousness is evoked when a student believes that the evaluative situation, such as an assessment, exceeds his or her intellectual, motivational, and social capabilities.
Psychologists Liebert and Morris (1967) originally attributed test anxiety to two main components: worry and emotionality. Worry refers to cognitive factors, such as negative expectations or feelings of inadequacy, and emotionality refers to the physical symptoms, such as increased heart rate, muscle tension, or butterflies. Both are aversive elements that can create anxiety, but it is the cognitive factors that have the strongest connection to performance.
Researchers Putwain, Woods & Symes (2010), found that a low academic self-concept was associated with higher worry and tension about their abilities to do well on a test. A student's metacognitive beliefs play an important role in the maintenance of negative self-beliefs.
Anxiety reactions can be generalized from previous experiences to testing situations. Feelings of inadequacy, helplessness, anticipations of punishment or loss of status and esteem manifest anxiety responses. As well, the presence of an audience can debilitate the performance of high anxious test takers and increase the performance of low anxious test takers. Interestingly, persons who score high on anxiety scales tend to describe themselves in negative, self-devaluing terms. Highly anxious test takers also blame themselves for their failure significantly more than low anxious test takers.
### Attentional Theories
There are two main groups of attentional theories that attempt to explain compromised performance in pressured situations.
- One group of theories are the explicit monitoring theories. They state that when a person is expected to perform a specific skill, the pressure may cause an increased self-consciousness and inward focus, which can disrupt their ability to successfully perform that task. Thinking about step-by-step procedures can inhibit one’s ability to execute a task. For example, a study by R. Gray found that baseball players put into the high-pressure condition had increased errors, and an increased ability to recall details like the direction their bat was moving. This indicates that the pressured players were monitoring themselves more, which impacted their ability to successfully hit the ball.
- A second group of theories are the distraction theories. These theories states that high-pressure environments create a dual-task situation, in which the person’s attention is divided between the task at hand and unhelpful thoughts about the situation and possible negative consequences of poor performance.
Attention is an important part of working memory, which is the system that actively holds several pieces of relevant information in the mind while inhibiting irrelevant information. Working memory has a limited capacity, and the addition of stress and anxiety reduces the resources available to focus on relevant information.
- In situations in which individuals need to concentrate their attention on a specific task, emotional stimuli can divert their attention to a greater degree than non-emotional stimuli. Emotional stimuli will often dominate a person’s thoughts, and any attempt to suppress them will require additional working memory resources. When working memory divides resources between the aversive cognitions and the task-relevant material, then the person’s ability to use the relevant information on a test will suffer.People who suffer from test anxiety are more likely to experience negative cognitions while in evaluative situations. Furthermore, test anxious persons have been found to bias their attention towards threatening and anxiety related stimuli more than nonemotional stimuli.Research has accordingly found that tasks that rely heavily on working memory are the ones that suffer the most during pressure. Shortfalls in performance that are caused by test anxiety seem to be related to the extent to which the student has full access to their working memory.
- When comparing these two theories in the context of academic performance, a majority of work supports distraction theories. One reason for this is that many of the skills performed in the classroom require heavy demands on working memory. However, there are different kinds of pressure situations. There is monitoring pressure, in which an individual’s performance is impacted due to the presence of an audience, and outcome pressure, in which an individual’s performance is influenced by the consequences of the testing results. In a study, DeCaro et al. found that performance on a rule-based task, that relies heavily on working memory, was impaired by outcome pressure, but not monitoring pressure, whereas performance on an information-integration task, which does not require attentional control, was hurt by monitoring pressure, but not outcome pressure. These findings indicate that performance is compromised in different ways depending on the type of task, and the types of pressure, and that both theories can be correct.
### Attentional Control
Eysenck et al. elaborate upon the distraction theories and propose the attentional control theory. This theory uses Baddeley's model of working memory to explain the effects of anxiety on working memory and on performance. In Baddeley's theory, working memory (WM) consists of four components, one of them the central executive that has a number of tasks such as coordination of the temporary stores of phonological and visual information (phonological loop and visuospatial sketchpad, respectively).
The attentional control theory assumes that anxiety primarily affects attentional control, which is a key function of the central executive. Attentional control is the balance between the two attentional systems, the goal-directed system, influenced by the individual's goals, and the stimulus-driven system, influenced by salient stimuli. According to the attentional control theory, anxiety disrupts the balance between these two systems. The stimulus-driven system becomes stronger at the expense of the goal-directed systsem, thereby impairing the efficiency of the inhibition and shifting functions of the central executive.
In support of this theory, there is strong evidence that anxiety largely impairs processing efficiency rather than performance effectiveness. Performance effectiveness refers to the quality of performance whereas processing efficiency refers to the amount of resources used to attain an effective performance. There is also evidence that anxiety impairs both the inhibition and the shifting function. Therefore, this theory suggests that students high in test anxiety will have to allocate more resources to the task at hand than non-test anxiety students in order to achieve the same results.
In general, people with higher working memory capacity do better on academic tasks, but this changes when people are under pressure. Beilock et al. found that pressure led individuals with a high working memory capacity to perform worse on a complicated task, whereas individuals with a low WM capacity got the same low results with or without pressure. This was because people with high WM could use more better but more demanding problem solving strategies in the low pressure condition, which they had to abandon in the high pressure condition. The low WM people never used these demanding strategies in the first place. Evidence contrary to Beilock's results comes from Johnson et al. who found individuals' performances on a task showed a decrease in accuracy due to anxiety for individuals with low or average WM capacity, but did not significantly decrease for individuals with high WM.
# Measurement Scales
Early scales, by authors such as Charles Spielberger, tended to focus on physiological and somatic features and on worry, commonly referred to as emotionality, while more recent offerings, such as that by Cassady & Johnson, emphasize cognitive processes. "Test anxiety" for these authors consists of physiological and mental processes, and impaired test performance is seen as the result.
The "Children's Test Anxiety Questionnaire" is specifically designed to measure test anxiety in children 8–12 years of age. It provides scores for three dimensions of test anxiety: "worrisome thoughts concerning failure (i.e. 'when I take tests, I worry about failing'), automatic reactions concerning students' general and specific somatic indications of anxiety (i.e. 'when I take tests, my heart beats fast'), and off-task behaviours concerning nervous habits and distracting behaviours (i.e. 'when I take tests, I play with my pencil')"
# Accommodations
Test anxiety prevents students from demonstrating their knowledge on examinations. To be covered by the Americans with Disabilities Act, test anxiety must pass two legal tests. First, it must be a "mental impairment." As a form of Social Phobia, a mental disorder included in the Diagnostic and Statistical Manual of Mental Disorders, it meets this first test. Second, it must "substantially limit one or more of the major life activities." Individuals for whom test anxiety is one manifestation of Social Phobia-Generalized are substantially limited in the major life activities of interacting with others and working. Individuals for whom test anxiety is the only manifestation of their Social Phobia are substantially limited in the major life activities of thinking and working, the latter because they are excluded from any career requiring a test for application, credentialing, licensure, or training. Accommodations may include taking the test in a separate room or taking an untimed examination. Documentation supporting a diagnosis of test anxiety should include evidence of significant impairment in test performance.
# Management
To gain an accurate assessment of student comprehension, instructors should be concerned with minimizing the effects of test anxiety. Instructors might offer "second chances" post test, familiarize students with test format and grading scheme, and lower the impact of any one test. If students have greater confidence in their test-taking skills, they are more likely to be comfortable and relaxed when the testing does occur. Having an intentional thinking strategy should help student performance improve.
For some individuals, poor academic performance is due to skill deficits, which could include problems in encoding (learning),rehearsal (study skills) or retrieval during a test (test-taking strategies).Skill deficits may lead to poor performance directly (failure to adequately learn the material) or indirectly (awareness of being ill-prepared causes anxiety that, in turn, leads to poor performance). Therefore, the most effective interventions are those that combine skill-focused strategies (i.e. study skills training, test-taking skills) with cognitive (i.e. cognitive restructuring) or behavioural approaches (i.e. relaxation training, systematic desensitization).
Research suggests that students do not gain as much from reading self-help material as students would from the same material received in therapy or in a participatory group setting.
# Treatment
Medication will not cure anxiety disorders but will keep them under control. Drug treatments for anxiety disorders work by downplaying threat detecting mechanisms in the body.
- Beta blockers — commonly used to treat performance anxiety. Propranolol (a beta blocker) blocks the physical manifestations of anxiety. It slows heart rate and reduces sweating. It is not to be taken on the first day of a test, as some people are shown to have adverse side effects which include, but are not limited to, lightheadedness and a very slow heart beat.
- Benzodiazepines — commonly used to treat test anxiety. Should be taken up to 30 minutes before the start of the test. Side effects include, but are not limited to, sleepiness and can impair memory and thought.
- Antidepressants — commonly used for general depression, which can accompany test anxiety. Side effects include, but are not limited to, the potential to cause agitation and suicidal thoughts. These need to be taken on a regular basis not when needed before an exam.
Another approach is the use of psychotherapy. Cognitive Behavioral Therapy (CBT) is very useful in treating anxiety disorders. CBT helps to change the pattern of thinking that support the fear and help the sufferer overcome the negative beliefs. CBT often lasts about two weeks and takes place in small groups.
Medication combined with psychotherapy has shown to be the most effective treatment approach for people suffering from anxiety disorders.
Cognitive interventions have only had limited results when it comes to improving test performance. Some cognitive strategies have even been shown to be detrimental to performance, particularly strategies such as thought suppression.One intervention that had promising results in a first study is "attentional cognitive bias modification" in which children learning to avoid paying attention to a threatening face. | Test anxiety
# Overview
Test anxiety is a psychological condition in which a person experiences distress before, during, or after an examor other assessment to such an extent that this anxiety causes poor performance or interferes with normal learning.
# Test Anxiety
Test anxiety is a combination of perceived physiological over-arousal, feelings of worry and dread, self-depreciating thoughts, tension, and somatic symptoms that occur during test situations.[1] It is a physiological condition in which people experience extreme stress, anxiety, and discomfort during and/or before taking a test. These responses can drastically hinder an individual's ability to perform well and negatively affects their social emotional and behavioural development and feelings about themselves and school.[2] Test anxiety is prevalent amongst the student populations of the world, and has been studied formally since the early 1950s beginning with researchers George Mandler and Seymour Sarason.[3] Sarason's brother, Irwin G. Sarason, then contributed to early investigation of test anxiety, clarifying the relationship between the focused effects of test anxiety, other focused forms of anxiety, and generalized anxiety.[4]
Test anxiety can also be labeled as anticipatory anxiety, situational anxiety or evaluation anxiety. Some anxiety is normal and often helpful to stay mentally and physically alert.[5] When one experiences too much anxiety, however, it can result in emotional or physical distress, difficulty concentrating, and emotional worry. Test anxiety has been shown to have a consistently negative relationship with test performance, and test-anxious students are found to perform about 12 percent below their non-anxious peers.[6][7] Inferior performance arises not because of intellectual problems or poor academic preparation, but because testing situations create a sense of threat for those experiencing test anxiety; anxiety resulting from the sense of threat then disrupts attention and memory function.[8][9][10][11]
Researchers suggest that between 25 to 40 percent of students experience test anxiety.[12] Students with disabilities and students in gifted educations classes tend to experience high rates of test anxiety. Students who experience test anxiety tend to be easily distracted during a test, experience difficulty with comprehending relatively simple instructions, and have trouble organizing or recalling relevant information.[1]
## Symptoms
- Physical — headaches, nausea or diarrhea, extreme body temperature changes, excessive sweating, shortness or breath, light-headedness or fainting, rapid heart beat, and/or dry mouth.
- Emotional — excessive feelings of fear, disappointment, anger, depression, uncontrollable crying or laughing, feelings of helplessness
- Behavioral — fidgeting, pacing, substance abuse, avoidance
- Cognitive — racing thoughts, 'going blank', difficulty concentrating, negative self-talk, feelings of dread, comparing yourself to others, difficulty organizing your thoughts.
# Clinical Presentation
Researchers believe that feelings of anxiety arise to prepare a person for threats.[13] In humans, anxiety symptoms are distributed along a continuum and different symptom levels of anxiety predict outcomes. Responses consist of increased heart rate, stress hormone secretion, restlessness, vigilance, and fear of a potentially dangerous environment.[13] Anxiety prepares the body physically, cognitively, and behaviourally to detect and deal with threats to survival. As a result, a person’s body begins to hyperventilate to allow more oxygen to enter the bloodstream, divert blood to muscles, and sweat to cool the skin.[13] In individuals, the degree to which an anxiety response is developed is based on the probability of bad things happening in the environment and the individual’s ability to cope with them. In the case of test taking, this might be a failing exam grade that prevents the student from being accepted to a post-secondary institution. A person's beliefs about their own competencies are a form of self-knowledge, which plays an important role in analyzing situations that might be threatening. When a person has feelings of low competence about their abilities they are likely to anticipate negative outcomes such as failure, under uncertain conditions. Thus, evaluative situations including tests and exams, are perceived as more threatening by students who have low competencies.[14]
There is a difference between generalized anxiety disorders (GAD) and test anxiety. GAD is characterized by "trait anxiety" which results in a person experiencing high levels of stress across a wide range of situations. In contrast, people with test anxiety have a "state anxiety" which results in high levels of nervousness specific to testing.[15]
Symptoms of test anxiety can range from moderate to severe. "Students who exhibit moderate symptoms are still able to perform relatively well on exams. Other students with severe anxiety will often experience panic attacks."[16]
Common physical symptoms include: headache, upset stomach, feeling of fear, feeling of dread, shortness of breath, sweating, pacing or fidgeting, crying, racing thoughts and blanking out
During states of excitement or stress, the body releases adrenaline. Adrenaline is known to cause physical symptoms that accompany test anxiety, such as increased heart rate, sweating, and rapid breathing.[17] In many cases having adrenaline is a good thing.[citation needed] It is helpful when dealing with stressful situations, ensuring alertness and preparation.[citation needed] But for some people the symptoms are difficult or impossible to handle, making it impossible to focus on tests.
Test Anxiety consists of:
- Physiological Overarousal — often termed emotionality. Somatic signs include headaches, stomach aches, nausea, diarrhea, excessive sweating, shortness of breath, light-headedness or fainting, rapid heartbeat and dry mouth. Test anxiety can also lead to panic attacks, in which the student may have a sudden intense fear, difficulty breathing, and extreme discomfort.
- Worry & Dread — maladaptive cognitions. This includes catastrophic expectations of gloom and doom, fear of failure, random thoughts, feelings of inadequacy, self-condemnation, negative self-talk, frustration and comparing oneself unfavorably to others.
- Cognitive/Behavioral — poor concentration, "going blank" or "freezing," confusion, and poor organization. The inability to concentrate leads to impaired performance on tests. Fidgeting during or outright avoidance of the test. Students often report "blanking out" even though they have studied sufficiently for the test.[18]
- Emotional — low self-esteem, depression, anger, and a feeling of hopelessness.[18]
# Causes
Test anxiety can develop for a number of reasons. There may be some prior negative experience with test taking that serves as the activating event. Students who have experienced, or have a fear of, blanking out on tests or the inability to perform in testing situations can develop anticipatory anxiety. Worrying about how anxiety will effect you can be as debilitating as the anxiety itself. This kind of anxiety can build as the testing situation approaches, and can interfere with the student's ability to prepare adequately. Lack of preparation is another factor that can contribute to test anxiety. Poor time management, poor study habits, and lack of organization can lead to a student feeling overwhelmed. Student's who are forced to cram at the last minute will feel less confident about the material covered than those who have been able to follow a structured plan for studying. Being able to anticipate what the exam will cover, and knowing all the information has been covered during the study sessions, can help students to enter the testing situation with a more positive attitude. Text anxiety can also develop genetically.
Lack of confidence, fear of failure, and other negative thought processes may also contribute to test anxiety. The pressure to perform well on exams is a great motivator unless it is so extreme that it becomes irrational. Perfectionism and feelings of unworthiness provide unreasonable goals to achieve through testing situations. When a student's self-esteem is too closely tied to the outcome of any one academic task, the results can be devastating. In these situations, students may spend more time focusing on the negative consequences of failure, than preparing to succeed.
Parents are often perceived by students as being a source of pressure, especially when they place a strong emphasis on obtaining high achievement scores on examinations and assessments instead of on the effort made. Research shows that parental pressure is associated with greater worry, test irrelevant thoughts, and stronger bodily symptoms relating to anxiety during a test.[14]
Other causes of test anxiety may include fear of failure, procrastination, and previous poor test performance.[19] As well, characteristics of the test environment such as: nature of the task, difficulty, atmosphere, time constraints, examiner characteristics, mode of administration and physical setting can affect the level of anxiousness felt by the student.[2][14] Researchers Putwain & Best (2011),[20] examined test performance among elementary children when the teacher put pressure on the students in an attempt to create a more high stress environment. Their findings showed that students performed worse in high threat situations and experienced more test anxiety and worrisome thoughts than when in a low threat environment.
Test anxiety is known to develop into a vicious cycle. After experiencing test anxiety on one test, the student may become so fearful of it happening again they become more anxious and upset than they would normally, or even than they experienced on the previous test. If the cycle continues without acknowledgement, or the student seeking help, the student may begin to feel helpless in the situation.[21]
People who experience test anxiety often have parents or siblings who have test anxiety or other types of anxiety. Anxiety does seem to have some genetic components.[22]
Other variables related to test anxiety are:
- Obsessive compulsive disorder
- Perfectionist tendencies and unrealistic expectations
- Negative self-esteem, self-statements, and criticism
- Poor motivation or lack of confidence
- Stereotype threat
- Inadequate study and test-taking skills
- Poor eating, sleeping and exercising habits.[23]
## Theories
Anxiety is defined as the “psychological mechanism whereby the current intensification of a dangerous drive results in the elicitation of defences.” [24] George Mandler and Seymour Sarason (1952), developed the theory that anxiety present in testing situations is an important determinate of test performance. Individuals that become highly anxious during tests typically perform more poorly on tests than low-test anxious persons, especially when tests are given under stressful evaluative conditions such as a post-secondary exam. The feelings of forgetfulness, or drawing a “blank” are developed because of anxiety-produced interference between relevant responses and irrelevant responses generated from the person’s anxious state. The difference in performance of a high-anxious test taker compared to a low-anxious test taker is largely due to the difference in their ability to focus on the tasks required.[25] A low-anxious test taker is able to focus greater attention on the tasks required of them while taking the test, while a high-anxious test taker is focused on their internal self, and the anxiety they are feeling. Anxious test takers do not perform adequately on the test as their attention is divided between themselves and the test. Therefore, students with high test anxiety are unable to focus their full attention on the test. Furthermore, anxiousness is evoked when a student believes that the evaluative situation, such as an assessment, exceeds his or her intellectual, motivational, and social capabilities.[14]
Psychologists Liebert and Morris (1967) originally attributed test anxiety to two main components: worry and emotionality.[26] Worry refers to cognitive factors, such as negative expectations or feelings of inadequacy, and emotionality refers to the physical symptoms, such as increased heart rate, muscle tension, or butterflies.[26] Both are aversive elements that can create anxiety, but it is the cognitive factors that have the strongest connection to performance.[27]
Researchers Putwain, Woods & Symes (2010), found that a low academic self-concept was associated with higher worry and tension about their abilities to do well on a test. A student's metacognitive beliefs play an important role in the maintenance of negative self-beliefs.[14]
Anxiety reactions can be generalized from previous experiences to testing situations.[28] Feelings of inadequacy, helplessness, anticipations of punishment or loss of status and esteem manifest anxiety responses. As well, the presence of an audience can debilitate the performance of high anxious test takers and increase the performance of low anxious test takers. Interestingly, persons who score high on anxiety scales tend to describe themselves in negative, self-devaluing terms. Highly anxious test takers also blame themselves for their failure significantly more than low anxious test takers.
### Attentional Theories
There are two main groups of attentional theories that attempt to explain compromised performance in pressured situations.[29]
- One group of theories are the explicit monitoring theories. They state that when a person is expected to perform a specific skill, the pressure may cause an increased self-consciousness and inward focus, which can disrupt their ability to successfully perform that task.[30] Thinking about step-by-step procedures can inhibit one’s ability to execute a task.[29] For example, a study by R. Gray found that baseball players put into the high-pressure condition had increased errors, and an increased ability to recall details like the direction their bat was moving. This indicates that the pressured players were monitoring themselves more, which impacted their ability to successfully hit the ball.[29]
- A second group of theories are the distraction theories. These theories states that high-pressure environments create a dual-task situation, in which the person’s attention is divided between the task at hand and unhelpful thoughts about the situation and possible negative consequences of poor performance.[30]
Attention is an important part of working memory,[30] which is the system that actively holds several pieces of relevant information in the mind while inhibiting irrelevant information.[30] Working memory has a limited capacity, and the addition of stress and anxiety reduces the resources available to focus on relevant information.[31]
- In situations in which individuals need to concentrate their attention on a specific task, emotional stimuli can divert their attention to a greater degree than non-emotional stimuli.[32] Emotional stimuli will often dominate a person’s thoughts, and any attempt to suppress them will require additional working memory resources.[31] When working memory divides resources between the aversive cognitions and the task-relevant material, then the person’s ability to use the relevant information on a test will suffer.[33]People who suffer from test anxiety are more likely to experience negative cognitions while in evaluative situations. Furthermore, test anxious persons have been found to bias their attention towards threatening and anxiety related stimuli more than nonemotional stimuli.[34]Research has accordingly found that tasks that rely heavily on working memory are the ones that suffer the most during pressure.[30] Shortfalls in performance that are caused by test anxiety seem to be related to the extent to which the student has full access to their working memory.[35]
- When comparing these two theories in the context of academic performance, a majority of work supports distraction theories.[30] One reason for this is that many of the skills performed in the classroom require heavy demands on working memory.[30] However, there are different kinds of pressure situations. There is monitoring pressure, in which an individual’s performance is impacted due to the presence of an audience, and outcome pressure, in which an individual’s performance is influenced by the consequences of the testing results.[29] In a study, DeCaro et al. found that performance on a rule-based task, that relies heavily on working memory, was impaired by outcome pressure, but not monitoring pressure, whereas performance on an information-integration task, which does not require attentional control, was hurt by monitoring pressure, but not outcome pressure.[29] These findings indicate that performance is compromised in different ways depending on the type of task, and the types of pressure, and that both theories can be correct.[29]
### Attentional Control
Eysenck et al.[36] elaborate upon the distraction theories and propose the attentional control theory.[37] This theory uses Baddeley's model of working memory to explain the effects of anxiety on working memory and on performance.[38] In Baddeley's theory, working memory (WM) consists of four components, one of them the central executive that has a number of tasks such as coordination of the temporary stores of phonological and visual information (phonological loop and visuospatial sketchpad, respectively).[39]
The attentional control theory assumes that anxiety primarily affects attentional control, which is a key function of the central executive.[38] Attentional control is the balance between the two attentional systems, the goal-directed system, influenced by the individual's goals, and the stimulus-driven system, influenced by salient stimuli.[38] According to the attentional control theory, anxiety disrupts the balance between these two systems. The stimulus-driven system becomes stronger at the expense of the goal-directed systsem, thereby impairing the efficiency of the inhibition and shifting functions of the central executive.[38]
In support of this theory, there is strong evidence that anxiety largely impairs processing efficiency rather than performance effectiveness.[38] Performance effectiveness refers to the quality of performance whereas processing efficiency refers to the amount of resources used to attain an effective performance.[38] There is also evidence that anxiety impairs both the inhibition and the shifting function.[38] Therefore, this theory suggests that students high in test anxiety will have to allocate more resources to the task at hand than non-test anxiety students in order to achieve the same results.[33]
In general, people with higher working memory capacity do better on academic tasks, but this changes when people are under pressure.[30] Beilock et al. found that pressure led individuals with a high working memory capacity to perform worse on a complicated task, whereas individuals with a low WM capacity got the same low results with or without pressure. This was because people with high WM could use more better but more demanding problem solving strategies in the low pressure condition, which they had to abandon in the high pressure condition. The low WM people never used these demanding strategies in the first place.[30] Evidence contrary to Beilock's results comes from Johnson et al. who found individuals' performances on a task showed a decrease in accuracy due to anxiety for individuals with low or average WM capacity, but did not significantly decrease for individuals with high WM.[40]
# Measurement Scales
Early scales, by authors such as Charles Spielberger, tended to focus on physiological and somatic features and on worry, commonly referred to as emotionality,[41] while more recent offerings, such as that by Cassady & Johnson, emphasize cognitive processes.[7] "Test anxiety" for these authors consists of physiological and mental processes, and impaired test performance is seen as the result.
The "Children's Test Anxiety Questionnaire" is specifically designed to measure test anxiety in children 8–12 years of age. It provides scores for three dimensions of test anxiety: "worrisome thoughts concerning failure (i.e. 'when I take tests, I worry about failing'), automatic reactions concerning students' general and specific somatic indications of anxiety (i.e. 'when I take tests, my heart beats fast'), and off-task behaviours concerning nervous habits and distracting behaviours (i.e. 'when I take tests, I play with my pencil')" [42]
# Accommodations
Test anxiety prevents students from demonstrating their knowledge on examinations. To be covered by the Americans with Disabilities Act, test anxiety must pass two legal tests. First, it must be a "mental impairment." As a form of Social Phobia, a mental disorder included in the Diagnostic and Statistical Manual of Mental Disorders, it meets this first test. Second, it must "substantially limit one or more of the major life activities." Individuals for whom test anxiety is one manifestation of Social Phobia-Generalized are substantially limited in the major life activities of interacting with others and working. Individuals for whom test anxiety is the only manifestation of their Social Phobia are substantially limited in the major life activities of thinking and working, the latter because they are excluded from any career requiring a test for application, credentialing, licensure, or training. Accommodations may include taking the test in a separate room or taking an untimed examination. Documentation supporting a diagnosis of test anxiety should include evidence of significant impairment in test performance.
# Management
To gain an accurate assessment of student comprehension, instructors should be concerned with minimizing the effects of test anxiety. Instructors might offer "second chances" post test, familiarize students with test format and grading scheme, and lower the impact of any one test.[43] If students have greater confidence in their test-taking skills, they are more likely to be comfortable and relaxed when the testing does occur. Having an intentional thinking strategy should help student performance improve.[citation needed]
For some individuals, poor academic performance is due to skill deficits, which could include problems in encoding (learning),rehearsal (study skills) or retrieval during a test (test-taking strategies).[44]Skill deficits may lead to poor performance directly (failure to adequately learn the material) or indirectly (awareness of being ill-prepared causes anxiety that, in turn, leads to poor performance). Therefore, the most effective interventions are those that combine skill-focused strategies (i.e. study skills training, test-taking skills) with cognitive (i.e. cognitive restructuring) or behavioural approaches (i.e. relaxation training, systematic desensitization).[45]
Research suggests that students do not gain as much from reading self-help material as students would from the same material received in therapy or in a participatory group setting.[46]
# Treatment
Medication will not cure anxiety disorders but will keep them under control.[citation needed] Drug treatments for anxiety disorders work by downplaying threat detecting mechanisms in the body.[13]
- Beta blockers — commonly used to treat performance anxiety. Propranolol (a beta blocker) blocks the physical manifestations of anxiety. It slows heart rate and reduces sweating. It is not to be taken on the first day of a test, as some people are shown to have adverse side effects which include, but are not limited to, lightheadedness and a very slow heart beat.[citation needed]
- Benzodiazepines — commonly used to treat test anxiety.[citation needed] Should be taken up to 30 minutes before the start of the test. Side effects include, but are not limited to, sleepiness and can impair memory and thought.[citation needed]
- Antidepressants — commonly used for general depression, which can accompany test anxiety. Side effects include, but are not limited to, the potential to cause agitation and suicidal thoughts. These need to be taken on a regular basis not when needed before an exam.[citation needed]
Another approach is the use of psychotherapy. Cognitive Behavioral Therapy (CBT) is very useful in treating anxiety disorders. CBT helps to change the pattern of thinking that support the fear and help the sufferer overcome the negative beliefs.[47] CBT often lasts about two weeks and takes place in small groups.[citation needed]
Medication combined with psychotherapy has shown to be the most effective treatment approach for people suffering from anxiety disorders.[citation needed]
Cognitive interventions have only had limited results when it comes to improving test performance.[33] Some cognitive strategies have even been shown to be detrimental to performance, particularly strategies such as thought suppression.[33]One intervention that had promising results in a first study is "attentional cognitive bias modification" in which children learning to avoid paying attention to a threatening face.[48] | https://www.wikidoc.org/index.php/Test_anxiety | |
6c3abe1b7fa350bf2802cd5bb3c9212390ee5739 | wikidoc | Tetrahedrane | Tetrahedrane
Tetrahedrane is a hypothetical hydrocarbon with chemical formula Template:Carbon4Template:Hydrogen4 and a tetrahedral structure. Extreme angle strain (carbon bond angles deviate considerably from the tetrahedral bond angle of 109.5°) prevents this molecule from existing.
In 1978 Günther Maier prepared a stable tetrahedrane with 4 tert-butyl substituents. These substituents are very bulky and completely envelop the tetrahedrane core. Bonds in the core are prevented from breaking because this would force the substituents closer together (corset effect) resulting in Van der Waals strain.
Tetrahedrane is one of the possible platonic hydrocarbons.
The IUPAC name of tetrahedrane is tricyclobutane.
In Tetra(trimethylsilyl)tetrahedrane (I) the tert-butyl groups have been replaced by trimethylsilyl groups. Remarkably this compound is far more stable than the tert-butyl analogue. The silicon to carbon bond is longer than a carbon carbon bond and therefore the corset effect is reduced. On the other hand the trimethylsilyl group is a sigma donor which explains the increased stabilization of the tetrahedrane. Whereas the tert-butyl tetrahedrane melts at 135 °C at which temperature decomposition to the cyclobutadiene starts, the trimethyl silyl tetrahedrane melts at a much higher temperature of 202 °C and is even stable up to 300 °C and this compound reverts back to the acetylene starting material.
The tetrahedrane skeleton is made up of banana bonds and hence the carbon atoms are high in s-orbital character. From NMR, sp hybridization can be deduced, normally reserved for triple bonds. As a consequence the bond lengths are unusually short with 1.52 angstroms (152 picometers). The latest development is the organic synthesis and characterization of the tetrahedrane dimer (II). The connecting bond is even shorter with 1.436 Å (143.6 pm). An ordinary carbon carbon bond has a length of 1.54 Å (154 pm).
In tetrasilatetrahedrane the carbon atoms in the tetrahedrane cage are replaced by silicon. The standard silicon silicon bond is much longer (235 pm) and the cage is again enveloped by a total of 16 trimethylsilyl groups. This makes the compound thermally stable. The silatetrahedrane can be reduced with potassium graphite to the tetrasilatetrahedranide potassium salt. In this compound one of the silicon atoms of the cage has lost a silyl substituent and carries a negative charge. The potassium cation can be captured by a crown ether and in the resulting complex potassium and the silyl anion are separated by a distance if 885 picometer. One of the Si- - Si bonds is now 272 picometer and its silicon atom has an inverted tetrahedral geometry. Furthermore the four cage silicon atoms are equivalent on the NMR timescale due to migrations of the silyl substituents over the cage.
The dimerization reaction observed for the carbon tetrahedrane compound is also attempted for a tetrasilatetrahedrane. In this tetrahedrane the cage is protected by 4 so-called super silyl groups in which a silicon atom has 4 tert-butyl substituents. The dimer does not materialize but a reaction with iodine in benzene followed by reaction with the tri-tert-butyl sila anion results in the formation of an eight membered silicon cluster compound which can be described as a Si2 dumbbell (length 229 picometer and with inversion of tetrahedral geometry) sandwiched between two almost parallel Si3 rings.
In known eight-membered clusters of in the same carbon group, tin Sn8R6 and germanium Ge8R6 the cluster atoms are located on the corners of a cube. | Tetrahedrane
Tetrahedrane is a hypothetical hydrocarbon with chemical formula Template:Carbon4Template:Hydrogen4 and a tetrahedral structure. Extreme angle strain (carbon bond angles deviate considerably from the tetrahedral bond angle of 109.5°) prevents this molecule from existing.
In 1978 Günther Maier prepared a stable tetrahedrane with 4 tert-butyl substituents.[1] These substituents are very bulky and completely envelop the tetrahedrane core. Bonds in the core are prevented from breaking because this would force the substituents closer together (corset effect) resulting in Van der Waals strain.
Tetrahedrane is one of the possible platonic hydrocarbons.
The IUPAC name of tetrahedrane is tricyclo[1.1.0.02,4]butane.
In Tetra(trimethylsilyl)tetrahedrane (I) the tert-butyl groups have been replaced by trimethylsilyl groups.[2] Remarkably this compound is far more stable than the tert-butyl analogue. The silicon to carbon bond is longer than a carbon carbon bond and therefore the corset effect is reduced. On the other hand the trimethylsilyl group is a sigma donor which explains the increased stabilization of the tetrahedrane. Whereas the tert-butyl tetrahedrane melts at 135 °C at which temperature decomposition to the cyclobutadiene starts, the trimethyl silyl tetrahedrane melts at a much higher temperature of 202 °C and is even stable up to 300 °C and this compound reverts back to the acetylene starting material.
The tetrahedrane skeleton is made up of banana bonds and hence the carbon atoms are high in s-orbital character. From NMR, sp hybridization can be deduced, normally reserved for triple bonds. As a consequence the bond lengths are unusually short with 1.52 angstroms (152 picometers). The latest development is the organic synthesis and characterization of the tetrahedrane dimer (II). The connecting bond is even shorter with 1.436 Å (143.6 pm). An ordinary carbon carbon bond has a length of 1.54 Å (154 pm).
In tetrasilatetrahedrane the carbon atoms in the tetrahedrane cage are replaced by silicon. The standard silicon silicon bond is much longer (235 pm) and the cage is again enveloped by a total of 16 trimethylsilyl groups. This makes the compound thermally stable. The silatetrahedrane can be reduced with potassium graphite to the tetrasilatetrahedranide potassium salt. In this compound one of the silicon atoms of the cage has lost a silyl substituent and carries a negative charge. The potassium cation can be captured by a crown ether and in the resulting complex potassium and the silyl anion are separated by a distance if 885 picometer. One of the Si- - Si bonds is now 272 picometer and its silicon atom has an inverted tetrahedral geometry. Furthermore the four cage silicon atoms are equivalent on the NMR timescale due to migrations of the silyl substituents over the cage.[3]
The dimerization reaction observed for the carbon tetrahedrane compound is also attempted for a tetrasilatetrahedrane.[4] In this tetrahedrane the cage is protected by 4 so-called super silyl groups in which a silicon atom has 4 tert-butyl substituents. The dimer does not materialize but a reaction with iodine in benzene followed by reaction with the tri-tert-butyl sila anion results in the formation of an eight membered silicon cluster compound which can be described as a Si2 dumbbell (length 229 picometer and with inversion of tetrahedral geometry) sandwiched between two almost parallel Si3 rings.
In known eight-membered clusters of in the same carbon group, tin Sn8R6 and germanium Ge8R6 the cluster atoms are located on the corners of a cube. | https://www.wikidoc.org/index.php/Tetrahedrane | |
5afe0e2706e1f1b500cdd4fd9879891ea464541c | wikidoc | Tetrodotoxin | Tetrodotoxin
Tetrodotoxin (anhydrotetrodotoxin 4-epitetrodotoxin, tetrodonic acid, TTX) is a potent neurotoxin with no known antidote, which blocks action potentials in nerves by binding to the pores of the voltage-gated, fast sodium channels in nerve cell membranes. The binding site of this toxin is located at the pore opening of the voltage-gated Na+ channel. Its name derives from Tetraodontiformes, the name of the order that includes the pufferfish, porcupinefish, ocean sunfish or mola, and triggerfish, several species of which carry the toxin. Although tetrodotoxin was discovered in these fish and found in several other animals, it is actually the product of certain bacteria such as Pseudoalteromonas tetraodonis, certain species of Pseudomonas and Vibrio, as well as some others.
Its mechanism was discovered in the early 1960s by Toshio Narahashi working at Duke University
# Tetrodotoxin sources in nature
Tetrodotoxin has also been isolated from widely differing animal species, including western newts of the genus Taricha (where it was termed "tarichatoxin"), parrotfish, toads of the genus Atelopus, several species of blue-ringed octopodes of the genus Hapalochlaena (where it was called "maculotoxin"), several starfish, an angelfish, a polyclad flatworm, several species of Chaetognatha (arrow worms), several nemerteans (ribbonworms) and several species of xanthid crabs. The toxin is variously used as a defensive biotoxin to ward off predation, or as both a defensive and predatory venom (the octopodes, chaetognaths and ribbonworms). Tarichatoxin and maculotoxin were shown to be identical to tetrodotoxin in 1964 and 1978, respectively. Recent evidence has shown the toxin to be produced by bacteria within blue-ringed octopodes
, and it is believed that pufferfish acquire the toxin through their diet. Evidence for the source of the toxin in other sources has not yet been determined. The most common source of bacteria associated with TTX production are 'Vibrio' bacteria, with Vibrio alginolyticus being the most common species. TTX has been found in nemerteans, Phylum nemertea, (sometimes called Ribbon worms), and both pufferfish and nemerteans have been shown to contain Vibrio alginolyticus and TTX.
# Biochemistry
Tetrodotoxin binds to what is known as site 1 of the fast voltage-gated sodium channel. Site 1 is located at the extracellular pore opening of the ion channel. The binding of any molecules to this site will temporarily disable the function of the ion channel. Saxitoxin and several of the conotoxins also bind the same site.
The use of this toxin as a biochemical probe has elucidated two distinct types of voltage-gated sodium channels present in humans: the tetrodotoxin-sensitive voltage-gated sodium channel (TTX-s Na+ channel) and the tetrodotoxin-resistant voltage-gated sodium channel (TTX-r Na+ channel). Tetrodotoxin binds to TTX-s Na+ channels with a binding affinity of 5-15 nanomolar, while the TTX-r Na+ channels bind TTX with low micromolar affinity. Nerve cells containing TTX-r Na+ channels are located primarily in cardiac tissue, while nerve cells containing TTX-s Na+ channels dominate the rest of the body. The prevalence of TTX-s Na+ channels in the central nervous system makes tetrodotoxin a valuable agent for the silencing of neural activity within a cell culture.
## Physiology
The toxin blocks the fast Na+ current in human myocytes (the contractile cells of the muscles), thereby inhibiting their contraction. By contrast, the sodium channels in pacemaker cells of the heart are of the slow variety, so action potentials in the cardiac nodes are not inhibited by the compound. The poisoned individual therefore dies not because the electrical activity of the heart is compromised, but because the diaphragm is effectively paralyzed and breathing ceases.
Blocking of fast Na+ channels has medicinal use in treating some cardiac arrhythmias. Tetrodotoxin has also proved useful in the treatment of pain (originally used in Japan in the 1930's) from such diverse problems as terminal cancer, migraines, & heroin withdrawal.
## Total synthesis
Y. Kishi et al Nagoya University, Nagoya, Japan, (now at Harvard University) reported the first total synthesis of D,L-tetrodotoxin in 1972. M. Isobe et al at Nagoya University, Japan and J. Du Bois et al at Stanford University, USA, reported the asymmetric total synthesis of tetrodotoxin in 2003. The two 2003 syntheses used very different strategies, with Isobe's route based on a Diels-Alder approach and Du Bois's work using C-H bond activation.
# Tetrodotoxin poisoning
Fish poisoning by consumption of members of the order Tetraodontiformes is extremely serious. The skin and organs of the pufferfish can contain levels of tetrodotoxin sufficient to produce paralysis of the diaphragm and death due to respiratory failure. Toxicity varies between species and at different seasons and geographic localities, and the flesh of many pufferfish may not usually be dangerously toxic.
## History
The first recorded cases of tetrodotoxin poisoning were from the logs of Captain James Cook. He recorded his crew eating some local tropic fish (pufferfish), then feeding the remains to the pigs kept on board. The crew experienced numbness and shortness of breath, while the pigs were all found dead the next morning. In hindsight, it is clear that the crew received a mild dose of tetrodotoxin, while the pigs ate the pufferfish body parts that contain most of the toxin, thus killing them.
The toxin was first isolated and named in 1909 by Japanese scientist Dr. Yoshizumi Tahara.
## Symptoms and diagnosis
The diagnosis of pufferfish poisoning is based on the observed symptomology and recent dietary history.
Symptoms typically develop within 30 min of ingestion but may be delayed by up to 4 h. Death has occurred within 17 min of ingestion. Paresthesias of the lips and tongue are followed by sialorrhea, sweating, headache, weakness, lethargy, ataxia, incoordination, tremor, paralysis, cyanosis, aphonia, dysphagia, seizures, dyspnea, bronchorrhea, bronchospasm, respiratory failure, coma, and hypotension. Gastroenteric symptoms are often severe and include nausea, vomiting, diarrhea,
and abdominal pain. Cardiac arrhythmias may precede complete respiratory failure and cardiovascular collapse.
### Differential Diagnosis
## Treatment
Therapy is supportive and based on symptoms, with aggressive early airway management. Alpha adrenergic agonists are recommended in addition to intravenous fluids to combat hypotension. Anticholinesterase agents have been used with mixed success. Nothing equivalent to an antivenom has been developed--presumably because the toxin acts quickly and binds with an affinity that is not easily overcome.
## Course of tetrodotoxin poisoning and complications
The first symptom of intoxication is a slight numbness of the lips and tongue, appearing between 20 minutes to three hours after eating poisonous pufferfish. The next symptom is increasing paresthesia in the face and extremities, which may be followed by sensations of lightness or floating. Headache, epigastric pain, nausea, diarrhea, and/or vomiting may occur. Occasionally, some reeling or difficulty in walking may occur. The second stage of the intoxication is increasing paralysis. Many victims are unable to move; even sitting may be difficult. There is increasing respiratory distress. Speech is affected, and the victim usually exhibits dyspnea, cyanosis, and hypotension. Paralysis increases and convulsions, mental impairment, and cardiac arrhythmia may occur. The victim, although completely paralyzed, may be conscious and in some cases completely lucid until shortly before death. Death usually occurs within 4 to 6 hours, with a known range of about 20 minutes to 8 hours.
# Geographic frequency of tetrodotoxin toxicity
Poisonings from tetrodotoxin have been almost exclusively associated with the consumption of pufferfish from waters of the Indo-Pacific ocean regions. Several reported cases of poisonings, including fatalities, involved pufferfish from the Atlantic Ocean, Gulf of Mexico, and Gulf of California. There have been no confirmed cases of tetrodotoxicity from the Atlantic pufferfish, Sphoeroides maculatus. However, in three studies, extracts from fish of this species were highly toxic in mice. Several recent intoxications from these fishes in Florida were due to saxitoxin, which causes paralytic shellfish poisoning with very similar symptoms and signs. The trumpet shell Charonia sauliae has been implicated in food poisonings, and evidence suggests that it contains a tetrodotoxin derivative. There have been several reported poisonings from mislabelled pufferfish and at least one report of a fatal episode in Oregon when an individual swallowed a Rough-skinned Newt, Taricha granulosa.
## Relative frequency of tetrodotoxin ingestive poisonings
From 1974 through 1983 there were 646 reported cases of pufferfish poisoning in Japan, with 179 fatalities. Estimates as high as 200 cases per year with mortality approaching 50% have been reported. Only a few cases have been reported in the United States, and outbreaks in countries outside the Indo-Pacific area are rare, except in Haiti, where Tetrodotoxin plays a key role in the creation of so called zombie poisons.
## Target populations
Genetic background is not a factor in susceptibility to tetrodotoxin poisoning. This toxicosis may be avoided by not consuming animal species known to contain tetrodotoxin, principally pufferfish; other tetrodotoxic species are not usually consumed by humans. Poisoning from tetrodotoxin is of particular public health concern in Japan, where pufferfish, "fugu", is a traditional delicacy. It is prepared and sold in special restaurants where trained and licensed chefs carefully remove the viscera to reduce the danger of poisoning. There is potential for misidentification and mislabelling, particularly of prepared, frozen fish products.
## Food analysis
The mouse bioassay developed for paralytic shellfish poisoning (PSP) can be used to monitor tetrodotoxin in pufferfish and is the current method of choice. An HPLC method with post-column reaction with alkali and fluorescence has been developed to determine tetrodotoxin and its associated toxins. The alkali degradation products can be confirmed as their trimethylsilyl derivatives by gas chromatography/mass spectrometry. These chromatographic methods have not yet been validated. | Tetrodotoxin
Template:Chembox new
Tetrodotoxin (anhydrotetrodotoxin 4-epitetrodotoxin, tetrodonic acid, TTX) is a potent neurotoxin with no known antidote, which blocks action potentials in nerves by binding to the pores of the voltage-gated, fast sodium channels in nerve cell membranes. The binding site of this toxin is located at the pore opening of the voltage-gated Na+ channel. Its name derives from Tetraodontiformes, the name of the order that includes the pufferfish, porcupinefish, ocean sunfish or mola, and triggerfish, several species of which carry the toxin. Although tetrodotoxin was discovered in these fish and found in several other animals, it is actually the product of certain bacteria such as Pseudoalteromonas tetraodonis, certain species of Pseudomonas and Vibrio, as well as some others.
Its mechanism was discovered in the early 1960s by Toshio Narahashi working at Duke University
# Tetrodotoxin sources in nature
Tetrodotoxin has also been isolated from widely differing animal species, including western newts of the genus Taricha (where it was termed "tarichatoxin"), parrotfish, toads of the genus Atelopus, several species of blue-ringed octopodes of the genus Hapalochlaena (where it was called "maculotoxin"), several starfish, an angelfish, a polyclad flatworm, several species of Chaetognatha (arrow worms), several nemerteans (ribbonworms) and several species of xanthid crabs. The toxin is variously used as a defensive biotoxin to ward off predation, or as both a defensive and predatory venom (the octopodes, chaetognaths and ribbonworms). Tarichatoxin and maculotoxin were shown to be identical to tetrodotoxin in 1964 and 1978, respectively. Recent evidence has shown the toxin to be produced by bacteria within blue-ringed octopodes
[1], and it is believed that pufferfish acquire the toxin through their diet. Evidence for the source of the toxin in other sources has not yet been determined[citation needed]. The most common source of bacteria associated with TTX production are 'Vibrio' bacteria, with Vibrio alginolyticus being the most common species. TTX has been found in nemerteans, Phylum nemertea, (sometimes called Ribbon worms), and both pufferfish and nemerteans have been shown to contain Vibrio alginolyticus and TTX.
# Biochemistry
Tetrodotoxin binds to what is known as site 1 of the fast voltage-gated sodium channel. Site 1 is located at the extracellular pore opening of the ion channel. The binding of any molecules to this site will temporarily disable the function of the ion channel. Saxitoxin and several of the conotoxins also bind the same site.
The use of this toxin as a biochemical probe has elucidated two distinct types of voltage-gated sodium channels present in humans: the tetrodotoxin-sensitive voltage-gated sodium channel (TTX-s Na+ channel) and the tetrodotoxin-resistant voltage-gated sodium channel (TTX-r Na+ channel). Tetrodotoxin binds to TTX-s Na+ channels with a binding affinity of 5-15 nanomolar, while the TTX-r Na+ channels bind TTX with low micromolar affinity. Nerve cells containing TTX-r Na+ channels are located primarily in cardiac tissue, while nerve cells containing TTX-s Na+ channels dominate the rest of the body. The prevalence of TTX-s Na+ channels in the central nervous system makes tetrodotoxin a valuable agent for the silencing of neural activity within a cell culture.
## Physiology
The toxin blocks the fast Na+ current in human myocytes (the contractile cells of the muscles), thereby inhibiting their contraction. By contrast, the sodium channels in pacemaker cells of the heart are of the slow variety, so action potentials in the cardiac nodes are not inhibited by the compound. The poisoned individual therefore dies not because the electrical activity of the heart is compromised, but because the diaphragm is effectively paralyzed and breathing ceases.
Blocking of fast Na+ channels has medicinal use in treating some cardiac arrhythmias. Tetrodotoxin has also proved useful in the treatment of pain (originally used in Japan in the 1930's) from such diverse problems as terminal cancer, migraines, & heroin withdrawal.
## Total synthesis
Y. Kishi et al Nagoya University, Nagoya, Japan, (now at Harvard University) reported the first total synthesis of D,L-tetrodotoxin in 1972.[2] M. Isobe et al at Nagoya University, Japan and J. Du Bois et al at Stanford University, USA, reported the asymmetric total synthesis of tetrodotoxin in 2003.[3][4] The two 2003 syntheses used very different strategies, with Isobe's route based on a Diels-Alder approach and Du Bois's work using C-H bond activation.
# Tetrodotoxin poisoning
Fish poisoning by consumption of members of the order Tetraodontiformes is extremely serious. The skin and organs of the pufferfish can contain levels of tetrodotoxin sufficient to produce paralysis of the diaphragm and death due to respiratory failure. Toxicity varies between species and at different seasons and geographic localities, and the flesh of many pufferfish may not usually be dangerously toxic.
## History
The first recorded cases of tetrodotoxin poisoning were from the logs of Captain James Cook. He recorded his crew eating some local tropic fish (pufferfish), then feeding the remains to the pigs kept on board. The crew experienced numbness and shortness of breath, while the pigs were all found dead the next morning. In hindsight, it is clear that the crew received a mild dose of tetrodotoxin, while the pigs ate the pufferfish body parts that contain most of the toxin, thus killing them.
The toxin was first isolated and named in 1909 by Japanese scientist Dr. Yoshizumi Tahara.
## Symptoms and diagnosis
The diagnosis of pufferfish poisoning is based on the observed symptomology and recent dietary history.
Symptoms typically develop within 30 min of ingestion but may be delayed by up to 4 h. Death has occurred within 17 min of ingestion. Paresthesias of the lips and tongue are followed by sialorrhea, sweating, headache, weakness, lethargy, ataxia, incoordination, tremor, paralysis, cyanosis, aphonia, dysphagia, seizures, dyspnea, bronchorrhea, bronchospasm, respiratory failure, coma, and hypotension. Gastroenteric symptoms are often severe and include nausea, vomiting, diarrhea,
and abdominal pain. Cardiac arrhythmias may precede complete respiratory failure and cardiovascular collapse.
### Differential Diagnosis
## Treatment
Therapy is supportive and based on symptoms, with aggressive early airway management. Alpha adrenergic agonists are recommended in addition to intravenous fluids to combat hypotension. Anticholinesterase agents have been used with mixed success. Nothing equivalent to an antivenom has been developed--presumably because the toxin acts quickly and binds with an affinity that is not easily overcome.
## Course of tetrodotoxin poisoning and complications
The first symptom of intoxication is a slight numbness of the lips and tongue, appearing between 20 minutes to three hours after eating poisonous pufferfish. The next symptom is increasing paresthesia in the face and extremities, which may be followed by sensations of lightness or floating. Headache, epigastric pain, nausea, diarrhea, and/or vomiting may occur. Occasionally, some reeling or difficulty in walking may occur. The second stage of the intoxication is increasing paralysis. Many victims are unable to move; even sitting may be difficult. There is increasing respiratory distress. Speech is affected, and the victim usually exhibits dyspnea, cyanosis, and hypotension. Paralysis increases and convulsions, mental impairment, and cardiac arrhythmia may occur. The victim, although completely paralyzed, may be conscious and in some cases completely lucid until shortly before death. Death usually occurs within 4 to 6 hours, with a known range of about 20 minutes to 8 hours.
# Geographic frequency of tetrodotoxin toxicity
Poisonings from tetrodotoxin have been almost exclusively associated with the consumption of pufferfish from waters of the Indo-Pacific ocean regions. Several reported cases of poisonings, including fatalities, involved pufferfish from the Atlantic Ocean, Gulf of Mexico, and Gulf of California. There have been no confirmed cases of tetrodotoxicity from the Atlantic pufferfish, Sphoeroides maculatus. However, in three studies, extracts from fish of this species were highly toxic in mice. Several recent intoxications from these fishes in Florida were due to saxitoxin, which causes paralytic shellfish poisoning with very similar symptoms and signs. The trumpet shell Charonia sauliae has been implicated in food poisonings, and evidence suggests that it contains a tetrodotoxin derivative. There have been several reported poisonings from mislabelled pufferfish and at least one report of a fatal episode in Oregon when an individual swallowed a Rough-skinned Newt, Taricha granulosa.
## Relative frequency of tetrodotoxin ingestive poisonings
From 1974 through 1983 there were 646 reported cases of pufferfish poisoning in Japan, with 179 fatalities. Estimates as high as 200 cases per year with mortality approaching 50% have been reported. Only a few cases have been reported in the United States, and outbreaks in countries outside the Indo-Pacific area are rare, except in Haiti, where Tetrodotoxin plays a key role in the creation of so called zombie poisons.
## Target populations
Genetic background is not a factor in susceptibility to tetrodotoxin poisoning. This toxicosis may be avoided by not consuming animal species known to contain tetrodotoxin, principally pufferfish; other tetrodotoxic species are not usually consumed by humans. Poisoning from tetrodotoxin is of particular public health concern in Japan, where pufferfish, "fugu", is a traditional delicacy. It is prepared and sold in special restaurants where trained and licensed chefs carefully remove the viscera to reduce the danger of poisoning. There is potential for misidentification and mislabelling, particularly of prepared, frozen fish products.
## Food analysis
The mouse bioassay developed for paralytic shellfish poisoning (PSP) can be used to monitor tetrodotoxin in pufferfish and is the current method of choice. An HPLC method with post-column reaction with alkali and fluorescence has been developed to determine tetrodotoxin and its associated toxins. The alkali degradation products can be confirmed as their trimethylsilyl derivatives by gas chromatography/mass spectrometry. These chromatographic methods have not yet been validated. | https://www.wikidoc.org/index.php/Tetrodotoxin | |
ea8c2a488602dc1ea0c24603199549263f5b12e8 | wikidoc | Thai massage | Thai massage
Thai massage is a type of massage in Thai style that involves stretching and deep massage. It is known in Thailand as "nuat phaen boran" (Thai: นวดแผนโบราณ, IPA: Template:IPA), literally, the ancient-manner massage; or just "nuat phaen thai" (นวดแผนไทย).
# Other Translations
"Nuat phaen boran" is the Thai name for a type of body work native to Thailand (nuat=massage, phaen=manner, boran=ancient). Thai massage is also known as northern-style Thai massage, Buntautuk style, Old Medicine Hospital Style, traditional Thai massage, Traditional Thai Medical Massage, Thai Yoga, Thai Yoga Massage, yoga massage, Thai classical massage, Thai bodywork, passive yoga, or assisted yoga.
# Description
Although, Thai Ayurveda and traditional medicine originates in Tibet, China and in India, nuat phaen boran is primarily local to the northern Chiangmai area. Virtually every practitioner using this term is either trained in Chiangmai or trained with someone who was. The original and oldest running school for Nuat Boran is "The Old Medicine School" or Shivago Komarpai School and Buntautuk Hospital Massage Program. This program was a popular site for tourists learning massage in Chiangmai primarily beginning in the late 80's and 90's. The founder was the famous Grand Master of Traditional Thai Ayurvedic Medicine, Aachan Sintorn Chaichgun. Aacharn Sintorn presided over daily classes for over 30 years until his death in 2005. His family and elder sons Suthat and Wasson carry on to the present day. Aacharn Sintorn was a product of the Wat Po System in the 50's. The Old Medicine school was a pioneer in teaching non-Thais a short form and ten-day program called "Nuad Boran" which was easy for the non-Thai speakers to learn. The course was primarily technique with little acknowledgement to theory, as a result of the language difficulty. Unfortunately, many non-Thai obtained the mistaken impression that the 10-day program was the sum total of traditional Thai Medicine. However, the hands-on portion for traditional expert or doctor of massage is about two years full time. However, the basic form of Nuad Boran can be said to be representitive and a fair introduction to the hands on healing as a distinctive modality.
There are as many as 7 to 10 regional variations of Thai massage. Many of these traditions claim exclusivity and compete with the others for students and notoriety, although today the Royal Thai Gov't is seeking to establish parity and common standards between all of the various schools.
The receiver is put into yoga-like positions during the course of the massage. In the northern style there are a lot of stretching movements whereas the southern style emphasis is given to acupressure. It was believed that the massage art was brought over to Thailand by Jivaka Kumar Baccha, known in Thailand as Dr Shivago, a contemporary of Buddha some 2500 years ago.
The massage recipient changes into pajamas and lies on a mat or firm mattress on the floor. (It can be done solo or in a group of a dozen or so patients in the same large room.) The massage giver leans on the recipient's body using hands and forearms to apply firm rhythmic pressure to almost every part of the receiver's body. The massage generally follows the Sen Energy lines on the body (the Sen are comparable to Chinese meridians). In some gestures, the legs and feet of the giver are used to fixate the body or limbs of the recipient. In other gestures, hands fixate the body, while the feet do the massaging action. Usually no oil is applied, but sometimes a hot herbal compress is used to warm and sooth the receiver's body. A full course of Thai massage typically lasts two hours or more, and includes pulling fingers, toes, ears etc., cracking the knuckles, walking on the recipient's back, arching the recipient's back in a rolling action etc. There is a standard procedure and rhythm to the massage. Sometimes in a large group massage, the practitioners do the procedures in unison.
A full massage in Thailand of typically two hours costs around 300-500 Thai Baht (8.5-14 USD in 2007) depending on location (it may cost 5 times more in a five star hotel). | Thai massage
Thai massage is a type of massage in Thai style that involves stretching and deep massage. It is known in Thailand as "nuat phaen boran" (Thai: นวดแผนโบราณ, IPA: Template:IPA), literally, the ancient-manner massage; or just "nuat phaen thai" (นวดแผนไทย).
# Other Translations
"Nuat phaen boran" is the Thai name for a type of body work native to Thailand (nuat=massage, phaen=manner, boran=ancient). Thai massage is also known as northern-style Thai massage, Buntautuk style, Old Medicine Hospital Style, traditional Thai massage, Traditional Thai Medical Massage, Thai Yoga, Thai Yoga Massage, yoga massage, Thai classical massage, Thai bodywork, passive yoga, or assisted yoga.
# Description
Although, Thai Ayurveda and traditional medicine originates in Tibet, China and in India, nuat phaen boran is primarily local to the northern Chiangmai area. Virtually every practitioner using this term is either trained in Chiangmai or trained with someone who was. The original and oldest running school for Nuat Boran is "The Old Medicine School" or Shivago Komarpai School and Buntautuk Hospital Massage Program. This program was a popular site for tourists learning massage in Chiangmai primarily beginning in the late 80's and 90's. The founder was the famous Grand Master of Traditional Thai Ayurvedic Medicine, Aachan Sintorn Chaichgun. Aacharn Sintorn presided over daily classes for over 30 years until his death in 2005. His family and elder sons Suthat and Wasson carry on to the present day. Aacharn Sintorn was a product of the Wat Po System in the 50's. The Old Medicine school was a pioneer in teaching non-Thais a short form and ten-day program called "Nuad Boran" which was easy for the non-Thai speakers to learn. The course was primarily technique with little acknowledgement to theory, as a result of the language difficulty. Unfortunately, many non-Thai obtained the mistaken impression that the 10-day program was the sum total of traditional Thai Medicine. However, the hands-on portion for traditional expert or doctor of massage is about two years full time. However, the basic form of Nuad Boran can be said to be representitive and a fair introduction to the hands on healing as a distinctive modality.
There are as many as 7 to 10 regional variations of Thai massage. Many of these traditions claim exclusivity and compete with the others for students and notoriety, although today the Royal Thai Gov't is seeking to establish parity and common standards between all of the various schools.
The receiver is put into yoga-like positions during the course of the massage. In the northern style there are a lot of stretching movements whereas the southern style emphasis is given to acupressure. It was believed that the massage art was brought over to Thailand by Jivaka Kumar Baccha, known in Thailand as Dr Shivago, a contemporary of Buddha some 2500 years ago.
The massage recipient changes into pajamas and lies on a mat or firm mattress on the floor. (It can be done solo or in a group of a dozen or so patients in the same large room.) The massage giver leans on the recipient's body using hands and forearms to apply firm rhythmic pressure to almost every part of the receiver's body. The massage generally follows the Sen Energy lines on the body (the Sen are comparable to Chinese meridians). In some gestures, the legs and feet of the giver are used to fixate the body or limbs of the recipient. In other gestures, hands fixate the body, while the feet do the massaging action. Usually no oil is applied, but sometimes a hot herbal compress is used to warm and sooth the receiver's body. A full course of Thai massage typically lasts two hours or more, and includes pulling fingers, toes, ears etc., cracking the knuckles, walking on the recipient's back, arching the recipient's back in a rolling action etc. There is a standard procedure and rhythm to the massage. Sometimes in a large group massage, the practitioners do the procedures in unison.
A full massage in Thailand of typically two hours costs around 300-500 Thai Baht (8.5-14 USD in 2007) depending on location (it may cost 5 times more in a five star hotel). | https://www.wikidoc.org/index.php/Thai_massage | |
b5c4479f706a004a0aeaea710de1d3241a6f5c83 | wikidoc | Thalamus Ltd | Thalamus Ltd
Thalamus Ltd (also known as Thalamus) was a British computer game developer that published titles for a number of 8-bit and 16-bit platforms during the late 1980s and early 1990s.
# History
## Genesis
Thalamus Ltd was created in 1986 as an in-house software publishing label of British magazine publisher Newsfield Publications Ltd, to take advantage of their leading position publishing computer game magazines, such as Crash and Zzap!64, during the mid-1980s. Ex-Activision PR Manager Andrew Wright was assigned the position of Company Director and Newsfield staff writer Gary Liddon was appointed Technical Executive. The company was initially based in Canonbury, North London, in an office shared with staff of Newsfield's newly launched lifestyle magazine LM.
## First Titles
Thalamus capitalised on the success of the Commodore 64 gaming scene by releasing their first batch of titles on this platform. Having established numerous contacts within the C64 development scene through the popularity of their Zzap!64 gaming magazine, Thalamus were able to sign up Finnish programmer Stavros Fasoulas to develop their first three titles, Sanxion, Delta and Quedex. Sanxion was the first release to bear the Thalamus name, and it garnered a Sizzler rating from Zzap!64 - this led to accusations of favouritism from rival publications, in particular Commodore User, despite the game deserving the award - it was technically competent, visually attractive, and ran at breakneck speed for its time. Legendary C64 musician Rob Hubbard came on board to provide the music for the first two titles, while Matt Gray provided the music for Quedex. "Thalamusik", the loading tune that accompanied the C64 version of Sanxion proved to be so popular amongst fans that Zzap!64 later included a full synthesised version of Rob Hubbard's classic tune on one of their cover cassettes.
The C64 version of Delta popularised the concept of the Mix-E-Load loading system. Provided as standard on the cassette versions of each game (and as a bonus on the floppy disk versions), the Mix-E-Load system allowed players to remix the loading music of the game, in real time, as the main program loaded in the background. Mix-E-Load was created by Gary Liddon in conjunction with Rob Hubbard and derived from an idea by Nick Pelling, author of well known BBC Micro games Frak! and Firetrack.
## The staff changes
During the development of Quedex, Liddon and Wright both left Thalamus, with Wright returning to Activision and Liddon pursuing a career in games programming. Ex-Electric Dreams development manager Paul Cooper was brought on board to head up the company.
Stavros Fasoulas was later recalled to Finland to serve in the National Guard, so for their next release Thalamus turned to upcoming C64 programmer Martin Walker. Having already programmed a number of well-received C64 titles, namely Rupert and the Toymaker's Party, Chameleon and Back to the Future, Martin Walker delivered an innovative puzzle/shooter hybrid named Hunter's Moon. Despite a favourable response from critics and gamers alike, the game didn't sell as well as previous Thalamus titles.
In the second half of 1988, Thalamus returned from a period of relative silence with two new titles. Hawkeye marked the commercial debut of The Boys Without Brains, a Dutch collective who had already made a name for themselves within the C64 demo scene. The game was an above average side-scroller with colourful graphics and an impressive soundtrack from Jeroen Tel. The first Thalamus game to be awarded a Gold Medal by Zzap!64, Armalyte was an impressive shoot-em up in the spirit of R-Type, originally conceived as its own unique identity but publicised as a sequel to Delta.
As the 1980s drew to a close, Thalamus continued to release a strong line-up of C64 games, including the surreal puzzle/shooter Snare, an impressive horizontal scroller, Retrograde, from the Rowlands brothers and Heatseaker, another original spin on the shoot-em up genre. A brief experimentation with the ZX Spectrum format saw conversions of Sanxion and Delta being released, but by this time the Spectrum market was in decline and Thalamus decided to halt development of a number of Spectrum projects. The title Thalamus were most reluctant to cut was The Search for Sharla, an epic exploration game that intended to combine the best elements of Spectrum classics such as Lords of Midnight and Driller.
## Final titles and dissolution
Thalamus entered the 1990s with a few more strong C64 titles, including Creatures and Creatures II: Torture Trouble from the Rowlands brothers, which have been lauded by several computer magazines for the strength of their gameplay and graphics on the aging machine. Cartoon-style platformers Summer Camp and Winter Camp were also released. But a multitude of problems began to overcome the company, threatening their demise. In 1991, Newsfield ran into serious financial trouble. Newsfield were forced to halt publication of their popular gaming magazines. Europress stepped in to save the magazines, but they slowly died out over the next year or two as their respective markets dwindled.
Thalamus managed to survive the liquidation of Newsfield, but funds were running low. With 8-bit gaming being superseded by 16-bit gaming, production costs were rising, forcing hundreds of independent publishers, such as Thalamus, to either close down or allow themselves to be consumed by a publishing giant. Thalamus released their final C64 game, Nobby the Aardvark in 1993, but it was too little too late. With their various Amiga projects spiralling out of budget and no further income, Thalamus had no choice but to close down their operations.
# List of games
## Commercial releases
- Sanxion (1986, C64)
- Delta (1987, C64)
- Quedex (1987, C64)
- Hunter's Moon (1987, C64)
- Armalyte (aka Delta 2) (1988, C64)
- Armalyte: Competition Edition (1988, C64)
- Hawkeye (1988, C64)
- Snare (1989, C64)
- Retrograde (1989, C64)
- Sanxion: The Spectrum Remix (1989, Spectrum/Spectrum 128)
- Hawkeye (1989, Amiga)
- Armalyte (1990, Amstrad CPC)
- Q8 Team Ford Rally Simulation (1990, Amstrad CPC)
- Delta Charge (1990, Spectrum)
- Creatures (1990, C64)
- Summer Camp (1990, C64)
- Heatseeker (1990, C64)
- Venom Wing (1990, Amiga)
- Armalyte: The Final Run (1991, Amiga)
- Creatures II: Torture Trouble (1992, C64)
- Winter Camp (1992, C64/Amiga)
- Borobodur (1992, Amiga)
- Nobby the Aardvark (1993, C64)
- Mindroll (1990, Amiga)
- Creatures (1993, Amiga)
- S.U.B. (1993, Amiga/PC)
## Unreleased titles
- Starline (1987, C64)
- Q8 Team Ford Rally Simulation (1990, Spectrum)
- The Search for Sharla (1990, Spectrum, C64, Amiga)
- Creatures (1990, Spectrum)
- Armalyte (1990, Spectrum)
- Armalyte II (1990, C64) - this would have also been Delta III and Sanxion IV, as each game was related to the previous one in some respect.
- Bombuzal (1990, Spectrum)
- Delta Patrol (1992, Amiga)
- Arsenal FC (1992, Amiga)
- Beastmaster (1992, Amiga)
- Nobby the Aardvark (1992, Amiga)
- Street Warriors (1993, Amiga)
- Restrictor (1993, Amiga) | Thalamus Ltd
Thalamus Ltd (also known as Thalamus) was a British computer game developer that published titles for a number of 8-bit and 16-bit platforms during the late 1980s and early 1990s.
# History
## Genesis
Thalamus Ltd was created in 1986 as an in-house software publishing label of British magazine publisher Newsfield Publications Ltd, to take advantage of their leading position publishing computer game magazines, such as Crash and Zzap!64, during the mid-1980s. Ex-Activision PR Manager Andrew Wright was assigned the position of Company Director and Newsfield staff writer Gary Liddon was appointed Technical Executive. The company was initially based in Canonbury, North London, in an office shared with staff of Newsfield's newly launched lifestyle magazine LM.
## First Titles
Thalamus capitalised on the success of the Commodore 64 gaming scene by releasing their first batch of titles on this platform. Having established numerous contacts within the C64 development scene through the popularity of their Zzap!64 gaming magazine, Thalamus were able to sign up Finnish programmer Stavros Fasoulas to develop their first three titles, Sanxion, Delta and Quedex. Sanxion was the first release to bear the Thalamus name, and it garnered a Sizzler rating from Zzap!64 - this led to accusations of favouritism from rival publications, in particular Commodore User, despite the game deserving the award - it was technically competent, visually attractive, and ran at breakneck speed for its time. Legendary C64 musician Rob Hubbard came on board to provide the music for the first two titles, while Matt Gray provided the music for Quedex. "Thalamusik", the loading tune that accompanied the C64 version of Sanxion proved to be so popular amongst fans that Zzap!64 later included a full synthesised version of Rob Hubbard's classic tune on one of their cover cassettes.
The C64 version of Delta popularised the concept of the Mix-E-Load loading system. Provided as standard on the cassette versions of each game (and as a bonus on the floppy disk versions), the Mix-E-Load system allowed players to remix the loading music of the game, in real time, as the main program loaded in the background. Mix-E-Load was created by Gary Liddon in conjunction with Rob Hubbard and derived from an idea by Nick Pelling, author of well known BBC Micro games Frak! and Firetrack.
## The staff changes
During the development of Quedex, Liddon and Wright both left Thalamus, with Wright returning to Activision and Liddon pursuing a career in games programming. Ex-Electric Dreams development manager Paul Cooper was brought on board to head up the company.
Stavros Fasoulas was later recalled to Finland to serve in the National Guard, so for their next release Thalamus turned to upcoming C64 programmer Martin Walker. Having already programmed a number of well-received C64 titles, namely Rupert and the Toymaker's Party, Chameleon and Back to the Future, Martin Walker delivered an innovative puzzle/shooter hybrid named Hunter's Moon. Despite a favourable response from critics and gamers alike, the game didn't sell as well as previous Thalamus titles.
In the second half of 1988, Thalamus returned from a period of relative silence with two new titles. Hawkeye marked the commercial debut of The Boys Without Brains, a Dutch collective who had already made a name for themselves within the C64 demo scene. The game was an above average side-scroller with colourful graphics and an impressive soundtrack from Jeroen Tel. The first Thalamus game to be awarded a Gold Medal by Zzap!64, Armalyte was an impressive shoot-em up in the spirit of R-Type, originally conceived as its own unique identity but publicised as a sequel to Delta.
As the 1980s drew to a close, Thalamus continued to release a strong line-up of C64 games, including the surreal puzzle/shooter Snare, an impressive horizontal scroller, Retrograde, from the Rowlands brothers and Heatseaker, another original spin on the shoot-em up genre. A brief experimentation with the ZX Spectrum format saw conversions of Sanxion and Delta being released, but by this time the Spectrum market was in decline and Thalamus decided to halt development of a number of Spectrum projects. The title Thalamus were most reluctant to cut was The Search for Sharla, an epic exploration game that intended to combine the best elements of Spectrum classics such as Lords of Midnight and Driller.
## Final titles and dissolution
Thalamus entered the 1990s with a few more strong C64 titles, including Creatures and Creatures II: Torture Trouble from the Rowlands brothers, which have been lauded by several computer magazines for the strength of their gameplay and graphics on the aging machine. Cartoon-style platformers Summer Camp and Winter Camp were also released. But a multitude of problems began to overcome the company, threatening their demise. In 1991, Newsfield ran into serious financial trouble. Newsfield were forced to halt publication of their popular gaming magazines. Europress stepped in to save the magazines, but they slowly died out over the next year or two as their respective markets dwindled.
Thalamus managed to survive the liquidation of Newsfield, but funds were running low. With 8-bit gaming being superseded by 16-bit gaming, production costs were rising, forcing hundreds of independent publishers, such as Thalamus, to either close down or allow themselves to be consumed by a publishing giant. Thalamus released their final C64 game, Nobby the Aardvark in 1993, but it was too little too late. With their various Amiga projects spiralling out of budget and no further income, Thalamus had no choice but to close down their operations.
# List of games
## Commercial releases
- Sanxion (1986, C64)
- Delta (1987, C64)
- Quedex (1987, C64)
- Hunter's Moon (1987, C64)
- Armalyte (aka Delta 2) (1988, C64)
- Armalyte: Competition Edition (1988, C64)
- Hawkeye (1988, C64)
- Snare (1989, C64)
- Retrograde (1989, C64)
- Sanxion: The Spectrum Remix (1989, Spectrum/Spectrum 128)
- Hawkeye (1989, Amiga)
- Armalyte (1990, Amstrad CPC)
- Q8 Team Ford Rally Simulation (1990, Amstrad CPC)
- Delta Charge (1990, Spectrum)
- Creatures (1990, C64)
- Summer Camp (1990, C64)
- Heatseeker (1990, C64)
- Venom Wing (1990, Amiga)
- Armalyte: The Final Run (1991, Amiga)
- Creatures II: Torture Trouble (1992, C64)
- Winter Camp (1992, C64/Amiga)
- Borobodur (1992, Amiga)
- Nobby the Aardvark (1993, C64)
- Mindroll (1990, Amiga)
- Creatures (1993, Amiga)
- S.U.B. (1993, Amiga/PC)
## Unreleased titles
- Starline (1987, C64)
- Q8 Team Ford Rally Simulation (1990, Spectrum)
- The Search for Sharla (1990, Spectrum, C64, Amiga)
- Creatures (1990, Spectrum)
- Armalyte (1990, Spectrum)
- Armalyte II (1990, C64) - this would have also been Delta III and Sanxion IV, as each game was related to the previous one in some respect.
- Bombuzal (1990, Spectrum)
- Delta Patrol (1992, Amiga)
- Arsenal FC (1992, Amiga)
- Beastmaster (1992, Amiga)
- Nobby the Aardvark (1992, Amiga)
- Street Warriors (1993, Amiga)
- Restrictor (1993, Amiga)
# External links
- Thalamus History article at C64HQ
- Zzap!64 review of Armalyte
- Interview with former Thalamus programmer Richard Underhill
- Gordon Houghton's Zzap!64 pages
fi:Stavros Fasoulas
sv:Thalamus (datorspelsföretag)
Template:WS | https://www.wikidoc.org/index.php/Thalamus_Ltd | |
8a310d2e1392e8d83a3661d8882ed42ec6170d4b | wikidoc | Thioescaline | Thioescaline
TE, or thioescaline, is a series of lesser-known psychedelic drugs similar in structure to Escaline. They were first synthesized by Alexander Shulgin and written up in his book PIHKAL (Phenethylamines I Have Known and Loved). Very little data is known about their dangers or toxicity.
# TE compounds
## 3-TE
Dosage: 60-80 mg
Duration: 8-12 hours
Effects: increased pleasure from art and music, lowering of pitch, and time distortion
## 4-TE
Dosage: 20-30 mg
Duration: 9-12 hours
Effects: open-eye visuals, easy conversation. +++ on the Shulgin Rating Scale | Thioescaline
TE, or thioescaline, is a series of lesser-known psychedelic drugs similar in structure to Escaline. They were first synthesized by Alexander Shulgin and written up in his book PIHKAL (Phenethylamines I Have Known and Loved). Very little data is known about their dangers or toxicity.
# TE compounds
## 3-TE
Dosage: 60-80 mg
Duration: 8-12 hours
Effects: increased pleasure from art and music, lowering of pitch, and time distortion
## 4-TE
Dosage: 20-30 mg
Duration: 9-12 hours
Effects: open-eye visuals, easy conversation. +++ on the Shulgin Rating Scale | https://www.wikidoc.org/index.php/Thioescaline | |
87fece38970b69557b938e5713580124d7254c80 | wikidoc | Thiofentanyl | Thiofentanyl
Thiofentanyl is an opioid analgesic that is an analogue of fentanyl.
Thiofentanyl was sold briefly on the black market in the early 1980s, before the introduction of the Federal Analog Act which for the first time attempted to control entire families of drugs based on their structural similarity rather than scheduling each drug individually as they appeared. Thiofentanyl is made with the same synthetic route as fentanyl, but by substituting 2-(2-bromoethyl)thiophene for phenethyl bromide in the synthesis.
Thiofentanyl has similar effects to fentanyl. Side effects of fentanyl analogues are similar to those of fentanyl itself, which include itching, nausea and potentially serious respiratory depression which can be life-threatening. | Thiofentanyl
Thiofentanyl is an opioid analgesic that is an analogue of fentanyl.
Thiofentanyl was sold briefly on the black market in the early 1980s, before the introduction of the Federal Analog Act which for the first time attempted to control entire families of drugs based on their structural similarity rather than scheduling each drug individually as they appeared. [1] Thiofentanyl is made with the same synthetic route as fentanyl, but by substituting 2-(2-bromoethyl)thiophene for phenethyl bromide in the synthesis.
Thiofentanyl has similar effects to fentanyl. Side effects of fentanyl analogues are similar to those of fentanyl itself, which include itching, nausea and potentially serious respiratory depression which can be life-threatening. | https://www.wikidoc.org/index.php/Thiofentanyl | |
1141b62dc38ea63a6a2abb76f50a1d6ffe15ab5d | wikidoc | Thiostrepton | Thiostrepton
Thiostrepton is a natural cyclic oligopeptide antibiotic, derived from several strains of strepromycetes, such as Streptomyces azureus, Streptomyces laurentii.
# Properties
- Synonyms: Alaninamide, Bryamycin , Thiactin
- CAS number: 1393-48-2
- Merck index: 14: 9364
- Molecular weight: 1664.89
- Molecular Formula: C72H85N19O18S5
- Melting point: decomposes at 246-256oC
- Solubility information: Soluble in chloroform, dichloromethane, dioxane, pyridine, glacial acetic acid, DMF. Practically insoluble in water, the lower alcohols, nonpolar organic solvents, diluted aqeous acids or bases. May be dissolved by methanolic acid or base, but with decomposition. Working solution of 1% in DMSO is unstable and should be freshly prepared and protected from light.
- Appearance: White to off-white powder
# History
Thiostrepton was discovered by DONOVICK R, PAGANO JF, STOUT HA, WEINSTEIN MJ. in 1955 (Antibiot Annu. 1955-1956;3:554-9), who desribed its antibacterial properties.
Dorothy Crowfoot Hodgkin solved the structure of Thiostrepton in 1970.
# Applications
Thiostrepton has been used in veterinary medicine in mastitis caused by gram-negative organisms and in dermatologic disorders. It is mostly used in complex ointments containing Neomycin, Nystatin, Thiostrepton and topical steroides. It is also active against gram-positive bacteria.
Recently, Thiostrepton has been reported to exhibit antimalarial and anticancer activities
Thiostrepton is used in molecular biology as a reagent for both positive and negative selection of genes involved in nucleotide metabolism. | Thiostrepton
Thiostrepton is a natural cyclic oligopeptide antibiotic, derived from several strains of strepromycetes, such as Streptomyces azureus, Streptomyces laurentii.
# Properties
- Synonyms: Alaninamide, Bryamycin , Thiactin
- CAS number: 1393-48-2
- Merck index: 14: 9364
- Molecular weight: 1664.89
- Molecular Formula: C72H85N19O18S5
- Melting point: decomposes at 246-256oC
- Solubility information: Soluble in chloroform, dichloromethane, dioxane, pyridine, glacial acetic acid, DMF. Practically insoluble in water, the lower alcohols, nonpolar organic solvents, diluted aqeous acids or bases. May be dissolved by methanolic acid or base, but with decomposition. Working solution of 1% in DMSO is unstable and should be freshly prepared and protected from light.
- Appearance: White to off-white powder
# History
Thiostrepton was discovered by DONOVICK R, PAGANO JF, STOUT HA, WEINSTEIN MJ. in 1955 (Antibiot Annu. 1955-1956;3:554-9), who desribed its antibacterial properties.
Dorothy Crowfoot Hodgkin solved the structure of Thiostrepton in 1970.
# Applications
Thiostrepton has been used in veterinary medicine in mastitis caused by gram-negative organisms and in dermatologic disorders. It is mostly used in complex ointments containing Neomycin, Nystatin, Thiostrepton and topical steroides. It is also active against gram-positive bacteria.
Recently, Thiostrepton has been reported to exhibit antimalarial and anticancer activities
Thiostrepton is used in molecular biology as a reagent for both positive and negative selection of genes involved in nucleotide metabolism. | https://www.wikidoc.org/index.php/Thiostrepton | |
a90daf6f50ec5f366fe6c8936b5943d2c7ecf507 | wikidoc | Wisdom teeth | Wisdom teeth
# Overview
Wisdom teeth are third molars that usually appear between the ages of 16 and 24. They are commonly extracted when they affect other teeth—this impaction is colloquially known as "coming in sideways." Most people have four wisdom teeth, but it is possible to have more or fewer. Absence of one or more wisdom teeth is an example of hypodontia. Any extra teeth are referred to as supernumerary teeth.
# Etymology
They are generally thought to be called wisdom teeth because they appear so late—much later than the other teeth, at an age where people are arguably wiser than as a child, when the other teeth erupt. The English wisdom tooth is derived from Latin dens sapientiae. The same root is shared by the following languages:
- Albanian Dhëmbi i pjekurisë
- Bangla Akkel Daat
- German Weisheitszahn
- Dutch verstandskies
- Afrikaans verstandtand
- Arabic Ders-al-a'qel
- Belgian-Dutch wijsheidstand
- Norwegian visdomstann
- Danish and Swedish visdomstand
- Finnish viisaudenhammas
- French dent de sagesse
- Portuguese dente siso or dente do juízo
- Spanish muela del juicio or muela cordal
- Italian dente del giudizio
- Romanian mǎsea de minte
- Slovenian modrostni zob
- Croatian and Serbian umnjaci
- Hungarian bölcsességfog
- Czech zuby moudrosti
- Polish zęby mądrości
- Russian зубы мудрости
- Bulgarian мъдрец (meaning wise man)
- Estonian tarkusehammas
- Lithuanian protiniai dantys
- Hebrew שן בינה (shen bina)
- Greek φρονιμίτες (fronheemeetes)
- Marathi akkal daad
- Bengali Akkel Daant
- Nepali Buddhee Bangaaraa
There exists an interesting Dutch folk etymology that the Dutch word verstandskies is derived from "far-standing" (ver-staand) molar, and that mistranslations of the Dutch word (in which verstand translates to wisdom) are the root for corresponding words in other European languages.
Turkish refers directly to the age at which wisdom teeth appear and calls it 20 yaş dişi (20th year tooth). In Arabic, its name is Ders-al-a'qel (ضرس العقل), literally meaning "The tooth of the mind" and hence similar to occidental names. In Korean, its name is Sa-rang-nee (사랑니, love teeth) referring to the young age and the pain of the first love. In Japanese, its name is Oyashirazu (親知らず), literally meaning "unknown to the parents," from the idea that they erupt after a child has moved away. The Indonesian term gigi bungsu for the latest teeth a person cuts refers to bungsu "youngest child". In Thailand the wisdom tooth is described fan-khut (ฟันคุด) "huddling tooth" due to its shortage of place.
# Impactions
Impacted wisdom teeth fall into one of several categories. Mesioangular impaction is the most common form (43%), and means the tooth is angled forward, towards the front of the mouth. Vertical impaction (38%) occurs when the formed tooth does not erupt fully through the gum line. Distoangular impaction (6%) means the tooth is angled backward, towards the rear of the mouth. And finally, Horizontal impaction (3%) is the least common form, which occurs when the tooth is angled fully ninety degrees forward, growing into the roots of the second molar.
Typically distoangular impactions are the easiest to extract in the maxilla and most difficult to extract in the mandible, while mesioangular impactions are the most difficult to extract in the maxilla and easiest to extract in the mandible.
Impacted wisdom teeth may also be categorized on whether they are still completely encased in the jawbone. If it is completely encased in the jawbone, it is a bony impaction. If the wisdom tooth has erupted out of the jawbone but not through the gumline, it is called a soft tissue impaction.
Sometimes the wisdom tooth fails to erupt completely through the gum bed and the gum at the back of the wisdom tooth extends over the biting surface, forming a soft tissue flap or lid around the tooth called an operculum. Teeth covered by an operculum can be difficult to clean with a toothbrush. Additional cleaning techniques can include using a needle-less plastic syringe to vigorously wash the tooth with moderately pressured water or to softly wash it with hydrogen peroxide.
However, debris and bacteria can easily accumulate under an operculum, which may cause pericoronitis, a common infection problem in young adults with partial impactions that is often exacerbated by occlusion with opposing 3rd or 2nd molars. Common symptoms include a swelling and redness of the gum around the eruption site, difficulty in opening the mouth, a bad odor or taste in the mouth, and pain in the general area which may also run down the entire lower jaw or possibly the neck. Untreated pericoronitis can progress to a much more severe infection.
If the operculum does not disappear, recommended treatment is extraction of the wisdom tooth. An alternative treatment involving removal of the operculum, called operculectomy, has been advocated. There is a high risk of permanent or temporary numbness of the tongue due to damage of the nerve with this treatment and it is no longer recommended as a standard treatment in oral surgery.
# Extraction
A wisdom tooth is extracted to correct an actual problem or to prevent problems that may come up in the future. Wisdom teeth are extracted for two general reasons: either the wisdom teeth have already become impacted, or the wisdom teeth could potentially become problematic if not extracted. Potential problems caused by the presence of properly grown-in wisdom teeth include infections caused by food particles easily trapped in the jaw area behind the wisdom teeth where regular brushing and flossing is difficult and ineffective. Such infections may be frequent, and cause considerable pain and medical danger. Another reason to have a wisdom tooth removed is if the tooth has grown in improperly, causing the tongue to brush up against it. The tongue can tolerate it for a limited time, until it causes a painful sensation, to the point where the sheer pain can numb the tongue affected, and the area around it (part of the lips, and the cheek). The numbness feels similar to the feeling of anesthesia, possibly meaning a nerve can be affected by the wisdom tooth improperly growing in. Also, it is a wise choice to have them removed if undergoing extensive orthodontic work because once the teeth have come in they could inflict some damage on expensive straightening.
The extraction of wisdom teeth should only be performed by dental professionals with proper training and experience performing such extractions. The precise reasons why an individual’s wisdom teeth need to be extracted should be explained to them by their dentist, after an examination which almost certainly will need to include x-rays. A panoramic x-ray (aka "panorex") is the best x-ray to view wisdom teeth and diagnose their problems.
# Post-extraction problems
There are several problems that can manifest themselves after the extraction(s) have been completed. Some of these problems are unavoidable and natural, while others are under the control of the patient. The suggestions contained in the sections below are general guidelines that a patient will be expected to abide by, but the patient should follow all directions that are given by the surgeon in addition to the following guidelines. Above all, the patient must not disregard the given instructions; doing so is extremely dangerous and could result in any number of problems ranging in severity from being merely inconvenient (dry socket) to potentially life-threatening (serious infection of the extraction sites).
## Bleeding and oozing
Bleeding and oozing is inevitable and should be expected to last up to three days (although by day three it should be less noticeable). Rinsing out one's mouth during this period is counter-productive, as the bleeding stops when the blood forms clots at the extraction sites, and rinsing out the mouth will most likely dislodge the clots. The end result will be a delay in healing time and a prolonged period of bleeding. However, after about 24 hours post-surgery, it is best to rinse with lukewarm saltwater to promote healing. This should be done every 2 hours until the swelling goes down and every 4-6 hours after that for at least a week. Gauze pads should be placed at the extraction sites, and then should be bitten down on with firm and even pressure. This will help to stop the bleeding, but should not be overdone as it is possible to irritate the extraction sites and prolong the bleeding. The bleeding should decrease gradually and noticeably upon changing the gauze. If the bleeding lasts for more than a day without decreasing despite having followed the surgeon's directions, the surgeon should be contacted as soon as possible. This is not supposed to happen under normal circumstances and signals that a serious problem is present. A wet tea bag can replace the gauze pads. Tannic acid contained in tea can help reduce the bleeding.
Due to the blood clots that form in the exposed sockets as well as the abundant bacterial flora in the mouth, an offensive smell may be noticeable a short time after surgery. The persistent odour often is accompanied by an equally rancid-tasting fluid seeping from the wounds. These symptoms will diminish over an indefinite amount of time, although one to two weeks is normal. While not a cause for great concern, a post-operative appointment with your surgeon seven to ten days after surgery is highly recommended to make sure that the healing process has no complications and that the wounds are relatively clean. If infection does enter the socket, a qualified dental professional can gently plunge a plastic syringe (minus the hypodermic needle) full of a mixture of equal parts hydrogen peroxide and water or chlorohexidine gluconate into the sockets to remove any food or bacteria that may collect in the back of the mouth. This is less likely if the person has his wisdom teeth removed at an early age.
## Dry socket
A dry socket is not an infection; it is the event where the blood clot at an extraction site is dislodged, falls out prematurely, or fails to form. It is still not known how they form or why they form. In some cases, this is beyond the control of the patient. However, in other cases this happens because the patient has disregarded the instructions given by the surgeon. Smoking, spitting, or drinking with a straw in disregard to the surgeon's instructions can cause this, along with other activities that change the pressure inside of the mouth, such as playing a musical instrument. The risk of developing a dry socket is greater in smokers, if the patient has had a previous dry socket, in the lower jaw, and following complicated extractions. The extraction site will become irritated and pain is due to the bone lining the tooth socket becoming inflamed (osteitis). The symptoms are made worse when food debris is trapped in the tooth socket. The patient should contact his/her surgeon if they suspect that they have a case of dry socket; the surgeon may elect to clean the socket under local anesthetic so another blood clot forms or prescribe medication in topical form to apply to the affected site. A non-steroidal anti-inflammatory drug such as ibuprofen may be prescribed by the surgeon for pain relief. Generally dry sockets are self limiting and heal in a couple of weeks without treatment.
## Swelling
Swelling should not be confused with dry socket, although painful swelling should be expected and is a sign that the healing process is progressing normally. There is no general duration for this problem; the severity and duration of the swelling vary from case to case. The instructions the surgeon gives the patient will tell the patient for how long they should expect swelling to last, including when to expect the swelling to peak and when the swelling will start to subside. If the swelling does not begin to subside when it is supposed to, the patient should contact his or her surgeon immediately. While the swelling will generally not disappear completely for several days after it peaks, swelling that does not begin to subside or gets worse may be an indication of infection. Swelling that re-appears after a few weeks is an indication of infection caused by a bone or tooth fragment still in the wound and should be treated immediately.
## Nerve injury
This is primarily an issue with extraction of third molars, but can occur with the extraction of any tooth should the nerve be in close proximity to the surgical site. Two nerves are typically of concern and are found in duplicate (on the left and right side):
- The inferior alveolar nerve, which enters the mandible at the mandibular foramen and exits the mandible at the sides of the chin from the mental foramen. This nerve supplies sensation to the lower teeth on the right or left half of the dental arch, as well as sense of touch to the right or left half of the chin and lower lip.
- The lingual nerve, which branches off the mandibular branches of the trigeminal nerve and courses just inside the jaw bone, entering the tongue and supplying sense of touch and taste to the right and left half of the anterior 2/3 of the tongue as well as the lingual gingiva (i.e. the gums on the inside surface of the dental arch).
Such injuries can occur while lifting teeth (typically the inferior alveolar) but are most commonly caused by inadvertent damage with a surgical drill. Such injuries are rare and are usually temporary. Depending on the type of injury (i.e. Seddon classification: neuropraxia, axonotmesis, and neurotmesis) they can be prolonged or permanent.
# Treatment controversy
Preventive removal of the third molars is a common practice in developed countries despite the lack of scientific data to support this practice. In 2006, the Cochrane Collaboration published a systematic review of randomized controlled trials in order to evaluate the effect of preventative removal of asymptomatic wisdom teeth. The authors found no evidence to either support or refute this practice. There was reliable evidence showing that preventative removal did not reduce or prevent late incisor crowding. The authors of the review suggested that the number of surgical procedures could be reduced by 60% or more.
Likewise, ClinicalEvidence published a summary , largely based on the Cochrane review, that concluded prophylactic extraction is "Likely to be ineffective or harmful". ClinicalEvidence offered the following details:
# Vestigiality and variation
Wisdom teeth are vestigial third molars. In earlier times, when tooth loss in early adulthood was common, an additional molar had the potential to fill in a gap left by the loss of another tooth. It has also been postulated that the skulls of human ancestors had larger jaws with more teeth, which were possibly used to help chew down foliage to compensate for a lack of ability to efficiently digest the cellulose that makes up a plant cell wall. As human diet changed, a smaller jaw was selected by evolution, yet the third molars, or "wisdom teeth", still commonly develop in human mouths.
Other findings suggest that a given culture's diet is a larger factor than genetics in the development of jaw size during human development (and, consequently, the space available for wisdom teeth).
Different human populations differ greatly in the percentage of the population which form wisdom teeth, ranging from 99.8% in Bantu speakers to nearly 0% in Mexican Indians. The difference is related to the PAX9 gene (and perhaps other genes). | Wisdom teeth
Template:Infobox Anatomy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Wisdom teeth are third molars that usually appear between the ages of 16 and 24. They are commonly extracted when they affect other teeth—this impaction is colloquially known as "coming in sideways."[1] Most people have four wisdom teeth, but it is possible to have more or fewer. Absence of one or more wisdom teeth is an example of hypodontia. Any extra teeth are referred to as supernumerary teeth.[2][3]
# Etymology
They are generally thought to be called wisdom teeth because they appear so late—much later than the other teeth, at an age where people are arguably wiser than as a child, when the other teeth erupt. The English wisdom tooth is derived from Latin dens sapientiae. The same root is shared by the following languages:
- Albanian Dhëmbi i pjekurisë
- Bangla Akkel Daat
- German Weisheitszahn
- Dutch verstandskies
- Afrikaans verstandtand
- Arabic Ders-al-a'qel
- Belgian-Dutch wijsheidstand
- Norwegian visdomstann
- Danish and Swedish visdomstand
- Finnish viisaudenhammas
- French dent de sagesse
- Portuguese dente siso or dente do juízo
- Spanish muela del juicio or muela cordal
- Italian dente del giudizio
- Romanian mǎsea de minte
- Slovenian modrostni zob
- Croatian and Serbian umnjaci
- Hungarian bölcsességfog
- Czech zuby moudrosti
- Polish zęby mądrości
- Russian зубы мудрости
- Bulgarian мъдрец (meaning wise man)
- Estonian tarkusehammas
- Lithuanian protiniai dantys
- Hebrew שן בינה (shen bina)
- Greek φρονιμίτες (fronheemeetes)
- Marathi akkal daad
- Bengali Akkel Daant
- Nepali Buddhee Bangaaraa
There exists an interesting Dutch folk etymology that the Dutch word verstandskies is derived from "far-standing" (ver-staand) molar, and that mistranslations of the Dutch word (in which verstand translates to wisdom) are the root for corresponding words in other European languages.
Turkish refers directly to the age at which wisdom teeth appear and calls it 20 yaş dişi (20th year tooth). In Arabic, its name is Ders-al-a'qel (ضرس العقل), literally meaning "The tooth of the mind" and hence similar to occidental names. In Korean, its name is Sa-rang-nee (사랑니, love teeth) referring to the young age and the pain of the first love. In Japanese, its name is Oyashirazu (親知らず), literally meaning "unknown to the parents," from the idea that they erupt after a child has moved away. The Indonesian term gigi bungsu for the latest teeth a person cuts refers to bungsu "youngest child". In Thailand the wisdom tooth is described fan-khut (ฟันคุด) "huddling tooth" due to its shortage of place.
# Impactions
Impacted wisdom teeth fall into one of several categories. Mesioangular impaction is the most common form (43%), and means the tooth is angled forward, towards the front of the mouth. Vertical impaction (38%) occurs when the formed tooth does not erupt fully through the gum line. Distoangular impaction (6%) means the tooth is angled backward, towards the rear of the mouth. And finally, Horizontal impaction (3%) is the least common form, which occurs when the tooth is angled fully ninety degrees forward, growing into the roots of the second molar.
Typically distoangular impactions are the easiest to extract in the maxilla and most difficult to extract in the mandible, while mesioangular impactions are the most difficult to extract in the maxilla and easiest to extract in the mandible.
Impacted wisdom teeth may also be categorized on whether they are still completely encased in the jawbone. If it is completely encased in the jawbone, it is a bony impaction. If the wisdom tooth has erupted out of the jawbone but not through the gumline, it is called a soft tissue impaction.
Sometimes the wisdom tooth fails to erupt completely through the gum bed and the gum at the back of the wisdom tooth extends over the biting surface, forming a soft tissue flap or lid around the tooth called an operculum. Teeth covered by an operculum can be difficult to clean with a toothbrush. Additional cleaning techniques can include using a needle-less plastic syringe to vigorously wash the tooth with moderately pressured water or to softly wash it with hydrogen peroxide.
However, debris and bacteria can easily accumulate under an operculum, which may cause pericoronitis, a common infection problem in young adults with partial impactions that is often exacerbated by occlusion with opposing 3rd or 2nd molars. Common symptoms include a swelling and redness of the gum around the eruption site, difficulty in opening the mouth, a bad odor or taste in the mouth, and pain in the general area which may also run down the entire lower jaw or possibly the neck. Untreated pericoronitis can progress to a much more severe infection.
If the operculum does not disappear, recommended treatment is extraction of the wisdom tooth. An alternative treatment involving removal of the operculum, called operculectomy, has been advocated. There is a high risk of permanent or temporary numbness of the tongue due to damage of the nerve with this treatment and it is no longer recommended as a standard treatment in oral surgery.
# Extraction
A wisdom tooth is extracted to correct an actual problem or to prevent problems that may come up in the future. Wisdom teeth are extracted for two general reasons: either the wisdom teeth have already become impacted, or the wisdom teeth could potentially become problematic if not extracted. Potential problems caused by the presence of properly grown-in wisdom teeth include infections caused by food particles easily trapped in the jaw area behind the wisdom teeth where regular brushing and flossing is difficult and ineffective. Such infections may be frequent, and cause considerable pain and medical danger. Another reason to have a wisdom tooth removed is if the tooth has grown in improperly, causing the tongue to brush up against it. The tongue can tolerate it for a limited time, until it causes a painful sensation, to the point where the sheer pain can numb the tongue affected, and the area around it (part of the lips, and the cheek). The numbness feels similar to the feeling of anesthesia, possibly meaning a nerve can be affected by the wisdom tooth improperly growing in. Also, it is a wise choice to have them removed if undergoing extensive orthodontic work because once the teeth have come in they could inflict some damage on expensive straightening.
The extraction of wisdom teeth should only be performed by dental professionals with proper training and experience performing such extractions. The precise reasons why an individual’s wisdom teeth need to be extracted should be explained to them by their dentist, after an examination which almost certainly will need to include x-rays. A panoramic x-ray (aka "panorex") is the best x-ray to view wisdom teeth and diagnose their problems.
# Post-extraction problems
There are several problems that can manifest themselves after the extraction(s) have been completed. Some of these problems are unavoidable and natural, while others are under the control of the patient. The suggestions contained in the sections below are general guidelines that a patient will be expected to abide by, but the patient should follow all directions that are given by the surgeon in addition to the following guidelines. Above all, the patient must not disregard the given instructions; doing so is extremely dangerous and could result in any number of problems ranging in severity from being merely inconvenient (dry socket) to potentially life-threatening (serious infection of the extraction sites).
## Bleeding and oozing
Bleeding and oozing is inevitable and should be expected to last up to three days (although by day three it should be less noticeable). Rinsing out one's mouth during this period is counter-productive, as the bleeding stops when the blood forms clots at the extraction sites, and rinsing out the mouth will most likely dislodge the clots. The end result will be a delay in healing time and a prolonged period of bleeding. However, after about 24 hours post-surgery, it is best to rinse with lukewarm saltwater to promote healing. This should be done every 2 hours until the swelling goes down and every 4-6 hours after that for at least a week. Gauze pads should be placed at the extraction sites, and then should be bitten down on with firm and even pressure. This will help to stop the bleeding, but should not be overdone as it is possible to irritate the extraction sites and prolong the bleeding. The bleeding should decrease gradually and noticeably upon changing the gauze. If the bleeding lasts for more than a day without decreasing despite having followed the surgeon's directions, the surgeon should be contacted as soon as possible. This is not supposed to happen under normal circumstances and signals that a serious problem is present. A wet tea bag can replace the gauze pads. Tannic acid contained in tea can help reduce the bleeding.
Due to the blood clots that form in the exposed sockets as well as the abundant bacterial flora in the mouth, an offensive smell may be noticeable a short time after surgery. The persistent odour often is accompanied by an equally rancid-tasting fluid seeping from the wounds. These symptoms will diminish over an indefinite amount of time, although one to two weeks is normal. While not a cause for great concern, a post-operative appointment with your surgeon seven to ten days after surgery is highly recommended to make sure that the healing process has no complications and that the wounds are relatively clean. If infection does enter the socket, a qualified dental professional can gently plunge a plastic syringe (minus the hypodermic needle) full of a mixture of equal parts hydrogen peroxide and water or chlorohexidine gluconate into the sockets to remove any food or bacteria that may collect in the back of the mouth. This is less likely if the person has his wisdom teeth removed at an early age.
## Dry socket
A dry socket is not an infection; it is the event where the blood clot at an extraction site is dislodged, falls out prematurely, or fails to form. It is still not known how they form or why they form. In some cases, this is beyond the control of the patient. However, in other cases this happens because the patient has disregarded the instructions given by the surgeon. Smoking, spitting, or drinking with a straw in disregard to the surgeon's instructions can cause this, along with other activities that change the pressure inside of the mouth, such as playing a musical instrument. The risk of developing a dry socket is greater in smokers, if the patient has had a previous dry socket, in the lower jaw, and following complicated extractions. The extraction site will become irritated and pain is due to the bone lining the tooth socket becoming inflamed (osteitis). The symptoms are made worse when food debris is trapped in the tooth socket. The patient should contact his/her surgeon if they suspect that they have a case of dry socket; the surgeon may elect to clean the socket under local anesthetic so another blood clot forms or prescribe medication in topical form to apply to the affected site. A non-steroidal anti-inflammatory drug such as ibuprofen may be prescribed by the surgeon for pain relief. Generally dry sockets are self limiting and heal in a couple of weeks without treatment.
## Swelling
Swelling should not be confused with dry socket, although painful swelling should be expected and is a sign that the healing process is progressing normally. There is no general duration for this problem; the severity and duration of the swelling vary from case to case. The instructions the surgeon gives the patient will tell the patient for how long they should expect swelling to last, including when to expect the swelling to peak and when the swelling will start to subside. If the swelling does not begin to subside when it is supposed to, the patient should contact his or her surgeon immediately. While the swelling will generally not disappear completely for several days after it peaks, swelling that does not begin to subside or gets worse may be an indication of infection. Swelling that re-appears after a few weeks is an indication of infection caused by a bone or tooth fragment still in the wound and should be treated immediately.
## Nerve injury
This is primarily an issue with extraction of third molars, but can occur with the extraction of any tooth should the nerve be in close proximity to the surgical site. Two nerves are typically of concern and are found in duplicate (on the left and right side):
- The inferior alveolar nerve, which enters the mandible at the mandibular foramen and exits the mandible at the sides of the chin from the mental foramen. This nerve supplies sensation to the lower teeth on the right or left half of the dental arch, as well as sense of touch to the right or left half of the chin and lower lip.
- The lingual nerve, which branches off the mandibular branches of the trigeminal nerve and courses just inside the jaw bone, entering the tongue and supplying sense of touch and taste to the right and left half of the anterior 2/3 of the tongue as well as the lingual gingiva (i.e. the gums on the inside surface of the dental arch).
Such injuries can occur while lifting teeth (typically the inferior alveolar) but are most commonly caused by inadvertent damage with a surgical drill. Such injuries are rare and are usually temporary. Depending on the type of injury (i.e. Seddon classification: neuropraxia, axonotmesis, and neurotmesis) they can be prolonged or permanent.
# Treatment controversy
Preventive removal of the third molars is a common practice in developed countries despite the lack of scientific data to support this practice. In 2006, the Cochrane Collaboration published a systematic review of randomized controlled trials in order to evaluate the effect of preventative removal of asymptomatic wisdom teeth[4]. The authors found no evidence to either support or refute this practice. There was reliable evidence showing that preventative removal did not reduce or prevent late incisor crowding. The authors of the review suggested that the number of surgical procedures could be reduced by 60% or more.
Likewise, ClinicalEvidence published a summary [5], largely based on the Cochrane review, that concluded prophylactic extraction is "Likely to be ineffective or harmful". ClinicalEvidence offered the following details:
# Vestigiality and variation
Wisdom teeth are vestigial third molars. In earlier times, when tooth loss in early adulthood was common, an additional molar had the potential to fill in a gap left by the loss of another tooth. It has also been postulated that the skulls of human ancestors had larger jaws with more teeth, which were possibly used to help chew down foliage to compensate for a lack of ability to efficiently digest the cellulose that makes up a plant cell wall. As human diet changed, a smaller jaw was selected by evolution, yet the third molars, or "wisdom teeth", still commonly develop in human mouths.[6]
Other findings suggest that a given culture's diet is a larger factor than genetics in the development of jaw size during human development (and, consequently, the space available for wisdom teeth).[7]
Different human populations differ greatly in the percentage of the population which form wisdom teeth, ranging from 99.8% in Bantu speakers to nearly 0% in Mexican Indians.[8] The difference is related to the PAX9 gene (and perhaps other genes).[8] | https://www.wikidoc.org/index.php/Third_molar | |
980c6309e555fb5bbeaf5126f540956036da4879 | wikidoc | Thomas Bayes | Thomas Bayes
# Overview
Thomas Bayes (c. 1702 – April 17,1761) was a British mathematician and Presbyterian minister, known for having formulated a special case of Bayes' theorem, which was published posthumously.
# Biography
Thomas Bayes was born in London. In 1719 he enrolled at the University of Edinburgh to study logic and theology: as a Nonconformist, Oxford and Cambridge were closed to him.
He is known to have published two works in his lifetime: Divine Benevolence, or an Attempt to Prove That the Principal End of the Divine Providence and Government is the Happiness of His Creatures (1731), and An Introduction to the Doctrine of Fluxions, and a Defence of the Mathematicians Against the Objections of the Author of the Analyst (published anonymously in 1736), in which he defended the logical foundation of Isaac Newton's calculus against the criticism of George Berkeley, author of The Analyst.
It is speculated that Bayes was elected as a Fellow of the Royal Society in 1742 on the strength of the Introduction to the Doctrine of Fluxions, as he is not known to have published any other mathematical works during his lifetime.
Bayes died in Tunbridge Wells, Kent. He is buried in Bunhill Fields Cemetery in London where many Nonconformists are buried.
# Bayes' theorem
Bayes' solution to a problem of "inverse probability" was presented in the Essay Towards Solving a Problem in the Doctrine of Chances (1764), published posthumously by his friend Richard Price in the Philosophical Transactions of the Royal Society of London.
This essay contains a statement of a special case of Bayes' theorem.
In the first decades of the eighteenth century,
many problems concerning the probability of certain events,
given specified conditions, were solved.
For example, given a specified number of white and black balls in an urn,
what is the probability of drawing a black ball?
These are sometimes called "forward probability" problems.
Attention soon turned to the converse of such a problem:
given that one or more balls has been drawn,
what can be said about the number of white and black balls in the urn?
The Essay of Bayes contains his solution to a similar problem,
posed by Abraham de Moivre, author of The Doctrine of Chances (1718).
In addition to the Essay Towards Solving a Problem,
a paper on asymptotic series was published posthumously.
# Bayes and Bayesianism
Bayesian probability is the name given to several related interpretations of probability,
which have in common the notion of probability as something like a partial belief, rather than a frequency. This allows the application of probability to all sorts of propositions rather than just ones that come with a reference class.
"Bayesian" has been used in this sense since about 1950. He was intrerested in probability after reading a paper by Simpson.
It is not at all clear that Bayes himself would have embraced the very broad interpretation now called Bayesian.
It is difficult to assess Bayes' philosophical views on probability,
as the only direct evidence is his essay, which does not go into questions of interpretation. In the essay, Bayes defines probability as follows (Definition 5).
In modern utility theory we would say that expected utility is - sometimes, because buying risk for small amounts or buying security for big amounts also happens - the probability of an event times the payoff received in case of that event.
Rearranging that to solve for the probability, we obtain Bayes' definition.
As Stigler (citation below) points out, this is a subjective definition, and does not require repeated events; however, it does require that the event in question be observable, for otherwise it could never be said to have "happened". (Some would argue, however, that things can happen without being observable.)
Thus it can be argued, as Stigler does,
that Bayes intended his results in a rather more limited way than modern Bayesians; given Bayes' definition of probability, his result concerning the parameter of a binomial distribution makes sense only to the extent that one can bet on its observable consequences. | Thomas Bayes
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Template:Infobox Scientist
Thomas Bayes (c. 1702 – April 17,1761) was a British mathematician and Presbyterian minister, known for having formulated a special case of Bayes' theorem, which was published posthumously.
# Biography
Thomas Bayes was born in London. In 1719 he enrolled at the University of Edinburgh to study logic and theology: as a Nonconformist, Oxford and Cambridge were closed to him.
He is known to have published two works in his lifetime: Divine Benevolence, or an Attempt to Prove That the Principal End of the Divine Providence and Government is the Happiness of His Creatures (1731), and An Introduction to the Doctrine of Fluxions, and a Defence of the Mathematicians Against the Objections of the Author of the Analyst (published anonymously in 1736), in which he defended the logical foundation of Isaac Newton's calculus against the criticism of George Berkeley, author of The Analyst.
It is speculated that Bayes was elected as a Fellow of the Royal Society in 1742 on the strength of the Introduction to the Doctrine of Fluxions, as he is not known to have published any other mathematical works during his lifetime.
Bayes died in Tunbridge Wells, Kent. He is buried in Bunhill Fields Cemetery in London where many Nonconformists are buried.
# Bayes' theorem
Bayes' solution to a problem of "inverse probability" was presented in the Essay Towards Solving a Problem in the Doctrine of Chances (1764), published posthumously by his friend Richard Price in the Philosophical Transactions of the Royal Society of London.
This essay contains a statement of a special case of Bayes' theorem.
In the first decades of the eighteenth century,
many problems concerning the probability of certain events,
given specified conditions, were solved.
For example, given a specified number of white and black balls in an urn,
what is the probability of drawing a black ball?
These are sometimes called "forward probability" problems.
Attention soon turned to the converse of such a problem:
given that one or more balls has been drawn,
what can be said about the number of white and black balls in the urn?
The Essay of Bayes contains his solution to a similar problem,
posed by Abraham de Moivre, author of The Doctrine of Chances (1718).
In addition to the Essay Towards Solving a Problem,
a paper on asymptotic series was published posthumously.
# Bayes and Bayesianism
Bayesian probability is the name given to several related interpretations of probability,
which have in common the notion of probability as something like a partial belief, rather than a frequency. This allows the application of probability to all sorts of propositions rather than just ones that come with a reference class.
"Bayesian" has been used in this sense since about 1950. He was intrerested in probability after reading a paper by Simpson.
It is not at all clear that Bayes himself would have embraced the very broad interpretation now called Bayesian.
It is difficult to assess Bayes' philosophical views on probability,
as the only direct evidence is his essay, which does not go into questions of interpretation. In the essay, Bayes defines probability as follows (Definition 5).
In modern utility theory we would say that expected utility is - sometimes, because buying risk for small amounts or buying security for big amounts also happens - the probability of an event times the payoff received in case of that event.
Rearranging that to solve for the probability, we obtain Bayes' definition.
As Stigler (citation below) points out, this is a subjective definition, and does not require repeated events; however, it does require that the event in question be observable, for otherwise it could never be said to have "happened". (Some would argue, however, that things can happen without being observable.)
Thus it can be argued, as Stigler does,
that Bayes intended his results in a rather more limited way than modern Bayesians; given Bayes' definition of probability, his result concerning the parameter of a binomial distribution makes sense only to the extent that one can bet on its observable consequences. | https://www.wikidoc.org/index.php/Thomas_Bayes | |
33886d4633658ceaac45c9e481e045a3731ffb97 | wikidoc | Thomas Diflo | Thomas Diflo
Thomas Diflo, M.D., F.A.C.S. is a transplant surgeon and Assistant Professor of Surgery (Kidney, Liver and Pancreatic Transplantation, General and Hepatobiliary Surgery) at New York University Medical Center.
In a Village Voice article, Dr. Diflo has claimed that organs from executed Chinese criminals have been used for transplantation and that within a three-year period he treated six patients who have paid for and received such transplants.
While many organs from condemned prisoners are transplanted in China, there is also, according to the article, "a thriving black market in organs sold by live, willing donors in poorer nations with medical know-how, like India. 'I believe that both are morally and ethically reprehensible,' Diflo says. 'If there are degrees of reprehensibility, however, China wins hands down' because the organs are coming from the executed...'."
# Biography
Diflo graduated from Boston University School of Medicine in 1984, and held a surgical internship at Boston University Medical Center from 1984 to 1985. His residency training in surgery was at Boston University Medical Center from 1985 to 1986 and from 1988 to 1991. He held clinical fellowships at New England Deaconess Hospital (Transplantation Research, 1986-1988 and 1991-1992). Diflo is Board Certified in Surgery (1992) and Surgical Critical Care (1995) and is co-author of over 50 published articles. | Thomas Diflo
Thomas Diflo, M.D., F.A.C.S. is a transplant surgeon and Assistant Professor of Surgery (Kidney, Liver and Pancreatic Transplantation, General and Hepatobiliary Surgery)[1] at New York University Medical Center.
In a Village Voice article, Dr. Diflo has claimed that organs from executed Chinese criminals[2] have been used for transplantation and that within a three-year period he treated six patients who have paid for and received such transplants.
While many organs from condemned prisoners are transplanted in China, there is also, according to the article, "a thriving black market in organs sold by live, willing donors in poorer nations with medical know-how, like India. 'I believe that both [practices] are morally and ethically reprehensible,' Diflo says. 'If there are degrees of reprehensibility, however, China wins hands down' because the organs are coming from the executed...'."
# Biography
Diflo graduated from Boston University School of Medicine in 1984, and held a surgical internship at Boston University Medical Center from 1984 to 1985. His residency training in surgery was at Boston University Medical Center from 1985 to 1986 and from 1988 to 1991. He held clinical fellowships at New England Deaconess Hospital (Transplantation Research, 1986-1988 and 1991-1992). Diflo is Board Certified in Surgery (1992) and Surgical Critical Care (1995) and is co-author of over 50 published articles. | https://www.wikidoc.org/index.php/Thomas_Diflo | |
3c3cc7e2091445604c2bfc4d9fabb2f3e1e9a00f | wikidoc | Thoracoscopy | Thoracoscopy
# Overview
Thoracoscopy is a medical procedure involving internal inspection of the pleural cavity. It was developed by Hans Christian Jacobaeus, a Swedish internist in 1910 for the treatment of tuberculous intra-thoracic adhesions. He used a cystoscope to examine the thoracic cavity, developing his technique over the next twenty years.
Thoracoscopy may be performed either under general anaesthesia or under sedation with local anaesthetic.
# Video-assisted thoracoscopic surgery
Video-assisted thoracoscopic surgery (VATS) is a surgical operation involving thoracoscopy, performed by a thoracic surgeon using general anaesthesia.
de:Thorakoskopie | Thoracoscopy
# Overview
Thoracoscopy is a medical procedure involving internal inspection of the pleural cavity. It was developed by Hans Christian Jacobaeus, a Swedish internist in 1910 for the treatment of tuberculous intra-thoracic adhesions. He used a cystoscope to examine the thoracic cavity, developing his technique over the next twenty years.
Thoracoscopy may be performed either under general anaesthesia or under sedation with local anaesthetic.
# Video-assisted thoracoscopic surgery
Video-assisted thoracoscopic surgery (VATS) is a surgical operation involving thoracoscopy, performed by a thoracic surgeon using general anaesthesia.
Template:Respiratory system surgeries and other procedures
de:Thorakoskopie
Template:WH
Template:WikiDoc Sources
Template:Jb1 | https://www.wikidoc.org/index.php/Thoracoscopy | |
58b99ee541923c6f2d0fee67e236ebd5bcfa4e53 | wikidoc | Thrombectomy | Thrombectomy
# Overview
A thrombectomy is the excision of an abnormal or dangerous thrombus (blood clot).
It is performed intraluminally (meaning directly in the cavity of a vessel) using a balloon catheter. The thrombus is then either pressed against the walls in order to restore at least part of the natural lumen; or the balloon is 'opened' after the thrombus and then carefully moved retrogradely so that the clot can be drawn out of the vessel.
Thrombectomies usually occur as a result of thrombosis or a blood clot in a vein or artery. Thrombectomies can be used to clear a blockage in a fistula (AV fistulas used for dialysis kidney treatment).
# Indications
- An unsuccessful treatment with fibrinolysis
- The occurrence of a mobile thrombosis
- Phlegmasia coerulea dolens
# Types
Catheter Thrombectomy: which is of further divided into
- Balloon Thrombectomy
- Aspiration Thrombectomy
Surgical Thrombectomy
# Video explaining Thrombectomy
# 2013 Revised ACCF/AHA Guidelines for the Management of ST-Elevation Myocardial Infarction and 2011, 2009 and 2005 ACCF/AHA/SCAI Guidelines for Percutaneous Coronary Intervention (DO NOT EDIT)
# 2011 ACCF/AHA/SCAI Guidelines for Percutaneous Coronary Intervention (DO NOT EDIT)
## Thrombectomy (DO NOT EDIT) | Thrombectomy
Template:Interventions infobox
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
A thrombectomy is the excision of an abnormal or dangerous thrombus (blood clot).
It is performed intraluminally (meaning directly in the cavity of a vessel) using a balloon catheter. The thrombus is then either pressed against the walls in order to restore at least part of the natural lumen; or the balloon is 'opened' after the thrombus and then carefully moved retrogradely so that the clot can be drawn out of the vessel.
Thrombectomies usually occur as a result of thrombosis or a blood clot in a vein or artery. Thrombectomies can be used to clear a blockage in a fistula (AV fistulas used for dialysis kidney treatment).
# Indications
- An unsuccessful treatment with fibrinolysis
- The occurrence of a mobile thrombosis
- Phlegmasia coerulea dolens
# Types
Catheter Thrombectomy: which is of further divided into
- Balloon Thrombectomy
- Aspiration Thrombectomy
Surgical Thrombectomy
# Video explaining Thrombectomy
# 2013 Revised ACCF/AHA Guidelines for the Management of ST-Elevation Myocardial Infarction and 2011, 2009 and 2005 ACCF/AHA/SCAI Guidelines for Percutaneous Coronary Intervention (DO NOT EDIT)[1][2][3][4]
# 2011 ACCF/AHA/SCAI Guidelines for Percutaneous Coronary Intervention (DO NOT EDIT)[2]
## Thrombectomy (DO NOT EDIT)[2] | https://www.wikidoc.org/index.php/Thrombectomy | |
20864c7fd03b615f853d974c2502e0bab6727ad5 | wikidoc | Thrombolysis | Thrombolysis
# Overview
Thrombolysis is the breakdown (lysis) of blood clots by pharmacological means. It is colloquially referred to as clot busting for this reason. It works by stimulating fibrinolysis by plasmin through infusion of analogs of tissue plasminogen activator, the protein that normally activates plasmin.
# Agents
Thrombolysis requires the use of thrombolytic drugs, which are either derived from Streptomyces spp. or (more recently) the effect of recombinant technology, where human activators of plasminogen (e.g. tissue plasminogen activator, tPA) are manufactured by bacteria.
Some commonly used thrombolytics are
- streptokinase
- urokinase
- alteplase (recombinant tissue plasminogen activator or rtPA).
- reteplase
- tenecteplase
# Principles
Formation of blood clots lies at the basis of a number of serious diseases (see below). By breaking down the clot, the disease process can be arrested, or the complications reduced. While other anticoagulants (such as heparin) decrease the "growth" of a clot, thrombolytic agents actively reduce the size of the clot.
All thrombolytic agents work by activating the enzyme plasminogen, which clears the cross-linked fibrin mesh (the backbone of a clot). This makes the clot soluble and subject to further proteolysis by other enzymes, and restores blood flow over occluded blood vessels.
# Uses
Diseases where thrombolysis is used:
- Myocardial infarction
- Stroke (ischemic stroke)
- Massive pulmonary embolism
- Acute limb ischaemia
- Deep venous thrombosis
Apart from streptokinase, all thrombolytic drugs are administered together with heparin (unfractionated or low molecular weight heparin), usually for 24-48 hours.
Thrombolysis is usually intravenous. It may also be used during an angiogram (intra-arterial thrombolysis), e.g. when patients present with stroke beyond three hours.
In some settings, emergency medical technicians may administer thrombolysis for heart attacks in prehospital settings.
# Contradictions
These are contraindicated in bleeding disorders, active bleeding and when there has been recent surgery. Diabetic retinopathy is a relative contraindication, as is untreated high blood pressure. Warfarin treatment increases risk of bleeding and is a relative contraindication.
Streptokinase is contraindicated in patients who have been previously treated with streptokinase, as there is a risk of anaphylaxis (life-threatening allergic reaction) due to the production of antibodies against the enzyme. | Thrombolysis
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Thrombolysis is the breakdown (lysis) of blood clots by pharmacological means. It is colloquially referred to as clot busting for this reason. It works by stimulating fibrinolysis by plasmin through infusion of analogs of tissue plasminogen activator, the protein that normally activates plasmin.
# Agents
Thrombolysis requires the use of thrombolytic drugs, which are either derived from Streptomyces spp. or (more recently) the effect of recombinant technology, where human activators of plasminogen (e.g. tissue plasminogen activator, tPA) are manufactured by bacteria.
Some commonly used thrombolytics are
- streptokinase
- urokinase
- alteplase (recombinant tissue plasminogen activator or rtPA).
- reteplase
- tenecteplase
# Principles
Formation of blood clots lies at the basis of a number of serious diseases (see below). By breaking down the clot, the disease process can be arrested, or the complications reduced. While other anticoagulants (such as heparin) decrease the "growth" of a clot, thrombolytic agents actively reduce the size of the clot.
All thrombolytic agents work by activating the enzyme plasminogen, which clears the cross-linked fibrin mesh (the backbone of a clot). This makes the clot soluble and subject to further proteolysis by other enzymes, and restores blood flow over occluded blood vessels.
# Uses
Diseases where thrombolysis is used:
- Myocardial infarction
- Stroke (ischemic stroke)
- Massive pulmonary embolism
- Acute limb ischaemia
- Deep venous thrombosis
Apart from streptokinase, all thrombolytic drugs are administered together with heparin (unfractionated or low molecular weight heparin), usually for 24-48 hours.
Thrombolysis is usually intravenous. It may also be used during an angiogram (intra-arterial thrombolysis), e.g. when patients present with stroke beyond three hours.
In some settings, emergency medical technicians may administer thrombolysis for heart attacks in prehospital settings.
# Contradictions
These are contraindicated in bleeding disorders, active bleeding and when there has been recent surgery. Diabetic retinopathy is a relative contraindication, as is untreated high blood pressure. Warfarin treatment increases risk of bleeding and is a relative contraindication.
Streptokinase is contraindicated in patients who have been previously treated with streptokinase, as there is a risk of anaphylaxis (life-threatening allergic reaction) due to the production of antibodies against the enzyme. | https://www.wikidoc.org/index.php/Thrombolysis | |
e750a19198119540152700f9590e7a15e3fb3fd0 | wikidoc | Thymopoietin | Thymopoietin
Lamina-associated polypeptide 2 (LAP2), isoforms beta/gamma is a protein that in humans is encoded by the TMPO gene. LAP2 is an inner nuclear membrane (INM) protein.
Thymopoietin is a protein involved in the induction of CD90 in the thymus. The thymopoetin (TMPO) gene encodes three alternatively spliced mRNAs encoding proteins of 75 kDa (alpha), 51 kDa (beta) and 39 kDa (gamma) which are ubiquitously expressed in all cells. The human TMPO gene maps to chromosome band 12q22 and consists of eight exons. TMPO alpha is present diffusely expressed with the cell nucleus while TMPO beta and gamma are localized to the nuclear membrane. TMPO beta is a human homolog of the murine protein LAP2. LAP2 plays a role in the regulation of nuclear architecture by binding lamin B1 and chromosomes. This interaction is regulated by phosphorylation during mitosis. Given the nuclear localization of the three TMPO isoforms, it is unlikely that these proteins play any role in CD90 induction.
# Interactions
Thymopoietin has been shown to interact with Barrier to autointegration factor 1, AKAP8L, LMNB1 and LMNA. | Thymopoietin
Lamina-associated polypeptide 2 (LAP2), isoforms beta/gamma is a protein that in humans is encoded by the TMPO gene.[1][2] LAP2 is an inner nuclear membrane (INM) protein.[3]
Thymopoietin is a protein involved in the induction of CD90 in the thymus. The thymopoetin (TMPO) gene encodes three alternatively spliced mRNAs encoding proteins of 75 kDa (alpha), 51 kDa (beta) and 39 kDa (gamma) which are ubiquitously expressed in all cells. The human TMPO gene maps to chromosome band 12q22 and consists of eight exons. TMPO alpha is present diffusely expressed with the cell nucleus while TMPO beta and gamma are localized to the nuclear membrane. TMPO beta is a human homolog of the murine protein LAP2. LAP2 plays a role in the regulation of nuclear architecture by binding lamin B1 and chromosomes. This interaction is regulated by phosphorylation during mitosis. Given the nuclear localization of the three TMPO isoforms, it is unlikely that these proteins play any role in CD90 induction.
# Interactions
Thymopoietin has been shown to interact with Barrier to autointegration factor 1,[4] AKAP8L,[5][6] LMNB1[7][8] and LMNA.[9][10] | https://www.wikidoc.org/index.php/Thymopoietin | |
510b7c409c293a5fd84e90014298255dad32cc77 | wikidoc | Tiabendazole | Tiabendazole
# Overview
Tiabendazole (INN, BAN), thiabendazole (AAN, USAN), TBZ and the trade names Mintezol, Tresaderm, and Arbotect) is a fungicide and parasiticide.
# Uses
## Fungicide
It is used primarily to control mold, blight, and other fungal diseases in fruits (e.g. oranges) and vegetables; it is also used as a prophylactic treatment for Dutch elm disease.
Use in treatment of aspergillosis has been reported.
## Parasiticide
As an antiparasitic, it is able to control roundworms (such as those causing strongyloidiasis), hookworms, and other helminth species which attack wild animals, livestock and humans.
## Angiogenesis inhibitor
Genes responsible for the maintenance of cell walls in yeast have been shown to be responsible for angiogenesis in vertebrates. Tiabendazole serves to block angiogenesis in both frog embryos and human cells. It has also been shown to serve as a vascular disrupting agent to reduce newly established blood vessels. Tiabendazole has been shown to effectively do this in certain cancer cells
# Pharmacodynamics
TBZ works by inhibition of the mitochondrial, helminth-specific enzyme, fumarate reductase, with possible interaction with endogenous quinone.
# Other
Medicinally, thiabendazole is also a chelating agent, which means it is used medicinally to bind metals in cases of metal poisoning, such as lead, mercury, or antimony poisoning.
In dogs and cats, thiabendazole is used to treat ear infections.
Thiabendazole is also used as a food additive, a preservative with E number E233 (INS number 233). For example, it is applied to bananas to ensure freshness, and is a common ingredient in the waxes applied to the skins of citrus fruits. It is not approved as a food additive in the EU, Australia and New Zealand.
# Safety
The substance appears to have a slight toxicity in higher doses, with effects such as liver and intestinal disorders at high exposure in test animals (just below Template:LD50 level). Some reproductive disorders and decreasing weaning weight have been observed, also at high exposure. Effects on humans from use as a drug include nausea, vomiting, loss of appetite, diarrhea, dizziness, drowsiness, or headache; very rarely also ringing in the ears, vision changes, stomach pain, yellowing eyes and skin, dark urine, fever, fatigue, increased thirst and change in the amount of urine occur. Carcinogenic effects have been shown at higher doses. | Tiabendazole
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Tiabendazole (INN, BAN), thiabendazole (AAN, USAN), TBZ and the trade names Mintezol, Tresaderm, and Arbotect) is a fungicide and parasiticide.
# Uses
## Fungicide
It is used primarily to control mold, blight, and other fungal diseases in fruits (e.g. oranges) and vegetables; it is also used as a prophylactic treatment for Dutch elm disease.
Use in treatment of aspergillosis has been reported.[1]
## Parasiticide
As an antiparasitic, it is able to control roundworms (such as those causing strongyloidiasis),[2] hookworms, and other helminth species which attack wild animals, livestock and humans.[3]
## Angiogenesis inhibitor
Genes responsible for the maintenance of cell walls in yeast have been shown to be responsible for angiogenesis in vertebrates. Tiabendazole serves to block angiogenesis in both frog embryos and human cells. It has also been shown to serve as a vascular disrupting agent to reduce newly established blood vessels. Tiabendazole has been shown to effectively do this in certain cancer cells [4]
# Pharmacodynamics
TBZ works by inhibition of the mitochondrial, helminth-specific enzyme, fumarate reductase, with possible interaction with endogenous quinone.[5]
# Other
Medicinally, thiabendazole is also a chelating agent, which means it is used medicinally to bind metals in cases of metal poisoning, such as lead, mercury, or antimony poisoning.
In dogs and cats, thiabendazole is used to treat ear infections.
Thiabendazole is also used as a food additive,[6][7] a preservative with E number E233 (INS number 233). For example, it is applied to bananas to ensure freshness, and is a common ingredient in the waxes applied to the skins of citrus fruits. It is not approved as a food additive in the EU,[8] Australia and New Zealand.[9]
# Safety
The substance appears to have a slight toxicity in higher doses, with effects such as liver and intestinal disorders at high exposure in test animals (just below Template:LD50 level).[citation needed] Some reproductive disorders and decreasing weaning weight have been observed, also at high exposure. Effects on humans from use as a drug include nausea, vomiting, loss of appetite, diarrhea, dizziness, drowsiness, or headache; very rarely also ringing in the ears, vision changes, stomach pain, yellowing eyes and skin, dark urine, fever, fatigue, increased thirst and change in the amount of urine occur.[citation needed] Carcinogenic effects have been shown at higher doses.[10] | https://www.wikidoc.org/index.php/Tiabendazole | |
9cdb0c003d120517feb02c567e0a5f8a3c134a01 | wikidoc | Tic disorder | Tic disorder
For patient information on Transient tic disorder, click here
For patient information on Chronic tic disorder, click here
For patient information on Tourette syndrome, click here
# Overview
Tic disorders are defined in the Diagnostic and Statistical Manual of Mental Disorders (DSM) based on type (motor or phonic) and duration of tics (sudden, rapid, nonrhythmic, stereotyped, involuntary movements). Tic disorders are defined similarly by the World Health Organization (ICD-10 codes).
# Classification
Tic disorders are classified as follows:
- Transient tic disorder consists of multiple motor and/or phonic tics with duration of at least 4 weeks, but less than 12 months.
- Chronic tic disorder is either single or multiple motor or phonic tics, but not both, which are present for more than a year.
- Tourette's disorder is diagnosed when both motor and phonic tics are present for more than a year.
- Tic Disorder NOS is diagnosed when tics are present, but do not meet the criteria for any specific tic disorder.
Tic disorders onset in childhood (before the age of 18), and are not due to the effects of medication or another medical condition.
DSM-IV-TR diagnosis codes for the tic disorders are:
- 307.20 Tic Disorder NOS (Not Otherwise Specified)
- 307.21 Transient Tic Disorder
- 307.22 Chronic Motor or Vocal Tic Disorder
- 307.23 Tourette's Disorder
ICD10 diagnosis codes are:
- F95.0 Transient tic disorder
- F95.1 Chronic motor or vocal tic disorder
- F95.2 Combined vocal and multiple motor tic disorder
- F95.8 Other tic disorders
- F95.9 Tic disorder, unspecified
# Prevalence
A large, community-based study suggested that over 19% of school-age children have tic disorders. The children with tic disorders in that study were usually undiagnosed. (Kurlan) As many as 1 in 100 people may experience some form of tic disorder, usually before the onset of puberty. (NIH) Tourette syndrome is the more severe expression of a spectrum of tic disorders, which are thought to be due to the same genetic vulnerability. Nevertheless, most cases of Tourette syndrome are not severe. Although a good body of investigative work indicates genetic linkage of the various tic disorders, further study is needed to confirm the relationship.
# Treatment
Treatment of tic disorders, although not usually necessary, is similar to treatment of Tourette syndrome. Tics should be distinguished from other causes of tourettism.
# Notes
- ↑ Evidente VG. "Is it a tic or Tourette's? Clues for differentiating simple from more complex tic disorders". Postgraduate medicine108 (5): 175-6, 179-82. PMID 11043089 Retrieved on 2007-05-24
- ↑ DSM-IV-TR: numerical listing of codes and diagnoses. BehaveNet® Clinical Capsule. Retrieved on 2007-05-24.
- ↑ ICD Version 2006. World Health Organization. Retrieved on 2007-05-24.
- ↑ Kurlan R, McDermott MP, Deeley C, et al. "Prevalence of tics in schoolchildren and association with placement in special education". Neurology 57 (8): 1383-8. PMID 11673576
- ↑ Swerdlow NR. "Tourette syndrome: current controversies and the battlefield landscape". Current neurology and neuroscience reports. 5 (5): 329-31. PMID 16131414 | Tic disorder
For patient information on Transient tic disorder, click here
For patient information on Chronic tic disorder, click here
For patient information on Tourette syndrome, click here
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Tic disorders are defined in the Diagnostic and Statistical Manual of Mental Disorders (DSM) based on type (motor or phonic) and duration of tics (sudden, rapid, nonrhythmic, stereotyped, involuntary movements). Tic disorders are defined similarly by the World Health Organization (ICD-10 codes).
# Classification
Tic disorders are classified as follows:[1]
- Transient tic disorder consists of multiple motor and/or phonic tics with duration of at least 4 weeks, but less than 12 months.
- Chronic tic disorder is either single or multiple motor or phonic tics, but not both, which are present for more than a year.
- Tourette's disorder is diagnosed when both motor and phonic tics are present for more than a year.
- Tic Disorder NOS is diagnosed when tics are present, but do not meet the criteria for any specific tic disorder.
Tic disorders onset in childhood (before the age of 18), and are not due to the effects of medication or another medical condition.
DSM-IV-TR diagnosis codes for the tic disorders are:[2]
- 307.20 Tic Disorder NOS (Not Otherwise Specified)
- 307.21 Transient Tic Disorder
- 307.22 Chronic Motor or Vocal Tic Disorder
- 307.23 Tourette's Disorder
ICD10 diagnosis codes are: [3]
- F95.0 Transient tic disorder
- F95.1 Chronic motor or vocal tic disorder
- F95.2 Combined vocal and multiple motor tic disorder [de la Tourette]
- F95.8 Other tic disorders
- F95.9 Tic disorder, unspecified
# Prevalence
A large, community-based study suggested that over 19% of school-age children have tic disorders.[4] The children with tic disorders in that study were usually undiagnosed. (Kurlan) As many as 1 in 100 people may experience some form of tic disorder, usually before the onset of puberty. (NIH) Tourette syndrome is the more severe expression of a spectrum of tic disorders, which are thought to be due to the same genetic vulnerability. Nevertheless, most cases of Tourette syndrome are not severe. Although a good body of investigative work indicates genetic linkage of the various tic disorders, further study is needed to confirm the relationship.[5]
# Treatment
Treatment of tic disorders, although not usually necessary, is similar to treatment of Tourette syndrome. Tics should be distinguished from other causes of tourettism.
# Notes
- ↑ Evidente VG. "Is it a tic or Tourette's? Clues for differentiating simple from more complex tic disorders". Postgraduate medicine108 (5): 175-6, 179-82. PMID 11043089 Retrieved on 2007-05-24
- ↑ DSM-IV-TR: numerical listing of codes and diagnoses. BehaveNet® Clinical Capsule. Retrieved on 2007-05-24.
- ↑ ICD Version 2006. World Health Organization. Retrieved on 2007-05-24.
- ↑ Kurlan R, McDermott MP, Deeley C, et al. "Prevalence of tics in schoolchildren and association with placement in special education". Neurology 57 (8): 1383-8. PMID 11673576
- ↑ Swerdlow NR. "Tourette syndrome: current controversies and the battlefield landscape". Current neurology and neuroscience reports. 5 (5): 329-31. PMID 16131414 | https://www.wikidoc.org/index.php/Tic_disorder | |
4381e765a09b7862c80280008f60233831c44846 | wikidoc | Tobacco barn | Tobacco barn
The tobacco barn, a type of functionally classified barn found in the United States, was once an essential ingredient in the process of air-curing tobacco. In the 21st century they are fast disappearing from the American landscape in places where they were once ubiquitous. The barns have declined with the tobacco industry in general, and U.S. states such as Maryland actively discourage tobacco farming. When the American tobacco industry was at its height, tobacco barns were found everywhere the crop was grown. Tobacco barns were as unique as each area in which they were erected, and there is no one design that can be described as a tobacco barn.
# History
The terminology "tobacco barn" has been used to describe myriad structures in the United States. Buildings used for strictly tobacco curing, buildings that have multiple agricultural uses, and dilapidated barns, among others, have all been called tobacco barns at one time or another.
### Design
Though tobacco barn designs varied greatly there were elements that were found in many American tobacco barns. Design elements which were common to American tobacco barns include: gabled roofs, frame construction, and some system of ventilation. The venting can appear in different incarnations but commonly hinges would be attached to some of the cladding boards, so that they could be opened. Often the venting system would be more elaborate, including a roof ventilation system. In addition, tobacco barns do cross over into other barn styles of their day. Some common types of barn designs integrated into tobacco barns include, English barns and bank barns.
The interior framing would be set up in bents up ten feet, but more often about four feet apart horizontally, so that laths with tobacco attached to them could be hung for drying. The tier poles were often supported by posts and cross beams, the space in between known as the "bents." The bents ranged in vertical spacing from 20 inches to five feet wide. The bent itself became an important earmarker in determining crop volume. Farmers would commonly refer to barn size in terms of bents and the rule of thumb was one bent will hang half an acre of tobacco.
# Current state
U.S. states, such as Maryland, have sponsored programs which discourage the cultivation of tobacco. In 2001 Maryland's state-sponsored program offered cash payments as buyouts to tobacco farmers. A majority of the farmers took the buyout, and hundreds of historic tobacco barns were rendered instantly obsolete. As tobacco barns disappear, farmers have been forced to change their methods for curing the crop. In Kentucky, instead of curing tobacco attached to laths in vented tobacco barns as they once did, farmers are increasingly curing tobacco on "scaffolds" in the fields. | Tobacco barn
The tobacco barn, a type of functionally classified barn found in the United States, was once an essential ingredient in the process of air-curing tobacco. In the 21st century they are fast disappearing from the American landscape in places where they were once ubiquitous.[1] The barns have declined with the tobacco industry in general, and U.S. states such as Maryland actively discourage tobacco farming.[1] When the American tobacco industry was at its height, tobacco barns were found everywhere the crop was grown. Tobacco barns were as unique as each area in which they were erected, and there is no one design that can be described as a tobacco barn.
# History
The terminology "tobacco barn" has been used to describe myriad structures in the United States. Buildings used for strictly tobacco curing, buildings that have multiple agricultural uses, and dilapidated barns, among others, have all been called tobacco barns at one time or another.[2]
### Design
Though tobacco barn designs varied greatly there were elements that were found in many American tobacco barns. Design elements which were common to American tobacco barns include: gabled roofs, frame construction, and some system of ventilation. The venting can appear in different incarnations but commonly hinges would be attached to some of the cladding boards, so that they could be opened.[3] Often the venting system would be more elaborate, including a roof ventilation system. In addition, tobacco barns do cross over into other barn styles of their day. Some common types of barn designs integrated into tobacco barns include, English barns and bank barns.[3]
The interior framing would be set up in bents up ten feet,[3] but more often about four feet apart horizontally,[2] so that laths with tobacco attached to them could be hung for drying.[3] The tier poles were often supported by posts and cross beams, the space in between known as the "bents." The bents ranged in vertical spacing from 20 inches to five feet wide. The bent itself became an important earmarker in determining crop volume. Farmers would commonly refer to barn size in terms of bents and the rule of thumb was one bent will hang half an acre of tobacco.[2]
# Current state
U.S. states, such as Maryland, have sponsored programs which discourage the cultivation of tobacco. In 2001 Maryland's state-sponsored program offered cash payments as buyouts to tobacco farmers.[1] A majority of the farmers took the buyout, and hundreds of historic tobacco barns were rendered instantly obsolete.[1] As tobacco barns disappear, farmers have been forced to change their methods for curing the crop. In Kentucky, instead of curing tobacco attached to laths in vented tobacco barns as they once did, farmers are increasingly curing tobacco on "scaffolds" in the fields.[4] | https://www.wikidoc.org/index.php/Tobacco_barn | |
858bf30fdd6588b70d367ec54286468b6dca05b4 | wikidoc | Tocofersolan | Tocofersolan
# Overview
Tocofersolan (INN) or tocophersolan is a synthetic water-soluble version of vitamin E. Natural forms of vitamin E are fat soluble, but not water-soluble. Tocofersolan is polyethylene glycol derivative of α-tocopherol that enables water solubility.
Tocofersolan is used as a vitamin E supplement or to treat vitamin E deficiency in individuals who cannot absorb fats due to disease.
On 24 July 2009 the European Medicines Agency approved tocofersolan under the trade name Vedrop 50 mg/ml oral solution for the treatment of vitamin E deficiency due to digestive malabsorption in paediatric patients suffering from congenital or hereditary chronic cholestasis, from birth (in term newborns) to 16 or 18 years of age (depending on the region).
Tocofersolan is also used in cosmetics and pharmaceuticals as an antioxidant. | Tocofersolan
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Tocofersolan (INN) or tocophersolan is a synthetic water-soluble version of vitamin E. Natural forms of vitamin E are fat soluble, but not water-soluble. Tocofersolan is polyethylene glycol derivative of α-tocopherol that enables water solubility.
Tocofersolan is used as a vitamin E supplement or to treat vitamin E deficiency in individuals who cannot absorb fats due to disease.[1]
On 24 July 2009 the European Medicines Agency approved tocofersolan under the trade name Vedrop 50 mg/ml oral solution for the treatment of vitamin E deficiency due to digestive malabsorption in paediatric patients suffering from congenital or hereditary chronic cholestasis, from birth (in term newborns) to 16 or 18 years of age (depending on the region).[2]
Tocofersolan is also used in cosmetics and pharmaceuticals as an antioxidant.[3] | https://www.wikidoc.org/index.php/Tocofersolan | |
26261c3a0eeb82176b52b0b6a3c9ec52cfc16061 | wikidoc | Tonsillolith | Tonsillolith
# Overview
A tonsillolith (also called tonsil stone or calculus of the tonsil) is a piece (or more commonly, a cluster) of calcareous matter which forms in the rear of the mouth, in the crevasses (called crypts) of the palatine tonsils (which are what most people commonly refer to as simply tonsils).
Tonsil stones, it is theorized, are the result of a combination of any of the following:
- food particles
- dead white blood cells (a.k.a. leukocytes)
- oral bacteria
- overactive salivary glands
Protruding tonsilloliths have the feel of a foreign object, lodged between the outside of wisdom teeth and the temporomandibular joint region of the fleshed jaw. They may be an especially uncomfortable nuisance, but are not often harmful. They are one possible cause of halitosis.
# Appearance and characteristics
Tonsilloliths or tonsil stones are calcifications that form in the crypts of the palatal tonsils. These calculi are composed of calcium salts either alone or in combination with other mineral salts, and are usually of small size - though there have been occasional reports of large tonsilloliths or calculi in peritonsillar locations.
Tonsilloliths are difficult to diagnose in the absence of clear manifestations, and often constitute casual findings of routine radiological studies.
These calculi are composed of calcium salts such as hydroxyapatite or calcium carbonate apatite, oxalates and other magnesium salts or containing ammonium radicals, and macroscopically appear white or yellowish in color. The mechanism by which these calculi form is subject to debate, though they appear to result from the accumulation of material retained within the crypts, along with the growth of bacteria and fungi such as Leptothrix buccalis – sometimes in association with persistent chronic purulent tonsillitis. In other words, "Because saliva contains digestive enzymes, trapped food begins to break down. Particularly, the starch or carbohydrate part of the food melts away, leaving firmer, harder remains of food in the tonsils."
Alternative mechanisms have been proposed for calculi that are located in peritonsillar areas, such as the existence of ectopic tonsillar tissue, the formation of calculi secondary to salivary stasis within the minor salivary gland secretory ducts in these locations, or the calcification of abscessified accumulations.
# Symptoms
Tonsilloliths occur more frequently in adults than in children. Symptoms are usually non-specific such as sore throat, chronic cough, bad taste in the back of the throat, or otalgia. A foreign body sensation may also exist in the back of throat with recurrent foul breath (halitosis). Treatment is usually removal of concretions by curettage; larger lesions may require local excision.
Tonsilloliths tend to be present in young adolescents and can manifest with bad breath and swallowing pain accompanied by a foreign body sensation and, in some cases, referred ear pain. The condition may also prove asymptomatic, with detection upon palpating a hard intratonsillar or submucosal mass.
# Differential diagnosis
Differential diagnosis of tonsilloliths includes foreign body, calcified granuloma, malignancy, an enlarged styloid process or rarely, isolated bone which is usually derived from embryonic rests originating from the branchial arches.
Imaging diagnostic techniques can identify a radiopaque mass that may be mistaken for foreign bodies, displaced teeth or calcified blood vessels. Computed tomography (CT) may reveal nonspecific calcified images in the tonsillar zone. The differential diagnosis must be established with acute and chronic tonsillitis, tonsillar hypertrophy, peritonsillar abscesses, foreign bodies, phlebolites, ectopic bone or cartilage, lymph nodes, granulomatous lesions or calcification of the stylohyoid ligament in the context of Eagle’s syndrome (elongated styloid process).
## Giant tonsilloliths
Much rarer than the typical tonsil stones are giant tonsilloliths. Giant tonsilloliths may often be mistaken for other oral maladies, including peritonsillar abscess, and tumours of the tonsil.
# Treatment and prevention
The most aggressive form of treatment involves surgical removal of the stone, via oral curette or a tonsillectomy to remove the tonsils.
Tonsilloliths can be removed by the patient. Using a medicine dropper (especially one with a curved tip) can help to suck out the stones if they are small enough. A cotton swab dipped in hydrogen peroxide applied directly on the tonsil stones will not necessarily dislodge them - it may help some sufferers of tonsilloliths while others may experience only an unpleasant gagging sensation. The use of a water pick (irrigator) to clear out the crypts of accumulated debris may also help (only use an adjustable unit on the low pressure setting as you may damage tissue with the high pressure units). Use a solution of salt water, or a mixture of hydrogen peroxide with mouthwash in the water pick tank instead of (or combined with) water to cleanse the tonsil crypts and help prevent future tonsilloliths. While difficult to perform due to the gag reflex, a quick brushing with a toothbrush will generally remove any tonsilloliths. Another effective way to remove tonsil stones is by pressing a finger against the bottom of the tonsil and pushing upward. The pressure squeezes out stones. Some people can even reach them with their tongue, which is the best method as the tongue doesn't stimulate the gag reflex.
For large crevices, an effective tool for digging out a stone is an ear curette. The curette is used primarily for the removal of ear wax, but is effective for removal of tonsil stones as well. It comprises a long thin metal stick with a tiny metal loop at the end. Alternatives include the curved end of a hair grip (bobby pin) or a cotton swab.
A longer term cure is possible by using laser resurfacing. The procedure is called laser tonsillotomy, or laser tonsillectomy. This technique can be performed under local anaesthetic, using the scanned carbon dioxide laser, which vaporises and removes the surface of the tonsils. In this way, the edges of the crypts and crevices that collect the debris are flattened out, so that they can no longer trap material. Therefore stones, which are almost like pearls forming from a grain of sand, cannot form.
The most drastic method, a tonsillectomy, is not usually indicated or recommended, but will provide permanent relief.
## Prevention
Prevention methods include gargling with salt water, cider vinegar, dissolvable paracetamol or a non-alcohol-, non-sugar-based mouth wash.
Some alternative practitioners state that reducing the amount of white sugar, alcohol, or dairy in the diet will reduce the frequency of buildup. There are, however, no reliable data that supports this theory. | Tonsillolith
# Overview
A tonsillolith (also called tonsil stone or calculus of the tonsil) is a piece (or more commonly, a cluster) of calcareous matter which forms in the rear of the mouth, in the crevasses (called crypts) of the palatine tonsils (which are what most people commonly refer to as simply tonsils).
Tonsil stones, it is theorized, are the result of a combination of any of the following[1]:
- food particles
- dead white blood cells (a.k.a. leukocytes)
- oral bacteria
- overactive salivary glands
Protruding tonsilloliths have the feel of a foreign object, lodged between the outside of wisdom teeth and the temporomandibular joint region of the fleshed jaw. They may be an especially uncomfortable nuisance, but are not often harmful. They are one possible cause of halitosis.[2]
# Appearance and characteristics
Tonsilloliths or tonsil stones are calcifications that form in the crypts of the palatal tonsils. These calculi are composed of calcium salts either alone or in combination with other mineral salts, and are usually of small size - though there have been occasional reports of large tonsilloliths or calculi in peritonsillar locations.
Tonsilloliths are difficult to diagnose in the absence of clear manifestations, and often constitute casual findings of routine radiological studies.
These calculi are composed of calcium salts such as hydroxyapatite or calcium carbonate apatite, oxalates and other magnesium salts or containing ammonium radicals, and macroscopically appear white or yellowish in color. The mechanism by which these calculi form is subject to debate, though they appear to result from the accumulation of material retained within the crypts, along with the growth of bacteria and fungi such as Leptothrix buccalis – sometimes in association with persistent chronic purulent tonsillitis. In other words, "Because saliva contains digestive enzymes, trapped food begins to break down. Particularly, the starch or carbohydrate part of the food melts away, leaving firmer, harder remains of food in the tonsils."
Alternative mechanisms have been proposed for calculi that are located in peritonsillar areas, such as the existence of ectopic tonsillar tissue, the formation of calculi secondary to salivary stasis within the minor salivary gland secretory ducts in these locations, or the calcification of abscessified accumulations.
# Symptoms
Tonsilloliths occur more frequently in adults than in children. Symptoms are usually non-specific such as sore throat, chronic cough, bad taste in the back of the throat, or otalgia. A foreign body sensation may also exist in the back of throat with recurrent foul breath (halitosis). Treatment is usually removal of concretions by curettage; larger lesions may require local excision.
Tonsilloliths tend to be present in young adolescents and can manifest with bad breath and swallowing pain accompanied by a foreign body sensation and, in some cases, referred ear pain. The condition may also prove asymptomatic, with detection upon palpating a hard intratonsillar or submucosal mass.
# Differential diagnosis
Differential diagnosis of tonsilloliths includes foreign body, calcified granuloma, malignancy, an enlarged styloid process or rarely, isolated bone which is usually derived from embryonic rests originating from the branchial arches.[3]
Imaging diagnostic techniques can identify a radiopaque mass that may be mistaken for foreign bodies, displaced teeth or calcified blood vessels. Computed tomography (CT) may reveal nonspecific calcified images in the tonsillar zone. The differential diagnosis must be established with acute and chronic tonsillitis, tonsillar hypertrophy, peritonsillar abscesses, foreign bodies, phlebolites, ectopic bone or cartilage, lymph nodes, granulomatous lesions or calcification of the stylohyoid ligament in the context of Eagle’s syndrome (elongated styloid process).[4]
## Giant tonsilloliths
Much rarer than the typical tonsil stones are giant tonsilloliths. Giant tonsilloliths may often be mistaken for other oral maladies, including peritonsillar abscess, and tumours of the tonsil.[5]
# Treatment and prevention
The most aggressive form of treatment involves surgical removal of the stone, via oral curette or a tonsillectomy to remove the tonsils.
Tonsilloliths can be removed by the patient. Using a medicine dropper (especially one with a curved tip) can help to suck out the stones if they are small enough. A cotton swab dipped in hydrogen peroxide applied directly on the tonsil stones will not necessarily dislodge them - it may help some sufferers of tonsilloliths while others may experience only an unpleasant gagging sensation. The use of a water pick (irrigator) to clear out the crypts of accumulated debris may also help (only use an adjustable unit on the low pressure setting as you may damage tissue with the high pressure units). Use a solution of salt water, or a mixture of hydrogen peroxide with mouthwash in the water pick tank instead of (or combined with) water to cleanse the tonsil crypts and help prevent future tonsilloliths. While difficult to perform due to the gag reflex, a quick brushing with a toothbrush will generally remove any tonsilloliths. Another effective way to remove tonsil stones is by pressing a finger against the bottom of the tonsil and pushing upward. The pressure squeezes out stones. Some people can even reach them with their tongue, which is the best method as the tongue doesn't stimulate the gag reflex.
For large crevices, an effective tool for digging out a stone is an ear curette. The curette is used primarily for the removal of ear wax, but is effective for removal of tonsil stones as well. It comprises a long thin metal stick with a tiny metal loop at the end. Alternatives include the curved end of a hair grip (bobby pin) or a cotton swab.
A longer term cure is possible by using laser resurfacing. The procedure is called laser tonsillotomy, or laser tonsillectomy. This technique can be performed under local anaesthetic, using the scanned carbon dioxide laser, which vaporises and removes the surface of the tonsils. In this way, the edges of the crypts and crevices that collect the debris are flattened out, so that they can no longer trap material. Therefore stones, which are almost like pearls forming from a grain of sand, cannot form.
The most drastic method, a tonsillectomy, is not usually indicated or recommended, but will provide permanent relief.
## Prevention
Prevention methods include gargling with salt water, cider vinegar, dissolvable paracetamol or a non-alcohol-, non-sugar-based mouth wash.
Some alternative practitioners state that reducing the amount of white sugar, alcohol, or dairy in the diet will reduce the frequency of buildup. There are, however, no reliable data that supports this theory. | https://www.wikidoc.org/index.php/Tonsillolith | |
1716eb53ec10758156ff0fb68ecb1745c7d90493 | wikidoc | Toxocariasis | Toxocariasis
# Overview
Toxocariasis is an infection caused by the dog or cat roundworm, Toxocara canis or Toxocara cati, respectively. Ingestion of these worms causes the condition, visceral larval migrans (VLM) and Ocular larvae migrans (OLM).
# Epidemiology
Toxocariasis occurs around the world. Epidemiologic surveys show a 2-5% positive rate in healthy adults from urban Western countries and 14.2-37% in rural areas. In tropical countries, surveys show a positive rate of 63.2% in Bali, 86% in Saint Lucia, and 92.8% in Réunion. Toxocariasis is most commonly a disease of children, typically children aged 2-7 years.
# Risk factors
- Exposure to contaminated soil.
- Presence of unwormed pups, unhygenic conditions.
- Geophagia (pica)- 2-10% of children aged 1-3 indulge in habitual geophagia.
# Pathophysiology
Adult worms of the Toxocara family often live in the small intestine of dogs and cats. They range from 4-12 cm in length. Almost all puppies are infected at or soon after birth. During the summer, Toxocara infective eggs are shed. They survive for years in the environment, and humans typically ingest the eggs orally by eating with contaminated hands. Once introduced into the human intestine, the eggs develop into larvae. The larval form is less than 0.5 mm in length and 0.02 mm wide. The larvae penetrate the bowel wall and migrate through blood vessels to reach the liver, muscles, and lungs. Sometimes the parasite penetrates into the eye and brain.
Disease severity is affected by the number of eggs ingested, duration of infection, tissue location of larvae, and the immune response to the infection.
# Features
- Weakness
- Pruritus (Itching)
- Rash
- Difficulty breathing
- Abdominal pain / Hepatosplenomegaly
- Hyper-eosinophilia
- Increased total serum Immunoglobulin E (IgE) level
- Elevated antibody titers to T. canis
# Diagnosis
In suspected cases, diagnosis is confirmed by an increase in the anti-Toxocara excretory-secretory antigen IgE level
History of exposure to dogs and cats
High Sustained eosinophilia + hyperglobulinemia + hepatomegaly
Liver Biopsy shows degenerated larvae at the centre of an eosinophilic granuloma
# Treatment
## Antimicrobial Regimen
- 1. Toxocariasis
- 1.1 Visceral toxocariasis
- Preferred regimen: Albendazole 400 mg PO bid for five days (both adult and pediatric dosage)
- Alternative regimen: Mebendazole 100-200 mg PO bid for five days (both adult and pediatric dosage)
- Note: Treatment is indicated for moderate-severe cases. Patients with mild symptoms of toxocariasis may not require anthelminthic therapy as symptoms are limited.
- 1.2 Ocular toxocariasis
- 1. Pathogen-directed antimicrobial therapy
- Preferred regimen: Albendazole 400 mg PO bid for 5 days
- Alternative regimen: Mebendazole 1 g PO qd for 3 weeks
- Note (1): Co-administration of corticosteroids is helpful for suppressing the intense allergic manifestations of the infection.
- Note (2): Ocular larval migrans is treated by surgery (vitrectomy) and antihelminthic chemotherapy with or without corticosteroids.
# Prognosis
Toxocariasis is always a benign, asymptomatic, and self-limiting disease, although brain involvement can cause brain damage, meningitis, encephalitis, or epilepsy. Ocular involvement, also known as 'ocular larvae migrans,' may cause loss of visual acuity or unilateral blindness. Pulmonary and hepatic forms can cause protracted symptoms if the patient does not receive treatment.
# Prevention
The eggs of Toxocara species are widespread in parks, playgrounds, yards, and in homes and apartments where the occupants have dogs or cats. Elimination of eggs from the environment is not possible; therefore, prevention depends on proper hygiene, including handwashing after contact with pets. Public policies that have attempted to eradicate Toxocara infection in dogs and cats have had limited success. | Toxocariasis
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Toxocariasis is an infection caused by the dog or cat roundworm, Toxocara canis or Toxocara cati, respectively. Ingestion of these worms causes the condition, visceral larval migrans (VLM) and Ocular larvae migrans (OLM).
# Epidemiology
Toxocariasis occurs around the world. Epidemiologic surveys show a 2-5% positive rate in healthy adults from urban Western countries and 14.2-37% in rural areas.[1] In tropical countries, surveys show a positive rate of 63.2% in Bali, 86% in Saint Lucia, and 92.8% in Réunion.[1] Toxocariasis is most commonly a disease of children, typically children aged 2-7 years.
# Risk factors
- Exposure to contaminated soil.
- Presence of unwormed pups, unhygenic conditions.
- Geophagia (pica)- 2-10% of children aged 1-3 indulge in habitual geophagia.
# Pathophysiology
Adult worms of the Toxocara family often live in the small intestine of dogs and cats. They range from 4-12 cm in length. Almost all puppies are infected at or soon after birth. During the summer, Toxocara infective eggs are shed. They survive for years in the environment, and humans typically ingest the eggs orally by eating with contaminated hands. Once introduced into the human intestine, the eggs develop into larvae. The larval form is less than 0.5 mm in length and 0.02 mm wide. The larvae penetrate the bowel wall and migrate through blood vessels to reach the liver, muscles, and lungs. Sometimes the parasite penetrates into the eye and brain.
Disease severity is affected by the number of eggs ingested, duration of infection, tissue location of larvae, and the immune response to the infection.
# Features
- Weakness
- Pruritus (Itching)
- Rash
- Difficulty breathing
- Abdominal pain / Hepatosplenomegaly
- Hyper-eosinophilia
- Increased total serum Immunoglobulin E (IgE) level
- Elevated antibody titers to T. canis
# Diagnosis
In suspected cases, diagnosis is confirmed by an increase in the anti-Toxocara excretory-secretory antigen IgE level
History of exposure to dogs and cats
High Sustained eosinophilia + hyperglobulinemia + hepatomegaly
Liver Biopsy shows degenerated larvae at the centre of an eosinophilic granuloma
# Treatment
## Antimicrobial Regimen
- 1. Toxocariasis
- 1.1 Visceral toxocariasis
- Preferred regimen: Albendazole 400 mg PO bid for five days (both adult and pediatric dosage)
- Alternative regimen: Mebendazole 100-200 mg PO bid for five days (both adult and pediatric dosage)
- Note: Treatment is indicated for moderate-severe cases. Patients with mild symptoms of toxocariasis may not require anthelminthic therapy as symptoms are limited.[2]
- 1.2 Ocular toxocariasis
- 1. Pathogen-directed antimicrobial therapy[3]
- Preferred regimen: Albendazole 400 mg PO bid for 5 days
- Alternative regimen: Mebendazole 1 g PO qd for 3 weeks
- Note (1): Co-administration of corticosteroids is helpful for suppressing the intense allergic manifestations of the infection.
- Note (2): Ocular larval migrans is treated by surgery (vitrectomy) and antihelminthic chemotherapy with or without corticosteroids.
# Prognosis
Toxocariasis is always a benign, asymptomatic, and self-limiting disease, although brain involvement can cause brain damage, meningitis, encephalitis, or epilepsy. Ocular involvement, also known as 'ocular larvae migrans,' may cause loss of visual acuity or unilateral blindness. Pulmonary and hepatic forms can cause protracted symptoms if the patient does not receive treatment.
# Prevention
The eggs of Toxocara species are widespread in parks, playgrounds, yards, and in homes and apartments where the occupants have dogs or cats. Elimination of eggs from the environment is not possible; therefore, prevention depends on proper hygiene, including handwashing after contact with pets. Public policies that have attempted to eradicate Toxocara infection in dogs and cats have had limited success. | https://www.wikidoc.org/index.php/Toxocara | |
0278cbc174944787f00a6a5b9d6b27674075707c | wikidoc | Traceability | Traceability
Traceability refers to the completeness of the information about every step in a process chain.
The formal definition: Traceability is ability to chronologically interrelate the uniquely identifiable entities in a way that matters.
Traceability is the ability to verify the history, location, or application of an item by means of recorded identification.
The term traceability is for example used to refer to an unbroken chain of measurements relating an instrument's measurements to a known standard. Traceability can be used to certify an instrument's accuracy relative to a known standard.
(In the USA, national standards for weights and measures are maintained by the National Institute of Standards and Technology. As defined by NIST, "Traceability requires the establishment of an unbroken chain of comparisons to stated references each with a stated uncertainty.")
- In logistics, traceability refers to the capability for tracing goods along the distribution chain on a batch number or series number basis. Traceability is an important aspect for example in the automotive industry, where it makes recalls possible, or in the food industry where it contributes to food safety. See Tracking and tracing.
- In materials, traceability refers to the capability to associate a finished part with destructive test results performed on material from the same ingot with the same heat treatment. Destructive tests typically include chemical composition and mechanical strength tests. A heat number is usually marked on the part or raw material which identifies the ingot it came from, and a lot number may identify the group of parts that experienced the same heat treatment. (i.e. were in the same oven at the same time.) Material traceability is important to the aerospace, nuclear, and process industry because they frequently make use of high strength materials that look identical to commercial low strength versions. In these industries, a part made of the wrong material is called "counterfeit," even if the substitution was accidental.
- In software development, the term traceability (or requirements traceability) refers to the ability to link requirements back to stakeholders' rationales and forward to corresponding design artifacts, code,and test cases. Traceability supports numerous software engineering activities such as change impact analysis, compliance verification of code, regression test selection, and requirements validation. It is usually accomplished in the form of a matrix created for the verification and validation of the project. Unfortunately the practice of constructing and maintaining a requirements trace matrix can be very arduous and over time the traces tend to erode into an inaccurate state. Alternate automated approaches for generating traces using information retrieval methods have been developed.
- In blood transfusion practice, the term traceability relates to the requirement for a continuous audit trail accounting for the whereabouts of a blood product and its current status in terms of processing, testing, storage, etc. at all points from initial collection from a donor right through to either transfusion to a recipient or disposal. This is particularly important with regards to prevention of transfusion-transmitted infection, and is a legal requirement in many countries including all member states of the European Union.
In transaction processing software, traceability implies use of a unique piece of data (e.g., order date/time or a serialized sequence number) which can be traced through the entire software flow of all relevant application programs. Messages and files at any point in the system can then be audited for correctness and completeness, using the traceability key to find the particular transaction. This is also sometimes referred to as the transaction footprint. | Traceability
Template:Wikt
Traceability refers to the completeness of the information about every step in a process chain.
The formal definition: Traceability is ability to chronologically interrelate the uniquely identifiable entities in a way that matters.[citation needed]
Traceability is the ability to verify the history, location, or application of an item by means of recorded identification.[1]
The term traceability is for example used to refer to an unbroken chain of measurements relating an instrument's measurements to a known standard. Traceability can be used to certify an instrument's accuracy relative to a known standard.
(In the USA, national standards for weights and measures are maintained by the National Institute of Standards and Technology. As defined by NIST, "Traceability requires the establishment of an unbroken chain of comparisons to stated references each with a stated uncertainty.")
- In logistics, traceability refers to the capability for tracing goods along the distribution chain on a batch number or series number basis. Traceability is an important aspect for example in the automotive industry, where it makes recalls possible, or in the food industry where it contributes to food safety. See Tracking and tracing.
- In materials, traceability refers to the capability to associate a finished part with destructive test results performed on material from the same ingot with the same heat treatment. Destructive tests typically include chemical composition and mechanical strength tests. A heat number is usually marked on the part or raw material which identifies the ingot it came from, and a lot number may identify the group of parts that experienced the same heat treatment. (i.e. were in the same oven at the same time.) Material traceability is important to the aerospace, nuclear, and process industry because they frequently make use of high strength materials that look identical to commercial low strength versions. In these industries, a part made of the wrong material is called "counterfeit," even if the substitution was accidental.
- In software development, the term traceability (or requirements traceability) refers to the ability to link requirements back to stakeholders' rationales and forward to corresponding design artifacts, code,and test cases. Traceability supports numerous software engineering activities such as change impact analysis, compliance verification of code, regression test selection, and requirements validation. It is usually accomplished in the form of a matrix created for the verification and validation of the project. Unfortunately the practice of constructing and maintaining a requirements trace matrix [RTM] can be very arduous and over time the traces tend to erode into an inaccurate state. Alternate automated approaches for generating traces using information retrieval methods have been developed.
- In blood transfusion practice, the term traceability relates to the requirement for a continuous audit trail accounting for the whereabouts of a blood product and its current status in terms of processing, testing, storage, etc. at all points from initial collection from a donor right through to either transfusion to a recipient or disposal. This is particularly important with regards to prevention of transfusion-transmitted infection, and is a legal requirement in many countries including all member states of the European Union.
In transaction processing software, traceability implies use of a unique piece of data (e.g., order date/time or a serialized sequence number) which can be traced through the entire software flow of all relevant application programs. Messages and files at any point in the system can then be audited for correctness and completeness, using the traceability key to find the particular transaction. This is also sometimes referred to as the transaction footprint. | https://www.wikidoc.org/index.php/Traceability | |
d3b80e0cf634ec690fc73591062c4da41fca95fb | wikidoc | Tracheostomy | Tracheostomy
For the WikiDoc page of the Main topic, click here
# Overview
Tracheostomy and tracheotomy are surgical procedures on the neck to open a direct airway through an incision in the trachea (the windpipe). They are performed by paramedics, emergency physicians and surgeons.
# Terminology
Tracheotomy, from the Greek root tom- meaning "to cut," refers to the procedure of cutting into the trachea and is an emergency procedure.
A tracheostomy, from the root stom- meaning "mouth," refers to the making of a semipermanent or permanent opening, and to the opening itself.
Some sources offer different definitions of the above terms. Part of the ambiguity is due to the uncertainty of the intended permanence of the stoma at the time it is created.
# Uses of tracheostomy
The conditions in which a tracheotomy may be used are:
- Acute setting - maxillofacial injuries, large tumors of the head and neck, congenital tumors, e.g. branchial cyst, acute inflammation of head and neck, and
- Chronic / elective setting - when there is need for long term mechanical ventilation and tracheal toilet, e.g. comatose patients, surgery to the head and neck.
In emergency settings, in the context of failed endotracheal intubation or where intubation is contraindicated, cricothyroidotomy or mini-tracheostomy may be performed in preference to a tracheostomy.
# Tracheostomy procedure
- Curvilinear skin incision along relaxed skin tension lines (RSTL) between sternal notch and cricoid cartilage.
- Midline vertical incision dividing strap muscles.
- Division of thyroid isthmus between ligatures.
- Elevation of cricoid with cricoid hook.
- Placement of tracheal incision. An inferior based flap or Björk flap (through second and third tracheal rings) is commonly used. The flap is then sutured to the inferior skin margin. Alternatives include a vertical tracheal incision (pediatric) or excision of an ellipse of anterior tracheal wall.
- Insert tracheostomy tube (with concomitant withdrawal of endotracheal tube), inflate cuff, secure with tape around neck or stay sutures.
- Connect ventilator tubing.
It is also possible to make a simple vertical incision between tracheal rings (typically 2nd and 3rd) for the incision. rear end flaps may produce more intratracheal granulation tissue at the site of the incisions, making it less favorable to some surgeons.
# Complications
- Immediate - pneumothorax or pneumomediastinum, tracheoesophageal fistula, injury to great vessels or recurrent laryngeal nerves, bleeding, e.g. from divided thyroid isthmus.
- Early - secretions and mucus plugging, dislodged tube, respiratory arrest and post obstructive pulmonary edema (when tracheostomy is performed in a patient with longstanding upper airway obstruction, and is dependent on hypoxic drive for respiration).
- Late - bleeding from tracheoinnominate fistula (can be torrential), tracheal stenosis (from ischemia induced by a cuffed tracheostomy tube), tracheoesophageal fistula, tracheocutaneous fistula and cosmetic deformity must be considered upon decannulation.
# Problems
- Immune problems - air inhaled through a stoma is not filtered or moistened like it is when inhaled through the nose, or even the mouth.
- Drowning - as little as two teaspoons of water in the stoma can drown the person; therefore, they cannot swim and bathing must be done with extreme care.
- Suffocation - if the stoma is covered, the person will suffocate, as in some cases they cannot breathe through their nose or their mouth. | Tracheostomy
For the WikiDoc page of the Main topic, click here
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Umar Ahmad, M.D.[2]
# Overview
Tracheostomy and tracheotomy are surgical procedures on the neck to open a direct airway through an incision in the trachea (the windpipe). They are performed by paramedics, emergency physicians and surgeons.
# Terminology
Tracheotomy, from the Greek root tom- meaning "to cut," refers to the procedure of cutting into the trachea and is an emergency procedure.
A tracheostomy, from the root stom- meaning "mouth," refers to the making of a semipermanent or permanent opening, and to the opening itself.[1]
Some sources offer different definitions of the above terms. Part of the ambiguity is due to the uncertainty of the intended permanence of the stoma at the time it is created.[2]
# Uses of tracheostomy
The conditions in which a tracheotomy may be used are:
- Acute setting - maxillofacial injuries, large tumors of the head and neck, congenital tumors, e.g. branchial cyst, acute inflammation of head and neck, and
- Chronic / elective setting - when there is need for long term mechanical ventilation and tracheal toilet, e.g. comatose patients, surgery to the head and neck.
In emergency settings, in the context of failed endotracheal intubation or where intubation is contraindicated, cricothyroidotomy or mini-tracheostomy may be performed in preference to a tracheostomy.
# Tracheostomy procedure
- Curvilinear skin incision along relaxed skin tension lines (RSTL) between sternal notch and cricoid cartilage.
- Midline vertical incision dividing strap muscles.
- Division of thyroid isthmus between ligatures.
- Elevation of cricoid with cricoid hook.
- Placement of tracheal incision. An inferior based flap or Björk flap (through second and third tracheal rings) is commonly used. The flap is then sutured to the inferior skin margin. Alternatives include a vertical tracheal incision (pediatric) or excision of an ellipse of anterior tracheal wall.
- Insert tracheostomy tube (with concomitant withdrawal of endotracheal tube), inflate cuff, secure with tape around neck or stay sutures.
- Connect ventilator tubing.
It is also possible to make a simple vertical incision between tracheal rings (typically 2nd and 3rd) for the incision. rear end flaps may produce more intratracheal granulation tissue at the site of the incisions, making it less favorable to some surgeons.
# Complications
- Immediate - pneumothorax or pneumomediastinum, tracheoesophageal fistula, injury to great vessels or recurrent laryngeal nerves, bleeding, e.g. from divided thyroid isthmus.
- Early - secretions and mucus plugging, dislodged tube, respiratory arrest and post obstructive pulmonary edema (when tracheostomy is performed in a patient with longstanding upper airway obstruction, and is dependent on hypoxic drive for respiration).
- Late - bleeding from tracheoinnominate fistula (can be torrential), tracheal stenosis (from ischemia induced by a cuffed tracheostomy tube), tracheoesophageal fistula, tracheocutaneous fistula and cosmetic deformity must be considered upon decannulation.
# Problems
- Immune problems - air inhaled through a stoma is not filtered or moistened like it is when inhaled through the nose, or even the mouth.
- Drowning - as little as two teaspoons of water in the stoma can drown the person; therefore, they cannot swim and bathing must be done with extreme care.
- Suffocation - if the stoma is covered, the person will suffocate, as in some cases they cannot breathe through their nose or their mouth. | https://www.wikidoc.org/index.php/Tracheostomy | |
b13cbfc6a1539ebc12285e41c3bda6c59dc989d8 | wikidoc | Trans-acting | Trans-acting
In the field of molecular biology, trans-acting generally means "acting from a different molecule". It may be considered the opposite of cis-acting which generally means "acting from the same molecule".
In the context of transcription regulation, a trans-acting element is usually a DNA sequence that contains a gene. This gene codes for a protein (or microRNA or other diffusible molecule) that will be used in the regulation of another target gene.
The trans-acting gene may be on the same chromosome as the target gene, but the activity is via the intermediary protein or RNA that it encodes. Cis-acting elements, on the other hand, do not code for protein or RNA. Both the trans-acting gene and the protein/RNA that it encodes are said to "act in trans" on the target gene. | Trans-acting
In the field of molecular biology, trans-acting generally means "acting from a different molecule". It may be considered the opposite of cis-acting which generally means "acting from the same molecule".
In the context of transcription regulation, a trans-acting element is usually a DNA sequence that contains a gene. This gene codes for a protein (or microRNA or other diffusible molecule) that will be used in the regulation of another target gene.[1]
The trans-acting gene may be on the same chromosome as the target gene, but the activity is via the intermediary protein or RNA that it encodes. Cis-acting elements, on the other hand, do not code for protein or RNA. Both the trans-acting gene and the protein/RNA that it encodes are said to "act in trans" on the target gene. | https://www.wikidoc.org/index.php/Trans-acting | |
d9f44e3f5991c93f53589d2c4e17b7d2cdafca53 | wikidoc | Trans effect | Trans effect
In inorganic chemistry, the trans effect is the labilization of ligands trans to certain other ligands, which can thus be regarded as trans directing ligands. It is attributed to electronic effects and it is most notable in square planar complexes, although it can also be observed for octahedral complexes.
In addition to this kinetic trans effect, trans ligands also have an influence on the ground state of the molecule, notably on bond lengths and stability. Some authors prefer the term trans influence to distinguish it from the kinetic effect, while others use more specific terms such as structural trans effect or thermodynamic trans effect.
The discovery of the trans effect is attributed to Ilya Ilich Chernyaev, who recognized it and gave it a name in 1926.
# Kinetic trans effect
The intensity of the trans effect (as measured by the increase in rate of substitution of the trans ligand) follows this sequence:
F−, H2O, OH− < NH3 < py < Cl− < Br− < I−, SCN−, NO2−, SC(NH2)2, Ph− < SO32− < PR3, AsR3, SR2, CH3− < H−, NO, CO, CN− C2H4
The classic example of the trans effect is the synthesis of cisplatin. Starting from PtCl42−, the first NH3 ligand is added to any of the four equivalent positions at random, but the second NH3 is added cis to the first one, because Cl− has a larger trans effect than NH3. If, on the other hand, one starts from Pt(NH3)42+, the trans product is obtained instead.
The trans effect in square complexes can be explained in terms of an addition/elimination mechanism that goes through a trigonal bipyramidal intermediate. Ligands with a high trans effect are generally those with high π acidity (as in the case of phosphines) or low ligand lone pair–dπ repulsions (as in the case of hydride), which prefer the more π-basic equatorial sites in the intermediate. The second equatorial position is occupied by the incoming ligand; due to the principle of microscopic reversibility, the departing ligand must also leave from an equatorial position. The third and final equatorial site is occupied by the trans ligand, so the net result is that the kinetically favored product is the one where the ligand trans to the one with the largest trans effect is eliminated.
# Structural trans effect
The structural trans effect can be measured experimentally using X-ray crystallography, and is observed as a stretching of the bonds between the metal and the ligand trans to a trans-influencing ligand. Stretching by as much as 0.2 Å occurs with strong trans-influencing ligands such as hydride. A cis influence can also be observed, but is smaller than the trans influence. The relative importance of the cis and trans influences depends on the formal electron configuration of the metal center, and explanations have been proposed based on the atomic orbitals involved. | Trans effect
In inorganic chemistry, the trans effect is the labilization of ligands trans to certain other ligands, which can thus be regarded as trans directing ligands. It is attributed to electronic effects and it is most notable in square planar complexes, although it can also be observed for octahedral complexes.[1]
In addition to this kinetic trans effect, trans ligands also have an influence on the ground state of the molecule, notably on bond lengths and stability. Some authors prefer the term trans influence to distinguish it from the kinetic effect,[2] while others use more specific terms such as structural trans effect or thermodynamic trans effect.[1]
The discovery of the trans effect is attributed to Ilya Ilich Chernyaev,[3] who recognized it and gave it a name in 1926.[4]
# Kinetic trans effect
The intensity of the trans effect (as measured by the increase in rate of substitution of the trans ligand) follows this sequence:
F−, H2O, OH− < NH3 < py < Cl− < Br− < I−, SCN−, NO2−, SC(NH2)2, Ph− < SO32− < PR3, AsR3, SR2, CH3− < H−, NO, CO, CN− C2H4
The classic example of the trans effect is the synthesis of cisplatin. Starting from PtCl42−, the first NH3 ligand is added to any of the four equivalent positions at random, but the second NH3 is added cis to the first one, because Cl− has a larger trans effect than NH3. If, on the other hand, one starts from Pt(NH3)42+, the trans product is obtained instead.
The trans effect in square complexes can be explained in terms of an addition/elimination mechanism that goes through a trigonal bipyramidal intermediate. Ligands with a high trans effect are generally those with high π acidity (as in the case of phosphines) or low ligand lone pair–dπ repulsions (as in the case of hydride), which prefer the more π-basic equatorial sites in the intermediate. The second equatorial position is occupied by the incoming ligand; due to the principle of microscopic reversibility, the departing ligand must also leave from an equatorial position. The third and final equatorial site is occupied by the trans ligand, so the net result is that the kinetically favored product is the one where the ligand trans to the one with the largest trans effect is eliminated.[2]
# Structural trans effect
The structural trans effect can be measured experimentally using X-ray crystallography, and is observed as a stretching of the bonds between the metal and the ligand trans to a trans-influencing ligand. Stretching by as much as 0.2 Å occurs with strong trans-influencing ligands such as hydride. A cis influence can also be observed, but is smaller than the trans influence. The relative importance of the cis and trans influences depends on the formal electron configuration of the metal center, and explanations have been proposed based on the atomic orbitals involved.[5] | https://www.wikidoc.org/index.php/Trans_effect | |
f6073ae895f172734abc59a49b01e46ee6766059 | wikidoc | Transduction | Transduction
Transduction has different meanings in different fields:
- Transduction (biology) is the transfer of genetic material from one microorgranism (usually a bacterial cell) to another by a filterable agent such as a bacteriophage or plasmid
- Transduction (biophysics) is the conveyance of energy from a donor electron to a receptor receptor electron, during which the class of energy changes
- Transduction (cybernetics) is a process or mechanism that converts signals from one form to another, notably in the Viable System Model
- Transduction (engineering) is a process that converts one type of energy to another. A device that does this is a transducer
- Transduction (genetics) is the transfer of viral, bacterial, or both bacterial and viral DNA from one cell to another using a bacteriophage vector
- Transduction (machine learning) is directly drawing conclusions about new data from previous data, without constructing a model
- Transduction (physics) is the conversion of energy into another form
- Transduction (physiology) is transportation of stimuli to the nervous system
- Transduction (psychology) is reasoning from specific cases to general cases, typically employed by children during their development
- Transduction (semiotics) is the translation from a sign or concept from one field of knowledge to a different one, involving a transformation that keeps an original connection in its phenomenological deepest level
- Signal transduction is any process by which a biological cell converts one kind of signal or stimulus into another
ar:تنبيغ
ur:انتقال (سائنس) | Transduction
Transduction has different meanings in different fields:
- Transduction (biology) is the transfer of genetic material from one microorgranism (usually a bacterial cell) to another by a filterable agent such as a bacteriophage or plasmid
- Transduction (biophysics) is the conveyance of energy from a donor electron to a receptor receptor electron, during which the class of energy changes
- Transduction (cybernetics) is a process or mechanism that converts signals from one form to another, notably in the Viable System Model
- Transduction (engineering) is a process that converts one type of energy to another. A device that does this is a transducer
- Transduction (genetics) is the transfer of viral, bacterial, or both bacterial and viral DNA from one cell to another using a bacteriophage vector
- Transduction (machine learning) is directly drawing conclusions about new data from previous data, without constructing a model
- Transduction (physics) is the conversion of energy into another form
- Transduction (physiology) is transportation of stimuli to the nervous system
- Transduction (psychology) is reasoning from specific cases to general cases, typically employed by children during their development
- Transduction (semiotics) is the translation from a sign or concept from one field of knowledge to a different one, involving a transformation that keeps an original connection in its phenomenological deepest level
- Signal transduction is any process by which a biological cell converts one kind of signal or stimulus into another
Template:Disambig
ar:تنبيغ
ur:انتقال (سائنس) | https://www.wikidoc.org/index.php/Transduction | |
0316e8f8d37e58d1cb1c7a1adbb5030bb3df5c1d | wikidoc | Transfection | Transfection
Transfection describes the introduction of foreign material into eukaryotic cells using a virus vector or other means of transfer. The term transfection for non-viral methods is most often used in reference to mammalian cells, while the term transformation is preferred to describe non-viral DNA transfer in bacteria and non-animal eukaryotic cells such as fungi, algae and plants.
Transfection of animal cells typically involves opening transient pores or 'holes' in the cell plasma membrane, to allow the uptake of material. Genetic material (such as supercoiled plasmid DNA or siRNA constructs), or even proteins such as antibodies, may be transfected. In addition to electroporation, transfection can be carried out by mixing a cationic lipid with the material to produce liposomes, which fuse with the cell plasma membrane and deposit their cargo inside.
The original meaning of transfection was 'infection by transformation', i.e. introduction of DNA (or RNA) from a eukaryote virus or bacteriophage into cells, resulting in an infection. Because the term transformation had another sense in animal cell biology (a genetic change allowing long-term propagation in culture, or acquisition of properties typical of cancer cells), the term transfection acquired, for animal cells, its present meaning of a change in cell properties caused by introduction of DNA.
# Methods
There are various methods of introducing foreign DNA into a eukaryotic cell. Many materials have been used as carriers for transfection, which can be divided into three kinds: (cationic) polymers, liposomes and nanoparticles.
One of the cheapest (and least reliable) methods is transfection by calcium phosphate, originally discovered by S. Bacchetti and F. L. Graham in 1977. HEPES-buffered saline solution (HeBS) containing phosphate ions is combined with a calcium chloride solution containing the DNA to be transfected. When the two are combined, a fine precipitate of the positively charged calcium and the negatively charged phosphate will form, binding the DNA to be transfected on its surface. The suspension of the precipitate is then added to the cells to be transfected (usually a cell culture grown in a monolayer). By a process not entirely understood, the cells take up some of the precipitate, and with it, the DNA.
Other methods use highly branched organic compounds, so-called dendrimers, to bind the DNA and get it into the cell. A very efficient method is the inclusion of the DNA to be transfected in liposomes, i.e. small, membrane-bounded bodies that are in some ways similar to the structure of a cell and can actually fuse with the cell membrane, releasing the DNA into the cell. For eukaryotic cells, lipid-cation based transfection is more typically used, because the cells are more sensitive.
Another method is the use of cationic polymers such as DEAE-dextran or polyethylenimine. The negatively charged DNA binds to the polycation and the complex is taken up by the cell via endocytosis.
A direct approach to transfection is the gene gun, where the DNA is coupled to a nanoparticle of an inert solid (commonly gold) which is then "shot" directly into the target cell's nucleus. DNA can also be introduced into cells using viruses as a carrier. In such cases, the technique is called viral transduction, and, the cells are said to be transduced.
Other methods of transfection include nucleofection, electroporation, heat shock, magnetofection and proprietary transfection reagents such as Lipofectamine, Dojindo Hilymax, Fugene, jetPEI, Effectene or DreamFect.
# Stable and transient transfection
For most applications of transfection, it is sufficient if the transfected gene is only transiently expressed. Since the DNA introduced in the transfection process is usually not inserted into the nuclear genome, the foreign DNA is lost at the later stage when the cells undergo mitosis. If it is desired that the transfected gene actually remains in the genome of the cell and its daughter cells, a stable transfection must occur.
To accomplish this, another gene is co-transfected, which gives the cell some selection advantage, such as resistance towards a certain toxin. Some (very few) of the transfected cells will, by chance, have inserted the foreign genetic material into their genome. If the toxin, towards which the co-transfected gene offers resistance, is then added to the cell culture, only those few cells with the foreign genes inserted into their genome will be able to proliferate, while other cells will die. After applying this selection pressure for some time, only the cells with a stable transfection remain and can be cultivated further.
A common agent for stable transfection is Geneticin, also known as G418, which is a toxin that can be neutralized by the product of the neomycin resistant gene. | Transfection
Transfection describes the introduction of foreign material into eukaryotic cells using a virus vector or other means of transfer. The term transfection for non-viral methods is most often used in reference to mammalian cells, while the term transformation is preferred to describe non-viral DNA transfer in bacteria and non-animal eukaryotic cells such as fungi, algae and plants.
Transfection of animal cells typically involves opening transient pores or 'holes' in the cell plasma membrane, to allow the uptake of material. Genetic material (such as supercoiled plasmid DNA or siRNA constructs), or even proteins such as antibodies, may be transfected. In addition to electroporation, transfection can be carried out by mixing a cationic lipid with the material to produce liposomes, which fuse with the cell plasma membrane and deposit their cargo inside.
The original meaning of transfection was 'infection by transformation', i.e. introduction of DNA (or RNA) from a eukaryote virus or bacteriophage into cells, resulting in an infection. Because the term transformation had another sense in animal cell biology (a genetic change allowing long-term propagation in culture, or acquisition of properties typical of cancer cells), the term transfection acquired, for animal cells, its present meaning of a change in cell properties caused by introduction of DNA.
# Methods
There are various methods of introducing foreign DNA into a eukaryotic cell. Many materials have been used as carriers for transfection, which can be divided into three kinds: (cationic) polymers, liposomes and nanoparticles.
One of the cheapest (and least reliable) methods is transfection by calcium phosphate, originally discovered by S. Bacchetti and F. L. Graham in 1977.[1] HEPES-buffered saline solution (HeBS) containing phosphate ions is combined with a calcium chloride solution containing the DNA to be transfected. When the two are combined, a fine precipitate of the positively charged calcium and the negatively charged phosphate will form, binding the DNA to be transfected on its surface. The suspension of the precipitate is then added to the cells to be transfected (usually a cell culture grown in a monolayer). By a process not entirely understood, the cells take up some of the precipitate, and with it, the DNA.
Other methods use highly branched organic compounds, so-called dendrimers, to bind the DNA and get it into the cell. A very efficient method is the inclusion of the DNA to be transfected in liposomes, i.e. small, membrane-bounded bodies that are in some ways similar to the structure of a cell and can actually fuse with the cell membrane, releasing the DNA into the cell. For eukaryotic cells, lipid-cation based transfection is more typically used, because the cells are more sensitive.
Another method is the use of cationic polymers such as DEAE-dextran or polyethylenimine. The negatively charged DNA binds to the polycation and the complex is taken up by the cell via endocytosis.
A direct approach to transfection is the gene gun, where the DNA is coupled to a nanoparticle of an inert solid (commonly gold) which is then "shot" directly into the target cell's nucleus. DNA can also be introduced into cells using viruses as a carrier. In such cases, the technique is called viral transduction, and, the cells are said to be transduced.
Other methods of transfection include nucleofection, electroporation, heat shock, magnetofection and proprietary transfection reagents such as Lipofectamine, Dojindo Hilymax, Fugene, jetPEI, Effectene or DreamFect.
# Stable and transient transfection
For most applications of transfection, it is sufficient if the transfected gene is only transiently expressed. Since the DNA introduced in the transfection process is usually not inserted into the nuclear genome, the foreign DNA is lost at the later stage when the cells undergo mitosis. If it is desired that the transfected gene actually remains in the genome of the cell and its daughter cells, a stable transfection must occur.
To accomplish this, another gene is co-transfected, which gives the cell some selection advantage, such as resistance towards a certain toxin. Some (very few) of the transfected cells will, by chance, have inserted the foreign genetic material into their genome. If the toxin, towards which the co-transfected gene offers resistance, is then added to the cell culture, only those few cells with the foreign genes inserted into their genome will be able to proliferate, while other cells will die. After applying this selection pressure for some time, only the cells with a stable transfection remain and can be cultivated further.
A common agent for stable transfection is Geneticin, also known as G418, which is a toxin that can be neutralized by the product of the neomycin resistant gene. | https://www.wikidoc.org/index.php/Transfection | |
ba850deb54bb962fba001e140c151003e13a18f8 | wikidoc | Transference | Transference
Transference is a phenomenon in psychology characterized by unconscious redirection of feelings for one person to another. One definition of transference is "the inappropriate repetition in the present of a relationship that was important in a person's childhood." Another definition is "the redirection of feelings and desires and esp. of those unconsciously retained from childhood toward a new object." Still another definition is "a reproduction of emotions relating to repressed experiences, esp. of childhood, and the substitution of another person . . . for the original object of the repressed impulses." Transference was first described by Sigmund Freud, who acknowledged its importance for psychoanalysis for better understanding of the patient's feelings.
It is common for people to transfer feelings from their parents to their partners (emotional incest) or to children (cross-generational entanglements). For instance, one could mistrust somebody who resembles an ex-spouse in manners, voice, or external appearance; or be overly compliant to someone who resembles a childhood friend.
In The Psychology of the Transference, Carl Jung states that within the transference dyad both participants typically experience a variety of opposites, that in love and in psychological growth, the key to success is the ability to endure the tension of the opposites without abandoning the process, and that this tension allows one to grow and to transform.
Transference is common. Only in a personally or socially harmful context can transference be described as a pathological issue.
A new theory of transference known as AMT (Abusive Multiple Transference) has been suggested by David W. Bernstein, in which abusers not only transfer negative feelings directed towards their former abusers to their own victims, but also transfer the power and dominance of the former abusers to themselves. This kind of transference is sometimes part of the psychological makeup of murderers -- for example the serial killer Carroll Cole. While his father was away in World War II, Cole's mother engaged in several extra-marital affairs, forcing Cole to watch. She later beat him to ensure that he would not alert his father. Cole would later come to murder many women whom he considered "loose," and those in general who reminded him of his mother. AMT also ties in very closely with Power/Control Killers, as the feeling and view of control is passed from one abuser to those succeeding him or her.
# Transference and counter-transference during psychotherapy
In a therapy context, transference refers to redirection of a client's feelings from a significant person to a therapist. Transference is often manifested as an erotic attraction towards a therapist, but can be seen in many other forms such as rage, hatred, mistrust, parentification, extreme dependence, or even placing the therapist in a god-like or guru status. When Freud initially encountered transference in his therapy with clients, he felt it was an obstacle to treatment success. But what he learned was that the analysis of the transference was actually the work that needed to be done. The focus in psychodynamic psychotherapy is, in large part, the therapist and client recognizing the transference relationship and exploring what the meaning of the relationship is. Because the transference between patient and therapist happens on an unconscious level, psychodynamic therapists who are largely concerned with a patient's unconscious material use the transference to reveal unresolved conflicts patients have with figures from their childhoods.
Counter-transference is defined as redirection of a therapist's feelings toward a client, or more generally as a therapist's emotional entanglement with a client. A therapist's attunement to their own countertransference is nearly as critical as their understanding of the transference. Not only does this help the therapist regulate his/her own emotions in the therapeutic relationship, but it also gives the therapist valuable insight into what the client is attempting to elicit in them. For example, if a male therapist feels a very strong sexual attraction to a female patient, he must understand this as countertransference and look at how the client is attempting to elicit this reaction in him. Once it has been identified, the therapist can ask the client what their feelings are toward the therapist and examine the feelings the client has and how they relate to unconscious motivations, desires, or fears.
Another contrasting perspective on transference and counter-transference is offered in Classical Adlerian psychotherapy. Rather than using the client's transference strategically in therapy, the positive or negative transference is diplomatically pointed out and explained as an obstacle to cooperation and improvement. For the therapist, any signs of counter-transference would suggest that his/her own personal training analysis needed to be continued to overcome these tendencies. | Transference
Transference is a phenomenon in psychology characterized by unconscious redirection of feelings for one person to another. One definition of transference is "the inappropriate repetition in the present of a relationship that was important in a person's childhood."[1] Another definition is "the redirection of feelings and desires and esp. of those unconsciously retained from childhood toward a new object."[2] Still another definition is "a reproduction of emotions relating to repressed experiences, esp. of childhood, and the substitution of another person . . . for the original object of the repressed impulses."[3] Transference was first described by Sigmund Freud, who acknowledged its importance for psychoanalysis for better understanding of the patient's feelings.
It is common for people to transfer feelings from their parents to their partners (emotional incest) or to children (cross-generational entanglements). For instance, one could mistrust somebody who resembles an ex-spouse in manners, voice, or external appearance; or be overly compliant to someone who resembles a childhood friend.
In The Psychology of the Transference, Carl Jung states that within the transference dyad both participants typically experience a variety of opposites, that in love and in psychological growth, the key to success is the ability to endure the tension of the opposites without abandoning the process, and that this tension allows one to grow and to transform.[4]
Transference is common. Only in a personally or socially harmful context can transference be described as a pathological issue.
A new theory of transference known as AMT (Abusive Multiple Transference) has been suggested by David W. Bernstein, in which abusers not only transfer negative feelings directed towards their former abusers to their own victims, but also transfer the power and dominance of the former abusers to themselves. This kind of transference is sometimes part of the psychological makeup of murderers -- for example the serial killer Carroll Cole. While his father was away in World War II, Cole's mother engaged in several extra-marital affairs, forcing Cole to watch. She later beat him to ensure that he would not alert his father. Cole would later come to murder many women whom he considered "loose," and those in general who reminded him of his mother. AMT also ties in very closely with Power/Control Killers, as the feeling and view of control is passed from one abuser to those succeeding him or her.
# Transference and counter-transference during psychotherapy
In a therapy context, transference refers to redirection of a client's feelings from a significant person to a therapist. Transference is often manifested as an erotic attraction towards a therapist, but can be seen in many other forms such as rage, hatred, mistrust, parentification, extreme dependence, or even placing the therapist in a god-like or guru status. When Freud initially encountered transference in his therapy with clients, he felt it was an obstacle to treatment success. But what he learned was that the analysis of the transference was actually the work that needed to be done. The focus in psychodynamic psychotherapy is, in large part, the therapist and client recognizing the transference relationship and exploring what the meaning of the relationship is. Because the transference between patient and therapist happens on an unconscious level, psychodynamic therapists who are largely concerned with a patient's unconscious material use the transference to reveal unresolved conflicts patients have with figures from their childhoods.
Counter-transference is defined as redirection of a therapist's feelings toward a client, or more generally as a therapist's emotional entanglement with a client. A therapist's attunement to their own countertransference is nearly as critical as their understanding of the transference. Not only does this help the therapist regulate his/her own emotions in the therapeutic relationship, but it also gives the therapist valuable insight into what the client is attempting to elicit in them. For example, if a male therapist feels a very strong sexual attraction to a female patient, he must understand this as countertransference and look at how the client is attempting to elicit this reaction in him. Once it has been identified, the therapist can ask the client what their feelings are toward the therapist and examine the feelings the client has and how they relate to unconscious motivations, desires, or fears.
Another contrasting perspective on transference and counter-transference is offered in Classical Adlerian psychotherapy. Rather than using the client's transference strategically in therapy, the positive or negative transference is diplomatically pointed out and explained as an obstacle to cooperation and improvement. For the therapist, any signs of counter-transference would suggest that his/her own personal training analysis needed to be continued to overcome these tendencies. | https://www.wikidoc.org/index.php/Transference | |
b4135f4777bd5237d8e2660952dd184b1506b4ed | wikidoc | Transistasis | Transistasis
Transistasis means the power or tendency of living things to keep changing themselves according to the transformation of circumstances. Transistasis is the antonym of "Homeostasis".
# Overview
Transistasis is the property of an open system, especially living organisms, to reform its functions to maintain a meaningful condition, by means of multiple dynamic equilibrium adjustments, controlled by interrelated regulation mechanisms. The term was coined from the Greek trans (across, beyond, on the opposite side) and stasis (to stand, posture).
The term is born in the sense of biological transistasis but most often used in the sense of sociological transistasis. Multicellular organisms require transistatic new functions in order to live beyond the reformations of the outside world ; many environmentalists believe this principle also applies to the internal environment.
Many ecological, biological, and social systems are homeostatic and transistatic. They almost oppose change to maintain equilibrium but sometimes chose change to keep or get some functions or profits. If the system does not succeed in reestablishing its balance and functions, it may ultimately lead the system to stop functioning.
Complex systems, such as a human body, must have homeostasis and transistasis to maintain stability and to survive. These systems do not only have to endure to survive; they must adapt themselves and evolve to modifications of the environment.
## Examples
- Thermoregulation
The skeletal muscles can shiver to produce heat if the body temperature is too low.
Non-shivering thermogenesis involves the decomposition of fat to produce heat.
Sweating cools the body with the use of evaporation.
- The skeletal muscles can shiver to produce heat if the body temperature is too low.
- Non-shivering thermogenesis involves the decomposition of fat to produce heat.
- Sweating cools the body with the use of evaporation.
- Chemical regulation
The pancreas produces insulin and glucagon to control blood-sugar concentration.
The lungs take in oxygen and give off carbon dioxide.
The kidneys remove urea, and adjust the concentrations of water and a wide variety of ions.
- The pancreas produces insulin and glucagon to control blood-sugar concentration.
- The lungs take in oxygen and give off carbon dioxide.
- The kidneys remove urea, and adjust the concentrations of water and a wide variety of ions.
Most of these organs are controlled by hormones secreted from the pituitary gland, which in turn is directed by the hypothalamus.
## Other fields
The term has come to be used in other fields, as well.
An actuary may refer to risk homeostasis, where (for example) people who have anti-lock brakes have no better safety record than those without anti-lock brakes, because they unconsciously compensate for the safer vehicle via less-safe driving habits. Previously, certain maneuvers involved minor skids, evoking fear and avoidance: now the anti-lock system moves the boundary for such feedback, and behaviour patterns expand into the no-longer punitive area.
Sociologists and psychologists may refer to stress homeostasis, the tendency of a population or an individual to stay at a certain level of stress, often generating artificial stresses if the "natural" level of stress is not enough.
# Transistasis: Topics
## Properties of transistasis
transistatic systems show several properties:
- They are ultraflexible: the system is capable of testing which way its variables should be adjusted.
- Their whole organization (internal, structural, and functional) contributes to the survival of the fittest.
Main examples of transistasis in mammals are as follows:
- The regulation of the amounts of water and minerals in the body. This is known as osmoregulation. This happens in the kidneys.
- The removal of metabolic waste. This is known as excretion. This is done by the excretory organs such as the kidneys and lungs.
- The regulation of body temperature. This is mainly done by the skin.
- The regulation of blood glucose level. This is mainly done by the liver and the insulin secreted by the pancreas in the body.
It is important to note that while organisms exhibit equilibrium, their physiological state is not necessarily static. Many organisms exhibit endogenous fluctuations in the form of circadian (period 20 to 28 hours), ultradian (period 28 hours) rhythms. Thus in transistasis, body temperature, blood pressure, heart rate and most metabolic indicators are not always at a constant level, but in homeostasis vary predictably over time.
## Mechanisms of transistasis: feedback
Main article: Feedback
When a change of variable occurs, there are two main types of feedback to which the system reacts:
- Negative feedback is a reaction in which the system responds in such a way as to reverse the direction of change. Since this tends to keep things constant, it allows the maintenance of homeostasis. For instance, when the concentration of carbon dioxide in the human body increases, the lungs are signaled to increase their activity and expel more carbon dioxide. Thermoregulation is another example of negative feedback. When body temperature rises (or falls), receptors in the skin and the hypothalamus sense a change, triggering a command from the brain. This command, in turn, effects the correct response, in this case a decrease in body temperature.
- In positive feedback, the response is to amplify the change in the variable. This has a destabilizing effect, so does not result in homeostasis. And such a case have the possibility to change over to transistasis. Positive feedback is less common in naturally occurring systems than negative feedback, but it has its applications. For example, in nerves, a threshold electric potential triggers the generation of a much larger action potential. (See also leverage points.) Blood clotting and events in childbirth are other types of positive feedback. For example, the release of oxytocin to intensify the contractions that take place during childbirth.
Sustainable systems require combinations of both kinds of feedback. Generally with the recognition of divergence from the homeostatic condition positive feedbacks are called into play, whereas once the homeostatic condition is approached, negative feedback is used for "fine tuning" responses. This creates a situation of "metastability", in which homeostatic conditions are maintained within fixed limits, but once these limits are exceeded, the system can shift wildly to a wholly new (and possibly less desirable) situation of homeostasis. Such catastrophic shifts may occur with increasing nutrient load in clear rivers suddenly producing a homeostatic condition of high eutrophication and turbidity, for instance. Thus a few cases of new homeostasis lead to transistasis.
# Transistasis: Applications
## Biological transistasis
Transistasis is one of the fundamental characteristics of living things. It is one of the methods for survival within tolerable limits.
The internal environment of a living organism's body features body fluids in multicellular animals. The body fluids include blood plasma, tissue fluid and intracellular fluid. The maintenance of a steady state in these fluids is essential to living things as the lack of it harms the genetic material. The genetic changes, however, may enables new transistasis, in other words, new species.
With regard to any parameter, an organism may be a conformer or a regulator. Regulators try to maintain the parameter at a constant level, regardless of what is happening in its environment. Conformers allow the environment to determine the parameter. For instance, endothermic animals maintain a constant body temperature, while ectothermic animals exhibit wide variation in body temperature.
This is not to say that conformers may not have behavioral adaptations that allow them to exert some control over the parameter in question. For instance, reptiles often sit on sun-heated rocks in the morning to raise their body temperatures.
An advantage of homeostatic regulation and transistatic flexibility is that it allows the organism to function more effectively. For instance, ectotherms tend to become sluggish at low temperatures, whereas endotherms are as active as always. On the other hand, regulation requires energy. One reason snakes are able to eat just once a week is that they use much less energy for maintaining homeostasis.
## Ecological transistasis
Ecological transistasis is found in a climax community of maximum permitted biodiversity, given the prevailing ecological conditions.
In disturbed ecosystems or sub-climax biological communities such as the island of Krakatoa, after its major eruption in 1883, the established stable homeostasis of the previous forest climax ecosystem was destroyed and all life eliminated from the island. Krakatoa, in the years after the eruption went through a sequence of ecological changes in which successive groups of new plant or animal species followed one another, leading to increasing biodiversity and eventually culminating in a re-established climax community. This ecological succession on Krakatoa occurred in a number of several stages, in which a sere is defined as "a stage in a sequence of events by which succession occurs". The complete chain of seres leading to a climax is called a prisere. In the case of Krakatoa, the island as reached its climax community with eight hundred different species being recorded in 1983, one hundred years after the eruption which cleared all life off the island. Evidence confirms that this number has been homeostatic for some time, with the introduction of new species rapidly leading to elimination of old ones.
The evidence of Krakatoa, and other disturbed or virgin ecosystems shows that the initial colonisation by pioneer or R strategy species occurs through positive feedback reproduction strategies, where species are weeds, producing huge numbers of possible offspring, but investing little in the success of any one. Rapid boom and bust plague or pest cycles are observed with such species. As an ecosystem starts to approach climax these species get replaced by more sophisticated climax species which through negative feedback, adapt themselves to specific environmental conditions. These species, closely controlled by carrying capacity, follow K strategies where species produce fewer numbers of potential offspring, but invest more heavily in securing the reproductive success of each one to the micro-environmental conditions of its specific ecological niche.
It begins with a pioneer community and ends with a climax community. This climax community occurs when the ultimate vegetation has become in equilibrium with the local environment.
Such ecosystems form nested communities or heterarchies, in which homeostasis at one level, contributes to homeostatic processes at another holonic level. For example, the loss of leaves on a mature rainforest tree gives a space for new growth, and contributes to the plant litter and soil humus build-up upon which such growth depends. Equally a mature rainforest tree reduces the sunlight falling on the forest floor and helps prevent invasion by other species. But trees too fall to the forest floor and a healthy forest glade is dependent upon a constant rate of forest regrowth, produced by the fall of logs, and the recycling of forest nutrients through the respiration of termites and other insect, fungal and bacterial decomposers. Similarly such forest glades contribute ecological services, such as the regulation of microclimates or of the hydrological cycle for an ecosystem, and a number of different ecosystems act together to maintain homeostasis perhaps of a number of river catchments within a bioregion. A diversity of bioregions similarly makes up a stable homeostatic biological region or biome. And in a few cases the problem to adapt to new environment is solved by the appearance of new living things that are occurred by transistasis.
In the Gaia hypothesis, James Lovelock stated that the entire mass of living matter on Earth (or any planet with life) functions as a vast homeostatic superorganism that actively modifies its planetary environment to produce the environmental conditions necessary for its own survival. In this view, the entire planet maintains homeostasis as the result of transistasis. Whether this sort of system is present on Earth is still open to debate. However, some relatively simple homeostatic mechanisms and potential transistatic possibility are generally accepted. For example, when atmospheric carbon dioxide levels rise, certain plants are able to grow better and thus act to remove more carbon dioxide from the atmosphere. When sunlight is plentiful and atmospheric temperature climbs, the phytoplankton of the ocean surface waters thrive and produce more dimethyl sulfide, DMS. The DMS molecules act as cloud condensation nuclei which produce more clouds and thus increase the atmospheric albedo and this feeds back to lower the temperature of the atmosphere. As scientists discover more about Gaia, vast numbers of positive and negative feedback loops are being discovered, that together maintain a metastable condition, sometimes within very broad range of environmental conditions.
## Medical transistasis
Life conditions can be maintained by (1) keeping the environmental factors within narrow boundaries despite structural and functional abnormalities (homeostasis), (2) keeping balanced functions despite unstable environmental conditions (enantiostasis), or (3) changing the structures and/or functions to maintain physiological viability, e.g.: surgically performed spondylodesis to improve spinal motion, (transistasis).
## Homeostasis and Transistasis in the human body
All sorts of factors affect the suitability of the human body fluids to sustain life; these include properties like temperature, salinity, and acidity, and the concentrations of nutrients such as glucose, various ions, oxygen, and wastes, such as carbon dioxide and urea. Since these properties affect the chemical reactions that keep bodies alive, there are built-in physiological mechanisms to maintain them at desirable levels.
Homeostasis is not the reason for these ongoing unconscious adjustments. It should be thought of as a general characterization of many normal processes in concert, not their proximal cause. Moreover, there are numerous biological phenomena which do not conform to this model, such as anabolism. | Transistasis
Transistasis means the power or tendency of living things to keep changing themselves according to the transformation of circumstances. Transistasis is the antonym of "Homeostasis".
# Overview
Transistasis is the property of an open system, especially living organisms, to reform its functions to maintain a meaningful condition, by means of multiple dynamic equilibrium adjustments, controlled by interrelated regulation mechanisms. The term was coined from the Greek trans (across, beyond, on the opposite side) and stasis (to stand, posture).
The term is born in the sense of biological transistasis but most often used in the sense of sociological transistasis.[1] Multicellular organisms require transistatic new functions in order to live beyond the reformations of the outside world ; many environmentalists believe this principle also applies to the internal environment.
Many ecological, biological, and social systems are homeostatic and transistatic. They almost oppose change to maintain equilibrium but sometimes chose change to keep or get some functions or profits. If the system does not succeed in reestablishing its balance and functions, it may ultimately lead the system to stop functioning.
Complex systems, such as a human body, must have homeostasis and transistasis to maintain stability and to survive. These systems do not only have to endure to survive; they must adapt themselves and evolve to modifications of the environment.
## Examples
- Thermoregulation
The skeletal muscles can shiver to produce heat if the body temperature is too low.
Non-shivering thermogenesis involves the decomposition of fat to produce heat.
Sweating cools the body with the use of evaporation.
- The skeletal muscles can shiver to produce heat if the body temperature is too low.
- Non-shivering thermogenesis involves the decomposition of fat to produce heat.
- Sweating cools the body with the use of evaporation.
- Chemical regulation
The pancreas produces insulin and glucagon to control blood-sugar concentration.
The lungs take in oxygen and give off carbon dioxide.
The kidneys remove urea, and adjust the concentrations of water and a wide variety of ions.
- The pancreas produces insulin and glucagon to control blood-sugar concentration.
- The lungs take in oxygen and give off carbon dioxide.
- The kidneys remove urea, and adjust the concentrations of water and a wide variety of ions.
Most of these organs are controlled by hormones secreted from the pituitary gland, which in turn is directed by the hypothalamus.
## Other fields
The term has come to be used in other fields, as well.
An actuary may refer to risk homeostasis, where (for example) people who have anti-lock brakes have no better safety record than those without anti-lock brakes, because they unconsciously compensate for the safer vehicle via less-safe driving habits. Previously, certain maneuvers involved minor skids, evoking fear and avoidance: now the anti-lock system moves the boundary for such feedback, and behaviour patterns expand into the no-longer punitive area.
Sociologists and psychologists may refer to stress homeostasis, the tendency of a population or an individual to stay at a certain level of stress, often generating artificial stresses if the "natural" level of stress is not enough.
# Transistasis: Topics
## Properties of transistasis
transistatic systems show several properties:
- They are ultraflexible: the system is capable of testing which way its variables should be adjusted.
- Their whole organization (internal, structural, and functional) contributes to the survival of the fittest.
Main examples of transistasis in mammals are as follows:
- The regulation of the amounts of water and minerals in the body. This is known as osmoregulation. This happens in the kidneys.
- The removal of metabolic waste. This is known as excretion. This is done by the excretory organs such as the kidneys and lungs.
- The regulation of body temperature. This is mainly done by the skin.
- The regulation of blood glucose level. This is mainly done by the liver and the insulin secreted by the pancreas in the body.
It is important to note that while organisms exhibit equilibrium, their physiological state is not necessarily static. Many organisms exhibit endogenous fluctuations in the form of circadian (period 20 to 28 hours), ultradian (period <20 hours) and infradian (period > 28 hours) rhythms. Thus in transistasis, body temperature, blood pressure, heart rate and most metabolic indicators are not always at a constant level, but in homeostasis vary predictably over time.
## Mechanisms of transistasis: feedback
Main article: Feedback
When a change of variable occurs, there are two main types of feedback to which the system reacts:
- Negative feedback is a reaction in which the system responds in such a way as to reverse the direction of change. Since this tends to keep things constant, it allows the maintenance of homeostasis. For instance, when the concentration of carbon dioxide in the human body increases, the lungs are signaled to increase their activity and expel more carbon dioxide. Thermoregulation is another example of negative feedback. When body temperature rises (or falls), receptors in the skin and the hypothalamus sense a change, triggering a command from the brain. This command, in turn, effects the correct response, in this case a decrease in body temperature.
- In positive feedback, the response is to amplify the change in the variable. This has a destabilizing effect, so does not result in homeostasis. And such a case have the possibility to change over to transistasis. Positive feedback is less common in naturally occurring systems than negative feedback, but it has its applications. For example, in nerves, a threshold electric potential triggers the generation of a much larger action potential. (See also leverage points.) Blood clotting and events in childbirth are other types of positive feedback. For example, the release of oxytocin to intensify the contractions that take place during childbirth.[2]
Sustainable systems require combinations of both kinds of feedback. Generally with the recognition of divergence from the homeostatic condition positive feedbacks are called into play, whereas once the homeostatic condition is approached, negative feedback is used for "fine tuning" responses. This creates a situation of "metastability", in which homeostatic conditions are maintained within fixed limits, but once these limits are exceeded, the system can shift wildly to a wholly new (and possibly less desirable) situation of homeostasis. Such catastrophic shifts may occur with increasing nutrient load in clear rivers suddenly producing a homeostatic condition of high eutrophication and turbidity, for instance. Thus a few cases of new homeostasis lead to transistasis.
# Transistasis: Applications
## Biological transistasis
Transistasis is one of the fundamental characteristics of living things. It is one of the methods for survival within tolerable limits.
The internal environment of a living organism's body features body fluids in multicellular animals. The body fluids include blood plasma, tissue fluid and intracellular fluid. The maintenance of a steady state in these fluids is essential to living things as the lack of it harms the genetic material. The genetic changes, however, may enables new transistasis, in other words, new species.
With regard to any parameter, an organism may be a conformer or a regulator. Regulators try to maintain the parameter at a constant level, regardless of what is happening in its environment. Conformers allow the environment to determine the parameter. For instance, endothermic animals maintain a constant body temperature, while ectothermic animals exhibit wide variation in body temperature.
This is not to say that conformers may not have behavioral adaptations that allow them to exert some control over the parameter in question. For instance, reptiles often sit on sun-heated rocks in the morning to raise their body temperatures.
An advantage of homeostatic regulation and transistatic flexibility is that it allows the organism to function more effectively. For instance, ectotherms tend to become sluggish at low temperatures, whereas endotherms are as active as always. On the other hand, regulation requires energy. One reason snakes are able to eat just once a week is that they use much less energy for maintaining homeostasis.
## Ecological transistasis
Ecological transistasis is found in a climax community of maximum permitted biodiversity, given the prevailing ecological conditions.
In disturbed ecosystems or sub-climax biological communities such as the island of Krakatoa, after its major eruption in 1883, the established stable homeostasis of the previous forest climax ecosystem was destroyed and all life eliminated from the island. Krakatoa, in the years after the eruption went through a sequence of ecological changes in which successive groups of new plant or animal species followed one another, leading to increasing biodiversity and eventually culminating in a re-established climax community. This ecological succession on Krakatoa occurred in a number of several stages, in which a sere is defined as "a stage in a sequence of events by which succession occurs". The complete chain of seres leading to a climax is called a prisere. In the case of Krakatoa, the island as reached its climax community with eight hundred different species being recorded in 1983, one hundred years after the eruption which cleared all life off the island. Evidence confirms that this number has been homeostatic for some time, with the introduction of new species rapidly leading to elimination of old ones.
The evidence of Krakatoa, and other disturbed or virgin ecosystems shows that the initial colonisation by pioneer or R strategy species occurs through positive feedback reproduction strategies, where species are weeds, producing huge numbers of possible offspring, but investing little in the success of any one. Rapid boom and bust plague or pest cycles are observed with such species. As an ecosystem starts to approach climax these species get replaced by more sophisticated climax species which through negative feedback, adapt themselves to specific environmental conditions. These species, closely controlled by carrying capacity, follow K strategies where species produce fewer numbers of potential offspring, but invest more heavily in securing the reproductive success of each one to the micro-environmental conditions of its specific ecological niche.
It begins with a pioneer community and ends with a climax community. This climax community occurs when the ultimate vegetation has become in equilibrium with the local environment.
Such ecosystems form nested communities or heterarchies, in which homeostasis at one level, contributes to homeostatic processes at another holonic level. For example, the loss of leaves on a mature rainforest tree gives a space for new growth, and contributes to the plant litter and soil humus build-up upon which such growth depends. Equally a mature rainforest tree reduces the sunlight falling on the forest floor and helps prevent invasion by other species. But trees too fall to the forest floor and a healthy forest glade is dependent upon a constant rate of forest regrowth, produced by the fall of logs, and the recycling of forest nutrients through the respiration of termites and other insect, fungal and bacterial decomposers. Similarly such forest glades contribute ecological services, such as the regulation of microclimates or of the hydrological cycle for an ecosystem, and a number of different ecosystems act together to maintain homeostasis perhaps of a number of river catchments within a bioregion. A diversity of bioregions similarly makes up a stable homeostatic biological region or biome. And in a few cases the problem to adapt to new environment is solved by the appearance of new living things that are occurred by transistasis.
In the Gaia hypothesis, James Lovelock stated that the entire mass of living matter on Earth (or any planet with life) functions as a vast homeostatic superorganism that actively modifies its planetary environment to produce the environmental conditions necessary for its own survival. In this view, the entire planet maintains homeostasis as the result of transistasis. Whether this sort of system is present on Earth is still open to debate. However, some relatively simple homeostatic mechanisms and potential transistatic possibility are generally accepted. For example, when atmospheric carbon dioxide levels rise, certain plants are able to grow better and thus act to remove more carbon dioxide from the atmosphere. When sunlight is plentiful and atmospheric temperature climbs, the phytoplankton of the ocean surface waters thrive and produce more dimethyl sulfide, DMS. The DMS molecules act as cloud condensation nuclei which produce more clouds and thus increase the atmospheric albedo and this feeds back to lower the temperature of the atmosphere. As scientists discover more about Gaia, vast numbers of positive and negative feedback loops are being discovered, that together maintain a metastable condition, sometimes within very broad range of environmental conditions.
## Medical transistasis
Life conditions can be maintained by (1) keeping the environmental factors within narrow boundaries despite structural and functional abnormalities (homeostasis), (2) keeping balanced functions despite unstable environmental conditions (enantiostasis), or (3) changing the structures and/or functions to maintain physiological viability, e.g.: surgically performed spondylodesis to improve spinal motion, (transistasis).[3]
## Homeostasis and Transistasis in the human body
All sorts of factors affect the suitability of the human body fluids to sustain life; these include properties like temperature, salinity, and acidity, and the concentrations of nutrients such as glucose, various ions, oxygen, and wastes, such as carbon dioxide and urea. Since these properties affect the chemical reactions that keep bodies alive, there are built-in physiological mechanisms to maintain them at desirable levels.
Homeostasis is not the reason for these ongoing unconscious adjustments. It should be thought of as a general characterization of many normal processes in concert, not their proximal cause. Moreover, there are numerous biological phenomena which do not conform to this model, such as anabolism. | https://www.wikidoc.org/index.php/Transistasis | |
78309919c6bd11f026a7649c7bffcda8ddc13525 | wikidoc | Translations | Translations
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This information courtesy of Wikipedia and its contributors,version ID=36515590 | Translations
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Linking to a page translation
- There are currently wiki docs in development in English, Romanian, Russian, Spanish, and Chinese.
- To include a link to a translation of a page (whether or not the translation yet exists), insert (for each language) a line as follows:
[[es:Name of Page in Spanish]]
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Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Translations | |
0292fd013d0c709ca43bd9bbc3b520362359b728 | wikidoc | Traumatology | Traumatology
Traumatology (from Greek "Trauma" meaning injury or wound), is the study of wounds and injuries caused by accidents or violence to a person, and the surgical therapy and repair of the damage. Traumatology is a branch of medicine. It is often considered a subset of surgery and in countries without the specialty of trauma surgery it is most often a subspecialty to orthopedic surgery. Traumatology may also be known as accident surgery.
Wounds and injuries are assessed as being serious or not serious (a process known as triage) upon admission to a hospital's Casualty department (Accident and Emergency A and E in UK, Emergency Room ER in US). A wound is usually caused by mechanical force, or sometimes by chemical reactions as in the case of burns.
Factors in the assessment of wounds are:
- the nature of the wound, whether it is a laceration, abrasion, bruise or burn
- the size of the wound in length, width and depth
- the extent of the overall area of tissue damage caused by the impact of a mechanical force, or the reaction to chemical agents in, for example, fires or exposure to caustic substances.
Forensic physicians, as well as pathologists may also be required to examine wounds (traumas) on persons alive or deceased.
Traumatology can also refer to the study, development and application of pyschological and counselling services for people who have experienced extreme events - e.g. see Wiki Glossary of Traumatology under External Links | Traumatology
Traumatology (from Greek "Trauma" meaning injury or wound), is the study of wounds and injuries caused by accidents or violence to a person, and the surgical therapy and repair of the damage. Traumatology is a branch of medicine. It is often considered a subset of surgery and in countries without the specialty of trauma surgery it is most often a subspecialty to orthopedic surgery. Traumatology may also be known as accident surgery.
Wounds and injuries are assessed as being serious or not serious (a process known as triage) upon admission to a hospital's Casualty department (Accident and Emergency A and E in UK, Emergency Room ER in US). A wound is usually caused by mechanical force, or sometimes by chemical reactions as in the case of burns.
Factors in the assessment of wounds are:
- the nature of the wound, whether it is a laceration, abrasion, bruise or burn
- the size of the wound in length, width and depth
- the extent of the overall area of tissue damage caused by the impact of a mechanical force, or the reaction to chemical agents in, for example, fires or exposure to caustic substances.
Forensic physicians, as well as pathologists may also be required to examine wounds (traumas) on persons alive or deceased.
Traumatology can also refer to the study, development and application of pyschological and counselling services for people who have experienced extreme events - e.g. see Wiki Glossary of Traumatology under External Links | https://www.wikidoc.org/index.php/Traumatology | |
90604273fa0005d47b3d50cba9b102a594041342 | wikidoc | Tremelimumab | Tremelimumab
Tremelimumab (anti-CTLA4 human monoclonal antibody CP-675,206) (formerly ticilimumab) is a fully human monoclonal antibody produced by Pfizer. It binds to the CTLA-4 molecule, which is expressed on the surface of activated T lymphocytes. Tremelimumab binds to CTLA4 and blocks the binding of the antigen-presenting cell ligands B7-1 and B7-2 to CTLA4, resulting in inhibition of B7-CTLA4-mediated downregulation of T-cell activation; subsequently, B7-1 or B7-2 may interact with another T-cell surface receptor protein, CD28, resulting in a B7-CD28-mediated T-cell activation unopposed by B7-CTLA4-mediated inhibition.
Tremelimumab is thought to stimulate patients’ immune systems to attack their tumors. Tremelimumab has been shown to induce durable tumor responses in patients with metastatic melanoma in Phase 1 and Phase 2 clinical studies. See Reuben JM et al., Biologic and immunomodulatory events after CTLA-4 blockade with tremelimumab in patients with advanced malignant melanoma. Cancer. 2006 Jun 1;106 (11):2437-44.
As of June 2007 there are two fully human anti CTLA-4 monoclonal antibodies in advanced clinical trials. Tremelimumab (from Pfizer) is an IgG2, and Ipilimumab (from Medarex and Bristol-Myers Squibb). | Tremelimumab
Template:Drugbox-mab
Tremelimumab (anti-CTLA4 human monoclonal antibody CP-675,206) (formerly ticilimumab) is a fully human monoclonal antibody produced by Pfizer. It binds to the CTLA-4 molecule, which is expressed on the surface of activated T lymphocytes. Tremelimumab binds to CTLA4 and blocks the binding of the antigen-presenting cell ligands B7-1 and B7-2 to CTLA4, resulting in inhibition of B7-CTLA4-mediated downregulation of T-cell activation; subsequently, B7-1 or B7-2 may interact with another T-cell surface receptor protein, CD28, resulting in a B7-CD28-mediated T-cell activation unopposed by B7-CTLA4-mediated inhibition.
Tremelimumab is thought to stimulate patients’ immune systems to attack their tumors. Tremelimumab has been shown to induce durable tumor responses in patients with metastatic melanoma in Phase 1 and Phase 2 clinical studies. See Reuben JM et al., Biologic and immunomodulatory events after CTLA-4 blockade with tremelimumab in patients with advanced malignant melanoma. Cancer. 2006 Jun 1;106 (11):2437-44.
As of June 2007 there are two fully human anti CTLA-4 [1] monoclonal antibodies in advanced clinical trials. Tremelimumab (from Pfizer) is an IgG2, and Ipilimumab (from Medarex and Bristol-Myers Squibb).
Template:Humanmonoclonals | https://www.wikidoc.org/index.php/Tremelimumab | |
301cbc4ce4c8a41f2f1f058d9c61a891bbe1b7f0 | wikidoc | Triceps suræ | Triceps suræ
The triceps surae is a term given by some anatomists to the gastrocnemius and soleus muscles together as they both insert into the calcaneus, the bone of the heel of the human foot, and form the major part of the muscle of the back part of the lower leg (the calf; otherwise known in Latin as the sura, see also the sural nerve).
Considering these 2 muscles as one, the triceps surae inserts into the Achilles' tendon (tendo calcanei) and has 3 heads deriving from the 2 major masses of muscle.
- The superficial portion (the gastrocnemius) gives off 2 heads attaching to the base of the femur directly above the knee.
- The deep (profundis) mass of muscle (the soleus) forms the remaining head which attaches to the superior posterior area of the tibia.
The triceps surae is innervated by the tibial nerve, specifically, nerve roots L5–S2. | Triceps suræ
Template:Infobox Muscle
The triceps surae is a term given by some anatomists to the gastrocnemius and soleus muscles together as they both insert into the calcaneus, the bone of the heel of the human foot, and form the major part of the muscle of the back part of the lower leg (the calf; otherwise known in Latin as the sura, see also the sural nerve).
Considering these 2 muscles as one, the triceps surae inserts into the Achilles' tendon (tendo calcanei) and has 3 heads deriving from the 2 major masses of muscle.
- The superficial portion (the gastrocnemius) gives off 2 heads attaching to the base of the femur directly above the knee.
- The deep (profundis) mass of muscle (the soleus) forms the remaining head which attaches to the superior posterior area of the tibia.
The triceps surae is innervated by the tibial nerve, specifically, nerve roots L5–S2. | https://www.wikidoc.org/index.php/Triceps_sur%C3%A6 | |
eece6ecf471ba1e9c0da827b333261eb7e63b088 | wikidoc | Trichohyalin | Trichohyalin
Trichohyalin is a protein that in mammals is encoded by the TCHH gene.
# Discovery
In 1903 the name “trichohyalin” was assigned to the granules of the inner root sheath (IRS) of hair follicles discovered by H. Voerner. In 1986 the name was re-assigned to a protein isolated from sheep wool follicles.
# Gene location
The human TCHH is located on the long (q) arm of chromosome 1 at region 2 band 1 sub-band 3 (1q21.3), from base pair 152,105,403 to base pair 152,116,368 (map). This region in chromosome 1q21 is known as the epidermal differentiation complex, since it harbors over fifty other genes involved in keratinocyte differentiation.
Gene coding sequence contains 5829 nucleotides. Gene orthologs were identified in most mammals including mice, chickens, rats, pigs, sheep, horses and other species.
# Protein localisation
Trichohyalin is highly expressed in the inner root sheath cells of the hair follicle and medulla. It was also detected in the granular layer and stratum corneum of normal epidermis , newborn human foreskin epidermis, the hard palate, in the nail matrix, the filiform papillae of dorsal tongue epithelium and in rodent forestomack.
# Function
The protein forms frequent links between the heads and tails of the keratin chains and, thus, participates in keratin intermediate filaments (KIF) inter-filamentous cross-linking. It also carries a function of a major reinforcement cross-bridging protein for the cell envelope (CE) barrier structure of the IRS and participates in coordination of CE structure.
Overall, trichohyalin confers mechanical strength to the hair follicle inner root sheath and to other toughened epithelial tissues.
# Structure
Trichohyalin belongs to the S100-fused protein family. It is a monomer, containing 1943 amino acids, and has elongated (>200 nm) single-stranded alpha-helical conformation based on its unusually high content of charged residues.
Molecular mass of the human trichohyalin is 253925 Da.
The protein includes nine domains. Domain 1 contains two EF-hand calcium-binding domains. Domains 2-4, 6, and 8 are almost entirely alpha-helical, configured as a series of peptide repeats of varying regularity, and are thought to form a single-stranded alpha-helical rod stabilised by ionic interactions. Domain 6 is the most regular and may bind KIF directly by ionic interactions. Domains 5 and 7 are less well organised and may induce folds in the molecule. Domain 9 contains the C-terminus, conserved among different species.
# Post-translational modifications
- Peptidylarginine deiminases (PAD) catalyse the deimination of arginine residues to citrullines.
- Cross-linking by transglutaminase (TGase) enzymes results in the formation of an isopeptide bond between peptide-bound glutamine and lysine residues and provide insolubility and the rigid structure to trichohyalin.
# Interactions
TCHH protein is extensively cross-linked to itself in the IRS tissue as well as to keratin intermediate filaments (KIF). All TCHH-keratin links involved only domain 6 or 8 sequences.
The protein can also form cross-links to all other CE proteins including involucrin, envoplakin, keratin, repetin, desmoplakin, SPR1, SPR2, and LEP.
TCHH-TCHH and TCHH-CE protein links are distributed among domains 2–5, but are uncommon in domains 6 and 8. Most intra-THH cross-links occurred in the least organised domain 5 region at a 3.5-fold higher frequency.
# Clinical significance
Trichohyalin is associated with uncombable hair syndrome , human alopecia areata and also may be linked to curly hair phenotype in Europeans.
A weak expression of the protein was discovered in the horny layer of psoriasis, ichthyosis, keratosis pilaris, porokeratosis, chronic dermatitis and callus. The same level of trichohyalin expression was found in epidermal tumours (seborrheic keratosis, actinic keratosis, Bowen's disease, well-differentiated squamous cell carcinoma) and follicular tumours (trichoepithelioma, keratotic basal cell epithelioma, proliferating trichilemmal tumour, trichilemmoma, pilomatricoma and keratoacanthoma). | Trichohyalin
Trichohyalin is a protein that in mammals is encoded by the TCHH gene.[1]
# Discovery
In 1903 the name “trichohyalin” was assigned to the granules of the inner root sheath (IRS) of hair follicles discovered by H. Voerner.[2] In 1986 the name was re-assigned to a protein isolated from sheep wool follicles.[3]
# Gene location
The human TCHH is located on the long (q) arm of chromosome 1 at region 2 band 1 sub-band 3 (1q21.3), from base pair 152,105,403 to base pair 152,116,368 (map).[4] This region in chromosome 1q21 is known as the epidermal differentiation complex, since it harbors over fifty other genes involved in keratinocyte differentiation.
Gene coding sequence contains 5829 nucleotides.[5] Gene orthologs were identified in most mammals including mice, chickens, rats, pigs, sheep, horses and other species.[6]
# Protein localisation
Trichohyalin is highly expressed in the inner root sheath cells of the hair follicle and medulla.[7] It was also detected in the granular layer and stratum corneum of normal epidermis [8], newborn human foreskin epidermis, the hard palate, in the nail matrix, the filiform papillae of dorsal tongue epithelium and in rodent forestomack.[9]
# Function
The protein forms frequent links between the heads and tails of the keratin chains and, thus, participates in keratin intermediate filaments (KIF) inter-filamentous cross-linking. It also carries a function of a major reinforcement cross-bridging protein for the cell envelope (CE) barrier structure of the IRS and participates in coordination of CE structure.[7]
Overall, trichohyalin confers mechanical strength to the hair follicle inner root sheath and to other toughened epithelial tissues. [7]
# Structure
Trichohyalin belongs to the S100-fused protein family. It is a monomer, containing 1943 amino acids[10], and has elongated (>200 nm) single-stranded alpha-helical conformation based on its unusually high content of charged residues.[11]
Molecular mass of the human trichohyalin is 253925 Da.[10]
The protein includes nine domains. Domain 1 contains two EF-hand calcium-binding domains. Domains 2-4, 6, and 8 are almost entirely alpha-helical, configured as a series of peptide repeats of varying regularity, and are thought to form a single-stranded alpha-helical rod stabilised by ionic interactions. Domain 6 is the most regular and may bind KIF directly by ionic interactions. Domains 5 and 7 are less well organised and may induce folds in the molecule. Domain 9 contains the C-terminus, conserved among different species.[10][11]
# Post-translational modifications
- Peptidylarginine deiminases (PAD) catalyse the deimination of arginine residues to citrullines.[12]
- Cross-linking by transglutaminase (TGase) enzymes results in the formation of an isopeptide bond between peptide-bound glutamine and lysine residues and provide insolubility and the rigid structure to trichohyalin.[12]
# Interactions
TCHH protein is extensively cross-linked to itself in the IRS tissue as well as to keratin intermediate filaments (KIF). All TCHH-keratin links involved only domain 6 or 8 sequences.[7]
The protein can also form cross-links to all other CE proteins including involucrin, envoplakin, keratin, repetin, desmoplakin, SPR1, SPR2, and LEP.[7]
TCHH-TCHH and TCHH-CE protein links are distributed among domains 2–5, but are uncommon in domains 6 and 8. Most intra-THH cross-links occurred in the least organised domain 5 region at a 3.5-fold higher frequency.[7]
# Clinical significance
Trichohyalin is associated with uncombable hair syndrome [13], human alopecia areata [14] and also may be linked to curly hair phenotype in Europeans.[15]
A weak expression of the protein was discovered in the horny layer of psoriasis, ichthyosis, keratosis pilaris, porokeratosis, chronic dermatitis and callus.[16] The same level of trichohyalin expression was found in epidermal tumours (seborrheic keratosis, actinic keratosis, Bowen's disease, well-differentiated squamous cell carcinoma) and follicular tumours (trichoepithelioma, keratotic basal cell epithelioma, proliferating trichilemmal tumour, trichilemmoma, pilomatricoma and keratoacanthoma).[16] | https://www.wikidoc.org/index.php/Trichohyalin | |
e15909c1d8bd196463d60eb35dc12f1f5253623b | wikidoc | Trifluridine | Trifluridine
# 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
Trifluridine is an antiviral that is FDA approved for the treatment of primary keratoconjunctivitis and recurrent epithelial keratitis due to herpes simplex virus, types 1 and 2. Common adverse reactions include burning sensation in eye, edema, palpebral.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Trifluridine Ophthalmic Solution is indicated for the treatment of primary keratoconjunctivitis and recurrent epithelial keratitis due to herpes simplex virus, types 1 and 2.
- Instill one drop of Trifluridine Ophthalmic Solution onto the cornea of the affected eye every 2 hours while awake for a maximum daily dosage of nine drops until the cornea ulcer has completely re-epithelialized. Following re-epithelialization, treatment for an additional 7 days of one drop every 4 hours while awake for a minimum daily dosage of five drops is recommended.
- If there are no signs of improvement after 7 days of therapy or complete re-epithelialization has not occurred after 14 days of therapy, other forms of therapy should be considered. Continuous administration of trifluridine for periods exceeding 21 days should be avoided because of potential ocular toxicity.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Trifluridine in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Trifluridine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Trifluridine in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Trifluridine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Trifluridine in pediatric patients.
# Contraindications
- Trifluridine Ophthalmic Solution is contraindicated for patients who develop hypersensitivity reactions or chemical intolerance to trifluridine.
# Warnings
- The recommended dosage and frequency of administration should not be exceeded.
# Adverse Reactions
## Clinical Trials Experience
There is limited information regarding Clinical Trial Experience of Trifluridine in the drug label.
## Postmarketing Experience
- The most frequent adverse reactions reported during controlled clinical trials were mild, transient burning or stinging upon instillation (4.6%) and palpebral edema (2.8%). Other adverse reactions in decreasing order of reported frequency were superficial punctate keratopathy, epithelial keratopathy, hypersensitivity reaction, stromal edema, irritation, keratitis sicca, hyperemia, and increased intraocular pressure.
# Drug Interactions
- Drug
- Description
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Trifluridine was not teratogenic at doses up to 5 mg/kg/day (23 times the estimated human exposure) when given subcutaneously to rats and rabbits. However, fetal toxicity consisting of delayed ossification of portions of the skeleton occurred at dose levels of 2.5 and 5 mg /kg /day in rats and at 2.5 mg/kg/day in rabbits. In addition, both 2.5 and 5 mg/kg/day produced fetal death and resorption in rabbits. In both rats and rabbits, 1 mg/kg/day (5 times the estimated human exposure) was a no-effect level. There were no teratogenic or fetotoxic effects after topical application of trifluridine (approximately 5 times the estimated human exposure) to the eyes of rabbits on the 6th through the 18th days of pregnancy. In a non-standard test, trifluridine solution has been shown to be teratogenic when injected directly into the yolk sac of chicken eggs. There are no adequate and well-controlled studies in pregnant women. Trifluridine Ophthalmic Solution should be used during pregnancy only if the potential benefit justifies the potential 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 Trifluridine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Trifluridine during labor and delivery.
### Nursing Mothers
- It is unlikely that trifluridine is excreted in human milk after ophthalmic instillation of trifluridine because of the relatively small dosage (≤ 5mg/day), its dilution in body fluids and its extremely short half-life (approximately 12 minutes). The drug should not be prescribed for nursing mothers unless the potential benefits outweigh the potential risks.
### Pediatric Use
Safety and effectiveness in pediatric patients below six years of age have not been established.
### Geriatic Use
No overall differences in safety or effectiveness have been observed between elderly and younger patients.
### Gender
There is no FDA guidance on the use of Trifluridine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Trifluridine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Trifluridine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Trifluridine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Trifluridine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Trifluridine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
- Intravenous
### Monitoring
There is limited information regarding Monitoring of Trifluridine in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Trifluridine in the drug label.
# Overdosage
Overdosage by ocular instillation is unlikely because any excess solution should be quickly expelled from the conjunctival sac.
Acute overdosage by accidental oral ingestion of trifluridine has not occurred. However, should such ingestion occur, the 75 mg dosage of trifluridine in a 7.5 mL bottle of Trifluridine Ophthalmic Solution is not likely to produce adverse effects. Single intravenous doses of 1.5 to 30 mg/kg/day in children and adults with neoplastic disease produce reversible bone marrow depression as the only potentially serious toxic effect and only after three to five courses of therapy. The acute oral LD50 in the mouse and rat was 4379 mg/kg or higher.
# Pharmacology
There is limited information regarding Trifluridine Pharmacology in the drug label.
## Mechanism of Action
## Structure
- Trifluridine Ophthalmic Solution (also known as trifluorothymidine, F3TdR, F3T), an antiviral drug for topical treatment of epithelial keratitis caused by herpes simplex virus. The chemical name of trifluridine is α,α,α-trifluorothymidine. Trifluridine has the following structural formula.
- Trifluridine sterile ophthalmic solution contains 1% trifluridine in an aqueous solution with acetic acid and sodium acetate (buffers), sodium chloride, and thimerosal 0.001% (added as a preservative). The pH range is 5.5 to 6.0 and osmolality is approximately 283 mOsm.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Trifluridine in the drug label.
## Pharmacokinetics
- Trifluridine is a fluorinated pyrimidine nucleoside with in vitro and in vivo activity against herpes simplex virus, types 1 and 2 and vacciniavirus. Some strains of adenovirus are also inhibited in vitro.
- Trifluridine is also effective in the treatment of epithelial keratitis that has not responded clinically to the topical administration of idoxuridine or when ocular toxicity or hypersensitivity to idoxuridine has occurred. In a smaller number of patients found to be resistant to topical vidarabine, trifluridine was also effective.
- Trifluridine interferes with DNA synthesis in cultured mammalian cells. However, its antiviral mechanism of action is not completely known.
- In vitro perfusion studies on excised rabbit corneas have shown that trifluridine penetrates the intact cornea as evidenced by recovery of parental drug and its major metabolite, 5-carboxy-2´-deoxyuridine, on the endothelial side of the cornea. Absence of the corneal epithelium enhances the penetration of trifluridine approximately two-fold.
- Intraocular penetration of trifluridine occurs after topical instillation of trifluridine into human eyes. Decreased corneal integrity or stromal or uveal inflammation may enhance the penetration of trifluridine into the aqueous humor. Unlike the results of ocular penetration of trifluridine in vitro, 5-carboxy-2´-deoxyuridine was not found in detectable concentrations within the aqueous humor of the human eye.
- Systemic absorption of trifluridine following therapeutic dosing with trifluridine appears to be negligible. No detectable concentrations of trifluridine or 5-carboxy-2´-deoxyuridine were found in the sera of adult healthy normal subjects who had trifluridine instilled into their eyes seven times daily for 14 consecutive days.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Trifluridine in the drug label.
# Clinical Studies
- Clinical Studies: During a controlled multicenter clinical trial, 92 of 97 (95%) patients (78 of 81 with dendritic and 14 of 16 with geographic ulcers) responded to therapy with trifluridine as evidenced by complete corneal re-epithelialization within the 14-day therapy period. Fifty-six of 75 (75%) patients (49 of 58 with dendritic and 7 of 17 with geographic ulcers) responded to idoxuridine therapy. The mean time to corneal reepithelialization for dendritic ulcers (6 days) and geographic ulcers (7 days) was similar for both therapies.
- In other clinical studies, trifluridine was evaluated in the treatment of herpes simplex virus keratitis in patients who were unresponsive or intolerant to the topical administration of idoxuridine or vidarabine. Trifluridine was effective in 138 of 150 (92%) patients (109 of 114 with dendritic and 29 of 36 with geographic ulcers) as evidenced by corneal re-epithelialization. The mean time to corneal re-epithelialization was 6 days for patients with dendritic ulcers and 12 days for patients with geographic ulcers.
- The clinical efficacy of trifluridine in the treatment of stromal keratitis and uveitis due to herpes simplex virus or ophthalmic infections caused by vacciniavirus and adenovirus has not been established by well-controlled clinical trials. Trifluridine has not been shown to be effective in the prophylaxis of herpes simplex virus keratoconjunctivitis and epithelial keratitis by well-controlled clinical trials. Trifluridine is not effective against bacterial, fungal or chlamydial infections of the cornea or nonviral trophic lesions.
# How Supplied
- Trifluridine Ophthalmic Solution, 1% in a 7.5 mL fill packaged in a natural plastic bottle with a natural plastic flat tip and a white plastic closure.
## Storage
Store under refrigeration 2°-8°C (36°-46°F).
# Images
## Drug Images
## Package and Label Display Panel
[File:Tri 03.jpg
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Trifluridine in the drug label.
# Precautions with Alcohol
- Alcohol-Trifluridine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- TRIFLURIDINE ®
# Look-Alike Drug Names
There is limited information regarding Trifluridine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Trifluridine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, 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
Trifluridine is an antiviral that is FDA approved for the treatment of primary keratoconjunctivitis and recurrent epithelial keratitis due to herpes simplex virus, types 1 and 2. Common adverse reactions include burning sensation in eye, edema, palpebral.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Trifluridine Ophthalmic Solution is indicated for the treatment of primary keratoconjunctivitis and recurrent epithelial keratitis due to herpes simplex virus, types 1 and 2.
- Instill one drop of Trifluridine Ophthalmic Solution onto the cornea of the affected eye every 2 hours while awake for a maximum daily dosage of nine drops until the cornea ulcer has completely re-epithelialized. Following re-epithelialization, treatment for an additional 7 days of one drop every 4 hours while awake for a minimum daily dosage of five drops is recommended.
- If there are no signs of improvement after 7 days of therapy or complete re-epithelialization has not occurred after 14 days of therapy, other forms of therapy should be considered. Continuous administration of trifluridine for periods exceeding 21 days should be avoided because of potential ocular toxicity.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Trifluridine in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Trifluridine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Trifluridine in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Trifluridine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Trifluridine in pediatric patients.
# Contraindications
- Trifluridine Ophthalmic Solution is contraindicated for patients who develop hypersensitivity reactions or chemical intolerance to trifluridine.
# Warnings
- The recommended dosage and frequency of administration should not be exceeded.
# Adverse Reactions
## Clinical Trials Experience
There is limited information regarding Clinical Trial Experience of Trifluridine in the drug label.
## Postmarketing Experience
- The most frequent adverse reactions reported during controlled clinical trials were mild, transient burning or stinging upon instillation (4.6%) and palpebral edema (2.8%). Other adverse reactions in decreasing order of reported frequency were superficial punctate keratopathy, epithelial keratopathy, hypersensitivity reaction, stromal edema, irritation, keratitis sicca, hyperemia, and increased intraocular pressure.
# Drug Interactions
- Drug
- Description
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Trifluridine was not teratogenic at doses up to 5 mg/kg/day (23 times the estimated human exposure) when given subcutaneously to rats and rabbits. However, fetal toxicity consisting of delayed ossification of portions of the skeleton occurred at dose levels of 2.5 and 5 mg /kg /day in rats and at 2.5 mg/kg/day in rabbits. In addition, both 2.5 and 5 mg/kg/day produced fetal death and resorption in rabbits. In both rats and rabbits, 1 mg/kg/day (5 times the estimated human exposure) was a no-effect level. There were no teratogenic or fetotoxic effects after topical application of trifluridine (approximately 5 times the estimated human exposure) to the eyes of rabbits on the 6th through the 18th days of pregnancy. In a non-standard test, trifluridine solution has been shown to be teratogenic when injected directly into the yolk sac of chicken eggs. There are no adequate and well-controlled studies in pregnant women. Trifluridine Ophthalmic Solution should be used during pregnancy only if the potential benefit justifies the potential 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 Trifluridine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Trifluridine during labor and delivery.
### Nursing Mothers
- It is unlikely that trifluridine is excreted in human milk after ophthalmic instillation of trifluridine because of the relatively small dosage (≤ 5mg/day), its dilution in body fluids and its extremely short half-life (approximately 12 minutes). The drug should not be prescribed for nursing mothers unless the potential benefits outweigh the potential risks.
### Pediatric Use
Safety and effectiveness in pediatric patients below six years of age have not been established.
### Geriatic Use
No overall differences in safety or effectiveness have been observed between elderly and younger patients.
### Gender
There is no FDA guidance on the use of Trifluridine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Trifluridine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Trifluridine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Trifluridine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Trifluridine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Trifluridine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
- Intravenous
### Monitoring
There is limited information regarding Monitoring of Trifluridine in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Trifluridine in the drug label.
# Overdosage
Overdosage by ocular instillation is unlikely because any excess solution should be quickly expelled from the conjunctival sac.
Acute overdosage by accidental oral ingestion of trifluridine has not occurred. However, should such ingestion occur, the 75 mg dosage of trifluridine in a 7.5 mL bottle of Trifluridine Ophthalmic Solution is not likely to produce adverse effects. Single intravenous doses of 1.5 to 30 mg/kg/day in children and adults with neoplastic disease produce reversible bone marrow depression as the only potentially serious toxic effect and only after three to five courses of therapy. The acute oral LD50 in the mouse and rat was 4379 mg/kg or higher.
# Pharmacology
There is limited information regarding Trifluridine Pharmacology in the drug label.
## Mechanism of Action
-
## Structure
- Trifluridine Ophthalmic Solution (also known as trifluorothymidine, F3TdR, F3T), an antiviral drug for topical treatment of epithelial keratitis caused by herpes simplex virus. The chemical name of trifluridine is α,α,α-trifluorothymidine. Trifluridine has the following structural formula.
- Trifluridine sterile ophthalmic solution contains 1% trifluridine in an aqueous solution with acetic acid and sodium acetate (buffers), sodium chloride, and thimerosal 0.001% (added as a preservative). The pH range is 5.5 to 6.0 and osmolality is approximately 283 mOsm.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Trifluridine in the drug label.
## Pharmacokinetics
- Trifluridine is a fluorinated pyrimidine nucleoside with in vitro and in vivo activity against herpes simplex virus, types 1 and 2 and vacciniavirus. Some strains of adenovirus are also inhibited in vitro.
- Trifluridine is also effective in the treatment of epithelial keratitis that has not responded clinically to the topical administration of idoxuridine or when ocular toxicity or hypersensitivity to idoxuridine has occurred. In a smaller number of patients found to be resistant to topical vidarabine, trifluridine was also effective.
- Trifluridine interferes with DNA synthesis in cultured mammalian cells. However, its antiviral mechanism of action is not completely known.
- In vitro perfusion studies on excised rabbit corneas have shown that trifluridine penetrates the intact cornea as evidenced by recovery of parental drug and its major metabolite, 5-carboxy-2´-deoxyuridine, on the endothelial side of the cornea. Absence of the corneal epithelium enhances the penetration of trifluridine approximately two-fold.
- Intraocular penetration of trifluridine occurs after topical instillation of trifluridine into human eyes. Decreased corneal integrity or stromal or uveal inflammation may enhance the penetration of trifluridine into the aqueous humor. Unlike the results of ocular penetration of trifluridine in vitro, 5-carboxy-2´-deoxyuridine was not found in detectable concentrations within the aqueous humor of the human eye.
- Systemic absorption of trifluridine following therapeutic dosing with trifluridine appears to be negligible. No detectable concentrations of trifluridine or 5-carboxy-2´-deoxyuridine were found in the sera of adult healthy normal subjects who had trifluridine instilled into their eyes seven times daily for 14 consecutive days.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Trifluridine in the drug label.
# Clinical Studies
- Clinical Studies: During a controlled multicenter clinical trial, 92 of 97 (95%) patients (78 of 81 with dendritic and 14 of 16 with geographic ulcers) responded to therapy with trifluridine as evidenced by complete corneal re-epithelialization within the 14-day therapy period. Fifty-six of 75 (75%) patients (49 of 58 with dendritic and 7 of 17 with geographic ulcers) responded to idoxuridine therapy. The mean time to corneal reepithelialization for dendritic ulcers (6 days) and geographic ulcers (7 days) was similar for both therapies.
- In other clinical studies, trifluridine was evaluated in the treatment of herpes simplex virus keratitis in patients who were unresponsive or intolerant to the topical administration of idoxuridine or vidarabine. Trifluridine was effective in 138 of 150 (92%) patients (109 of 114 with dendritic and 29 of 36 with geographic ulcers) as evidenced by corneal re-epithelialization. The mean time to corneal re-epithelialization was 6 days for patients with dendritic ulcers and 12 days for patients with geographic ulcers.
- The clinical efficacy of trifluridine in the treatment of stromal keratitis and uveitis due to herpes simplex virus or ophthalmic infections caused by vacciniavirus and adenovirus has not been established by well-controlled clinical trials. Trifluridine has not been shown to be effective in the prophylaxis of herpes simplex virus keratoconjunctivitis and epithelial keratitis by well-controlled clinical trials. Trifluridine is not effective against bacterial, fungal or chlamydial infections of the cornea or nonviral trophic lesions.
# How Supplied
- Trifluridine Ophthalmic Solution, 1% in a 7.5 mL fill packaged in a natural plastic bottle with a natural plastic flat tip and a white plastic closure.
## Storage
Store under refrigeration 2°-8°C (36°-46°F).
# Images
## Drug Images
## Package and Label Display Panel
[File:Tri 03.jpg
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Trifluridine in the drug label.
# Precautions with Alcohol
- Alcohol-Trifluridine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- TRIFLURIDINE ®[1]
# Look-Alike Drug Names
There is limited information regarding Trifluridine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Trifluridine | |
22c8dc66316f26a8850ef6a8c86d0398e8e88b7b | wikidoc | Trimetrexate | Trimetrexate
# 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
Trimetrexate is an antibiotic that is FDA approved for the treatment of moderate-to-severe Pneumocystis carinii pneumonia (PCP) in immunocompromised patients, including patients with the acquired immunodeficiency syndrome (AIDS), who are intolerant of, or are refractory to, trimethoprim-sulfamethoxazole therapy or for whom trimethoprim-sulfamethoxazole is contraindicated. There is a Black Box Warning for this drug as shown here. Common adverse reactions include hypersensitivity.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Trimetrexate glucuronate for injection with concurrent leucovorin administration (leucovorin protection) is indicated as an alternative therapy for the treatment of moderate-to-severe Pneumocystis carinii pneumonia (PCP) in immunocompromised patients, including patients with the acquired immunodeficiency syndrome (AIDS), who are intolerant of, or are refractory to, trimethoprim-sulfamethoxazole therapy or for whom trimethoprim-sulfamethoxazole is contraindicated.
- This indication is based on the results of a randomized, controlled double-blind trial comparing Neutrexin with concurrent leucovorin protection (TMTX/LV) to trimethoprim‑sulfamethoxazole (TMP/SMX) in patients with moderate-to-severe Pneumocystis carinii pneumonia, as well as results of a Treatment IND. These studies are summarized below:
- This double-blind, randomized trial initiated by the AIDS Clinical Trials Group (ACTG) in 1988 was designed to compare the safety and efficacy of TMTX/LV to that of TMP/SMX for the treatment of histologically confirmed, moderate-to-severe PCP, defined as (A-a) baseline gradient >30 mmHg, in patients with AIDS.
- Of the 220 patients with histologically confirmed PCP, 109 were randomized to receive TMTX/LV and 111 to TMP/SMX. Study patients randomized to TMTX/LV treatment were to receive 45 mg/m2 of TMTX daily for 21 days plus 20 mg/m2 of LV every 6 hours for 24 days. Those randomized to TMP/SMX were to receive 5 mg/kg TMP plus 25 mg/kg SMX four times daily for 21 days.
- Response to therapy, defined as alive and off ventilatory support at completion of therapy, with no change in anti-pneumocystis therapy, or addition of supraphysiologic doses of steroids, occurred in fifty percent of patients in each treatment group.
- The observed mortality in the TMTX/LV treatment group was approximately twice that in the TMP/SMX treatment group (95% CI: 0.99 - 4.11). Thirty of 109 (27%) patients treated with TMTX/LV and 18 of 111 (16%) patients receiving TMP/SMX died during the 21-day treatment course or 4-week follow-up period. Twenty-seven of 30 deaths in the TMTX/LV arm were attributed to PCP; all 18 deaths in the TMP/SMX arm were attributed to PCP.
- A significantly smaller proportion of patients who received TMTX/LV compared to TMP/SMX failed therapy due to toxicity (10% vs. 25%), and a significantly greater proportion of patients failed due to lack of efficacy (40% vs. 24%). Six patients (12%) who responded to TMTX/LV relapsed during the one-month follow-up period; no patient responding to TMP/SMX relapsed during this period. Information is not available as to whether these patients received prophylaxis therapy for PCP.
- The FDA granted a Treatment IND for Neutrexin with leucovorin protection in February 1988 to make trimetrexate therapy available to HIV-infected patients with histologically confirmed PCP who had disease refractory to or who were intolerant of TMP/SMX and/or intravenous pentamidine.
- Over 500 physicians in the United States participated in the Treatment IND. Of the first 753 patients enrolled, 577 were evaluable for efficacy. Of these, 227 patients were intolerant of both TMP/SMX and pentamidine (IST - patients intolerant of both standard therapies), 146 were intolerant of one therapy and refractory to the other (RIST - patients refractory to one therapy and intolerant of the other) and 204 were refractory to both therapies (RST - refractory to both standard therapies). This was a very ill patient population; 38% required ventilatory support at entry (Table 1). These studies did not have concurrent control groups.
- Caution: Trimetrexate must be administered with concurrent leucovorin (leucovorin protection) to avoid potentially serious or life-threatening toxicities. Leucovorin therapy must extend for 72 hours past the last dose of Neutrexin.
- Trimetrexate glucuronate for injection is administered at a dose of 45 mg/m2 once daily by intravenous infusion over 60 minutes. Leucovorin must be administered daily during treatment with trimetrexate and for 72 hours past the last dose of trimetrexate. Leucovorin may be administered intravenously at a dose of 20 mg/m2 over 5 to 10 minutes every 6 hours for a total daily dose of 80 mg/m2, or orally as 4 doses of 20 mg/m2 spaced equally throughout the day. The oral dose should be rounded up to the next higher 25 mg increment. The recommended course of therapy is 21 days of trimetrexate and 24 days of leucovorin.
- Trimetrexate and leucovorin may alternatively be dosed on a mg/kg basis, depending on the patient’s body weight, using the conversion factors shown in the table below:
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Trimetrexate in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Trimetrexate in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Trimetrexate in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Trimetrexate in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Trimetrexate in pediatric patients.
# Contraindications
- (trimetrexate glucuronate for injection) is contraindicated in patients with clinically significant sensitivity to trimetrexate, leucovorin, or methotrexate.
# Warnings
- Trimetrexate glucuronate for injection must be used with concurrent leucovorin to avoid potentially serious or life-threatening complications including bone marrow suppression, oral and gastrointestinal mucosal ulceration, and renal and hepatic dysfunction.
- Leucovorin therapy must extend for 72 hours past the last dose of Neutrexin.
- Patients should be informed that failure to take the recommended dose and duration of leucovorin can lead to fatal toxicity. Patients should be closely monitored for the development of serious hematologic adverse reactions.
- Trimetrexate can cause fetal harm. Trimetrexate when administered to a pregnant woman. Trimetrexate has been shown to be fetotoxic and teratogenic in rats and rabbits. Rats administered 1.5 and 2.5 mg/kg/day intravenously on gestational days 6-15 showed substantial postimplantation loss and severe inhibition of maternal weight gain.
- Trimetrexate administered intravenously to rats at 0.5 and 1.0 mg/kg/day on gestational days 6-15 retarded normal fetal development and was teratogenic. Rabbits administered trimetrexate intravenously at daily doses of 2.5 and 5.0 mg/kg/day on gestational days 6-18 resulted in significant maternal and fetal toxicity. In rabbits, trimetrexate at 0.1 mg/kg/day was teratogenic in the absence of significant maternal toxicity. These effects were observed using doses 1/20 to 1/2 the equivalent human therapeutic dose based on a mg/m2 basis. Teratogenic effects included skeletal, visceral, ocular, and cardiovascular abnormalities. If trimetrexate 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.
# Adverse Reactions
## Clinical Trials Experience
- Because many patients who participated in clinical trials of trimetrexate had complications of advanced HIV disease, it is difficult to distinguish adverse events caused by trimetrexate from those resulting from underlying medical conditions.
- Table 3 lists the adverse events that occurred in ≥ 1% of the patients who participated in the Comparative Study of trimetrexate plus leucovorin versus TMP/SMX.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Trimetrexate in the drug label.
# Drug Interactions
- Drug
- Description
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Trimetrexate in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Trimetrexate during labor and delivery.
### Nursing Mothers
- It is not known if trimetrexate is 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 trimetrexate, it is recommended that breast feeding be discontinued if the mother is treated with trimetrexate.
### Pediatric Use
- The safety and effectiveness of trimetrexate for the treatment of histologically confirmed PCP has not been established for patients under 18 years of age. Two children, ages 15 months and 9 months, were treated with trimetrexate and leucovorin using a dose of 45 mg/m2 of trimetrexate per day for 21 days and 20 mg/m2 of leucovorin every 6 hours for 24 days. There were no serious or unexpected adverse effects.
### Geriatic Use
There is no FDA guidance on the use of Trimetrexate with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Trimetrexate with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Trimetrexate with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Trimetrexate in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Trimetrexate in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Trimetrexate in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Trimetrexate in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Trimetrexate in the drug label.
- Description
# IV Compatibility
There is limited information regarding IV Compatibility of Trimetrexate in the drug label.
# Overdosage
- Trimetrexate administered without concurrent
leucovorin can cause lethal complications. There has been no extensive experience in humans receiving single intravenous doses of trimetrexate greater than 90 mg/m2/day with concurrent leucovorin. The toxicities seen at this dose were primarily hematologic. In the event of overdose, trimetrexate should be stopped and leucovorin should be administered at a dose of 40 mg/m2 every 6 hours for 3 days. The LD50 of intravenous trimetrexate in mice is 62 mg/kg (186 mg/m2).
# Pharmacology
## Mechanism of Action
- In vitro studies have shown that trimetrexate is a competitive inhibitor of dihydrofolate reductase (DHFR) from bacterial, protozoan, and mammalian sources. DHFR catalyzes the reduction of intracellular dihydrofolate to the active coenzyme tetrahydrofolate. Inhibition of DHFR results in the depletion of this coenzyme, leading directly to interference with thymidylate biosynthesis, as well as inhibition of folate-dependent formyltransferases, and indirectly to inhibition of purine biosynthesis. The end result is disruption of DNA, RNA, and protein synthesis, with consequent cell death. Leucovorin (folinic acid) is readily transported into mammalian cells by an active, carrier‑mediated process and can be assimilated into cellular folate pools following its metabolism. In vitro studies have shown that leucovorin provides a source of reduced folates necessary for normal cellular biosynthetic processes. Because the Pneumocystis carinii organism lacks the reduced folate carrier-mediated transport system, leucovorin is prevented from entering the organism. Therefore, at concentrations achieved with therapeutic doses of trimetrexate plus leucovorin, the selective transport of trimetrexate, but not leucovorin, into the Pneumocystis carinii organism allows the concurrent administration of leucovorin to protect normal host cells from the cytotoxicity of trimetrexate without inhibiting the antifolate's inhibition of Pneumocystis carinii. It is not known if considerably higher doses of leucovorin would affect trimetrexate's effect on Pneumocystis carinii.
## Structure
- Neutrexin (trimetrexate glucuronate for injection) administered without concurrent leucovorin can cause lethal complications. There has been no extensive experience in humans receiving single intravenous doses of trimetrexate greater than 90 mg/m2/day with concurrent leucovorin.
- The toxicities seen at this dose were primarily hematologic. In the event of overdose, trimetrexate should be stopped and leucovorin should be administered at a dose of 40 mg/m2 every 6 hours for 3 days. The LD50 of intravenous trimetrexate in mice is 62 mg/kg (186 mg/m2).
- The empirical formula for trimetrexate glucuronate is C19H23N5O3- C6H10O7 with a molecular weight of 563.56. The active ingredient, trimetrexate free base, has an empirical formula of C19H23N5O3 with a molecular weight of 369.42. Trimetrexate glucuronate for injection is a pale greenish-yellow powder or cake. Trimetrexate glucuronate is soluble in water (>50 mg/mL), whereas trimetrexate free base is practically insoluble in water (<0.1 mg/mL). The pKa of trimetrexate free base in 50% methanol/water is 8.0. The logarithm10 of the partition coefficient of trimetrexate free base between octanol and water is 1.63.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Trimetrexate in the drug label.
## Pharmacokinetics
- Trimetrexate pharmacokinetics were assessed in six patients with acquired immunodeficiency syndrome (AIDS) who had Pneumocystis carinii pneumonia (4 patients) or toxoplasmosis (2 patients). Trimetrexate was administered intravenously as a bolus injection at a dose of 30 mg/m2/day along with leucovorin 20 mg/m2 every 6 hours for 21 days. Trimetrexate clearance (mean ± SD) was 38 ± 15 mL/min/m2 and volume of distribution at steady state (Vdss) was 20 ± 8 L/m2. The plasma concentration time profile declined in a biphasic manner over 24 hours with a terminal half-life of 11 ± 4 hours.
- The pharmacokinetics of trimetrexate without the concomitant administration of leucovorin have been evaluated in cancer patients with advanced solid tumors using various dosage regimens. The decline in plasma concentrations over time has been described by either biexponential or triexponential equations. Following the single-dose administration of 10 to 130 mg/m2 to 37 patients, plasma concentrations were obtained for 72 hours. Nine plasma concentration time profiles were described as biexponential. The alpha phase half-life was 57 ± 28 minutes, followed by a terminal phase with a half-life of 16 ± 3 hours. The plasma concentrations in the remaining patients exhibited a triphasic decline with half-lives of 8.6 ± 6.5 minutes, 2.4 ± 1.3 hours, and 17.8 ± 8.2 hours.
- Trimetrexate clearance in cancer patients has been reported as 53 ± 41 mL/min (14 patients) and 32 ± 18 mL/min/m2 (23 patients) following single-dose administration. After a five-day infusion of trimetrexate to 16 patients, plasma clearance was 30 ± 8 mL/min/m2.
- Renal clearance of trimetrexate in cancer patients has varied from about 4 ± 2 mL/min/m2 to 10 ± 6 mL/min/m2. Ten to 30% of the administered dose is excreted unchanged in the urine. Considering the free fraction of trimetrexate, active tubular secretion may possibly contribute to the renal clearance of trimetrexate. Renal clearance has been associated with urine flow, suggesting the possibility of tubular reabsorption as well.
- The Vdss of trimetrexate in cancer patients after single-dose administration and for whom plasma concentrations were obtained for 72 hours was 36.9 ± 17.6 L/m2 (n=23) and 0.62 ± 0.24 L/kg (n=14). Following a constant infusion of trimetrexate for five days, Vdss was 32.8 ± 16.6 L/m2. The volume of the central compartment has been estimated as 0.17 ± 0.08 L/kg and 4.0 ± 2.9 L/m2.
- There have been inconsistencies in the reporting of trimetrexate protein binding. The in vitro plasma protein binding of trimetrexate using ultrafiltration is approximately 95% over the concentration range of 18.75 to 1000 ng/mL. There is a suggestion of capacity limited binding (saturable binding) at concentrations greater than about 1000 ng/mL, with free fraction progressively increasing to about 9.3% as concentration is increased to 15 μg/mL. Other reports have declared trimetrexate to be greater than 98% bound at concentrations of 0.1 to 10 μg/mL; however, specific free fractions were not stated. The free fraction of trimetrexate also has been reported to be about 15 to 16% at a concentration of 60 ng/mL, increasing to about 20% at a trimetrexate concentration of 6 μg/mL.
- Trimetrexate metabolism in man has not been characterized. Preclinical data strongly suggest that the major metabolic pathway is oxidative O-demethylation, followed by conjugation to either glucuronide or the sulfate. N-demethylation and oxidation is a related minor pathway. Preliminary findings in humans indicate the presence of a glucuronide conjugate with DHFR inhibition and a demethylated metabolite in urine.
- The presence of metabolite(s) in human plasma following the administration of trimetrexate is suggested by the differences seen in trimetrexate plasma concentrations when measured by HPLC and a nonspecific DHFR inhibition assay. The profiles are similar initially, but diverge with time; concentrations determined by DHFR being higher than those determined by HPLC. This suggests the presence of one or more metabolites with DHFR inhibition activity. After intravenous administration of trimetrexate to humans, urinary recovery averaged about 40%, using a DHFR assay, in comparison to 10% urinary recovery as determined by HPLC, suggesting the presence of one or more metabolites that retain inhibitory activity against DHFR. Fecal recovery of trimetrexate over 48 hours after intravenous administration ranged from 0.09 to 7.6% of the dose as determined by DHFR inhibition and 0.02 to 5.2% of the dose as determined by HPLC.
- The pharmacokinetics of trimetrexate have not been determined in patients with renal insufficiency or hepatic dysfunction.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Trimetrexate in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Trimetrexate in the drug label.
# How Supplied
- Trimetrexate is supplied as a sterile lyophilized powder in either 5 mL or 30 mL vials. Each 5 mL vial contains trimetrexate glucuronate equivalent to 25 mg of trimetrexate. Each 30 mL vial contains trimetrexate glucuronate equivalent to 200 mg of trimetrexate. The 5 mL vials are packaged and available in two market presentations as listed below:
- 10 Pack - 10 vials in a white chip-board carton (NDC 58178-020-10)
- 50 Pack - 2 trays of 25 vials per shrink-wrapped tray (NDC 58178-020-50)
- The 30 mL vials are packaged and available as listed below:
- Single Pack - 1 vial (NDC 58178-021-01)
## Storage
Store at controlled room temperature 20° to 25°C (68° to 77°F). Protect from exposure to light.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Trimetrexate in the drug label.
# Precautions with Alcohol
- Alcohol-Trimetrexate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Neutrexin®
# Look-Alike Drug Names
There is limited information regarding Trimetrexate Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Trimetrexate
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, 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.
# Black Box Warning
# Overview
Trimetrexate is an antibiotic that is FDA approved for the treatment of moderate-to-severe Pneumocystis carinii pneumonia (PCP) in immunocompromised patients, including patients with the acquired immunodeficiency syndrome (AIDS), who are intolerant of, or are refractory to, trimethoprim-sulfamethoxazole therapy or for whom trimethoprim-sulfamethoxazole is contraindicated. There is a Black Box Warning for this drug as shown here. Common adverse reactions include hypersensitivity.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Trimetrexate glucuronate for injection with concurrent leucovorin administration (leucovorin protection) is indicated as an alternative therapy for the treatment of moderate-to-severe Pneumocystis carinii pneumonia (PCP) in immunocompromised patients, including patients with the acquired immunodeficiency syndrome (AIDS), who are intolerant of, or are refractory to, trimethoprim-sulfamethoxazole therapy or for whom trimethoprim-sulfamethoxazole is contraindicated.
- This indication is based on the results of a randomized, controlled double-blind trial comparing Neutrexin with concurrent leucovorin protection (TMTX/LV) to trimethoprim‑sulfamethoxazole (TMP/SMX) in patients with moderate-to-severe Pneumocystis carinii pneumonia, as well as results of a Treatment IND. These studies are summarized below:
- This double-blind, randomized trial initiated by the AIDS Clinical Trials Group (ACTG) in 1988 was designed to compare the safety and efficacy of TMTX/LV to that of TMP/SMX for the treatment of histologically confirmed, moderate-to-severe PCP, defined as (A-a) baseline gradient >30 mmHg, in patients with AIDS.
- Of the 220 patients with histologically confirmed PCP, 109 were randomized to receive TMTX/LV and 111 to TMP/SMX. Study patients randomized to TMTX/LV treatment were to receive 45 mg/m2 of TMTX daily for 21 days plus 20 mg/m2 of LV every 6 hours for 24 days. Those randomized to TMP/SMX were to receive 5 mg/kg TMP plus 25 mg/kg SMX four times daily for 21 days.
- Response to therapy, defined as alive and off ventilatory support at completion of therapy, with no change in anti-pneumocystis therapy, or addition of supraphysiologic doses of steroids, occurred in fifty percent of patients in each treatment group.
- The observed mortality in the TMTX/LV treatment group was approximately twice that in the TMP/SMX treatment group (95% CI: 0.99 - 4.11). Thirty of 109 (27%) patients treated with TMTX/LV and 18 of 111 (16%) patients receiving TMP/SMX died during the 21-day treatment course or 4-week follow-up period. Twenty-seven of 30 deaths in the TMTX/LV arm were attributed to PCP; all 18 deaths in the TMP/SMX arm were attributed to PCP.
- A significantly smaller proportion of patients who received TMTX/LV compared to TMP/SMX failed therapy due to toxicity (10% vs. 25%), and a significantly greater proportion of patients failed due to lack of efficacy (40% vs. 24%). Six patients (12%) who responded to TMTX/LV relapsed during the one-month follow-up period; no patient responding to TMP/SMX relapsed during this period. Information is not available as to whether these patients received prophylaxis therapy for PCP.
- The FDA granted a Treatment IND for Neutrexin with leucovorin protection in February 1988 to make trimetrexate therapy available to HIV-infected patients with histologically confirmed PCP who had disease refractory to or who were intolerant of TMP/SMX and/or intravenous pentamidine.
- Over 500 physicians in the United States participated in the Treatment IND. Of the first 753 patients enrolled, 577 were evaluable for efficacy. Of these, 227 patients were intolerant of both TMP/SMX and pentamidine (IST - patients intolerant of both standard therapies), 146 were intolerant of one therapy and refractory to the other (RIST - patients refractory to one therapy and intolerant of the other) and 204 were refractory to both therapies (RST - refractory to both standard therapies). This was a very ill patient population; 38% required ventilatory support at entry (Table 1). These studies did not have concurrent control groups.
- Caution: Trimetrexate must be administered with concurrent leucovorin (leucovorin protection) to avoid potentially serious or life-threatening toxicities. Leucovorin therapy must extend for 72 hours past the last dose of Neutrexin.
- Trimetrexate glucuronate for injection is administered at a dose of 45 mg/m2 once daily by intravenous infusion over 60 minutes. Leucovorin must be administered daily during treatment with trimetrexate and for 72 hours past the last dose of trimetrexate. Leucovorin may be administered intravenously at a dose of 20 mg/m2 over 5 to 10 minutes every 6 hours for a total daily dose of 80 mg/m2, or orally as 4 doses of 20 mg/m2 spaced equally throughout the day. The oral dose should be rounded up to the next higher 25 mg increment. The recommended course of therapy is 21 days of trimetrexate and 24 days of leucovorin.
- Trimetrexate and leucovorin may alternatively be dosed on a mg/kg basis, depending on the patient’s body weight, using the conversion factors shown in the table below:
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Trimetrexate in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Trimetrexate in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Trimetrexate in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Trimetrexate in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Trimetrexate in pediatric patients.
# Contraindications
- (trimetrexate glucuronate for injection) is contraindicated in patients with clinically significant sensitivity to trimetrexate, leucovorin, or methotrexate.
# Warnings
- Trimetrexate glucuronate for injection must be used with concurrent leucovorin to avoid potentially serious or life-threatening complications including bone marrow suppression, oral and gastrointestinal mucosal ulceration, and renal and hepatic dysfunction.
- Leucovorin therapy must extend for 72 hours past the last dose of Neutrexin.
- Patients should be informed that failure to take the recommended dose and duration of leucovorin can lead to fatal toxicity. Patients should be closely monitored for the development of serious hematologic adverse reactions.
- Trimetrexate can cause fetal harm. Trimetrexate when administered to a pregnant woman. Trimetrexate has been shown to be fetotoxic and teratogenic in rats and rabbits. Rats administered 1.5 and 2.5 mg/kg/day intravenously on gestational days 6-15 showed substantial postimplantation loss and severe inhibition of maternal weight gain.
- Trimetrexate administered intravenously to rats at 0.5 and 1.0 mg/kg/day on gestational days 6-15 retarded normal fetal development and was teratogenic. Rabbits administered trimetrexate intravenously at daily doses of 2.5 and 5.0 mg/kg/day on gestational days 6-18 resulted in significant maternal and fetal toxicity. In rabbits, trimetrexate at 0.1 mg/kg/day was teratogenic in the absence of significant maternal toxicity. These effects were observed using doses 1/20 to 1/2 the equivalent human therapeutic dose based on a mg/m2 basis. Teratogenic effects included skeletal, visceral, ocular, and cardiovascular abnormalities. If trimetrexate 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.
# Adverse Reactions
## Clinical Trials Experience
- Because many patients who participated in clinical trials of trimetrexate had complications of advanced HIV disease, it is difficult to distinguish adverse events caused by trimetrexate from those resulting from underlying medical conditions.
- Table 3 lists the adverse events that occurred in ≥ 1% of the patients who participated in the Comparative Study of trimetrexate plus leucovorin versus TMP/SMX.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Trimetrexate in the drug label.
# Drug Interactions
- Drug
- Description
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
-
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Trimetrexate in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Trimetrexate during labor and delivery.
### Nursing Mothers
- It is not known if trimetrexate is 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 trimetrexate, it is recommended that breast feeding be discontinued if the mother is treated with trimetrexate.
### Pediatric Use
- The safety and effectiveness of trimetrexate for the treatment of histologically confirmed PCP has not been established for patients under 18 years of age. Two children, ages 15 months and 9 months, were treated with trimetrexate and leucovorin using a dose of 45 mg/m2 of trimetrexate per day for 21 days and 20 mg/m2 of leucovorin every 6 hours for 24 days. There were no serious or unexpected adverse effects.
### Geriatic Use
There is no FDA guidance on the use of Trimetrexate with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Trimetrexate with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Trimetrexate with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Trimetrexate in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Trimetrexate in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Trimetrexate in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Trimetrexate in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Trimetrexate in the drug label.
- Description
# IV Compatibility
There is limited information regarding IV Compatibility of Trimetrexate in the drug label.
# Overdosage
- Trimetrexate administered without concurrent
leucovorin can cause lethal complications. There has been no extensive experience in humans receiving single intravenous doses of trimetrexate greater than 90 mg/m2/day with concurrent leucovorin. The toxicities seen at this dose were primarily hematologic. In the event of overdose, trimetrexate should be stopped and leucovorin should be administered at a dose of 40 mg/m2 every 6 hours for 3 days. The LD50 of intravenous trimetrexate in mice is 62 mg/kg (186 mg/m2).
# Pharmacology
## Mechanism of Action
- In vitro studies have shown that trimetrexate is a competitive inhibitor of dihydrofolate reductase (DHFR) from bacterial, protozoan, and mammalian sources. DHFR catalyzes the reduction of intracellular dihydrofolate to the active coenzyme tetrahydrofolate. Inhibition of DHFR results in the depletion of this coenzyme, leading directly to interference with thymidylate biosynthesis, as well as inhibition of folate-dependent formyltransferases, and indirectly to inhibition of purine biosynthesis. The end result is disruption of DNA, RNA, and protein synthesis, with consequent cell death. Leucovorin (folinic acid) is readily transported into mammalian cells by an active, carrier‑mediated process and can be assimilated into cellular folate pools following its metabolism. In vitro studies have shown that leucovorin provides a source of reduced folates necessary for normal cellular biosynthetic processes. Because the Pneumocystis carinii organism lacks the reduced folate carrier-mediated transport system, leucovorin is prevented from entering the organism. Therefore, at concentrations achieved with therapeutic doses of trimetrexate plus leucovorin, the selective transport of trimetrexate, but not leucovorin, into the Pneumocystis carinii organism allows the concurrent administration of leucovorin to protect normal host cells from the cytotoxicity of trimetrexate without inhibiting the antifolate's inhibition of Pneumocystis carinii. It is not known if considerably higher doses of leucovorin would affect trimetrexate's effect on Pneumocystis carinii.
## Structure
- Neutrexin (trimetrexate glucuronate for injection) administered without concurrent leucovorin can cause lethal complications. There has been no extensive experience in humans receiving single intravenous doses of trimetrexate greater than 90 mg/m2/day with concurrent leucovorin.
- The toxicities seen at this dose were primarily hematologic. In the event of overdose, trimetrexate should be stopped and leucovorin should be administered at a dose of 40 mg/m2 every 6 hours for 3 days. The LD50 of intravenous trimetrexate in mice is 62 mg/kg (186 mg/m2).
- The empirical formula for trimetrexate glucuronate is C19H23N5O3• C6H10O7 with a molecular weight of 563.56. The active ingredient, trimetrexate free base, has an empirical formula of C19H23N5O3 with a molecular weight of 369.42. Trimetrexate glucuronate for injection is a pale greenish-yellow powder or cake. Trimetrexate glucuronate is soluble in water (>50 mg/mL), whereas trimetrexate free base is practically insoluble in water (<0.1 mg/mL). The pKa of trimetrexate free base in 50% methanol/water is 8.0. The logarithm10 of the partition coefficient of trimetrexate free base between octanol and water is 1.63.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Trimetrexate in the drug label.
## Pharmacokinetics
- Trimetrexate pharmacokinetics were assessed in six patients with acquired immunodeficiency syndrome (AIDS) who had Pneumocystis carinii pneumonia (4 patients) or toxoplasmosis (2 patients). Trimetrexate was administered intravenously as a bolus injection at a dose of 30 mg/m2/day along with leucovorin 20 mg/m2 every 6 hours for 21 days. Trimetrexate clearance (mean ± SD) was 38 ± 15 mL/min/m2 and volume of distribution at steady state (Vdss) was 20 ± 8 L/m2. The plasma concentration time profile declined in a biphasic manner over 24 hours with a terminal half-life of 11 ± 4 hours.
- The pharmacokinetics of trimetrexate without the concomitant administration of leucovorin have been evaluated in cancer patients with advanced solid tumors using various dosage regimens. The decline in plasma concentrations over time has been described by either biexponential or triexponential equations. Following the single-dose administration of 10 to 130 mg/m2 to 37 patients, plasma concentrations were obtained for 72 hours. Nine plasma concentration time profiles were described as biexponential. The alpha phase half-life was 57 ± 28 minutes, followed by a terminal phase with a half-life of 16 ± 3 hours. The plasma concentrations in the remaining patients exhibited a triphasic decline with half-lives of 8.6 ± 6.5 minutes, 2.4 ± 1.3 hours, and 17.8 ± 8.2 hours.
- Trimetrexate clearance in cancer patients has been reported as 53 ± 41 mL/min (14 patients) and 32 ± 18 mL/min/m2 (23 patients) following single-dose administration. After a five-day infusion of trimetrexate to 16 patients, plasma clearance was 30 ± 8 mL/min/m2.
- Renal clearance of trimetrexate in cancer patients has varied from about 4 ± 2 mL/min/m2 to 10 ± 6 mL/min/m2. Ten to 30% of the administered dose is excreted unchanged in the urine. Considering the free fraction of trimetrexate, active tubular secretion may possibly contribute to the renal clearance of trimetrexate. Renal clearance has been associated with urine flow, suggesting the possibility of tubular reabsorption as well.
- The Vdss of trimetrexate in cancer patients after single-dose administration and for whom plasma concentrations were obtained for 72 hours was 36.9 ± 17.6 L/m2 (n=23) and 0.62 ± 0.24 L/kg (n=14). Following a constant infusion of trimetrexate for five days, Vdss was 32.8 ± 16.6 L/m2. The volume of the central compartment has been estimated as 0.17 ± 0.08 L/kg and 4.0 ± 2.9 L/m2.
- There have been inconsistencies in the reporting of trimetrexate protein binding. The in vitro plasma protein binding of trimetrexate using ultrafiltration is approximately 95% over the concentration range of 18.75 to 1000 ng/mL. There is a suggestion of capacity limited binding (saturable binding) at concentrations greater than about 1000 ng/mL, with free fraction progressively increasing to about 9.3% as concentration is increased to 15 μg/mL. Other reports have declared trimetrexate to be greater than 98% bound at concentrations of 0.1 to 10 μg/mL; however, specific free fractions were not stated. The free fraction of trimetrexate also has been reported to be about 15 to 16% at a concentration of 60 ng/mL, increasing to about 20% at a trimetrexate concentration of 6 μg/mL.
- Trimetrexate metabolism in man has not been characterized. Preclinical data strongly suggest that the major metabolic pathway is oxidative O-demethylation, followed by conjugation to either glucuronide or the sulfate. N-demethylation and oxidation is a related minor pathway. Preliminary findings in humans indicate the presence of a glucuronide conjugate with DHFR inhibition and a demethylated metabolite in urine.
- The presence of metabolite(s) in human plasma following the administration of trimetrexate is suggested by the differences seen in trimetrexate plasma concentrations when measured by HPLC and a nonspecific DHFR inhibition assay. The profiles are similar initially, but diverge with time; concentrations determined by DHFR being higher than those determined by HPLC. This suggests the presence of one or more metabolites with DHFR inhibition activity. After intravenous administration of trimetrexate to humans, urinary recovery averaged about 40%, using a DHFR assay, in comparison to 10% urinary recovery as determined by HPLC, suggesting the presence of one or more metabolites that retain inhibitory activity against DHFR. Fecal recovery of trimetrexate over 48 hours after intravenous administration ranged from 0.09 to 7.6% of the dose as determined by DHFR inhibition and 0.02 to 5.2% of the dose as determined by HPLC.
- The pharmacokinetics of trimetrexate have not been determined in patients with renal insufficiency or hepatic dysfunction.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Trimetrexate in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Trimetrexate in the drug label.
# How Supplied
- Trimetrexate is supplied as a sterile lyophilized powder in either 5 mL or 30 mL vials. Each 5 mL vial contains trimetrexate glucuronate equivalent to 25 mg of trimetrexate. Each 30 mL vial contains trimetrexate glucuronate equivalent to 200 mg of trimetrexate. The 5 mL vials are packaged and available in two market presentations as listed below:
- 10 Pack - 10 vials in a white chip-board carton (NDC 58178-020-10)
- 50 Pack - 2 trays of 25 vials per shrink-wrapped tray (NDC 58178-020-50)
- The 30 mL vials are packaged and available as listed below:
- Single Pack - 1 vial (NDC 58178-021-01)
## Storage
Store at controlled room temperature 20° to 25°C (68° to 77°F). Protect from exposure to light.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Trimetrexate in the drug label.
# Precautions with Alcohol
- Alcohol-Trimetrexate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Neutrexin®[1]
# Look-Alike Drug Names
There is limited information regarding Trimetrexate Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Trimetrexate | |
c206db23e9d9128050d7467a1ad60de9b9f548f8 | wikidoc | Trimipramine | Trimipramine
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# Black Box Warning
# Overview
Trimipramine is a Tricyclic antidepressant that is FDA approved for the {{{indicationType}}} of depression. There is a Black Box Warning for this drug as shown here. Common adverse reactions include hypotension, tachycardia, constipation, xerostomia, dizziness, somnolence, blurred vision.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Depression
- 75 mg PO (divided into 1-3 doses per day);
- Increase gradually over a few days to 150 mg/day (in divided doses); max dosage is 200 mg/day
- Maintenance, 50-150 mg/day PO at bedtime; therapy should be continued for about 3 months
- Inpatients, 100 mg PO (divided into 1-3 doses per day); increase gradually over a few days to 200 mg/day (in divided doses);
- If no improvement in 2-3 weeks may increase to a max of 250-300 mg/day
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information about Off-Label Guideline-Supported Use of Trimipramine in adult patients.
### Non–Guideline-Supported Use
There is limited information about Off-Label Non–Guideline-Supported Use of Trimipramine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Depression
- Not FDA-approved for use in children
- Adolescents, 50 mg/day PO increase up to 100 mg/day;
- Maintenance therapy should be continued for about 3 months.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information about Off-Label Guideline-Supported Use of Trimipramine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information about Off-Label Non–Guideline-Supported Use of Trimipramine in pediatric patients.
# Contraindications
- Monoamine Oxidase Inhibitors (MAOIs)
- The use of MAOIs intended to treat psychiatric disorders with trimipramine maleate or within 14 days of stopping treatment with trimipramine maleate is contraindicated because of an increased risk of serotonin syndrome. The use of trimipramine maleate within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated.
- Starting trimipramine maleate in a patient who is being treaetd with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome.
- Hypersensitivity to Tricyclic Antidepressants
- Cross-sensitivity between trimipramine maleate and other dibenzazepines is a possibility.
- Myocardial Infarction
- The drug is contraindicated during the acute recovery period after a myocardial infarction.
# Warnings
- Clinical Worsening and Suicide Risk
- 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 (aged 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 analysis of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD) or other psychiatric disorders including 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 with age strada and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1.
- 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 non-psychiatric, 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 health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for trimipramine maleate should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose.
- Screening Patients for Bipolar Disorder: 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, patients with depression 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. It should be noted that trimipramine maleate is not approved for use in treating bipolar depression.
- Serotonin Syndrome
- The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including trimipramine maleate, alone, but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John’s Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
- Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g, nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome.
- The concomitant use of trimipramine maleate with MAOIs intended to treat psychiatric disorders is contraindicated. Trimipramine maleate should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking trimipramine maleate. Trimipramine maleate should be discontinued before initiating treatment with the MAOI.
- If concomitant use of trimipramine maleate with other serotonergic drugs, including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John’s Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.
Treatment with trimipramine maleate and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.
- General Consideration for Use
- Extreme caution should be used when this drug is given to patients with any evidence of cardiovascular disease because of the possibility of conduction defects, arrhythmias, myocardial infarction, strokes, and tachycardia.
- Caution is advised in patients with increased intraocular pressure, history of urinary retention, or history of narrow-angle glaucoma because of the drug’s anticholinergic properties; hyperthyroid patients or those on thyroid medication because of the possibility of cardiovascular toxicity; patients with a history of seizure disorder, because this drug has been shown to lower the seizure threshold; patients receiving guanethidine or similar agents, since trimipramine maleate may block the pharmacologic effects of these drugs.
- Since the drug may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as operating an automobile or machinery, the patient should be cautioned accordingly.
- General
- The possibility of suicide is inherent in any severely depressed patient and persists until a significant remission occurs. When a patient with a serious suicidal potential is not hospitalized, the prescription should be for the smallest amount feasible.
- In schizophrenic patients activation of the psychosis may occur and require reduction of dosage or the addition of a major tranquilizer to the therapeutic regime.
- Manic or hypomanic episodes may occur in some patients, in particular those with cyclic-type disorders. In some cases therapy with trimipramine maleate must be discontinued until the episode is relieved, after which therapy may be reinstituted at lower dosages if still required.
- Concurrent administration of trimipramine maleate and electroshock therapy may increase the hazards of therapy. Such treatment should be limited to those patients for whom it is essential. :*When possible, discontinue the drug for several days prior to elective surgery.
- Trimipramine maleate should be used with caution in patients with impaired liver function.
- Chronic animal studies showed occasional occurrence of hepatic congestion, fatty infiltration, or increased serum liver enzymes at the highest dose of 60 mg/kg/day.
- Both elevation and lowering of blood sugar have been reported with tricyclic antidepressants.
- Information for Patients
- Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with trimipramine maleate 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 trimipramine maleate. 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 trimipramine maleate.
- Clinical Worsening and Suicide Risk:
- 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.
# Adverse Reactions
## Clinical Trials Experience
Note: The pharmacological similarities among the tricyclic antidepressants require that each of the reactions be considered when trimipramine maleate is administered. Some of the adverse reactions included in this listing have not in fact been reported with trimipramine maleate.
- Cardiovascular
- Hypotension, hypertension, tachycardia, palpitation, myocardial infarction, arrhythmias, heart block, stroke.
- Psychiatric
- Confusional states (especially the elderly) with hallucinations, disorientation, delusions; anxiety, restlessness, agitation; insomnia and nightmares; hypomania; exacerbation of psychosis.
- Neurological
- Numbness, tingling, paresthesias of extremities; incoordination, ataxia, tremors; peripheral neuropathy; extrapyramidal symptoms; seizures, alterations in EEG patterns; tinnitus; syndrome of inappropriate ADH (antidiuretic hormone) secretion.
- Anticholinergic
- Dry mouth and, rarely, associated sublingual adenitis; blurred vision, disturbances of accommodation, mydriasis, constipation, paralytic ileus; urinary retention, delayed micturition, dilation of the urinary tract.
- Allergic
- Skin rash, petechiae, urticaria, itching, photosensitization, edema of face and tongue.
- Hematologic
- Bone-marrow depression including agranulocytosis, eosinophilia; purpura; thrombocytopenia. Leukocyte and differential counts should be performed in any patient who develops fever and sore throat during therapy; the drug should be discontinued if there is evidence of pathological neutrophil depression.
- Gastrointestinal
- Nausea and vomiting, anorexia, epigastric distress, diarrhea, peculiar taste, stomatitis, abdominal cramps, black tongue.
- Endocrine
- Gynecomastia in the male; breast enlargement and galactorrhea in the female; increased or decreased libido, impotence; testicular swelling; elevation or depression of blood-sugar levels.
- Other
- Jaundice (simulating obstructive); altered liver function; weight gain or loss; perspiration; flushing; urinary frequency; drowsiness, dizziness, weakness, and fatigue; headache; parotid swelling; alopecia.
- Withdrawal Symptoms
- Though not indicative of addiction, abrupt cessation of treatment after prolonged therapy may produce nausea, headache, and malaise.
## Postmarketing Experience
There is limited information regarding Trimipramine Postmarketing Experience in the drug label.
# Drug Interactions
- Cimetidine
- There is evidence that cimetidine inhibits the elimination of tricyclic antidepressants. Downward adjustment of trimipramine maleate dosage may be required if cimetidine therapy is initiated; upward adjustment if cimetidine therapy is discontinued.
- Alcohol
- Patients should be warned that the concomitant use of alcoholic beverages may be associated with exaggerated effects.
- Catecholamines/Anticholinergics
- It has been reported that tricyclic antidepressants can potentiate the effects of catecholamines. Similarly, atropine-like effects may be more pronounced in patients receiving anticholinergic therapy. Therefore, particular care should be exercised when it is necessary to administer tricyclic antidepressants with sympathomimetic amines, local decongestants, local anesthetics containing epinephrine, atropine or drugs with an anticholinergic effect. In resistant cases of depression in adults, a dose of 2.5 mg/kg/day may have to be exceeded. If a higher dose is needed, ECG monitoring should be maintained during the initiation of therapy and at appropriate intervals during stabilization of dose.
- Drugs Metabolized by P450 2D6
- The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the caucasian population (about 7-10% of caucasians are so called “poor metabolizers”); reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African, and other populations are not yet available. Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses. Depending on the fraction of drug metabolized by P450 2D6, the increase in plasma concentration may be small, or quite large (8 fold increase in plasma AUC of the TCA).
- In addition, certain drugs inhibit the activity of the isozyme and make normal metabolizers resemble poor metabolizers. An individual who is stable on a given dose of TCA may become abruptly toxic when given one of these inhibiting drugs as concomitant therapy. The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzyme (quinidine; cimetidine) and many that are substrates for P450 2D6 (many other antidepressants, phenothiazines, and the Type 1C antiarrhythmics propafenone and flecainide). While all the selective serotonin reuptake inhibitors (SSRIs), e.g., fluoxetine, sertraline, and paroxetine, inhibit P450 2D6, they may vary in the extent of inhibition.
- The extent to which SSRI TCA interactions may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is indicated in the co-administration of TCAs with any of the SSRIs and also in switching from one class to the other. Of particular importance, sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary).
- Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug. Furthermore, whenever one of these other drugs is withdrawn from co-therapy, an increased dose of tricyclic antidepressant may be required. It is desirable to monitor TCA plasma levels whenever a TCA is going to be co-administered with another drug known to be an inhibitor of P450 2D6.
- Monoamine Oxidase Inhibitors (MAOIs)
- Serotonergic Drugs
- Carcinogenesis, Mutagenesis, Impairment of Fertility
- Semen studies in man (four schizophrenics and nine normal volunteers) revealed no significant changes in sperm morphology. It is recognized that drugs having a parasympathetic effect, including tricyclic antidepressants, may alter the ejaculatory response.
- Chronic animal studies showed occasional evidence of degeneration of seminiferous tubules at the highest dose of 60 mg/kg/day.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
Trimipramine maleate has shown evidence of embryotoxicity and/or increased incidence of major anomalies in rats or rabbits at doses 20 times the human dose. There are no adequate and well-controlled studies in pregnant women. Trimipramine maleate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Trimipramine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Trimipramine during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Trimipramine in women who are nursing.
### Pediatric Use
Safety and effectiveness in the pediatric population have not been established. Anyone considering the use of trimipramine maleate in a child or adolescent must balance the potential risks with the clinical need.
### Geriatic Use
Clinical studies of trimipramine maleate were not adequate to determine whether subjects aged 65 and over respond differently from younger subjects.
The pharmacokinetics of trimipramine maleate was not substantially altered in the elderly.
Trimipramine maleate is known to be substantially excreted by the kidney. Clinical circumstances, some of which may be more common in the elderly, such as hepatic or renal impairment, should be considered.
Greater sensitivity (e.g., confusional states, sedation) of some older individuals cannot be ruled out. In general, dose selection for an elderly patient should be cautious, usually starting at a lower dose.
### Gender
There is no FDA guidance on the use of Trimipramine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Trimipramine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Trimipramine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Trimipramine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Trimipramine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Trimipramine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Dosage should be initiated at a low level and increased gradually, noting carefully the clinical response and any evidence of intolerance.
- Lower dosages are recommended for elderly patients and adolescents. Lower dosages are also recommended for outpatients as compared to hospitalized patients who will be under close supervision. It is not possible to prescribe a single dosage schedule of trimipramine maleate that will be therapeutically effective in all patients. The physical psychodynamic factors contributing to depressive symptomatology are very complex; spontaneous remissions or exacerbations of depressive symptoms may occur with or without drug therapy. Consequently, the recommended dosage regimens are furnished as a guide which may be modified by factors such as the age of the patient, chronicity and severity of the disease, medical condition of the patient, and degree of psychotherapeutic support.
- Most antidepressant drugs have a lag period of ten days to four weeks before a therapeutic response is noted. Increasing the dose will not shorten this period but rather increase the incidence of adverse reactions.
- Usual Adult Dose
- Outpatients and Office Patients—Initially, 75 mg/day in divided doses, increased to 150 mg/day. Dosages over 200 mg/day are not recommended. Maintenance therapy is in the range of 50 to 150 mg/day. For convenient therapy and to facilitate patient compliance, the total dosage requirement may be given at bedtime.
- Hospitalized Patients—Initially, 100 mg/day in divided doses. This may be increased gradually in a few days to 200 mg/day, depending upon individual response and tolerance. If improvement does not occur in 2 to 3 weeks, the dose may be increased to the maximum recommended dose of 250 to 300 mg/day.
- Adolescent and Geriatric Patients—Initially, a dose of 50 mg/day is recommended, with gradual increments up to 100 mg/day, depending upon patient response and tolerance.
- Maintenance—Following remission, maintenance medication may be required for a longer period of time, at the lowest dose that will maintain remission. :*Maintenance therapy is preferably administered as a single dose at bedtime. To minimize relapse, maintenance therapy should be continued for about three months.
- Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders: At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with trimipramine maleate. Conversely, at least 14 days should be allowed after stopping trimipramine maleate before starting an MAOI intended to treat psychiatric disorders .
- Use of Trimipramine Maleate With Other MAOIs, Such as Linezolid or Methylene Blue: Do not start trimipramine maleate in a patient who is being treated with linezolid or intravenous methylene blue because there is increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered.
- In some cases, a patient already receiving therapy with trimipramine maleate may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, trimipramine maleate should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for 2 weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with trimipramine maleate may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue.
- The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with trimipramine maleate is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use.
### Monitoring
There is limited information regarding Trimipramine Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Trimipramine and IV administrations.
# Overdosage
- Deaths may occur from overdosage with this class of drugs. Multiple drug ingestion (including alcohol) is common in deliberate tricyclic antidepressant overdose. As the management is complex and changing, it is recommended that the physician contact a poison control center for current information on treatment. Signs and symptoms of toxicity develop rapidly after tricyclic antidepressant overdose, therefore, hospital monitoring is required as soon as possible.
- Manifestations
- Critical manifestations of overdose include: cardiac dysrhythmias, severe hypotension, convulsions, and CNS depression, including coma. Changes in the electrocardiogram, particularly in QRS axis or width, are clinically significant indicators of tricyclic antidepressant toxicity.
- Other signs of overdose may include: confusion, disturbed concentration, transient visual hallucinations, dilated pupils, agitation, hyperactive reflexes, stupor, drowsiness, muscle rigidity, vomiting, hypothermia, hyperpyrexia, or any of the symptoms.
- Management
- General: Obtain an ECG and immediately initiate cardiac monitoring. Protect the patient’s airway, establish an intravenous line and initiate gastric decontamination. A minimum of six hours of observation with cardiac monitoring and observation for signs of CNS or respiratory depression, hypotension, cardiac dysrhythmias and/or conduction blocks, and seizures is necessary. If signs of toxicity occur at any time during this period, extended monitoring is required. There are case reports of patients succumbing to fatal dysrhythmias late after overdose; these patients had clinical evidence of significant poisoning prior to death and most received inadequate gastrointestinal decontamination. Plasma drug levels may not reflect the severity of the poisoning. Therefore, monitoring of plasma drug levels alone should not guide management of the patient.
- Gastrointestinal Decontamination: All patients suspected of tricyclic antidepressant overdose should receive gastrointestinal decontamination. This should include large volume gastric lavage followed by activated charcoal. If consciousness is impaired, the airway should be secured prior to lavage. Emesis is contraindicated.
- Cardiovascular: A maximal limb-lead QRS duration of > 0.10 seconds has been associated with an increased incidence of seizures. A QRS duration of > 0.16 seconds has been associated with an increased incidence of ventricular dysrhythmias. Intravenous sodium bicarbonate should be used to maintain the serum pH in the range of 7.45 to 7.55. If the pH response is inadequate, hyperventilation may also be used. Concomitant use of hyperventilation and sodium bicarbonate should be done with extreme caution, with frequent pH monitoring. A pH > 7.60 or a pCO2 < 20 mm Hg is undesirable. Dysrhythmias unresponsive to sodium bicarbonate therapy/hyperventilation may respond to lidocaine, bretylium or phenytoin. Type 1A and 1C antiarrhythmics are generally contraindicated (e.g., quinidine, disopyramide, and procainamide).
- In rare instances, hemoperfusion may be beneficial in acute refractory cardiovascular instability in patients with acute toxicity. However, hemodialysis, peritoneal dialysis, exchange transfusions, and forced diuresis generally have been reported as ineffective in tricyclic antidepressant poisoning.
- CNS: In patients with CNS depression, early intubation is advised because of the potential for abrupt deterioration. Seizures should be controlled with benzodiazepines, or if these are ineffective, other anticonvulsants (e.g., phenobarbital, phenytoin). Physostigmine is not recommended except to treat life-threatening symptoms that have been unresponsive to other therapies, and then only in consultation with a poison control center.
- Psychiatric Follow-up: Since overdosage is often deliberate, patients may attempt suicide by other means during the recovery phase. Psychiatric referral may be appropriate.
- Pediatric Management: The principles of management of child and adult overdosages are similar. It is strongly recommended that the physician contact the local poison control center for specific pediatric treatment.
- Poisindex® Toxicologic Management. Topic: Antidepressants, Tricyclic Micromedex Inc. Vol. 85.
# Pharmacology
## Mechanism of Action
Trimipramine maleate is an antidepressant with an anxiety-reducing sedative component to its action. The mode of action of trimipramine maleate on the central nervous system is not known. However, unlike amphetamine-type compounds it does not act primarily by stimulation of the central nervous system. It does not act by inhibition of the monoamine oxidase system.
The single-dose pharmacokinetics of trimipramine was evaluated in a comparative study of 24 elderly subjects and 24 younger subjects; no clinically relevant differences were demonstrated based on age or gender.
## Structure
Trimipramine maleate is 5-(3-dimethylamino-2-methylpropyl)-10, 11-dihydro-5H-dibenz (b,f) azepine acid maleate (racemic form).
Trimipramine maleate capsules contain trimipramine maleate equivalent to 25 mg, 50 mg or 100 mg of trimipramine as the base.
Inactive Ingredients: Each capsule contains lactose monohydrate and magnesium stearate.
The capsule shell contains the following ingredients: D&C Yellow 10 (25 mg and 50 mg), FD&C Blue #1 (25 mg, 50 mg and 100 mg), FD&C Red #40 (50 mg), gelatin, and titanium dioxide.
The capsules are imprinted in black ink that contains: alcohol, D&C yellow No.10 aluminum lake, FD&C blue No. 2/indigo carmine aluminum lake, FD&C blue No. 1/brilliant blue FCF aluminum lake, FD&C red No. 40/allura red AC aluminum lake, propylene glycol, iron oxide black and shellac glaze.
Trimipramine maleate is prepared as a racemic mixture which can be resolved into levorotatory and dextrorotatory isomers. The asymmetric center responsible for optical isomerism is marked in the formula by an asterisk. Trimipramine maleate is an almost odorless, white or slightly cream-colored, crystalline substance, melting at 140°-144°C. It is very slightly soluble in ether and water, is slightly soluble in ethyl alcohol and acetone, and freely soluble in chloroform and methanol at 20°C.
## Pharmacodynamics
There is limited information regarding Trimipramine Pharmacodynamics in the drug label.
## Pharmacokinetics
There is limited information regarding Trimipramine Pharmacokinetics in the drug label.
## Nonclinical Toxicology
There is limited information regarding Trimipramine Nonclinical Toxicology in the drug label.
# Clinical Studies
There is limited information regarding Trimipramine Clinical Studies in the drug label.
# How Supplied
Trimipramine Maleate Capsules equivalent to 25 mg of Trimipramine are #2 Capsules, light blue opaque cap, yellow opaque body, imprinted “A-293” in black ink on cap and body, filled with white to off-white powder.
Capsules are supplied in bottles of:
30 (NDC 45963-293-30) with a child-resistant closure.
90 (NDC 45963-293-08) with a child-resistant closure.
270 (NDC 45963-293-27) with a non-child resistant closure.
Trimipramine Maleate Capsules equivalent to 50 mg of Trimipramine are #2 Capsules, light blue opaque cap, medium orange opaque body, imprinted “A-294” in black ink on cap and body, filled with white to off-white powder.
Capsules are supplied in bottles of:
30 (NDC 45963-294-30) with a child-resistant closure.
90 (NDC 45963-294-08) with a child-resistant closure.
270 (NDC 45963-294-27) with a non-child resistant closure.
Trimipramine Maleate Capsules equivalent to 100 mg of Trimipramine are #2 Capsules, light blue opaque cap, white opaque body, imprinted “A-295” in black ink on cap and body, filled with white to off-white powder.
Capsules are supplied in bottles of:
30 (NDC 45963-295-30) with a child-resistant closure
Dispense in a tight, light-resistant container as defined in the USP. Preserve in tight container. Protect from excessive heat.
## Storage
Store at 20° to 25°C (68° to 77°F) . Protect from Moisture.
Keep this and all medication out of the reach of children. Keep tightly closed.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Trimipramine Maleate Capsules
- Antidepressant Medicines, Depression and other Serious Mental Illnesses, and Suicidal Thoughts or Actions
- Read the Medication Guide that comes with you or your family member’s antidepressant medicine. This Medication Guide is only about the risk of suicidal thoughts and actions with antidepressant medicines.
- 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
- What is the most important information I should know about antidepressant medicines, depression and other serious mental illnesses, and suicidal thoughts or actions?
- 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) 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
- Who should not take trimipramine maleate capsules?
- If you take a monoamine oxidase inhibitor (MAOI). Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI, including the antibiotic linezolid.
- Do not take an MAOI within 2 weeks of stopping trimipramine maleate capsules unless directed to do so by your physician.
- Do not start trimipramine maleate capsules if you stopped taking an MAOI in the last 2 weeks unless directed to do so by your physician.
- What else do I need to know about antidepressant medicines?
- Never stop an antidepressant medicine without first talking to a 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 takes. 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.
This Medication Guide has been approved by the U.S. Food and Drug Administration for all antidepressants.
- Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
# Precautions with Alcohol
Patients should be warned that the concomitant use of alcoholic beverages may be associated with exaggerated effects.
# Brand Names
There is limited information regarding Trimipramine Brand Names in the drug label.
# Look-Alike Drug Names
There is limited information regarding Trimipramine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Trimipramine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Pratik Bahekar, MBBS [2]
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# Black Box Warning
# Overview
Trimipramine is a Tricyclic antidepressant that is FDA approved for the {{{indicationType}}} of depression. There is a Black Box Warning for this drug as shown here. Common adverse reactions include hypotension, tachycardia, constipation, xerostomia, dizziness, somnolence, blurred vision.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Depression
- 75 mg PO (divided into 1-3 doses per day);
- Increase gradually over a few days to 150 mg/day (in divided doses); max dosage is 200 mg/day
- Maintenance, 50-150 mg/day PO at bedtime; therapy should be continued for about 3 months
- Inpatients, 100 mg PO (divided into 1-3 doses per day); increase gradually over a few days to 200 mg/day (in divided doses);
- If no improvement in 2-3 weeks may increase to a max of 250-300 mg/day
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information about Off-Label Guideline-Supported Use of Trimipramine in adult patients.
### Non–Guideline-Supported Use
There is limited information about Off-Label Non–Guideline-Supported Use of Trimipramine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Depression
- Not FDA-approved for use in children
- Adolescents, 50 mg/day PO increase up to 100 mg/day;
- Maintenance therapy should be continued for about 3 months.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information about Off-Label Guideline-Supported Use of Trimipramine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information about Off-Label Non–Guideline-Supported Use of Trimipramine in pediatric patients.
# Contraindications
- Monoamine Oxidase Inhibitors (MAOIs)
- The use of MAOIs intended to treat psychiatric disorders with trimipramine maleate or within 14 days of stopping treatment with trimipramine maleate is contraindicated because of an increased risk of serotonin syndrome. The use of trimipramine maleate within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated.
- Starting trimipramine maleate in a patient who is being treaetd with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome.
- Hypersensitivity to Tricyclic Antidepressants
- Cross-sensitivity between trimipramine maleate and other dibenzazepines is a possibility.
- Myocardial Infarction
- The drug is contraindicated during the acute recovery period after a myocardial infarction.
# Warnings
- Clinical Worsening and Suicide Risk
- 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 (aged 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 analysis of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD) or other psychiatric disorders including 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 with age strada and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1.
- 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 non-psychiatric, 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 health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for trimipramine maleate should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose.
- Screening Patients for Bipolar Disorder: 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, patients with depression 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. It should be noted that trimipramine maleate is not approved for use in treating bipolar depression.
- Serotonin Syndrome
- The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including trimipramine maleate, alone, but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John’s Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
- Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g, nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome.
- The concomitant use of trimipramine maleate with MAOIs intended to treat psychiatric disorders is contraindicated. Trimipramine maleate should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking trimipramine maleate. Trimipramine maleate should be discontinued before initiating treatment with the MAOI.
- If concomitant use of trimipramine maleate with other serotonergic drugs, including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John’s Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.
Treatment with trimipramine maleate and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.
- General Consideration for Use
- Extreme caution should be used when this drug is given to patients with any evidence of cardiovascular disease because of the possibility of conduction defects, arrhythmias, myocardial infarction, strokes, and tachycardia.
- Caution is advised in patients with increased intraocular pressure, history of urinary retention, or history of narrow-angle glaucoma because of the drug’s anticholinergic properties; hyperthyroid patients or those on thyroid medication because of the possibility of cardiovascular toxicity; patients with a history of seizure disorder, because this drug has been shown to lower the seizure threshold; patients receiving guanethidine or similar agents, since trimipramine maleate may block the pharmacologic effects of these drugs.
- Since the drug may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as operating an automobile or machinery, the patient should be cautioned accordingly.
- General
- The possibility of suicide is inherent in any severely depressed patient and persists until a significant remission occurs. When a patient with a serious suicidal potential is not hospitalized, the prescription should be for the smallest amount feasible.
- In schizophrenic patients activation of the psychosis may occur and require reduction of dosage or the addition of a major tranquilizer to the therapeutic regime.
- Manic or hypomanic episodes may occur in some patients, in particular those with cyclic-type disorders. In some cases therapy with trimipramine maleate must be discontinued until the episode is relieved, after which therapy may be reinstituted at lower dosages if still required.
- Concurrent administration of trimipramine maleate and electroshock therapy may increase the hazards of therapy. Such treatment should be limited to those patients for whom it is essential. :*When possible, discontinue the drug for several days prior to elective surgery.
- Trimipramine maleate should be used with caution in patients with impaired liver function.
- Chronic animal studies showed occasional occurrence of hepatic congestion, fatty infiltration, or increased serum liver enzymes at the highest dose of 60 mg/kg/day.
- Both elevation and lowering of blood sugar have been reported with tricyclic antidepressants.
- Information for Patients
- Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with trimipramine maleate 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 trimipramine maleate. 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 trimipramine maleate.
- Clinical Worsening and Suicide Risk:
- 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.
# Adverse Reactions
## Clinical Trials Experience
Note: The pharmacological similarities among the tricyclic antidepressants require that each of the reactions be considered when trimipramine maleate is administered. Some of the adverse reactions included in this listing have not in fact been reported with trimipramine maleate.
- Cardiovascular
- Hypotension, hypertension, tachycardia, palpitation, myocardial infarction, arrhythmias, heart block, stroke.
- Psychiatric
- Confusional states (especially the elderly) with hallucinations, disorientation, delusions; anxiety, restlessness, agitation; insomnia and nightmares; hypomania; exacerbation of psychosis.
- Neurological
- Numbness, tingling, paresthesias of extremities; incoordination, ataxia, tremors; peripheral neuropathy; extrapyramidal symptoms; seizures, alterations in EEG patterns; tinnitus; syndrome of inappropriate ADH (antidiuretic hormone) secretion.
- Anticholinergic
- Dry mouth and, rarely, associated sublingual adenitis; blurred vision, disturbances of accommodation, mydriasis, constipation, paralytic ileus; urinary retention, delayed micturition, dilation of the urinary tract.
- Allergic
- Skin rash, petechiae, urticaria, itching, photosensitization, edema of face and tongue.
- Hematologic
- Bone-marrow depression including agranulocytosis, eosinophilia; purpura; thrombocytopenia. Leukocyte and differential counts should be performed in any patient who develops fever and sore throat during therapy; the drug should be discontinued if there is evidence of pathological neutrophil depression.
- Gastrointestinal
- Nausea and vomiting, anorexia, epigastric distress, diarrhea, peculiar taste, stomatitis, abdominal cramps, black tongue.
- Endocrine
- Gynecomastia in the male; breast enlargement and galactorrhea in the female; increased or decreased libido, impotence; testicular swelling; elevation or depression of blood-sugar levels.
- Other
- Jaundice (simulating obstructive); altered liver function; weight gain or loss; perspiration; flushing; urinary frequency; drowsiness, dizziness, weakness, and fatigue; headache; parotid swelling; alopecia.
- Withdrawal Symptoms
- Though not indicative of addiction, abrupt cessation of treatment after prolonged therapy may produce nausea, headache, and malaise.
## Postmarketing Experience
There is limited information regarding Trimipramine Postmarketing Experience in the drug label.
# Drug Interactions
- Cimetidine
- There is evidence that cimetidine inhibits the elimination of tricyclic antidepressants. Downward adjustment of trimipramine maleate dosage may be required if cimetidine therapy is initiated; upward adjustment if cimetidine therapy is discontinued.
- Alcohol
- Patients should be warned that the concomitant use of alcoholic beverages may be associated with exaggerated effects.
- Catecholamines/Anticholinergics
- It has been reported that tricyclic antidepressants can potentiate the effects of catecholamines. Similarly, atropine-like effects may be more pronounced in patients receiving anticholinergic therapy. Therefore, particular care should be exercised when it is necessary to administer tricyclic antidepressants with sympathomimetic amines, local decongestants, local anesthetics containing epinephrine, atropine or drugs with an anticholinergic effect. In resistant cases of depression in adults, a dose of 2.5 mg/kg/day may have to be exceeded. If a higher dose is needed, ECG monitoring should be maintained during the initiation of therapy and at appropriate intervals during stabilization of dose.
- Drugs Metabolized by P450 2D6
- The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the caucasian population (about 7-10% of caucasians are so called “poor metabolizers”); reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African, and other populations are not yet available. Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses. Depending on the fraction of drug metabolized by P450 2D6, the increase in plasma concentration may be small, or quite large (8 fold increase in plasma AUC of the TCA).
- In addition, certain drugs inhibit the activity of the isozyme and make normal metabolizers resemble poor metabolizers. An individual who is stable on a given dose of TCA may become abruptly toxic when given one of these inhibiting drugs as concomitant therapy. The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzyme (quinidine; cimetidine) and many that are substrates for P450 2D6 (many other antidepressants, phenothiazines, and the Type 1C antiarrhythmics propafenone and flecainide). While all the selective serotonin reuptake inhibitors (SSRIs), e.g., fluoxetine, sertraline, and paroxetine, inhibit P450 2D6, they may vary in the extent of inhibition.
- The extent to which SSRI TCA interactions may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is indicated in the co-administration of TCAs with any of the SSRIs and also in switching from one class to the other. Of particular importance, sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary).
- Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug. Furthermore, whenever one of these other drugs is withdrawn from co-therapy, an increased dose of tricyclic antidepressant may be required. It is desirable to monitor TCA plasma levels whenever a TCA is going to be co-administered with another drug known to be an inhibitor of P450 2D6.
- Monoamine Oxidase Inhibitors (MAOIs)
- Serotonergic Drugs
- Carcinogenesis, Mutagenesis, Impairment of Fertility
- Semen studies in man (four schizophrenics and nine normal volunteers) revealed no significant changes in sperm morphology. It is recognized that drugs having a parasympathetic effect, including tricyclic antidepressants, may alter the ejaculatory response.
- Chronic animal studies showed occasional evidence of degeneration of seminiferous tubules at the highest dose of 60 mg/kg/day.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
Trimipramine maleate has shown evidence of embryotoxicity and/or increased incidence of major anomalies in rats or rabbits at doses 20 times the human dose. There are no adequate and well-controlled studies in pregnant women. Trimipramine maleate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Trimipramine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Trimipramine during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Trimipramine in women who are nursing.
### Pediatric Use
Safety and effectiveness in the pediatric population have not been established. Anyone considering the use of trimipramine maleate in a child or adolescent must balance the potential risks with the clinical need.
### Geriatic Use
Clinical studies of trimipramine maleate were not adequate to determine whether subjects aged 65 and over respond differently from younger subjects.
The pharmacokinetics of trimipramine maleate was not substantially altered in the elderly.
Trimipramine maleate is known to be substantially excreted by the kidney. Clinical circumstances, some of which may be more common in the elderly, such as hepatic or renal impairment, should be considered.
Greater sensitivity (e.g., confusional states, sedation) of some older individuals cannot be ruled out. In general, dose selection for an elderly patient should be cautious, usually starting at a lower dose.
### Gender
There is no FDA guidance on the use of Trimipramine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Trimipramine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Trimipramine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Trimipramine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Trimipramine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Trimipramine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Dosage should be initiated at a low level and increased gradually, noting carefully the clinical response and any evidence of intolerance.
- Lower dosages are recommended for elderly patients and adolescents. Lower dosages are also recommended for outpatients as compared to hospitalized patients who will be under close supervision. It is not possible to prescribe a single dosage schedule of trimipramine maleate that will be therapeutically effective in all patients. The physical psychodynamic factors contributing to depressive symptomatology are very complex; spontaneous remissions or exacerbations of depressive symptoms may occur with or without drug therapy. Consequently, the recommended dosage regimens are furnished as a guide which may be modified by factors such as the age of the patient, chronicity and severity of the disease, medical condition of the patient, and degree of psychotherapeutic support.
- Most antidepressant drugs have a lag period of ten days to four weeks before a therapeutic response is noted. Increasing the dose will not shorten this period but rather increase the incidence of adverse reactions.
- Usual Adult Dose
- Outpatients and Office Patients—Initially, 75 mg/day in divided doses, increased to 150 mg/day. Dosages over 200 mg/day are not recommended. Maintenance therapy is in the range of 50 to 150 mg/day. For convenient therapy and to facilitate patient compliance, the total dosage requirement may be given at bedtime.
- Hospitalized Patients—Initially, 100 mg/day in divided doses. This may be increased gradually in a few days to 200 mg/day, depending upon individual response and tolerance. If improvement does not occur in 2 to 3 weeks, the dose may be increased to the maximum recommended dose of 250 to 300 mg/day.
- Adolescent and Geriatric Patients—Initially, a dose of 50 mg/day is recommended, with gradual increments up to 100 mg/day, depending upon patient response and tolerance.
- Maintenance—Following remission, maintenance medication may be required for a longer period of time, at the lowest dose that will maintain remission. :*Maintenance therapy is preferably administered as a single dose at bedtime. To minimize relapse, maintenance therapy should be continued for about three months.
- Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders: At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with trimipramine maleate. Conversely, at least 14 days should be allowed after stopping trimipramine maleate before starting an MAOI intended to treat psychiatric disorders .
- Use of Trimipramine Maleate With Other MAOIs, Such as Linezolid or Methylene Blue: Do not start trimipramine maleate in a patient who is being treated with linezolid or intravenous methylene blue because there is increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered.
- In some cases, a patient already receiving therapy with trimipramine maleate may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, trimipramine maleate should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for 2 weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with trimipramine maleate may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue.
- The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with trimipramine maleate is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use.
### Monitoring
There is limited information regarding Trimipramine Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Trimipramine and IV administrations.
# Overdosage
- Deaths may occur from overdosage with this class of drugs. Multiple drug ingestion (including alcohol) is common in deliberate tricyclic antidepressant overdose. As the management is complex and changing, it is recommended that the physician contact a poison control center for current information on treatment. Signs and symptoms of toxicity develop rapidly after tricyclic antidepressant overdose, therefore, hospital monitoring is required as soon as possible.
- Manifestations
- Critical manifestations of overdose include: cardiac dysrhythmias, severe hypotension, convulsions, and CNS depression, including coma. Changes in the electrocardiogram, particularly in QRS axis or width, are clinically significant indicators of tricyclic antidepressant toxicity.
- Other signs of overdose may include: confusion, disturbed concentration, transient visual hallucinations, dilated pupils, agitation, hyperactive reflexes, stupor, drowsiness, muscle rigidity, vomiting, hypothermia, hyperpyrexia, or any of the symptoms.
- Management
- General: Obtain an ECG and immediately initiate cardiac monitoring. Protect the patient’s airway, establish an intravenous line and initiate gastric decontamination. A minimum of six hours of observation with cardiac monitoring and observation for signs of CNS or respiratory depression, hypotension, cardiac dysrhythmias and/or conduction blocks, and seizures is necessary. If signs of toxicity occur at any time during this period, extended monitoring is required. There are case reports of patients succumbing to fatal dysrhythmias late after overdose; these patients had clinical evidence of significant poisoning prior to death and most received inadequate gastrointestinal decontamination. Plasma drug levels may not reflect the severity of the poisoning. Therefore, monitoring of plasma drug levels alone should not guide management of the patient.
- Gastrointestinal Decontamination: All patients suspected of tricyclic antidepressant overdose should receive gastrointestinal decontamination. This should include large volume gastric lavage followed by activated charcoal. If consciousness is impaired, the airway should be secured prior to lavage. Emesis is contraindicated.
- Cardiovascular: A maximal limb-lead QRS duration of > 0.10 seconds has been associated with an increased incidence of seizures. A QRS duration of > 0.16 seconds has been associated with an increased incidence of ventricular dysrhythmias. Intravenous sodium bicarbonate should be used to maintain the serum pH in the range of 7.45 to 7.55. If the pH response is inadequate, hyperventilation may also be used. Concomitant use of hyperventilation and sodium bicarbonate should be done with extreme caution, with frequent pH monitoring. A pH > 7.60 or a pCO2 < 20 mm Hg is undesirable. Dysrhythmias unresponsive to sodium bicarbonate therapy/hyperventilation may respond to lidocaine, bretylium or phenytoin. Type 1A and 1C antiarrhythmics are generally contraindicated (e.g., quinidine, disopyramide, and procainamide).
- In rare instances, hemoperfusion may be beneficial in acute refractory cardiovascular instability in patients with acute toxicity. However, hemodialysis, peritoneal dialysis, exchange transfusions, and forced diuresis generally have been reported as ineffective in tricyclic antidepressant poisoning.
- CNS: In patients with CNS depression, early intubation is advised because of the potential for abrupt deterioration. Seizures should be controlled with benzodiazepines, or if these are ineffective, other anticonvulsants (e.g., phenobarbital, phenytoin). Physostigmine is not recommended except to treat life-threatening symptoms that have been unresponsive to other therapies, and then only in consultation with a poison control center.
- Psychiatric Follow-up: Since overdosage is often deliberate, patients may attempt suicide by other means during the recovery phase. Psychiatric referral may be appropriate.
- Pediatric Management: The principles of management of child and adult overdosages are similar. It is strongly recommended that the physician contact the local poison control center for specific pediatric treatment.
- Poisindex® Toxicologic Management. Topic: Antidepressants, Tricyclic Micromedex Inc. Vol. 85.
# Pharmacology
## Mechanism of Action
Trimipramine maleate is an antidepressant with an anxiety-reducing sedative component to its action. The mode of action of trimipramine maleate on the central nervous system is not known. However, unlike amphetamine-type compounds it does not act primarily by stimulation of the central nervous system. It does not act by inhibition of the monoamine oxidase system.
The single-dose pharmacokinetics of trimipramine was evaluated in a comparative study of 24 elderly subjects and 24 younger subjects; no clinically relevant differences were demonstrated based on age or gender.
## Structure
Trimipramine maleate is 5-(3-dimethylamino-2-methylpropyl)-10, 11-dihydro-5H-dibenz (b,f) azepine acid maleate (racemic form).
Trimipramine maleate capsules contain trimipramine maleate equivalent to 25 mg, 50 mg or 100 mg of trimipramine as the base.
Inactive Ingredients: Each capsule contains lactose monohydrate and magnesium stearate.
The capsule shell contains the following ingredients: D&C Yellow 10 (25 mg and 50 mg), FD&C Blue #1 (25 mg, 50 mg and 100 mg), FD&C Red #40 (50 mg), gelatin, and titanium dioxide.
The capsules are imprinted in black ink that contains: alcohol, D&C yellow No.10 aluminum lake, FD&C blue No. 2/indigo carmine aluminum lake, FD&C blue No. 1/brilliant blue FCF aluminum lake, FD&C red No. 40/allura red AC aluminum lake, propylene glycol, iron oxide black and shellac glaze.
Trimipramine maleate is prepared as a racemic mixture which can be resolved into levorotatory and dextrorotatory isomers. The asymmetric center responsible for optical isomerism is marked in the formula by an asterisk. Trimipramine maleate is an almost odorless, white or slightly cream-colored, crystalline substance, melting at 140°-144°C. It is very slightly soluble in ether and water, is slightly soluble in ethyl alcohol and acetone, and freely soluble in chloroform and methanol at 20°C.
## Pharmacodynamics
There is limited information regarding Trimipramine Pharmacodynamics in the drug label.
## Pharmacokinetics
There is limited information regarding Trimipramine Pharmacokinetics in the drug label.
## Nonclinical Toxicology
There is limited information regarding Trimipramine Nonclinical Toxicology in the drug label.
# Clinical Studies
There is limited information regarding Trimipramine Clinical Studies in the drug label.
# How Supplied
Trimipramine Maleate Capsules equivalent to 25 mg of Trimipramine are #2 Capsules, light blue opaque cap, yellow opaque body, imprinted “A-293” in black ink on cap and body, filled with white to off-white powder.
Capsules are supplied in bottles of:
30 (NDC 45963-293-30) with a child-resistant closure.
90 (NDC 45963-293-08) with a child-resistant closure.
270 (NDC 45963-293-27) with a non-child resistant closure.
Trimipramine Maleate Capsules equivalent to 50 mg of Trimipramine are #2 Capsules, light blue opaque cap, medium orange opaque body, imprinted “A-294” in black ink on cap and body, filled with white to off-white powder.
Capsules are supplied in bottles of:
30 (NDC 45963-294-30) with a child-resistant closure.
90 (NDC 45963-294-08) with a child-resistant closure.
270 (NDC 45963-294-27) with a non-child resistant closure.
Trimipramine Maleate Capsules equivalent to 100 mg of Trimipramine are #2 Capsules, light blue opaque cap, white opaque body, imprinted “A-295” in black ink on cap and body, filled with white to off-white powder.
Capsules are supplied in bottles of:
30 (NDC 45963-295-30) with a child-resistant closure
Dispense in a tight, light-resistant container as defined in the USP. Preserve in tight container. Protect from excessive heat.
## Storage
Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Protect from Moisture.
Keep this and all medication out of the reach of children. Keep tightly closed.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Trimipramine Maleate Capsules
- Antidepressant Medicines, Depression and other Serious Mental Illnesses, and Suicidal Thoughts or Actions
- Read the Medication Guide that comes with you or your family member’s antidepressant medicine. This Medication Guide is only about the risk of suicidal thoughts and actions with antidepressant medicines.
- 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
- What is the most important information I should know about antidepressant medicines, depression and other serious mental illnesses, and suicidal thoughts or actions?
- 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) 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
- Who should not take trimipramine maleate capsules?
- If you take a monoamine oxidase inhibitor (MAOI). Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI, including the antibiotic linezolid.
- Do not take an MAOI within 2 weeks of stopping trimipramine maleate capsules unless directed to do so by your physician.
- Do not start trimipramine maleate capsules if you stopped taking an MAOI in the last 2 weeks unless directed to do so by your physician.
- What else do I need to know about antidepressant medicines?
- Never stop an antidepressant medicine without first talking to a 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 takes. 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.
This Medication Guide has been approved by the U.S. Food and Drug Administration for all antidepressants.
- Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
# Precautions with Alcohol
Patients should be warned that the concomitant use of alcoholic beverages may be associated with exaggerated effects.
# Brand Names
There is limited information regarding Trimipramine Brand Names in the drug label.
# Look-Alike Drug Names
There is limited information regarding Trimipramine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Trimipramine | |
2a05d317963e06e7c9c8b2276487a98243d4e50d | wikidoc | Triploblasty | Triploblasty
# Overview
Triploblasty is a condition of the blastula in which there are three primary germ layers: the ectoderm, mesoderm, and endoderm. Additionally, the term may refer to any ovum in which the blastoderm splits into three layers.
In higher and intermediate animals (from flat worms to humans), all organisms arise from a triploblastic ovum. Triploblastic organisms are organisms which evolve from such an ovum. Generally speaking, triploblastic organisms belong to the Bilateria subregnum.
Compare to simpler diploblastic animals such as cnidaria with two germ layers and even simpler animals such as sponges with only one germ layer.
ca:Triploblàstia
it:Triploblastico | Triploblasty
# Overview
Triploblasty is a condition of the blastula in which there are three primary germ layers: the ectoderm, mesoderm, and endoderm. Additionally, the term may refer to any ovum in which the blastoderm splits into three layers.
In higher and intermediate animals (from flat worms to humans), all organisms arise from a triploblastic ovum. Triploblastic organisms are organisms which evolve from such an ovum. Generally speaking, triploblastic organisms belong to the Bilateria subregnum.
Compare to simpler diploblastic animals such as cnidaria with two germ layers and even simpler animals such as sponges with only one germ layer.
ca:Triploblàstia
it:Triploblastico
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Triploblastic | |
7234baaa966fee2b564b00a96f68980c51c6b83b | wikidoc | Triprolidine | Triprolidine
# 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
Triprolidine is a antihistamine that is FDA approved for the treatment of symptoms due to hay fever (allergic rhinitis) or other upper respiratory allergies, runny nose, sneezing, itching of the nose or throat and itchy, watery eyes. Common adverse reactions include xerostomia, sedation, nasal mucosa dry, pharyngeal dryness, thick bronchial sputum.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Triprolidine in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Triprolidine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Triprolidine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Triprolidine in pediatric patients.
# Contraindications
There is limited information regarding Triprolidine Contraindications in the drug label.
# Warnings
Do not exceed recommended dosage
Ask a doctor before use if you have:
- a breathing problem such as emphysema or chronic bronchitis
- glaucoma
- trouble urinating due to an enlarged prostate gland
Ask a doctor before use if you are taking sedatives or tranquilizers
When using this product
- excitability may occur, especially in children
- may cause drowsiness
- alcohol, sedatives and tranquilizers may increase the drowsiness effect
- avoid alcoholic beverages
- use caution when driving a motor vehicle or operating machinery
Stop use and ask a doctor if new symptoms occur
If pregnant or breast-feeding, ask a health professional before use.
Keep out of the reach of children.
In case of overdose, get medical help or contact a Poison Control Center right away.
# Adverse Reactions
## Clinical Trials Experience
There is limited information regarding Triprolidine Clinical Trials Experience in the drug label.
## Postmarketing Experience
There is limited information regarding Triprolidine Postmarketing Experience in the drug label.
# Drug Interactions
There is limited information regarding Triprolidine Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
There is no FDA guidance on usage of Triprolidine in women who are pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Triprolidine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Triprolidine during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Triprolidine in women who are nursing.
### Pediatric Use
There is no FDA guidance on the use of Triprolidine in pediatric settings.
### Geriatic Use
There is no FDA guidance on the use of Triprolidine in geriatric settings.
### Gender
There is no FDA guidance on the use of Triprolidine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Triprolidine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Triprolidine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Triprolidine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Triprolidine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Triprolidine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Triprolidine Administration in the drug label.
### Monitoring
There is limited information regarding Triprolidine Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Triprolidine and IV administrations.
# Overdosage
There is limited information regarding Triprolidine 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 Triprolidine Mechanism of Action in the drug label.
## Structure
There is limited information regarding Triprolidine Structure in the drug label.
## Pharmacodynamics
There is limited information regarding Triprolidine Pharmacodynamics in the drug label.
## Pharmacokinetics
There is limited information regarding Triprolidine Pharmacokinetics in the drug label.
## Nonclinical Toxicology
There is limited information regarding Triprolidine Nonclinical Toxicology in the drug label.
# Clinical Studies
There is limited information regarding Triprolidine Clinical Studies in the drug label.
# How Supplied
There is limited information regarding Triprolidine How Supplied in the drug label.
## Storage
There is limited information regarding Triprolidine Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Triprolidine Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Triprolidine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Zymine
- Tripohist
# Look-Alike Drug Names
There is limited information regarding Triprolidine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Triprolidine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alberto Plate [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
Triprolidine is a antihistamine that is FDA approved for the treatment of symptoms due to hay fever (allergic rhinitis) or other upper respiratory allergies, runny nose, sneezing, itching of the nose or throat and itchy, watery eyes. Common adverse reactions include xerostomia, sedation, nasal mucosa dry, pharyngeal dryness, thick bronchial sputum.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Triprolidine in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Triprolidine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Triprolidine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Triprolidine in pediatric patients.
# Contraindications
There is limited information regarding Triprolidine Contraindications in the drug label.
# Warnings
Do not exceed recommended dosage
Ask a doctor before use if you have:
- a breathing problem such as emphysema or chronic bronchitis
- glaucoma
- trouble urinating due to an enlarged prostate gland
Ask a doctor before use if you are taking sedatives or tranquilizers
When using this product
- excitability may occur, especially in children
- may cause drowsiness
- alcohol, sedatives and tranquilizers may increase the drowsiness effect
- avoid alcoholic beverages
- use caution when driving a motor vehicle or operating machinery
Stop use and ask a doctor if new symptoms occur
If pregnant or breast-feeding, ask a health professional before use.
Keep out of the reach of children.
In case of overdose, get medical help or contact a Poison Control Center right away.
# Adverse Reactions
## Clinical Trials Experience
There is limited information regarding Triprolidine Clinical Trials Experience in the drug label.
## Postmarketing Experience
There is limited information regarding Triprolidine Postmarketing Experience in the drug label.
# Drug Interactions
There is limited information regarding Triprolidine Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
There is no FDA guidance on usage of Triprolidine in women who are pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Triprolidine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Triprolidine during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Triprolidine in women who are nursing.
### Pediatric Use
There is no FDA guidance on the use of Triprolidine in pediatric settings.
### Geriatic Use
There is no FDA guidance on the use of Triprolidine in geriatric settings.
### Gender
There is no FDA guidance on the use of Triprolidine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Triprolidine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Triprolidine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Triprolidine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Triprolidine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Triprolidine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Triprolidine Administration in the drug label.
### Monitoring
There is limited information regarding Triprolidine Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Triprolidine and IV administrations.
# Overdosage
There is limited information regarding Triprolidine 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 Triprolidine Mechanism of Action in the drug label.
## Structure
There is limited information regarding Triprolidine Structure in the drug label.
## Pharmacodynamics
There is limited information regarding Triprolidine Pharmacodynamics in the drug label.
## Pharmacokinetics
There is limited information regarding Triprolidine Pharmacokinetics in the drug label.
## Nonclinical Toxicology
There is limited information regarding Triprolidine Nonclinical Toxicology in the drug label.
# Clinical Studies
There is limited information regarding Triprolidine Clinical Studies in the drug label.
# How Supplied
There is limited information regarding Triprolidine How Supplied in the drug label.
## Storage
There is limited information regarding Triprolidine Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Triprolidine Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Triprolidine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Zymine
- Tripohist
# Look-Alike Drug Names
There is limited information regarding Triprolidine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Tripohist | |
a8d482dd32717f4b6437046bc2e55d53500669f9 | wikidoc | Triune brain | Triune brain
The triune brain is a model proposed by Paul D. MacLean to explain the function of traces of evolution existing in the structure of the human brain. In this model, the brain is broken down into three separate brains that have their own special intelligence, subjectivity, sense of time and space, and memory. The triune brain consists of the R-complex, the limbic system, and the neocortex.
# The R-Complex
The R-complex, also known as the "Reptilian Brain", includes the brain stem and cerebellum. The term "Reptilian brain" comes from the fact that a reptile's brain is dominated by the brain stem and cerebellum which controls instinctive survival behavior and thinking. This is similar in humans. This brain controls the muscles, balance and autonomic functions (e.g. breathing and heartbeat); thus it is primarily reactive to direct stimuli.
# The Limbic System
MacLean first introduced the term "limbic system" in a paper in 1952. This portion of the brain derives from "the old mammalian brain". The limbic system is the source of emotions and instincts
(e.g.. feeding, fighting, fleeing, and sexual behaviour). When this part of the brain is stimulated, such as by mild electric current, emotions are produced.
MacLean observed that everything in the limbic system is either "agreeable or disagreeable." Survival is based upon the avoidance of pain (disagreeable) and the recurrence of pleasure (agreeable).
The limbic system comprises the amygdala, the hypothalamus, and the hippocampus. The limbic system must interact with the neocortex in some way. The limbic system cannot function entirely on its own. It needs to interact with the neocortex to process the emotions.
# The Neocortex
The neocortex, also known as the cerebral cortex, is similar to the brain of higher mammals and controls higher-order thinking skills, reason and speech. | Triune brain
The triune brain is a model proposed by Paul D. MacLean to explain the function of traces of evolution existing in the structure of the human brain. In this model, the brain is broken down into three separate brains that have their own special intelligence, subjectivity, sense of time and space, and memory[1]. The triune brain consists of the R-complex, the limbic system, and the neocortex.
## The R-Complex
The R-complex, also known as the "Reptilian Brain", includes the brain stem and cerebellum. The term "Reptilian brain" comes from the fact that a reptile's brain is dominated by the brain stem and cerebellum which controls instinctive survival behavior and thinking. This is similar in humans. This brain controls the muscles, balance and autonomic functions (e.g. breathing and heartbeat)[1]; thus it is primarily reactive to direct stimuli.
## The Limbic System
MacLean first introduced the term "limbic system" in a paper in 1952. This portion of the brain derives from "the old mammalian brain"[1]. The limbic system is the source of emotions and instincts
(e.g.. feeding, fighting, fleeing, and sexual behaviour). When this part of the brain is stimulated, such as by mild electric current, emotions are produced.
MacLean observed that everything in the limbic system is either "agreeable or disagreeable." Survival is based upon the avoidance of pain (disagreeable) and the recurrence of pleasure (agreeable)[1].
The limbic system comprises the amygdala, the hypothalamus, and the hippocampus. The limbic system must interact with the neocortex in some way. The limbic system cannot function entirely on its own. It needs to interact with the neocortex to process the emotions.
## The Neocortex
The neocortex, also known as the cerebral cortex, is similar to the brain of higher mammals and controls higher-order thinking skills, reason and speech. | https://www.wikidoc.org/index.php/Triune_brain | |
ff8040d0e319cc9a2bc4930852471b3896d90548 | wikidoc | Tromethamine | Tromethamine
# 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
Tromethamine is an acid base disorder agent that is FDA approved for the prevention of metabolic acidosis associated with certain conditions like cardiac bypass surgery and cardiac arrest.. Common adverse reactions include hypervolemia, hypoglycemia, hepatocellular necrosis and respiratory depression..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
# Indications
- Tham Solution (tromethamine injection) is indicated for the prevention and correction of metabolic acidosis. In the following conditions it may help to sustain vital functions and thus provide time for treatment of the primary disease:
Metabolic Acidosis Associated with Cardiac Bypass Surgery.
- Tham Solution has been found to be primarily beneficial in correcting metabolic acidosis which may occur during or immediately following cardiac bypass surgical procedures.
Correction of Acidity of ACD Blood in Cardiac Bypass Surgery.
- It is well known that ACD blood is acidic and becomes more acidic on storage. Tromethamine effectively corrects this acidity. Tham Solution may be added directly to the blood used to prime the pump-oxygenator. When ACD blood is brought to a normal pH range the patient is spared an initial acid load. Additional tromethamine may be indicated during cardiac bypass surgery should metabolic acidosis appear.
Metabolic Acidosis Associated with Cardiac Arrest.
- Acidosis is nearly always one of the consequences of cardiac arrest and, in some instances, may even be a causative factor in arrest. It is important therefore, that the correction of acidosis should be started promptly with other resuscitative efforts. By correcting acidosis, Tham Solution (tromethamine injection) has caused the arrested heart to respond to resuscitative efforts after standard methods alone had failed. In these cases, tromethamine was given intraventricularly. It is to be noted, however, that such precariously ill patients often have died subsequently of causes unrelated to the administration of tromethamine. With administration by the peripheral venous route, metabolic acidosis has been corrected in a majority of patients. The success in reinstitution of cardiac rhythm by this means probably has not been of the same order of magnitude as with the intraventricular route.
# Dosage
- Tham Solution (tromethamine injection) is administered by slow intravenous infusion, by addition to pump-oxygenator ACD blood or other priming fluid or by injection into the ventricular cavity during cardiac arrest. For infusion by peripheral vein, a large needle should be used in the largest antecubital vein or an indwelling catheter placed in a large vein of an elevated limb to minimize chemical irritation of the alkaline solution during infusion. Catheters are recommended.
- Dosage and rate of administration should be carefully supervised to avoid overtreatment (alkalosis). Pretreatment and subsequent determinations of blood values (e.g. pH, PCO2, PO2, glucose and electrolytes) and urinary output should be made as necessary to monitor dosage and progress of treatment. In general, dosage should be limited to an amount sufficient to increase blood pH to normal limits (7.35 to 7.45) and to correct acid-base derangements. The total quantity to be administered during the period of illness will depend upon the severity and progression of the acidosis. The possibility of some retention of tromethamine, especially in patients with impaired renal function, should be kept in mind.
- The intravenous dosage of Tham Solution (tromethamine injection) may be estimated from the buffer base deficit of the extracellular fluid in mEq/liter determined by means of the Siggaard-Andersen nomogram. The following formula is intended as a general guide:
- Tham Solution (mL of 0.3 M) Required =
Body Weight (kg) X
Base Deficit (mEq/liter) X 1.1*
- Thus, a 70 kg patient with a buffer base deficit (“negative base excess”) of 5 mEq/liter would require 70 x 5 x 1.1 = 385 mL of Tham Solution containing 13.9 g (115 mEq) of tromethamine. The need for administration of additional Tham Solution is determined by serial determinations of the existing base deficit.
- Factor of 1.1 accounts for an approximate reduction of 10% in buffering capacity due to the presence of sufficient acetic acid to lower pH of the 0.3 M solution to approximately 8.6.
Correction of Metabolic Acidosis Associated with Cardiac Bypass Surgery: An adverse dose of approximately 9.0 mL/kg (324 mg/kg) has been used in clinical studies with Tham Solution (tromethamine injection). This is equivalent to a total dose of 630 mL (189 mEq) for 70 kg patient. A total single dose of 500 mL (150 mEq) is considered adequate for most adults. Larger single doses (up to 1000 mL) may be required in unusually severe cases.
- It is recommended that individual doses should not exceed 500 mg/kg (227 mg/lb) over a period of not less than one hour. Thus, for a 70 kg (154 pound) patient the dose should not exceed a maximum of 35 g per hour (1078 mL of a 0.3 M solution). Repeated determinations of pH and other clinical observations should be used as a guide to the need for repeat doses.
Correction of Acidity of ACD Blood in Cardiac Bypass Surgery: The pH of stored blood ranges from 6.80 to 6.22 depending upon the duration of storage. The amount of Tham Solution used to correct this acidity ranges from 0.5 to 2.5 g (15 to 77 mL of a 0.3 M solution) added to each 500 mL of ACD blood used for priming the pump-oxygenator. Clinical experience indicates that 2 g (62 mL of a 0.3 M solution) added to 500 mL of ACD blood is usually adequate.
Correction of Metabolic Acidosis Associated with Cardiac Arrest: In the treatment of cardiac arrest, Tham Solution should be given at the same time that other standard resuscitative measures, including manual systole, are being applied. If the chest is open, Tham Solution is injected directly into the ventricular cavity. From 2 to 6 g (62 to 185 mL of a 0.3 M solution) should be injected immediately. Do not inject into the cardiac muscle.
- If the chest is not open, from 3.6 to 10.8 g (111 to 333 mL of a 0.3 M solution) should be injected immediately into a larger peripheral vein. Additional amounts may be required to control acidosis persisting after cardiac arrest is reversed.
Correction of Metabolic Acidosis Associated with RDS in Neonates and Infants: The initial dose of Tham Solution should be based on initial pH and birthweight amounting to approximately 1 mL per kg for each pH unit below 7.4. Further doses have been given according to changes in PaO2, pH and PCO2.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Tromethamine in adult patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Tromethamine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- There is limited information regarding FDA-Labeled Use of Tromethamine in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Tromethamine in pediatric patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Tromethamine in pediatric patients.
# Contraindications
- Tham Solution (tromethamine injection) is contraindicated in uremia and anuria. In neonates it is also contraindicated in chronic respiratory acidosis and salicylate intoxication.
# Warnings
- Large doses of Tham Solution may depress ventilation, as a result of increased blood pH and reduced CO2 concentration. Thus, dosage should be adjusted so that blood pH is not allowed to increase above normal. In situations in which respiratory acidosis may be present concomitantly with metabolic acidosis, the drug may be used with mechanical assistance to ventilation.
- Care must be exercised to prevent perivascular infiltration since this can cause inflammation, necrosis and sloughing of tissue. Venospasm and intravenous thrombosis, which may occur during infusion, can be minimized by insuring that the injection needle is well within the largest available vein and that solutions are slowly infused. Intravenous catheters are recommended. If perivascular infiltration occurs, institute appropriate countermeasures.
- Tham Solution (tromethamine injection) should be administered slowly and in amounts sufficient only to correct the existing acidosis, and to avoid overdosage and alkalosis. Overdosage in terms of total drug and/or too rapid administration, may cause hypoglycemia of a prolonged duration (several hours). Therefore, frequent blood glucose determinations should be made during and after therapy.
- Extreme care should be exercised in patients with renal disease or reduced urinary output because of potential hyperkalemia and the possibility of a decreased excretion of tromethamine. In such patients, the drug should be used cautiously with electrocardiographic monitoring and frequent serum potassium determinations.
- Because clinical experience has been limited generally to short-term use, the drug should not be administered for more than a period of one day except in a life-threatening situation.
- The intravenous administration of Tham Solution can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states or pulmonary edema.
- Additives may be incompatible. Consult with pharmacist, if available. When introducing additives, use aseptic technique, mix thoroughly and do not store.
# Adverse Reactions
## Clinical Trials Experience
- Generally, side effects have been infrequent.
- Respiratory: Although the incidence of ventilatory depression is low, it is important to keep in mind that such depression may occur. Respiratory depression may be more likely to occur in patients who have chronic hypoventilation or those who have been treated with drugs which depress respiration. In patients with associated respiratory acidosis, tromethamine should be administered with mechanical assistance to ventilation.
- Vascular: Extreme care should be taken to avoid perivascular infiltration. Local tissue damage and subsequent sloughing may occur if extravasation occurs. Chemical phlebitis and venospasm also have been reported.
- Hematologic: Transient depression of blood glucose may occur.
- Hepatic: Infusion via low-lying umbilical venous catheters has been associated with hepatocellular necrosis.
- Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection extravasation and hypervolemia.
- If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary.
## Postmarketing Experience
- There is limited information regarding Postmarketing Experience of Tromethamine in the drug label.
# Drug Interactions
There is limited information regarding Tromethamine Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Pregnancy Category C
- Animal reproduction studies have not been conducted with tromethamine. It is also not known whether tromethamine can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Tromethamine should be given to a pregnant woman only if clearly needed.
Pregnancy Category (AUS):
- There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tromethamine in women who are pregnant.
### Labor and Delivery
- There is no FDA guidance on use of Tromethamine during labor and delivery.
### Nursing Mothers
- 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 THAM Solution is administered to a nursing mother.
### Pediatric Use
- The safety and effectiveness of THAM Solution in pediatric patients is based on over 30 years’ clinical experience documented in the literature and on safety surveillance. THAM Solution has been used to treat severe cases of metabolic acidosis with concurrent respiratory acidosis because it does not raise PCO2 as bicarbonate does in neonates and infants with respiratory failure. It has also been used in neonates and infants with hypernatremia and metabolic acidosis to avoid the additional sodium given with the bicarbonate. However, because the osmotic effects of THAM Solution are greater and large continuous doses are required, bicarbonate is preferred to THAM Solution in the treatment of acidotic neonates and infants with RDS. Hypoglycemia may occur when this product is used in premature and even full-term neonates.
### Geriatic Use
- Clinical studies of Tham solution did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in response between the elderly and younger patients. In general, 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.
- This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
### Gender
There is no FDA guidance on the use of Tromethamine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Tromethamine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Tromethamine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Tromethamine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Tromethamine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Tromethamine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
### Monitoring
- There is limited information regarding Monitoring of Tromethamine in the drug
# IV Compatibility
- There is limited information regarding IV Compatibility of Tromethamine in the drug label.
# Overdosage
- Too rapid administration and/or excessive amounts of tromethamine may cause alkalosis, hypoglycemia, overhydration or solute overload. In the event of overdosage, discontinue the infusion, evaluate the patient and institute appropriate countermeasures.
- The LD50 values for the acute intravenous toxicity of THAM are influenced by the rate of infusion of the dose administered.
- Intravenous LD50 Mice = 3500 mg/kg
- Intravenous LD50 Rats = 2300 mg/kg
# Pharmacology
There is limited information regarding Tromethamine Pharmacology in the drug label.
## Mechanism of Action
- There is limited information regarding Mechanism of Action of Tromethamine in the drug label.
## Structure
- Tham Solution (tromethamine injection) is a sterile, non-pyrogenic 0.3 M solution of tromethamine, adjusted to a pH of approximately 8.6 with glacial acetic acid. It is administered by intravenous injection, by addition to ACD blood for priming cardiac bypass equipment and by injection into the ventricular cavity during cardiac arrest.
- Each 100 mL contains tromethamine 3.6 g (30 mEq) in water for injection. The solution is hypertonic 389 mOsmol/L (calc.). pH 8.6 (8.4-8.7).
- The solution contains no bacteriostat, antimicrobial agent or added buffer (except acetic acid for pH adjustment) and is intended only for use as a single-dose injection. When smaller doses are required the unused portion should be discarded.
- Tham solution is a parenteral systemic alkalizer and fluid replenisher.
- Tromethamine, USP (sometimes called “tris” or “tris buffer”) is chemically designated 2-amino-2-(hydroxymethyl)-1, 3-propanediol, a solid readily soluble in water, also classified as an organic amine buffer. It has the following structural formula:
- Water for Injection, USP is chemically designated H20.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Tromethamine in the drug label.
## Pharmacokinetics
There is limited information regarding Pharmacokinetics of Tromethamine in the drug label.
## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility:
- Studies with THAM Solution have not been performed to evaluate carcinogenic potential, mutagenic potential or effects on fertility.
# Clinical Studies
- There is limited information regarding Clinical Studies of Tromethamine in the drug label.
# How Supplied
- Tham Solution (tromethamine injection) is supplied in a single-dose 500 mL large volume glass container (List No. 1593).
## Storage
- Store at 20 to 25°C (68 to 77°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Tromethamine in the drug label.
# Precautions with Alcohol
- Alcohol-Tromethamine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- THAM®
# Look-Alike Drug Names
- A® — B®
# Drug Shortage Status
# Price | Tromethamine
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
Tromethamine is an acid base disorder agent that is FDA approved for the prevention of metabolic acidosis associated with certain conditions like cardiac bypass surgery and cardiac arrest.. Common adverse reactions include hypervolemia, hypoglycemia, hepatocellular necrosis and respiratory depression..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
# Indications
- Tham Solution (tromethamine injection) is indicated for the prevention and correction of metabolic acidosis. In the following conditions it may help to sustain vital functions and thus provide time for treatment of the primary disease:
Metabolic Acidosis Associated with Cardiac Bypass Surgery.
- Tham Solution has been found to be primarily beneficial in correcting metabolic acidosis which may occur during or immediately following cardiac bypass surgical procedures.
Correction of Acidity of ACD Blood in Cardiac Bypass Surgery.
- It is well known that ACD blood is acidic and becomes more acidic on storage. Tromethamine effectively corrects this acidity. Tham Solution may be added directly to the blood used to prime the pump-oxygenator. When ACD blood is brought to a normal pH range the patient is spared an initial acid load. Additional tromethamine may be indicated during cardiac bypass surgery should metabolic acidosis appear.
Metabolic Acidosis Associated with Cardiac Arrest.
- Acidosis is nearly always one of the consequences of cardiac arrest and, in some instances, may even be a causative factor in arrest. It is important therefore, that the correction of acidosis should be started promptly with other resuscitative efforts. By correcting acidosis, Tham Solution (tromethamine injection) has caused the arrested heart to respond to resuscitative efforts after standard methods alone had failed. In these cases, tromethamine was given intraventricularly. It is to be noted, however, that such precariously ill patients often have died subsequently of causes unrelated to the administration of tromethamine. With administration by the peripheral venous route, metabolic acidosis has been corrected in a majority of patients. The success in reinstitution of cardiac rhythm by this means probably has not been of the same order of magnitude as with the intraventricular route.
# Dosage
- Tham Solution (tromethamine injection) is administered by slow intravenous infusion, by addition to pump-oxygenator ACD blood or other priming fluid or by injection into the ventricular cavity during cardiac arrest. For infusion by peripheral vein, a large needle should be used in the largest antecubital vein or an indwelling catheter placed in a large vein of an elevated limb to minimize chemical irritation of the alkaline solution during infusion. Catheters are recommended.
- Dosage and rate of administration should be carefully supervised to avoid overtreatment (alkalosis). Pretreatment and subsequent determinations of blood values (e.g. pH, PCO2, PO2, glucose and electrolytes) and urinary output should be made as necessary to monitor dosage and progress of treatment. In general, dosage should be limited to an amount sufficient to increase blood pH to normal limits (7.35 to 7.45) and to correct acid-base derangements. The total quantity to be administered during the period of illness will depend upon the severity and progression of the acidosis. The possibility of some retention of tromethamine, especially in patients with impaired renal function, should be kept in mind.
- The intravenous dosage of Tham Solution (tromethamine injection) may be estimated from the buffer base deficit of the extracellular fluid in mEq/liter determined by means of the Siggaard-Andersen nomogram. The following formula is intended as a general guide:
- Tham Solution (mL of 0.3 M) Required =
Body Weight (kg) X
Base Deficit (mEq/liter) X 1.1*
- Thus, a 70 kg patient with a buffer base deficit (“negative base excess”) of 5 mEq/liter would require 70 x 5 x 1.1 = 385 mL of Tham Solution containing 13.9 g (115 mEq) of tromethamine. The need for administration of additional Tham Solution is determined by serial determinations of the existing base deficit.
- Factor of 1.1 accounts for an approximate reduction of 10% in buffering capacity due to the presence of sufficient acetic acid to lower pH of the 0.3 M solution to approximately 8.6.
Correction of Metabolic Acidosis Associated with Cardiac Bypass Surgery: An adverse dose of approximately 9.0 mL/kg (324 mg/kg) has been used in clinical studies with Tham Solution (tromethamine injection). This is equivalent to a total dose of 630 mL (189 mEq) for 70 kg patient. A total single dose of 500 mL (150 mEq) is considered adequate for most adults. Larger single doses (up to 1000 mL) may be required in unusually severe cases.
- It is recommended that individual doses should not exceed 500 mg/kg (227 mg/lb) over a period of not less than one hour. Thus, for a 70 kg (154 pound) patient the dose should not exceed a maximum of 35 g per hour (1078 mL of a 0.3 M solution). Repeated determinations of pH and other clinical observations should be used as a guide to the need for repeat doses.
Correction of Acidity of ACD Blood in Cardiac Bypass Surgery: The pH of stored blood ranges from 6.80 to 6.22 depending upon the duration of storage. The amount of Tham Solution used to correct this acidity ranges from 0.5 to 2.5 g (15 to 77 mL of a 0.3 M solution) added to each 500 mL of ACD blood used for priming the pump-oxygenator. Clinical experience indicates that 2 g (62 mL of a 0.3 M solution) added to 500 mL of ACD blood is usually adequate.
Correction of Metabolic Acidosis Associated with Cardiac Arrest: In the treatment of cardiac arrest, Tham Solution should be given at the same time that other standard resuscitative measures, including manual systole, are being applied. If the chest is open, Tham Solution is injected directly into the ventricular cavity. From 2 to 6 g (62 to 185 mL of a 0.3 M solution) should be injected immediately. Do not inject into the cardiac muscle.
- If the chest is not open, from 3.6 to 10.8 g (111 to 333 mL of a 0.3 M solution) should be injected immediately into a larger peripheral vein. Additional amounts may be required to control acidosis persisting after cardiac arrest is reversed.
Correction of Metabolic Acidosis Associated with RDS in Neonates and Infants: The initial dose of Tham Solution should be based on initial pH and birthweight amounting to approximately 1 mL per kg for each pH unit below 7.4. Further doses have been given according to changes in PaO2, pH and PCO2.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Tromethamine in adult patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Tromethamine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- There is limited information regarding FDA-Labeled Use of Tromethamine in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Tromethamine in pediatric patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Tromethamine in pediatric patients.
# Contraindications
- Tham Solution (tromethamine injection) is contraindicated in uremia and anuria. In neonates it is also contraindicated in chronic respiratory acidosis and salicylate intoxication.
# Warnings
- Large doses of Tham Solution may depress ventilation, as a result of increased blood pH and reduced CO2 concentration. Thus, dosage should be adjusted so that blood pH is not allowed to increase above normal. In situations in which respiratory acidosis may be present concomitantly with metabolic acidosis, the drug may be used with mechanical assistance to ventilation.
- Care must be exercised to prevent perivascular infiltration since this can cause inflammation, necrosis and sloughing of tissue. Venospasm and intravenous thrombosis, which may occur during infusion, can be minimized by insuring that the injection needle is well within the largest available vein and that solutions are slowly infused. Intravenous catheters are recommended. If perivascular infiltration occurs, institute appropriate countermeasures.
- Tham Solution (tromethamine injection) should be administered slowly and in amounts sufficient only to correct the existing acidosis, and to avoid overdosage and alkalosis. Overdosage in terms of total drug and/or too rapid administration, may cause hypoglycemia of a prolonged duration (several hours). Therefore, frequent blood glucose determinations should be made during and after therapy.
- Extreme care should be exercised in patients with renal disease or reduced urinary output because of potential hyperkalemia and the possibility of a decreased excretion of tromethamine. In such patients, the drug should be used cautiously with electrocardiographic monitoring and frequent serum potassium determinations.
- Because clinical experience has been limited generally to short-term use, the drug should not be administered for more than a period of one day except in a life-threatening situation.
- The intravenous administration of Tham Solution can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states or pulmonary edema.
- Additives may be incompatible. Consult with pharmacist, if available. When introducing additives, use aseptic technique, mix thoroughly and do not store.
# Adverse Reactions
## Clinical Trials Experience
- Generally, side effects have been infrequent.
- Respiratory: Although the incidence of ventilatory depression is low, it is important to keep in mind that such depression may occur. Respiratory depression may be more likely to occur in patients who have chronic hypoventilation or those who have been treated with drugs which depress respiration. In patients with associated respiratory acidosis, tromethamine should be administered with mechanical assistance to ventilation.
- Vascular: Extreme care should be taken to avoid perivascular infiltration. Local tissue damage and subsequent sloughing may occur if extravasation occurs. Chemical phlebitis and venospasm also have been reported.
- Hematologic: Transient depression of blood glucose may occur.
- Hepatic: Infusion via low-lying umbilical venous catheters has been associated with hepatocellular necrosis.
- Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection extravasation and hypervolemia.
- If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary.
## Postmarketing Experience
- There is limited information regarding Postmarketing Experience of Tromethamine in the drug label.
# Drug Interactions
There is limited information regarding Tromethamine Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Pregnancy Category C
- Animal reproduction studies have not been conducted with tromethamine. It is also not known whether tromethamine can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Tromethamine should be given to a pregnant woman only if clearly needed.
Pregnancy Category (AUS):
- There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tromethamine in women who are pregnant.
### Labor and Delivery
- There is no FDA guidance on use of Tromethamine during labor and delivery.
### Nursing Mothers
- 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 THAM Solution is administered to a nursing mother.
### Pediatric Use
- The safety and effectiveness of THAM Solution in pediatric patients is based on over 30 years’ clinical experience documented in the literature and on safety surveillance. THAM Solution has been used to treat severe cases of metabolic acidosis with concurrent respiratory acidosis because it does not raise PCO2 as bicarbonate does in neonates and infants with respiratory failure. It has also been used in neonates and infants with hypernatremia and metabolic acidosis to avoid the additional sodium given with the bicarbonate. However, because the osmotic effects of THAM Solution are greater and large continuous doses are required, bicarbonate is preferred to THAM Solution in the treatment of acidotic neonates and infants with RDS. Hypoglycemia may occur when this product is used in premature and even full-term neonates.
### Geriatic Use
- Clinical studies of Tham solution did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in response between the elderly and younger patients. In general, 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.
- This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
### Gender
There is no FDA guidance on the use of Tromethamine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Tromethamine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Tromethamine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Tromethamine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Tromethamine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Tromethamine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
### Monitoring
- There is limited information regarding Monitoring of Tromethamine in the drug
# IV Compatibility
- There is limited information regarding IV Compatibility of Tromethamine in the drug label.
# Overdosage
- Too rapid administration and/or excessive amounts of tromethamine may cause alkalosis, hypoglycemia, overhydration or solute overload. In the event of overdosage, discontinue the infusion, evaluate the patient and institute appropriate countermeasures.
- The LD50 values for the acute intravenous toxicity of THAM are influenced by the rate of infusion of the dose administered.
- Intravenous LD50 Mice = 3500 mg/kg
- Intravenous LD50 Rats = 2300 mg/kg
# Pharmacology
There is limited information regarding Tromethamine Pharmacology in the drug label.
## Mechanism of Action
- There is limited information regarding Mechanism of Action of Tromethamine in the drug label.
## Structure
- Tham Solution (tromethamine injection) is a sterile, non-pyrogenic 0.3 M solution of tromethamine, adjusted to a pH of approximately 8.6 with glacial acetic acid. It is administered by intravenous injection, by addition to ACD blood for priming cardiac bypass equipment and by injection into the ventricular cavity during cardiac arrest.
- Each 100 mL contains tromethamine 3.6 g (30 mEq) in water for injection. The solution is hypertonic 389 mOsmol/L (calc.). pH 8.6 (8.4-8.7).
- The solution contains no bacteriostat, antimicrobial agent or added buffer (except acetic acid for pH adjustment) and is intended only for use as a single-dose injection. When smaller doses are required the unused portion should be discarded.
- Tham solution is a parenteral systemic alkalizer and fluid replenisher.
- Tromethamine, USP (sometimes called “tris” or “tris buffer”) is chemically designated 2-amino-2-(hydroxymethyl)-1, 3-propanediol, a solid readily soluble in water, also classified as an organic amine buffer. It has the following structural formula:
- Water for Injection, USP is chemically designated H20.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Tromethamine in the drug label.
## Pharmacokinetics
There is limited information regarding Pharmacokinetics of Tromethamine in the drug label.
## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility:
- Studies with THAM Solution have not been performed to evaluate carcinogenic potential, mutagenic potential or effects on fertility.
# Clinical Studies
- There is limited information regarding Clinical Studies of Tromethamine in the drug label.
# How Supplied
- Tham Solution (tromethamine injection) is supplied in a single-dose 500 mL large volume glass container (List No. 1593).
## Storage
- Store at 20 to 25°C (68 to 77°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Tromethamine in the drug label.
# Precautions with Alcohol
- Alcohol-Tromethamine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- THAM®[1]
# Look-Alike Drug Names
- A® — B®[2]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Tromethamine | |
efe0f01d24502361eebf081cb34629918a092666 | wikidoc | Tubocurarine | Tubocurarine
# Overview
Tubocurarine (also known as d-tubocurarine or DTC) is a toxic alkaloid and skeletal muscle relaxant in the category of non-depolarizing neuromuscular-blocking drugs, used adjunctively in anesthesia to provide skeletal muscle relaxation during surgery or mechanical ventilation. Unlike a number of other related skeletal muscle relaxants, it is now rarely considered clinically to facilitate endotracheal intubation.
Tubocurarine is classified as a long-duration, antagonist for Nicotinic acetylcholine receptor. It is the active agent of one of the forms of curare.
Currently, tubocurarine is rarely used as an adjunct for clinical anesthesia because safer alternatives, such as cisatracurium and rocuronium, are available.
# History
Tubocurare is a naturally occurring mono-quaternary alkaloid obtained from the bark of the South American plant Chondrodendron tomentosum, a climbing vine known to the European world since the Spanish conquest of South America. Curare had been used as a source of arrow poison by South American natives to hunt animals, and they were able to eat the animals' contaminated flesh subsequently without any untoward effects, because tubocurarine cannot easily cross mucous membranes. Tubocurarine is thus effective only if given parenterally, as demonstrated by Bernard, who also showed the site of its action was at the neuromuscular junction. Virchow and Munter confirmed the paralyzing action was limited to voluntary and not involuntary muscles. Thus, a conscious individual administered this agent will be unable to move any voluntary muscles, including the diaphragm: a large enough dose will therefore result in death from respiratory failure unless artificial ventilation is initiated.
The word "curare" comes from the South American Indian name for the arrow poison, ourare. Presumably, the initial syllable was pronounced with a heavy glottal stroke. Tubocurarine is so-called because the plant samples containing the curare were stored and shipped to Europe in tubes. Likewise, curare stored in calabash containers was called calabash curare.
Structurally, tubocurarine is a benzylisoquinoline derivative. For many years, its structure, when first elucidated in 1948, was wrongly thought to be bis-quaternary: in other words, it was thought to be an N,N-dimethylated alkaloid. In 1970, the correct structure was finally established, showing one of the two nitrogens to be tertiary, actually a mono-N-methylated alkaloid.
Griffith and Johnson are credited with pioneering the formal clinical introduction of tubocurarine as an adjunct to anesthetic practice on 23 January 1942, at the Montreal Homeopathic Hospital. In this sense, tubocurarine is the prototypical adjunctive neuromuscular blocking agent. However, others before Griffith and Johnson had attempted use of tubocurare in several situations: some under controlled study conditions while others not quite controlled and remained unpublished. Regardless, all in all some ~30,000 patients had been given tubocurare by 1941, although it was Griffith and Johnson's 1942 publication that provided the impetus to the standard use of neuromuscular blocking agents in clinical anesthestic practice - a revolution that rapidly metamorphosized into the standard practice of "balanced" anesthesia: the triad of barbiturate hypnosis, light inhalational anesthesia and muscle relaxation. The technique as described by Gray and Halton was widely known as the "Liverpool technique", and became the standard anesthetic technique in England in the 1950s and 1960s for patients of all ages and physical status. Present clinical anesthetic practice still employs the central principle of balanced anesthesia though with some differences to accommodate subsequent technological advances and introductions of new and better gaseous anesthetic, hypnotic and neuromuscular blocking agents, and tracheal intubation, as well as monitoring techniques that were nonexistent in the day of Gray and Halton: pulse oximetry, capnography, peripheral nerve stimulation, noninvasive blood pressure monitoring, etc.
# Biosynthesis
Tubocurarine biosynthesis involves a radical coupling of two enantiomeric tetrahydrobenzylisoquinolines, more specifically, the two enantiomers of N-methyl-coclaurine. (R) and (S)-N-methyl-coclaurine come from a Mannich-like reaction between dopamine and 4-hydroxyphenyl-acetaldehyde, facilitated by norcoclaurine synthase (NCS). Both dopamine and 4-hydroxyphenylacetyladehyde originate from L-tyrosine. The biosynthetic pathway is described in more detail in the figures. Methylation of the amine and hydroxyl substituents are facilitated by S-adenosyl methionine (SAM).
# Clinical pharmacology and pharmacokinetics
Tubocurarine has a time of onset of 300 seconds or more (which is relatively slow among neuromuscular-blocking drugs), and has a duration of action of 60 to 120 minutes (which is relatively long time).
It also causes histamine release, now a recognized hallmark of the tetrahydroisioquinolinium class of neuromuscular blocking agents. The amount of histamine release in some instances following tubocurarine administration is such that it is contraindicated in asthmatics and patients with allergies. However, the main disadvantage in the use of tubocurarine is its significant ganglion-blocking effect, that manifests as hypotension, in many patients; this constitutes a relative contraindication to its use in patients with myocardial ischaemia.
Because of the shortcomings of tubocurare, much research effort was undertaken soon after its clinical introduction to find a suitable replacement. The efforts unleashed a multitude of compounds borne from structure-activity relations developed from the tubocurare molecule. Some key compounds that have seen clinical use are identified in the muscle relaxants template box below. Of the many tried as replacements, only a few enjoyed as much popularity as tubocurarine: pancuronium, vecuronium, rocuronium, atracurium, and cisatracurium. Succinylcholine is a widely used paralytic drug which acts by activating, instead of blocking, the ACh receptor.
The potassium channel blocker tetraethylammonium (TEA) has been shown to reverse the effects of tubocurarine. It is thought to do so by increasing ACh release, which counteracts the antagonistic effects of tubocurarine on the ACh receptor. | Tubocurarine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Tubocurarine (also known as d-tubocurarine or DTC) is a toxic alkaloid and skeletal muscle relaxant in the category of non-depolarizing neuromuscular-blocking drugs, used adjunctively in anesthesia to provide skeletal muscle relaxation during surgery or mechanical ventilation. Unlike a number of other related skeletal muscle relaxants, it is now rarely considered clinically to facilitate endotracheal intubation.
Tubocurarine is classified as a long-duration,[1] antagonist for Nicotinic acetylcholine receptor.[2] It is the active agent of one of the forms of curare.
Currently, tubocurarine is rarely used as an adjunct for clinical anesthesia because safer alternatives, such as cisatracurium and rocuronium, are available.
# History
Tubocurare is a naturally occurring mono-quaternary alkaloid obtained from the bark of the South American plant Chondrodendron tomentosum, a climbing vine known to the European world since the Spanish conquest of South America. Curare had been used as a source of arrow poison by South American natives to hunt animals, and they were able to eat the animals' contaminated flesh subsequently without any untoward effects, because tubocurarine cannot easily cross mucous membranes. Tubocurarine is thus effective only if given parenterally, as demonstrated by Bernard, who also showed the site of its action was at the neuromuscular junction.[3] Virchow and Munter confirmed the paralyzing action was limited to voluntary and not involuntary muscles.[4] Thus, a conscious individual administered this agent will be unable to move any voluntary muscles, including the diaphragm: a large enough dose will therefore result in death from respiratory failure unless artificial ventilation is initiated.
The word "curare" comes from the South American Indian name for the arrow poison, ourare. Presumably, the initial syllable was pronounced with a heavy glottal stroke. Tubocurarine is so-called because the plant samples containing the curare were stored and shipped to Europe in tubes. Likewise, curare stored in calabash containers was called calabash curare.
Structurally, tubocurarine is a benzylisoquinoline derivative. For many years, its structure, when first elucidated in 1948,[5] was wrongly thought to be bis-quaternary: in other words, it was thought to be an N,N-dimethylated alkaloid. In 1970, the correct structure was finally established,[6] showing one of the two nitrogens to be tertiary, actually a mono-N-methylated alkaloid.
Griffith and Johnson are credited with pioneering the formal clinical introduction of tubocurarine as an adjunct to anesthetic practice on 23 January 1942, at the Montreal Homeopathic Hospital.[7] In this sense, tubocurarine is the prototypical adjunctive neuromuscular blocking agent. However, others before Griffith and Johnson had attempted use of tubocurare in several situations:[8][9][10] some under controlled study conditions[11][12] while others not quite controlled and remained unpublished.[13] Regardless, all in all some ~30,000 patients had been given tubocurare by 1941, although it was Griffith and Johnson's 1942 publication[7] that provided the impetus to the standard use of neuromuscular blocking agents in clinical anesthestic practice - a revolution that rapidly metamorphosized into the standard practice of "balanced" anesthesia: the triad of barbiturate hypnosis, light inhalational anesthesia and muscle relaxation.[14] The technique as described by Gray and Halton was widely known as the "Liverpool technique",[14] and became the standard anesthetic technique in England in the 1950s and 1960s for patients of all ages and physical status. Present clinical anesthetic practice still employs the central principle of balanced anesthesia though with some differences to accommodate subsequent technological advances and introductions of new and better gaseous anesthetic, hypnotic and neuromuscular blocking agents, and tracheal intubation, as well as monitoring techniques that were nonexistent in the day of Gray and Halton: pulse oximetry, capnography, peripheral nerve stimulation, noninvasive blood pressure monitoring, etc.
# Biosynthesis
Tubocurarine biosynthesis involves a radical coupling of two enantiomeric tetrahydrobenzylisoquinolines, more specifically, the two enantiomers of N-methyl-coclaurine. (R) and (S)-N-methyl-coclaurine come from a Mannich-like reaction between dopamine and 4-hydroxyphenyl-acetaldehyde, facilitated by norcoclaurine synthase (NCS). Both dopamine and 4-hydroxyphenylacetyladehyde originate from L-tyrosine. The biosynthetic pathway is described in more detail in the figures. Methylation of the amine and hydroxyl substituents are facilitated by S-adenosyl methionine (SAM).[15]
# Clinical pharmacology and pharmacokinetics
Tubocurarine has a time of onset of 300 seconds or more (which is relatively slow among neuromuscular-blocking drugs), and has a duration of action of 60 to 120 minutes (which is relatively long time).[16]
It also causes histamine release,[17] now a recognized hallmark of the tetrahydroisioquinolinium class of neuromuscular blocking agents. The amount of histamine release in some instances following tubocurarine administration is such that it is contraindicated in asthmatics and patients with allergies.[citation needed] However, the main disadvantage in the use of tubocurarine is its significant ganglion-blocking effect,[18] that manifests as hypotension,[19] in many patients; this constitutes a relative contraindication to its use in patients with myocardial ischaemia.
Because of the shortcomings of tubocurare, much research effort was undertaken soon after its clinical introduction to find a suitable replacement. The efforts unleashed a multitude of compounds borne from structure-activity relations developed from the tubocurare molecule. Some key compounds that have seen clinical use are identified in the muscle relaxants template box below. Of the many tried as replacements, only a few enjoyed as much popularity as tubocurarine: pancuronium, vecuronium, rocuronium, atracurium, and cisatracurium. Succinylcholine is a widely used paralytic drug which acts by activating, instead of blocking, the ACh receptor.
The potassium channel blocker tetraethylammonium (TEA) has been shown to reverse the effects of tubocurarine. It is thought to do so by increasing ACh release, which counteracts the antagonistic effects of tubocurarine on the ACh receptor. | https://www.wikidoc.org/index.php/Tubocurarine | |
2760c00be9831e75e8dc33fa1f7d5d45e9868230 | wikidoc | Tumor marker | Tumor marker
# Overview
Tumor markers are substances found in the blood, urine or body tissues that can be elevated in cancer. There are many different tumor markers. They are used in oncology to help determine the presence of cancer. An elevated level of a tumor marker can indicate cancer, however there can often also be other causes of the elevation.
Tumor markers can be produced directly by the tumor or by non-tumor cells as a response to the presence of a tumor.
Koepke outlines a hierarchy of clinical laboratory tests, from least to most informative. As used in oncology, they are as follows:
Screening for common cancers on a population basis
- Example: elevated prostate specific antigen suggests prostate cancer
Monitoring of cancer survivors after treatment
- Example: elevated AFP in a child previously treated for teratoma suggests relapse with endodermal sinus tumor
Diagnosis of specific tumor types, particularly in certain brain tumors and other instances where biopsy is not feasible
Tumor markers can be classified in two groups: Cancer-specific markers and tissue-specific markers.
# Cancer-specific markers
Cancer-specific markers are related to the presence of certain cancerous tissue. Because there is a large overlap between the many different tumor tissue types and the markers produced these cancer tissue might not be specific in making a diagnosis. They can, however, be useful in the follow-up of treated patients to describe progress of the disease or response to treatment. A few examples of these markers are CEA, CA19-9, CA125.
An example of a cancer-specific marker, CEA, or carcinoembryonic antigen, is a blood-borne protein, first noted to be produced by tumors of the gastrointestinal system. Further investigation showed that it was produced by the occasional lung and breast cancer case, meaning that an elevated level does not mean a bowel cancer. However, in a patient with a history of a treated bowel cancer, a rising CEA level can be an early sign of bowel cancer return. This usually occurs before the site of return can be identified on imaging or examination and so many oncologists question the wisdom of doing a blood test for CEA when the end result is bad news that alarms the patient. Nevertheless, a sequence of steady low CEA readings can provide much needed reassurance to the post-operative patient. Also, a rising sequence of CEA readings should alert the physician to the need for diagnostic tests such as PET scans.
# Tissue-specific markers
Tissue-specific markers are related to specific tissues which have developed cancer. Generally speaking, these substances are not specifically related to the tumor, and may be present at elevated levels when no cancer is present. But unlike the previous group, elevated levels point to a specific tissue being at fault. Examples include PSA, beta-HCG - (Human chorionic gonadotropin), AFP - (Alpha-fetoprotein), AFP-L3 - (a lectin-reactive AFP) and Thyroglobulin. For example, if man has an elevated PSA, a search for prostate cancer will be undertaken. If an individual has an elevated level of beta-HCG, AFP or AFP-L3%, a search for a testicular or liver cancer, respectively, will be made.
- PSA (Prostate specific antigen) is produced by the normal prostate. It is a protein enzyme called a serine protease that usually acts as an anticoagulant to keep semen liquid. Only small amounts leak into the circulation in normal circumstances. Enlarged prostates leak more substantial amounts, and cancerous prostates also leak substantial amounts. An accurate way to tell if an elevated PSA level results from cancer is to biopsy the prostate.
- β-hCG: Elevated levels cannot prove the presence of a tumor, and low levels do not rule it out (an exception is in males who do not naturally produce β-hCG). Nevertheless, elevated βhCG levels fall after successful treatment (e.g. surgical intervention or chemotherapy), and a recurrence can often be detected by the finding of rising levels.
# Hook effect
The hook effect (also known as high dose hook effect) is an artifact of tumor marker immunoassay kits, that causes the reported quantity of tumor marker to be incorrectly low when the quantity is high. An undetected hook effect may cause delayed recognition of a tumor. The hook effect can be detected by analyzing serial dilutions. Absent hook effect, reported quantities of tumor marker in a serial dilution should be proportional to the dilution.
# Serial monitoring
If repeated measurements of tumor marker are needed, some clinical testing laboratories provide a special reporting mechanism, a serial monitor, that links test results and other data pertaining to the person being tested. This requires a unique identifier for the person. In the United States commonly a Social Security number is used for this. One important function of this mechanism is to ensure that each test is performed using the same assay kit. For example, for AFP many different commercial assay kits, based on different technologies, are available. AFP measurements obtained using different assay kits are not comparable unless special calculations are performed.
# Standardization
Interlaboratory proficiency testing for tumor marker tests, and for clinical tests more generally, is an emerging field. In the United States, New York state is leading the way. | Tumor marker
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Tumor markers are substances found in the blood, urine or body tissues that can be elevated in cancer. There are many different tumor markers. They are used in oncology to help determine the presence of cancer. An elevated level of a tumor marker can indicate cancer, however there can often also be other causes of the elevation.
Tumor markers can be produced directly by the tumor or by non-tumor cells as a response to the presence of a tumor.
Koepke[1] outlines a hierarchy of clinical laboratory tests, from least to most informative. As used in oncology, they are as follows:
Screening for common cancers on a population basis
- Example: elevated prostate specific antigen suggests prostate cancer
Monitoring of cancer survivors after treatment
- Example: elevated AFP in a child previously treated for teratoma suggests relapse with endodermal sinus tumor
Diagnosis of specific tumor types, particularly in certain brain tumors and other instances where biopsy is not feasible
Tumor markers can be classified in two groups: Cancer-specific markers and tissue-specific markers.
# Cancer-specific markers
Cancer-specific markers are related to the presence of certain cancerous tissue. Because there is a large overlap between the many different tumor tissue types and the markers produced these cancer tissue might not be specific in making a diagnosis. They can, however, be useful in the follow-up of treated patients to describe progress of the disease or response to treatment. A few examples of these markers are CEA, CA19-9, CA125.
An example of a cancer-specific marker, CEA, or carcinoembryonic antigen, is a blood-borne protein, first noted to be produced by tumors of the gastrointestinal system. Further investigation showed that it was produced by the occasional lung and breast cancer case, meaning that an elevated level does not mean a bowel cancer. However, in a patient with a history of a treated bowel cancer, a rising CEA level can be an early sign of bowel cancer return. This usually occurs before the site of return can be identified on imaging or examination and so many oncologists question the wisdom of doing a blood test for CEA when the end result is bad news that alarms the patient. Nevertheless, a sequence of steady low CEA readings can provide much needed reassurance to the post-operative patient. Also, a rising sequence of CEA readings should alert the physician to the need for diagnostic tests such as PET scans.
+
# Tissue-specific markers
Tissue-specific markers are related to specific tissues which have developed cancer. Generally speaking, these substances are not specifically related to the tumor, and may be present at elevated levels when no cancer is present. But unlike the previous group, elevated levels point to a specific tissue being at fault. Examples include PSA, beta-HCG - (Human chorionic gonadotropin), AFP - (Alpha-fetoprotein), AFP-L3 - (a lectin-reactive AFP) and Thyroglobulin. For example, if man has an elevated PSA, a search for prostate cancer will be undertaken. If an individual has an elevated level of beta-HCG, AFP or AFP-L3%, a search for a testicular or liver cancer, respectively, will be made.
- PSA (Prostate specific antigen) is produced by the normal prostate. It is a protein enzyme called a serine protease that usually acts as an anticoagulant to keep semen liquid. Only small amounts leak into the circulation in normal circumstances. Enlarged prostates leak more substantial amounts, and cancerous prostates also leak substantial amounts. An accurate way to tell if an elevated PSA level results from cancer is to biopsy the prostate.
- β-hCG: Elevated levels cannot prove the presence of a tumor, and low levels do not rule it out (an exception is in males who do not naturally produce β-hCG). Nevertheless, elevated βhCG levels fall after successful treatment (e.g. surgical intervention or chemotherapy), and a recurrence can often be detected by the finding of rising levels.
# Hook effect
The hook effect (also known as high dose hook effect) is an artifact of tumor marker immunoassay kits, that causes the reported quantity of tumor marker to be incorrectly low when the quantity is high. An undetected hook effect may cause delayed recognition of a tumor.[2] The hook effect can be detected by analyzing serial dilutions. Absent hook effect, reported quantities of tumor marker in a serial dilution should be proportional to the dilution.
# Serial monitoring
If repeated measurements of tumor marker are needed, some clinical testing laboratories provide a special reporting mechanism, a serial monitor, that links test results and other data pertaining to the person being tested. This requires a unique identifier for the person. In the United States commonly a Social Security number is used for this. One important function of this mechanism is to ensure that each test is performed using the same assay kit. For example, for AFP many different commercial assay kits, based on different technologies, are available. AFP measurements obtained using different assay kits are not comparable unless special calculations are performed.
# Standardization
Interlaboratory proficiency testing for tumor marker tests, and for clinical tests more generally, is an emerging field.[1] In the United States, New York state is leading the way.[3] | https://www.wikidoc.org/index.php/Tumor_marker | |
a24c97bf3bc4fc8698cc6f7aac64f44bec5998b6 | wikidoc | Tympanometry | Tympanometry
# Overview
Tympanometry is an examination used to test the condition of the middle ear and mobility of the eardrum (tympanic membrane) and the conduction bones, by creating variations of air pressure in the ear canal.
Tympanometry is an objective test of middle-ear function. It is not a hearing test, but rather, a measure of energy transmission through the middle ear. This test should not be used to assess the sensitivity of hearing and the results of this test should always be viewed in conjunction with pure tone audiometry.
Tympanometry is a valuable component of the audiometric evaluation. In the evaluation of hearing loss, tympanometry is a valuable component of the distinction between sensorinueural and conductive hearing loss, when evaluation is not apparent via Weber and Rinne testing.
# Basic operation
The basis of operation is that the probe tone is sent into the ear canal--the sound strikes the tympanic membrane causing vibration of the middle ear, which in turn results in conscious perception of hearing. Some of this sound is reflected back and picked up by the tympanogram which records the amplitude of feedback. The more sound that enters the middle ear, the less that is reflected back. Conversely, the less sound that enters the middle ear, the more that is reflected back. Most middle ear problems result in a stiffening of the middle ear, resulting in increased amplitude of reflection to the tympanogram.
The instrument does not plot the amount of sound reflected back--it plots some measure of admittance. Admittance is a general term that describes how energy is transmitted through the middle ear. The specific terms that we use typically in clinical settings are admittance and compliance.
The unit for admittance is the millimho (mmho) and cubic centimeters (cm3 or cc). So basically--the instrument measures the dB SPL reflected back and converts it into some measure of admittance. The relation between sound pressure and compliance, is fairly simple; when more sound is reflected back, it means the middle ear is stiffer than normal and therefore the compliance is lower.
Normally, the air pressure in the ear canal is the same as ambient pressure (air pressure in the area where you are). Also, under normal conditions, the air pressure in the middle ear is about the same as ambient pressure since the eustachian tube opens periodically to ventilate the middle ear and to equalize pressure.
In a healthy individual Maximum sound is transmitted through the middle ear when the air pressure in the ear canal is equal to air pressure in the middle ear. The air pressure in the middle ear is whatever is it is--when the air pressure in the ear canal is equal to it, maximum transfer of sound will occur and the most sound will go through the middle ear (and the least amount of sound will be reflected back).
# Procedure
After an otoscopy (examination of the ear with an otoscope) to ensure that the path to the eardrum is clear and that it isn't perforated, the test is performed by inserting a device in the ear canal that will change the pressure in the ear, produce a pure tone, and measure the eardrum responses to the sound and different pressures. Results are shown in a curve called: Tympanogram.
Type A tympanogram is considered normal, that means that there is a normal pressure in the middle ear with normal mobility of the eardrum and the conduction bones.
Type B or C tympanograms may reveal fluid in the middle ear, scarring of the tympanic membrane, lack of contact between the conduction bones of the middle ear or a tumor in the middle ear. | Tympanometry
# Overview
Tympanometry is an examination used to test the condition of the middle ear and mobility of the eardrum (tympanic membrane) and the conduction bones, by creating variations of air pressure in the ear canal.
Tympanometry is an objective test of middle-ear function. It is not a hearing test, but rather, a measure of energy transmission through the middle ear. This test should not be used to assess the sensitivity of hearing and the results of this test should always be viewed in conjunction with pure tone audiometry.
Tympanometry is a valuable component of the audiometric evaluation. In the evaluation of hearing loss, tympanometry is a valuable component of the distinction between sensorinueural and conductive hearing loss, when evaluation is not apparent via Weber and Rinne testing.
# Basic operation
The basis of operation is that the probe tone is sent into the ear canal--the sound strikes the tympanic membrane causing vibration of the middle ear, which in turn results in conscious perception of hearing. Some of this sound is reflected back and picked up by the tympanogram which records the amplitude of feedback. The more sound that enters the middle ear, the less that is reflected back. Conversely, the less sound that enters the middle ear, the more that is reflected back. Most middle ear problems result in a stiffening of the middle ear, resulting in increased amplitude of reflection to the tympanogram.
The instrument does not plot the amount of sound reflected back--it plots some measure of admittance. Admittance is a general term that describes how energy is transmitted through the middle ear. The specific terms that we use typically in clinical settings are admittance and compliance.
The unit for admittance is the millimho (mmho) and cubic centimeters (cm3 or cc). So basically--the instrument measures the dB SPL reflected back and converts it into some measure of admittance. The relation between sound pressure and compliance, is fairly simple; when more sound is reflected back, it means the middle ear is stiffer than normal and therefore the compliance is lower.
Normally, the air pressure in the ear canal is the same as ambient pressure (air pressure in the area where you are). Also, under normal conditions, the air pressure in the middle ear is about the same as ambient pressure since the eustachian tube opens periodically to ventilate the middle ear and to equalize pressure.
In a healthy individual Maximum sound is transmitted through the middle ear when the air pressure in the ear canal is equal to air pressure in the middle ear. The air pressure in the middle ear is whatever is it is--when the air pressure in the ear canal is equal to it, maximum transfer of sound will occur and the most sound will go through the middle ear (and the least amount of sound will be reflected back).
# Procedure
After an otoscopy (examination of the ear with an otoscope) to ensure that the path to the eardrum is clear and that it isn't perforated, the test is performed by inserting a device in the ear canal that will change the pressure in the ear, produce a pure tone, and measure the eardrum responses to the sound and different pressures. Results are shown in a curve called: Tympanogram.
Type A tympanogram is considered normal, that means that there is a normal pressure in the middle ear with normal mobility of the eardrum and the conduction bones.
Type B or C tympanograms may reveal fluid in the middle ear, scarring of the tympanic membrane, lack of contact between the conduction bones of the middle ear or a tumor in the middle ear.
# External links
- Impedance audiometry at Otolaryngology Online by drtbalu
de:Tympanometrie
nl:Tympanometrie
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Tympanogram | |
7160bbaf3407fca17e23810d241e9cbfa3b4ec3b | wikidoc | Ugi reaction | Ugi reaction
The Ugi reaction is a multi-component reaction in organic chemistry involving a ketone or aldehyde, an amine, an isocyanide and a carboxylic acid to form a bis-amide.
The reaction is named after Ivar Karl Ugi, who first published this reaction in 1962.
The Ugi reaction is exothermic and usually complete within minutes of adding the isocyanide. High concentration (0.5M - 2.0M) of reactants give the highest yields. Polar, aprotic solvents, like DMF, work well. However, methanol and ethanol have also been used successfully. This uncatalyzed reaction has an inherent high atom economy as only a molecule of water is lost and chemical yield in general are high. Recent research has shown that the Ugi reaction is accelerated in water.
Several reviews have been published.
# Reaction mechanism
In the Ugi reaction, the initial reaction is the formation of an imine (1) from the amine and the ketone. Subsequent reaction of the imine with the isocyanide and the carboxylic acid gives intermediate 2, which rearranges via an acyl transfer into the bis-amide 3. The exact mechanism of the trimolecular reaction to form intermediate 2 is not known.
The reaction can also be performed with a pre-formed imine. This results in an increased yield.
One plausible reaction mechanism is depicted below:
Amine 1 and ketone 2 form the imine 3 with loss of one equivalent of water. Proton exchange with carboxylic acid 4 activates the iminium ion 5 for nucleophilic addition of the isocyanide 6 with its terminal carbon atom to nitrilium ion 7. A second nucleophilic addition takes place at this intermediate with the carboxylic acid anion to 8. The final step is a Mumm rearrangement with transfer of the R4 acyl group from oxygen to nitrogen. Note that in the related Passerini reaction (lacking the amine) the isocyanide reacts directly with the carbonyl group but other aspects of the reaction are the same. All reaction steps are reversible except for the Mumm rearrangement, which drives the whole reaction sequence.
# Variations
## Combination of reaction components
The usage of bifunctional reaction components greatly increases the diversity of possible reaction products. Likewise, several combinations lead to structurally interesting products. The Ugi reaction has been applied in combination with an intramolecular Diels-Alder reaction in an extended multistep reaction.
A reaction in its own right is the Ugi-Smiles reaction with the carboxylic acid component replaced by a phenol. In this reaction the Mumm rearrangement in the final step is replaced by the Smiles rearrangement .
Another combination (with separate workup of the Ugi intermediate) is one with the Buchwald-Hartwig reaction . In the Ugi-Heck reaction a Heck aryl-aryl coupling takes place in a second step
### Combination of amine and carboxylic acid
Several groups have used β-amino acids in the Ugi reaction to prepare β-lactams.
This approach relies on acyl transfer in the Mumm rearrangement to form the four-membered ring. The reaction proceeds in moderate yield at room temperature in methanol with formaldehyde or a variety of aryl aldehydes. For example, p-nitrobenzaldehyde reacts to form the β-lactam shown in 71% yield as a 4:1 diastereomeric mixture:
### Combination of carbonyl compound and carboxylic acid
Zhang et al. have combined aldehydes with carboxylic acids and used the Ugi reaction to create lactams of various sizes. Short et al. have prepared γ-lactams from keto-acids on solid-support.
# Applications
## Chemical libraries
The Ugi reaction is one of the first reactions to be exploited explicitly to develop chemical libraries. These chemical libraries are sets of compounds that can be tested repeatedly. Using the principles of combinatorial chemistry, the Ugi reaction offers the possibility to synthesize a great number of different compounds in one reaction, by the reaction of various ketones (or aldehydes), amines, isocyanides and carboxylic acids. These libraries can then be tested with enzymes or living organisms to find new active pharmaceutical substances. One drawback is the lack of chemical diversity of the products. Using the Ugi reaction in combination with other reactions enlarges the chemical diversity of possible products.
Examples of Ugi reaction combinations:
- Isoquinolines from Ugi and Heck reactions.
## Pharmaceutical industry
Crixivan can be prepared using the Ugi reaction.
Additionally, many of the caine-type anesthetics are synthesized using this reaction. Examples include lidocaine and bupivacaine. | Ugi reaction
The Ugi reaction is a multi-component reaction in organic chemistry involving a ketone or aldehyde, an amine, an isocyanide and a carboxylic acid to form a bis-amide.[1][2][3]
The reaction is named after Ivar Karl Ugi, who first published this reaction in 1962.
The Ugi reaction is exothermic and usually complete within minutes of adding the isocyanide. High concentration (0.5M - 2.0M) of reactants give the highest yields. Polar, aprotic solvents, like DMF, work well. However, methanol and ethanol have also been used successfully. This uncatalyzed reaction has an inherent high atom economy as only a molecule of water is lost and chemical yield in general are high. Recent research has shown that the Ugi reaction is accelerated in water.[4]
Several reviews have been published.[5][6][7][8][9][10][11]
# Reaction mechanism
In the Ugi reaction, the initial reaction is the formation of an imine (1) from the amine and the ketone. Subsequent reaction of the imine with the isocyanide and the carboxylic acid gives intermediate 2, which rearranges via an acyl transfer into the bis-amide 3. The exact mechanism of the trimolecular reaction to form intermediate 2 is not known.[citation needed]
The reaction can also be performed with a pre-formed imine. This results in an increased yield.[citation needed]
One plausible reaction mechanism is depicted below:[12]
Amine 1 and ketone 2 form the imine 3 with loss of one equivalent of water. Proton exchange with carboxylic acid 4 activates the iminium ion 5 for nucleophilic addition of the isocyanide 6 with its terminal carbon atom to nitrilium ion 7. A second nucleophilic addition takes place at this intermediate with the carboxylic acid anion to 8. The final step is a Mumm rearrangement with transfer of the R4 acyl group from oxygen to nitrogen. Note that in the related Passerini reaction (lacking the amine) the isocyanide reacts directly with the carbonyl group but other aspects of the reaction are the same. All reaction steps are reversible except for the Mumm rearrangement, which drives the whole reaction sequence.
# Variations
## Combination of reaction components
The usage of bifunctional reaction components greatly increases the diversity of possible reaction products. Likewise, several combinations lead to structurally interesting products. The Ugi reaction has been applied in combination with an intramolecular Diels-Alder reaction [13] in an extended multistep reaction.
A reaction in its own right is the Ugi-Smiles reaction with the carboxylic acid component replaced by a phenol. In this reaction the Mumm rearrangement in the final step is replaced by the Smiles rearrangement [14].
Another combination (with separate workup of the Ugi intermediate) is one with the Buchwald-Hartwig reaction [15]. In the Ugi-Heck reaction a Heck aryl-aryl coupling takes place in a second step [16]
### Combination of amine and carboxylic acid
Several groups have used β-amino acids in the Ugi reaction to prepare β-lactams.[19]
This approach relies on acyl transfer in the Mumm rearrangement to form the four-membered ring. The reaction proceeds in moderate yield at room temperature in methanol with formaldehyde or a variety of aryl aldehydes. For example, p-nitrobenzaldehyde reacts to form the β-lactam shown in 71% yield as a 4:1 diastereomeric mixture:
### Combination of carbonyl compound and carboxylic acid
Zhang et al.[20] have combined aldehydes with carboxylic acids and used the Ugi reaction to create lactams of various sizes. Short et al.[21] have prepared γ-lactams from keto-acids on solid-support.
# Applications
## Chemical libraries
The Ugi reaction is one of the first reactions to be exploited explicitly to develop chemical libraries. These chemical libraries are sets of compounds that can be tested repeatedly. Using the principles of combinatorial chemistry, the Ugi reaction offers the possibility to synthesize a great number of different compounds in one reaction, by the reaction of various ketones (or aldehydes), amines, isocyanides and carboxylic acids. These libraries can then be tested with enzymes or living organisms to find new active pharmaceutical substances. One drawback is the lack of chemical diversity of the products. Using the Ugi reaction in combination with other reactions enlarges the chemical diversity of possible products.
Examples of Ugi reaction combinations:
- Isoquinolines from Ugi and Heck reactions.[22]
## Pharmaceutical industry
Crixivan can be prepared using the Ugi reaction.[23]
Additionally, many of the caine-type anesthetics are synthesized using this reaction. Examples include lidocaine and bupivacaine. | https://www.wikidoc.org/index.php/Ugi_reaction | |
2f4a0d9434ce2e95b8c32cbc2695e48c14d76d4c | wikidoc | Ulnar artery | Ulnar artery
The ulnar artery is the main blood vessel, with oxygenated blood, of the medial aspect of the forearm. It arises from the brachial artery and terminates in the superficial palmar arch, which joins with the superficial branch of the radial artery. It is palpable on the anterior and medial aspect of the wrist.
Along its course, it is accompanied by a similarly named vein or veins, the ulnar vein or ulnar veins.
The ulnar artery, the larger of the two terminal branches of the brachial, begins a little below the bend of the elbow, and, passing obliquely downward, reaches the ulnar side of the forearm at a point about midway between the elbow and the wrist. It then runs along the ulnar border to the wrist, crosses the transverse carpal ligament on the radial side of the pisiform bone, and immediately beyond this bone divides into two branches, which enter into the formation of the superficial and deep volar arches.
# Relations
## Forearm
In its upper half, it is deeply seated, being covered by the Pronator teres, Flexor carpi radialis, Palmaris longus, and Flexor digitorum sublimis; it lies upon the Brachialis and Flexor digitorum profundus.
The median nerve is in relation with the medial side of the artery for about 2.5 cm. and then crosses the vessel, being separated from it by the ulnar head of the Pronator teres.
In the lower half of the forearm it lies upon the Flexor digitorum profundus, being covered by the integument and the superficial and deep fasciæ, and placed between the Flexor carpi ulnaris and Flexor digitorum sublimis.
It is accompanied by two venæ comitantes, and is overlapped in its middle third by the Flexor carpi ulnaris; the ulnar nerve lies on the medial side of the lower two-thirds of the artery, and the palmar cutaneous branch of the nerve descends on the lower part of the vessel to the palm of the hand.
## Wrist
At the wrist the ulnar artery is covered by the integument and the volar carpal ligament, and lies upon the transverse carpal ligament. On its medial side is the pisiform bone, and, somewhat behind the artery, the ulnar nerve
# Peculiarities
The ulnar artery varies in its origin in the proportion of about one in thirteen cases; it may arise about 5 to 7 cm. below the elbow, but more frequently higher, the brachial being more often the source of origin than the axillary.
Variations in the position of this vessel are more common than in the radial. When its origin is normal, the course of the vessel is rarely changed.
When it arises high up, it is almost invariably superficial to the Flexor muscles in the forearm, lying commonly beneath the fascia, more rarely between the fascia and integument.
In a few cases, its position was subcutaneous in the upper part of the forearm, and subaponeurotic in the lower part. | Ulnar artery
Template:Infobox Artery
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
The ulnar artery is the main blood vessel, with oxygenated blood, of the medial aspect of the forearm. It arises from the brachial artery and terminates in the superficial palmar arch, which joins with the superficial branch of the radial artery. It is palpable on the anterior and medial aspect of the wrist.
Along its course, it is accompanied by a similarly named vein or veins, the ulnar vein or ulnar veins.
The ulnar artery, the larger of the two terminal branches of the brachial, begins a little below the bend of the elbow, and, passing obliquely downward, reaches the ulnar side of the forearm at a point about midway between the elbow and the wrist. It then runs along the ulnar border to the wrist, crosses the transverse carpal ligament on the radial side of the pisiform bone, and immediately beyond this bone divides into two branches, which enter into the formation of the superficial and deep volar arches.
# Relations
## Forearm
In its upper half, it is deeply seated, being covered by the Pronator teres, Flexor carpi radialis, Palmaris longus, and Flexor digitorum sublimis; it lies upon the Brachialis and Flexor digitorum profundus.
The median nerve is in relation with the medial side of the artery for about 2.5 cm. and then crosses the vessel, being separated from it by the ulnar head of the Pronator teres.
In the lower half of the forearm it lies upon the Flexor digitorum profundus, being covered by the integument and the superficial and deep fasciæ, and placed between the Flexor carpi ulnaris and Flexor digitorum sublimis.
It is accompanied by two venæ comitantes, and is overlapped in its middle third by the Flexor carpi ulnaris; the ulnar nerve lies on the medial side of the lower two-thirds of the artery, and the palmar cutaneous branch of the nerve descends on the lower part of the vessel to the palm of the hand.
## Wrist
At the wrist the ulnar artery is covered by the integument and the volar carpal ligament, and lies upon the transverse carpal ligament. On its medial side is the pisiform bone, and, somewhat behind the artery, the ulnar nerve
# Peculiarities
The ulnar artery varies in its origin in the proportion of about one in thirteen cases; it may arise about 5 to 7 cm. below the elbow, but more frequently higher, the brachial being more often the source of origin than the axillary.
Variations in the position of this vessel are more common than in the radial. When its origin is normal, the course of the vessel is rarely changed.
When it arises high up, it is almost invariably superficial to the Flexor muscles in the forearm, lying commonly beneath the fascia, more rarely between the fascia and integument.
In a few cases, its position was subcutaneous in the upper part of the forearm, and subaponeurotic in the lower part. | https://www.wikidoc.org/index.php/Ulnar_artery | |
5c4c4706b3dafc48d521dbdddeac5fe30163079d | wikidoc | Ulysses pact | Ulysses pact
A Ulysses pact is a freely made decision that is designed and intended to bind oneself in the future. The term is used in medicine, especially in reference to advance directives or living wills, where there is some controversy over whether a decision made by a person in one state of health should be considered binding upon that person when he or she is in a markedly different, usually worse, state of health.
# Origin of the name
The term refers to the pact that Ulysses (Greek name Odysseus) made with his men as they approached the Sirens. Ulysses wanted to hear the Sirens' song although he knew that doing so would render him incapable of rational thought. He put wax in his men's ears so that they could not hear, and had them tie him to the mast so that he could not jump into the sea. He ordered them not to change course under any circumstances, and to keep their swords upon him to attack him if he should break free of his bonds.
Upon hearing the Sirens' song, Ulysses was driven temporarily insane and struggled with all of his might to break free so that he might join the Sirens, which would have meant his death. | Ulysses pact
A Ulysses pact is a freely made decision that is designed and intended to bind oneself in the future. The term is used in medicine, especially in reference to advance directives or living wills, where there is some controversy over whether a decision made by a person in one state of health should be considered binding upon that person when he or she is in a markedly different, usually worse, state of health.
# Origin of the name
The term refers to the pact that Ulysses (Greek name Odysseus) made with his men as they approached the Sirens. Ulysses wanted to hear the Sirens' song although he knew that doing so would render him incapable of rational thought. He put wax in his men's ears so that they could not hear, and had them tie him to the mast so that he could not jump into the sea. He ordered them not to change course under any circumstances, and to keep their swords upon him to attack him if he should break free of his bonds.
Upon hearing the Sirens' song, Ulysses was driven temporarily insane and struggled with all of his might to break free so that he might join the Sirens, which would have meant his death. | https://www.wikidoc.org/index.php/Ulysses_pact | |
5ea33f6d995225f4b081f415d51cdc8ee500943e | wikidoc | Umeclidinium | Umeclidinium
# 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
Umeclidinium is a respiratory agent that is FDA approved for the treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema. Common adverse reactions include nasopharyngitis, upper respiratory infection.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Umeclidinium is an anticholinergic indicated for the long-term, once-daily, maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema.
- Umeclidinium(umeclidinium 62.5 mcg) should be administered as 1 inhalation once daily by the orally inhaled route only.
- Umeclidiniumshould be taken at the same time every day. Do not use Umeclidinium more than 1 time every 24 hours.
- No dosage adjustment is required for geriatric patients, patients with renal impairment, or patients with moderate hepatic impairment
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Umeclidinium in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Umeclidinium in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Umeclidinium in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Umeclidinium in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Umeclidinium in pediatric patients.
# Contraindications
- The use of Umeclidinium is contraindicated in the following conditions:
- Severe hypersensitivity to milk proteins
- Hypersensitivity to umeclidinium or any of the excipients
# Warnings
- Umeclidinium should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of COPD. Umeclidiniumh as not been studied in subjects with acutely deteriorating COPD. *The initiation of Umeclidinium in this setting is not appropriate.
- Umeclidinium should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. Umeclidiniumhas not been studied in the relief of acute symptoms and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled, short-acting beta2-agonist.
- COPD may deteriorate acutely over a period of hours or chronically over several days or longer. If Umeclidiniumno longer controls symptoms of bronchoconstriction; the patient’s inhaled, short-acting beta2-agonist becomes less effective; or the patient needs more short-acting beta2-agonist than usual, these may be markers of deterioration of disease. In this setting a re-evaluation of the patient and the COPD treatment regimen should be undertaken at once. Increasing the daily dose of Umeclidinium beyond the recommended dose is not appropriate in this situation.
- As with other inhaled medicines, Umeclidinium can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with Umeclidinium, it should be treated immediately with an inhaled, short-acting bronchodilator; Umeclidinium should be discontinued immediately; and alternative therapy should be instituted.
- Hypersensitivity reactions may occur after administration of Umeclidinium. There have been reports of anaphylactic reactions in patients with severe milk protein allergy after inhalation of other powder products containing lactose; therefore, patients with severe milk protein allergy should not use Umeclidinium.
- Umeclidinium should be used with caution in patients with narrow-angle glaucoma. Prescribers and patients should be alert for signs and symptoms of acute narrow-angle glaucoma (e.g., eye pain or discomfort, blurred vision, visual halos or colored images in association with red eyes from conjunctival congestion and corneal edema). Instruct patients to consult a physician immediately if any of these signs or symptoms develops.
- Umeclidinium should be used with caution in patients with urinary retention. Prescribers and patients should be alert for signs and symptoms of urinary retention (e.g., difficulty passing urine, painful urination), especially in patients with prostatic hyperplasia or bladder-neck obstruction. Instruct patients to consult a physician immediately if any of these signs or symptoms develops.
# Adverse Reactions
## Clinical Trials Experience
- The following adverse reactions are described in greater detail in other sections:
- Paradoxical bronchospasm
- Worsening of narrow-angle glaucoma
- Worsening of urinary retention
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- A total of 1,663 subjects with COPD across 8 clinical trials (mean age: 62.7 years; 89% white; 65% male across all treatments, including placebo) received at least 1 inhalation dose of umeclidinium at doses of 62.5 or 125 mcg. In the 4 randomized, double-blind, placebo- or active-controlled, efficacy clinical trials, 1,185 subjects received umeclidinium for up to 24 weeks, of which 487 subjects received the recommended dose of umeclidinium 62.5 mcg. In a 12-month, randomized, double-blind, placebo-controlled, long-term safety trial, 227 subjects received umeclidinium 125 mcg for up to 52 weeks.
- The incidence of adverse reactions associated with Umeclidinium in Table 1 is based upon 2 placebo-controlled efficacy trials: one 12-week trial and one 24-week trial.
- Other adverse reactions with Umeclidinium observed with an incidence less than 1% but more common than placebo included atrial fibrillation.
- In a long-term safety trial, 336 subjects (n = 227 umeclidinium 125 mcg, n = 109 placebo) were treated for up to 52 weeks with umeclidinium 125 mcg or placebo. The demographic and baseline characteristics of the long-term safety trial were similar to those of the efficacy trials described above. Adverse reactions that occurred with a frequency greater than or equal to 1% in subjects receiving umeclidinium 125 mcg that exceeded that in placebo in this trial were: nasopharyngitis, upper respiratory tract infection, urinary tract infection, pharyngitis, pneumonia, lower respiratory tract infection, rhinitis, supraventricular tachycardia, supraventricular extrasystoles, sinus tachycardia, idioventricular rhythm, headache, dizziness, sinus headache, cough, back pain, arthralgia, pain in extremity, neck pain, myalgia, nausea, dyspepsia, diarrhea, rash, depression, and vertigo.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Umeclidinium in the drug label.
# Drug Interactions
- There is potential for an additive interaction with concomitantly used anticholinergic medicines. Therefore, avoid coadministration of Umeclidiniumwith other anticholinergic-containing drugs as this may lead to an increase in anticholinergic adverse effects
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Teratogenic Effects:There are no adequate and well-controlled trials with Umeclidinium in pregnant women. Because animal reproduction studies are not always predictive of human response, Umeclidinium should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Women should be advised to contact their physicians if they become pregnant while taking Umeclidinium.
- There was no evidence of teratogenic effects in rats and rabbits at approximately 50 and 200 times, respectively, the MRHDID (maximum recommended human daily inhaled dose) in adults (on an AUC basis at maternal inhaled doses up to 278 mcg/kg/day in rats and maternal subcutaneous doses up to 180 mcg/kg/day in rabbits).
- Nonteratogenic Effects: There were no effects on perinatal and postnatal developments in rats at approximately 80 times the MRHDID in adults (on an AUC basis at maternal subcutaneous doses up to 180 mcg/kg/day).
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Umeclidinium in women who are pregnant.
### Labor and Delivery
- There are no adequate and well-controlled human trials that have investigated the effects of Umeclidinium during labor and delivery. Umeclidinium should be used during labor only if the potential benefit justifies the potential risk.
### Nursing Mothers
- It is not known whether Umeclidinium is excreted in human breast milk. Because many drugs are excreted in human milk, caution should be exercised when Umeclidinium is administered to a nursing woman. Since there are no data from well-controlled human studies on the use of Umeclidinium by nursing mothers, a decision should be made whether to discontinue nursing or to discontinue Umeclidinium,taking into account the importance of Umeclidinium to the mother.
- Subcutaneous administration of umeclidinium to lactating rats at approximately 25 times the MRHDID in adults resulted in a quantifiable level of umeclidinium in 2 pups, which may indicate transfer of umeclidinium in milk.
### Pediatric Use
- Umeclidinium is not indicated for use in children. The safety and efficacy in pediatric patients have not been established.
### Geriatic Use
- Based on available data, no adjustment of the dosage of Umeclidinium in geriatric patients is necessary, but greater sensitivity in some older individuals cannot be ruled out.
- Clinical trials of Umeclidiniumincluded 810 subjects aged 65 years and older, and, of those, 183 subjects were aged 75 years and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger subjects.
### Gender
There is no FDA guidance on the use of Umeclidinium with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Umeclidinium with respect to specific racial populations.
### Renal Impairment
- Patients with severe renal impairment (creatinine clearance less than 30 mL/min) showed no relevant increases in Cmax or AUC, nor did protein binding differ between subjects with severe renal impairment and their healthy controls. No dosage adjustment is required in patients with renal impairment
### Hepatic Impairment
- Patients with moderate hepatic impairment (Child-Pugh score of 7-9) showed no relevant increases in Cmax or AUC, nor did protein binding differ between subjects with moderate hepatic impairment and their healthy controls. Studies in subjects with severe hepatic impairment have not been performed
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Umeclidinium in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Umeclidinium in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
- Inhalation
### Monitoring
There is limited information regarding Monitoring of Umeclidinium in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Umeclidinium in the drug label.
# Overdosage
- No case of overdose has been reported with umeclidinium.
- High doses of umeclidinium may lead to anticholinergic signs and symptoms. However, there were no systemic anticholinergic adverse effects following a once-daily inhaled dose of up to 1,000 mcg umeclidinium (16 times the maximum recommended daily dose) for 14 days in subjects with COPD.
- Treatment of overdosage consists of discontinuation of Umeclidinium together with institution of appropriate symptomatic and/or supportive therapy.
# Pharmacology
## Mechanism of Action
- Umeclidinium is a long-acting, antimuscarinic agent, which is often referred to as an anticholinergic. It has similar affinity to the subtypes of muscarinic receptors M1 to M5. In the airways, it exhibits pharmacological effects through the inhibition of M3 receptor at the smooth muscle leading to bronchodilation. The competitive and reversible nature of antagonism was shown with human and animal origin receptors and isolated organ preparations. In preclinical in vitro as well as in vivostudies, prevention of methacholine and acetylcholine-induced bronchoconstrictive effects was dose-dependent and lasted longer than 24 hours. The clinical relevance of these findings is unknown. The bronchodilation following inhalation of umeclidinium is predominantly a site-specific effect.
## Structure
- Umeclidiniumcontains the active ingredient umeclidinium, an anticholinergic.
Umeclidinium bromide has the chemical name 1--4-(hydroxydiphenylmethyl)-1-azoniabicyclooctane bromide and the following chemical structure:
- Umeclidinium bromide is a white powder with a molecular weight of 508.5, and the empirical formula is C29H34NO2Br (as a quaternary ammonium bromide compound). It is slightly soluble in water.
- Umeclidinium is a light grey and light green plastic inhaler containing a double-foil blister strip. Each blister on the strip contains a white powder mix of micronized umeclidinium bromide (74.2 mcg equivalent to 62.5 mcg of umeclidinium), magnesium stearate (75 mcg), and lactose monohydrate (to 12.5 mg). The lactose monohydrate contains milk proteins. After the inhaler is activated, the powder within the blister is exposed and ready for dispersion into the airstream created by the patient inhaling through the mouthpiece.
- Under standardized in vitro test conditions, Umeclidinium delivers 55 mcg of umeclidinium per dose when tested at a flow rate of 60 L/min for 4 seconds.
- In adult subjects with obstructive lung disease and severely compromised lung function (COPD with forced expiratory volume in 1 second/forced vital capacity less than 70% and FEV1 less than 30% predicted or FEV1 less than 50% predicted plus chronic respiratory failure), mean peak inspiratory flow through the ELLIPTA inhaler was 67.5 L/min (range: 41.6 to 83.3 L/min).
- The actual amount of drug delivered to the lung will depend on patient factors, such as inspiratory flow profile.
## Pharmacodynamics
- Cardiac Electrophysiology: QTc interval prolongation was studied in a double-blind, multiple dose, placebo- and positive-controlled, crossover trial in 86 healthy subjects. Following repeat doses of umeclidinium 500 mcg once daily (8 times the recommended dosage) for 10 days, umeclidinium does not prolong QTc to any clinically relevant extent.
## Pharmacokinetics
- Linear pharmacokinetics was observed for umeclidinium (62.5 to 500 mcg).
- Absorption: Umeclidinium plasma levels may not predict therapeutic effect. Following inhaled administration of umeclidinium in healthy subjects, Cmax occurred at 5 to 15 minutes. Umeclidinium is mostly absorbed from the lung after inhaled doses with minimum contribution from oral absorption. Following repeat dosing of inhaled umeclidinium, steady state was achieved within 14 days with 1.8-fold accumulation.
- Distribution: Following intravenous administration to healthy subjects, the mean volume of distribution was 86 L. In vitro plasma protein binding in human plasma was on average 89%.
- Metabolism: In vitro data showed that umeclidinium is primarily metabolized by the enzyme cytochrome P450 2D6 (CYP2D6) and is a substrate for the P-glycoprotein (P-gp) transporter. The primary metabolic routes for umeclidinium are oxidative (hydroxylation, O-dealkylation) followed by conjugation (e.g., glucuronidation), resulting in a range of metabolites with either reduced pharmacological activity or for which the pharmacological activity has not been established. Systemic exposure to the metabolites is low.
- Elimination: Following intravenous dosing with radiolabeled umeclidinium, mass balance showed 58% of the radiolabel in the feces and 22% in the urine. The excretion of the drug-related material in the feces following intravenous dosing indicated elimination in the bile. Following oral dosing to healthy male subjects, radiolabel recovered in feces was 92% of the total dose and that in urine was less than 1% of the total dose, suggesting negligible oral absorption. The effective half-life after once daily dosing is 11 hours.
- Special Populations: Population pharmacokinetic analysis showed no evidence of a clinically significant effect of age (40 to 93 years) (see Figure 1), gender (69% male) (see Figure 1), inhaled corticosteroid use (48%), or weight (34 to 161 kg) on systemic exposure of umeclidinium. In addition, there was no evidence of a clinically significant effect of race.
- Hepatic Impairment: The impact of hepatic impairment on the pharmacokinetics of Umeclidinium has been evaluated in subjects with moderate hepatic impairment (Child-Pugh score of 7-9). There was no evidence of an increase in systemic exposure to umeclidinium (Cmax and AUC) (see Figure 1). There was no evidence of altered protein binding in subjects with moderate hepatic impairment compared with healthy subjects. Umeclidinium has not been evaluated in subjects with severe hepatic impairment.
- Renal Impairment: The pharmacokinetics of Umeclidinium has been evaluated in subjects with severe renal impairment (creatinine clearance less than 30 mL/min). There was no evidence of an increase in systemic exposure to umeclidinium (Cmax and AUC) (see Figure 1). There was no evidence of altered protein binding in subjects with severe renal impairment compared with healthy subjects.
- Drug Interactions: Umeclidinium and P-glycoprotein Transporter: Umeclidinium is a substrate of P-gp. The effect of the moderate P-gp transporter inhibitor verapamil (240 mg once daily) on the steady-state pharmacokinetics of umeclidinium was assessed in healthy subjects. No effect on umeclidinium Cmax was observed; however, an approximately 1.4-fold increase in umeclidinium AUC was observed (see Figure 1).
- Umeclidinium and Cytochrome P450 2D6: In vitro metabolism of umeclidinium is mediated primarily by CYP2D6. However, no clinically meaningful difference in systemic exposure to umeclidinium (500 mcg) (8 times the approved dose) was observed following repeat daily inhaled dosing to normal (ultrarapid, extensive, and intermediate metabolizers) and CYP2D6 poor metabolizer subjects (see Figure 1).
## Nonclinical Toxicology
- Umeclidinium produced no treatment-relaed increases in the incidence of tumors in 2-year inhalation studies in rats and mice at inhaled doses up to 137 and 295/200 mcg/kg/day (male/female), respectively (approximately 20 and 25/20 times the MRHDID in adults on an AUC basis, respectively).
- Umeclidinium tested negative in the following genotoxicity assays: the in vitro Ames assay, in vitromouse lymphoma assay, and in vivo rat bone marrow micronucleus assay.
- No evidence of impairment of fertility was observed in male and female rats at subcutaneous doses up to 180 mcg/kg/day and inhaled doses up to 294 mcg/kg/day, respectively (approximately 100 and 50 times, respectively, the MRHDID in adults on an AUC basis).
# Clinical Studies
- The safety and efficacy of umeclidinium 62.5 mcg were evaluated in 3 dose-ranging trials, 2 placebo-controlled clinical trials (one 12-week trial and one 24-week trial), and a 12-month long-term safety trial. The efficacy of Umeclidinium is based primarily on the dose-ranging trials in 624 subjects with COPD and the 2 placebo-controlled confirmatory trials in 1,738 subjects with COPD.
- Dose selection for umeclidinium in COPD was supported by a 7-day, randomized, double-blind, placebo-controlled, crossover trial evaluating 4 doses of umeclidinium (15.6 to 125 mcg) or placebo dosed once daily in the morning in 163 subjects with COPD. A dose ordering was observed, with the 62.5- and 125-mcg doses demonstrating larger improvements in FEV1 over 24 hours compared with the lower doses of 15.6 and 31.25 mcg (Figure 2).
- The differences in trough FEV1 from baseline after 7 days for placebo and the 15.6-, 31.25-, 62.5-, and 125-mcg doses were -74 mL (95% CI: -118, -31), 38 mL (95% CI: -6, 83), 27 mL (95% CI: -18, 72), 49 mL (95% CI: 6, 93), and 109 mL (95% CI: 65, 152), respectively. Two additional dose-ranging trials in subjects with COPD demonstrated minimal additional benefit at doses above 125 mcg. The dose-ranging results supported the evaluation of 2 doses of umeclidinium, 62.5 and 125 mcg, in the confirmatory COPD trials to further assess dose response.
- Evaluations of dosing interval by comparing once- and twice-daily dosing supported selection of a once-daily dosing interval for further evaluation in the confirmatory COPD trials.
- The clinical development program for Umeclidiniumincluded 2 randomized, double-blind, placebo-controlled, parallel-group trials in subjects with COPD designed to evaluate the efficacy of Umeclidiniumon lung function. Trial 1 was a 24-week placebo-controlled trial, and Trial 2 was a 12-week placebo-controlled trial. These trials treated subjects that had a clinical diagnosis of COPD, were 40 years of age or older, had a history of smoking greater than or equal to 10 pack-years, had a post-albuterol FEV1 less than or equal to 70% of predicted normal values, had a ratio of FEV1/FVC of less than 0.7, and had a Modified Medical Research Council (mMRC) score greater than or equal to 2. Subjects in Trial 1 had a mean age of 63 years and an average smoking history of 46 pack-years, with 50% identified as current smokers. At screening, the mean post-bronchodilator percent predicted FEV1was 47% (range: 13% to 74%), the mean post-bronchodilator FEV1/FVC ratio was 0.47 (range: 0.20 to 0.74), and the mean percent reversibility was 15% (range: -35% to 109%). Baseline demographics and lung function for subjects in Trial 2 were similar to those in Trial 1.
- Trial 1 evaluated umeclidinium 62.5 mcg and placebo. The primary endpoint was change from baseline in trough (predose) FEV1 at Day 169 (defined as the mean of the FEV1 values obtained at 23 and 24 hours after the previous dose on Day 168) compared with placebo. Umeclidinium62.5 mcg demonstrated a larger increase in mean change from baseline in trough (predose) FEV1 relative to placebo (see Table 2). Similar results were obtained from Trial 2.
- In Trial 1, the mean peak FEV1 (over the first 6 hours relative to baseline) at Day 1 and at Day 168 for the group receiving umeclidinium 62.5 mcg compared with placebo was 126 and 130 mL, respectively.
- Health-related quality of life was measured using St. George’s Respiratory Questionnaire (SGRQ). Umeclidinium demonstrated an improvement in mean SGRQ total score compared with placebo treatment at Day 168: -4.69 (95% CI: -7.07,-2.31). The proportion of patients with a clinically meaningful decrease (defined as a decrease of at least 4 units from baseline) at Week 24 was greater for Umeclidinium62.5 mcg (42%; 172/410) compared with placebo (31%; 86/274).
# How Supplied
- Umeclidiniumis supplied as a disposable light grey and light green plastic inhaler containing a double-foil blister strip with 30 blisters. The inhaler is packaged in a moisture-protective foil tray with a desiccant and a peelable lid (NDC 0173-0873-10).
- Umeclidiniumis also supplied in an institutional pack of a disposable light grey and light green plastic inhaler containing a double-foil blister strip with 7 blisters. The inhaler is packaged in a moisture-protective foil tray with a desiccant and a peelable lid (NDC 0173-0873-06).
## Storage
- Store at room temperature between 68°F and 77°F (20°C and 25°C); excursions permitted from 59°F to 86°F (15°C to 30°C) . Store in a dry place away from direct heat or sunlight. Keep out of reach of children.
- Umeclidiniumshould be stored inside the unopened moisture-protective foil tray and only removed from the tray immediately before initial use. Discard Umeclidinium 6 weeks after opening the foil tray or when the counter reads “0” (after all blisters have been used), whichever comes first. The inhaler is not reusable. Do not attempt to take the inhaler apart.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).
- Not for Acute Symptoms: Inform patients that Umeclidiniumis not meant to relieve acute symptoms of COPD and extra doses should not be used for that purpose. Advise them to treat acute symptoms with a rescue inhaler such as albuterol. Provide patients with such medicine and instruct them in how it should be used.
- Instruct patients to seek medical attention immediately if they experience any of the following:
- Symptoms get worse
- Need for more inhalations than usual of their rescue inhaler
- Patients should not stop therapy with Umeclidiniumwithout physician/provider guidance since symptoms may recur after discontinuation.
- Paradoxical Bronchospasm: As with other inhaled medicines, Umeclidinium can cause paradoxical bronchospasm. If paradoxical bronchospasm occurs, instruct patients to discontinue Umeclidinium
- Worsening of Narrow-Angle Glaucoma: Instruct patients to be alert for signs and symptoms of acute narrow-angle glaucoma (e.g., eye pain or discomfort, blurred vision, visual halos or colored images in association with red eyes from conjunctival congestion and corneal edema). Instruct patients to consult a physician immediately if any of these signs or symptoms develops.
- Worsening of Urinary Retention: Instruct patients to be alert for signs and symptoms of urinary retention (e.g., difficulty passing urine, painful urination). Instruct patients to consult a physician immediately if any of these signs or symptoms develops.
# Precautions with Alcohol
- Alcohol-Umeclidinium interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Incruse Ellipta
# Look-Alike Drug Names
There is limited information regarding Umeclidinium Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Umeclidinium
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aparna Vuppala, M.B.B.S. [2]
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# Overview
Umeclidinium is a respiratory agent that is FDA approved for the treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema. Common adverse reactions include nasopharyngitis, upper respiratory infection.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Umeclidinium is an anticholinergic indicated for the long-term, once-daily, maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema.
- Umeclidinium(umeclidinium 62.5 mcg) should be administered as 1 inhalation once daily by the orally inhaled route only.
- Umeclidiniumshould be taken at the same time every day. Do not use Umeclidinium more than 1 time every 24 hours.
- No dosage adjustment is required for geriatric patients, patients with renal impairment, or patients with moderate hepatic impairment
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Umeclidinium in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Umeclidinium in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Umeclidinium in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Umeclidinium in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Umeclidinium in pediatric patients.
# Contraindications
- The use of Umeclidinium is contraindicated in the following conditions:
- Severe hypersensitivity to milk proteins
- Hypersensitivity to umeclidinium or any of the excipients
# Warnings
- Umeclidinium should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of COPD. Umeclidiniumh as not been studied in subjects with acutely deteriorating COPD. *The initiation of Umeclidinium in this setting is not appropriate.
- Umeclidinium should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. Umeclidiniumhas not been studied in the relief of acute symptoms and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled, short-acting beta2-agonist.
- COPD may deteriorate acutely over a period of hours or chronically over several days or longer. If Umeclidiniumno longer controls symptoms of bronchoconstriction; the patient’s inhaled, short-acting beta2-agonist becomes less effective; or the patient needs more short-acting beta2-agonist than usual, these may be markers of deterioration of disease. In this setting a re-evaluation of the patient and the COPD treatment regimen should be undertaken at once. Increasing the daily dose of Umeclidinium beyond the recommended dose is not appropriate in this situation.
- As with other inhaled medicines, Umeclidinium can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with Umeclidinium, it should be treated immediately with an inhaled, short-acting bronchodilator; Umeclidinium should be discontinued immediately; and alternative therapy should be instituted.
- Hypersensitivity reactions may occur after administration of Umeclidinium. There have been reports of anaphylactic reactions in patients with severe milk protein allergy after inhalation of other powder products containing lactose; therefore, patients with severe milk protein allergy should not use Umeclidinium.
- Umeclidinium should be used with caution in patients with narrow-angle glaucoma. Prescribers and patients should be alert for signs and symptoms of acute narrow-angle glaucoma (e.g., eye pain or discomfort, blurred vision, visual halos or colored images in association with red eyes from conjunctival congestion and corneal edema). Instruct patients to consult a physician immediately if any of these signs or symptoms develops.
- Umeclidinium should be used with caution in patients with urinary retention. Prescribers and patients should be alert for signs and symptoms of urinary retention (e.g., difficulty passing urine, painful urination), especially in patients with prostatic hyperplasia or bladder-neck obstruction. Instruct patients to consult a physician immediately if any of these signs or symptoms develops.
# Adverse Reactions
## Clinical Trials Experience
- The following adverse reactions are described in greater detail in other sections:
- Paradoxical bronchospasm
- Worsening of narrow-angle glaucoma
- Worsening of urinary retention
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- A total of 1,663 subjects with COPD across 8 clinical trials (mean age: 62.7 years; 89% white; 65% male across all treatments, including placebo) received at least 1 inhalation dose of umeclidinium at doses of 62.5 or 125 mcg. In the 4 randomized, double-blind, placebo- or active-controlled, efficacy clinical trials, 1,185 subjects received umeclidinium for up to 24 weeks, of which 487 subjects received the recommended dose of umeclidinium 62.5 mcg. In a 12-month, randomized, double-blind, placebo-controlled, long-term safety trial, 227 subjects received umeclidinium 125 mcg for up to 52 weeks.
- The incidence of adverse reactions associated with Umeclidinium in Table 1 is based upon 2 placebo-controlled efficacy trials: one 12-week trial and one 24-week trial.
- Other adverse reactions with Umeclidinium observed with an incidence less than 1% but more common than placebo included atrial fibrillation.
- In a long-term safety trial, 336 subjects (n = 227 umeclidinium 125 mcg, n = 109 placebo) were treated for up to 52 weeks with umeclidinium 125 mcg or placebo. The demographic and baseline characteristics of the long-term safety trial were similar to those of the efficacy trials described above. Adverse reactions that occurred with a frequency greater than or equal to 1% in subjects receiving umeclidinium 125 mcg that exceeded that in placebo in this trial were: nasopharyngitis, upper respiratory tract infection, urinary tract infection, pharyngitis, pneumonia, lower respiratory tract infection, rhinitis, supraventricular tachycardia, supraventricular extrasystoles, sinus tachycardia, idioventricular rhythm, headache, dizziness, sinus headache, cough, back pain, arthralgia, pain in extremity, neck pain, myalgia, nausea, dyspepsia, diarrhea, rash, depression, and vertigo.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Umeclidinium in the drug label.
# Drug Interactions
- There is potential for an additive interaction with concomitantly used anticholinergic medicines. Therefore, avoid coadministration of Umeclidiniumwith other anticholinergic-containing drugs as this may lead to an increase in anticholinergic adverse effects
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Teratogenic Effects:There are no adequate and well-controlled trials with Umeclidinium in pregnant women. Because animal reproduction studies are not always predictive of human response, Umeclidinium should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Women should be advised to contact their physicians if they become pregnant while taking Umeclidinium.
- There was no evidence of teratogenic effects in rats and rabbits at approximately 50 and 200 times, respectively, the MRHDID (maximum recommended human daily inhaled dose) in adults (on an AUC basis at maternal inhaled doses up to 278 mcg/kg/day in rats and maternal subcutaneous doses up to 180 mcg/kg/day in rabbits).
- Nonteratogenic Effects: There were no effects on perinatal and postnatal developments in rats at approximately 80 times the MRHDID in adults (on an AUC basis at maternal subcutaneous doses up to 180 mcg/kg/day).
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Umeclidinium in women who are pregnant.
### Labor and Delivery
- There are no adequate and well-controlled human trials that have investigated the effects of Umeclidinium during labor and delivery. Umeclidinium should be used during labor only if the potential benefit justifies the potential risk.
### Nursing Mothers
- It is not known whether Umeclidinium is excreted in human breast milk. Because many drugs are excreted in human milk, caution should be exercised when Umeclidinium is administered to a nursing woman. Since there are no data from well-controlled human studies on the use of Umeclidinium by nursing mothers, a decision should be made whether to discontinue nursing or to discontinue Umeclidinium,taking into account the importance of Umeclidinium to the mother.
- Subcutaneous administration of umeclidinium to lactating rats at approximately 25 times the MRHDID in adults resulted in a quantifiable level of umeclidinium in 2 pups, which may indicate transfer of umeclidinium in milk.
### Pediatric Use
- Umeclidinium is not indicated for use in children. The safety and efficacy in pediatric patients have not been established.
### Geriatic Use
- Based on available data, no adjustment of the dosage of Umeclidinium in geriatric patients is necessary, but greater sensitivity in some older individuals cannot be ruled out.
- Clinical trials of Umeclidiniumincluded 810 subjects aged 65 years and older, and, of those, 183 subjects were aged 75 years and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger subjects.
### Gender
There is no FDA guidance on the use of Umeclidinium with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Umeclidinium with respect to specific racial populations.
### Renal Impairment
- Patients with severe renal impairment (creatinine clearance less than 30 mL/min) showed no relevant increases in Cmax or AUC, nor did protein binding differ between subjects with severe renal impairment and their healthy controls. No dosage adjustment is required in patients with renal impairment
### Hepatic Impairment
- Patients with moderate hepatic impairment (Child-Pugh score of 7-9) showed no relevant increases in Cmax or AUC, nor did protein binding differ between subjects with moderate hepatic impairment and their healthy controls. Studies in subjects with severe hepatic impairment have not been performed
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Umeclidinium in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Umeclidinium in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
- Inhalation
### Monitoring
There is limited information regarding Monitoring of Umeclidinium in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Umeclidinium in the drug label.
# Overdosage
- No case of overdose has been reported with umeclidinium.
- High doses of umeclidinium may lead to anticholinergic signs and symptoms. However, there were no systemic anticholinergic adverse effects following a once-daily inhaled dose of up to 1,000 mcg umeclidinium (16 times the maximum recommended daily dose) for 14 days in subjects with COPD.
- Treatment of overdosage consists of discontinuation of Umeclidinium together with institution of appropriate symptomatic and/or supportive therapy.
# Pharmacology
## Mechanism of Action
- Umeclidinium is a long-acting, antimuscarinic agent, which is often referred to as an anticholinergic. It has similar affinity to the subtypes of muscarinic receptors M1 to M5. In the airways, it exhibits pharmacological effects through the inhibition of M3 receptor at the smooth muscle leading to bronchodilation. The competitive and reversible nature of antagonism was shown with human and animal origin receptors and isolated organ preparations. In preclinical in vitro as well as in vivostudies, prevention of methacholine and acetylcholine-induced bronchoconstrictive effects was dose-dependent and lasted longer than 24 hours. The clinical relevance of these findings is unknown. The bronchodilation following inhalation of umeclidinium is predominantly a site-specific effect.
## Structure
- Umeclidiniumcontains the active ingredient umeclidinium, an anticholinergic.
Umeclidinium bromide has the chemical name 1-[2-(benzyloxy)ethyl]-4-(hydroxydiphenylmethyl)-1-azoniabicyclo[2.2.2]octane bromide and the following chemical structure:
- Umeclidinium bromide is a white powder with a molecular weight of 508.5, and the empirical formula is C29H34NO2•Br (as a quaternary ammonium bromide compound). It is slightly soluble in water.
- Umeclidinium is a light grey and light green plastic inhaler containing a double-foil blister strip. Each blister on the strip contains a white powder mix of micronized umeclidinium bromide (74.2 mcg equivalent to 62.5 mcg of umeclidinium), magnesium stearate (75 mcg), and lactose monohydrate (to 12.5 mg). The lactose monohydrate contains milk proteins. After the inhaler is activated, the powder within the blister is exposed and ready for dispersion into the airstream created by the patient inhaling through the mouthpiece.
- Under standardized in vitro test conditions, Umeclidinium delivers 55 mcg of umeclidinium per dose when tested at a flow rate of 60 L/min for 4 seconds.
- In adult subjects with obstructive lung disease and severely compromised lung function (COPD with forced expiratory volume in 1 second/forced vital capacity [FEV1/FVC] less than 70% and FEV1 less than 30% predicted or FEV1 less than 50% predicted plus chronic respiratory failure), mean peak inspiratory flow through the ELLIPTA inhaler was 67.5 L/min (range: 41.6 to 83.3 L/min).
- The actual amount of drug delivered to the lung will depend on patient factors, such as inspiratory flow profile.
## Pharmacodynamics
- Cardiac Electrophysiology: QTc interval prolongation was studied in a double-blind, multiple dose, placebo- and positive-controlled, crossover trial in 86 healthy subjects. Following repeat doses of umeclidinium 500 mcg once daily (8 times the recommended dosage) for 10 days, umeclidinium does not prolong QTc to any clinically relevant extent.
## Pharmacokinetics
- Linear pharmacokinetics was observed for umeclidinium (62.5 to 500 mcg).
- Absorption: Umeclidinium plasma levels may not predict therapeutic effect. Following inhaled administration of umeclidinium in healthy subjects, Cmax occurred at 5 to 15 minutes. Umeclidinium is mostly absorbed from the lung after inhaled doses with minimum contribution from oral absorption. Following repeat dosing of inhaled umeclidinium, steady state was achieved within 14 days with 1.8-fold accumulation.
- Distribution: Following intravenous administration to healthy subjects, the mean volume of distribution was 86 L. In vitro plasma protein binding in human plasma was on average 89%.
- Metabolism: In vitro data showed that umeclidinium is primarily metabolized by the enzyme cytochrome P450 2D6 (CYP2D6) and is a substrate for the P-glycoprotein (P-gp) transporter. The primary metabolic routes for umeclidinium are oxidative (hydroxylation, O-dealkylation) followed by conjugation (e.g., glucuronidation), resulting in a range of metabolites with either reduced pharmacological activity or for which the pharmacological activity has not been established. Systemic exposure to the metabolites is low.
- Elimination: Following intravenous dosing with radiolabeled umeclidinium, mass balance showed 58% of the radiolabel in the feces and 22% in the urine. The excretion of the drug-related material in the feces following intravenous dosing indicated elimination in the bile. Following oral dosing to healthy male subjects, radiolabel recovered in feces was 92% of the total dose and that in urine was less than 1% of the total dose, suggesting negligible oral absorption. The effective half-life after once daily dosing is 11 hours.
- Special Populations: Population pharmacokinetic analysis showed no evidence of a clinically significant effect of age (40 to 93 years) (see Figure 1), gender (69% male) (see Figure 1), inhaled corticosteroid use (48%), or weight (34 to 161 kg) on systemic exposure of umeclidinium. In addition, there was no evidence of a clinically significant effect of race.
- Hepatic Impairment: The impact of hepatic impairment on the pharmacokinetics of Umeclidinium has been evaluated in subjects with moderate hepatic impairment (Child-Pugh score of 7-9). There was no evidence of an increase in systemic exposure to umeclidinium (Cmax and AUC) (see Figure 1). There was no evidence of altered protein binding in subjects with moderate hepatic impairment compared with healthy subjects. Umeclidinium has not been evaluated in subjects with severe hepatic impairment.
- Renal Impairment: The pharmacokinetics of Umeclidinium has been evaluated in subjects with severe renal impairment (creatinine clearance less than 30 mL/min). There was no evidence of an increase in systemic exposure to umeclidinium (Cmax and AUC) (see Figure 1). There was no evidence of altered protein binding in subjects with severe renal impairment compared with healthy subjects.
- Drug Interactions: Umeclidinium and P-glycoprotein Transporter: Umeclidinium is a substrate of P-gp. The effect of the moderate P-gp transporter inhibitor verapamil (240 mg once daily) on the steady-state pharmacokinetics of umeclidinium was assessed in healthy subjects. No effect on umeclidinium Cmax was observed; however, an approximately 1.4-fold increase in umeclidinium AUC was observed (see Figure 1).
- Umeclidinium and Cytochrome P450 2D6: In vitro metabolism of umeclidinium is mediated primarily by CYP2D6. However, no clinically meaningful difference in systemic exposure to umeclidinium (500 mcg) (8 times the approved dose) was observed following repeat daily inhaled dosing to normal (ultrarapid, extensive, and intermediate metabolizers) and CYP2D6 poor metabolizer subjects (see Figure 1).
## Nonclinical Toxicology
- Umeclidinium produced no treatment-relaed increases in the incidence of tumors in 2-year inhalation studies in rats and mice at inhaled doses up to 137 and 295/200 mcg/kg/day (male/female), respectively (approximately 20 and 25/20 times the MRHDID in adults on an AUC basis, respectively).
- Umeclidinium tested negative in the following genotoxicity assays: the in vitro Ames assay, in vitromouse lymphoma assay, and in vivo rat bone marrow micronucleus assay.
- No evidence of impairment of fertility was observed in male and female rats at subcutaneous doses up to 180 mcg/kg/day and inhaled doses up to 294 mcg/kg/day, respectively (approximately 100 and 50 times, respectively, the MRHDID in adults on an AUC basis).
# Clinical Studies
- The safety and efficacy of umeclidinium 62.5 mcg were evaluated in 3 dose-ranging trials, 2 placebo-controlled clinical trials (one 12-week trial and one 24-week trial), and a 12-month long-term safety trial. The efficacy of Umeclidinium is based primarily on the dose-ranging trials in 624 subjects with COPD and the 2 placebo-controlled confirmatory trials in 1,738 subjects with COPD.
- Dose selection for umeclidinium in COPD was supported by a 7-day, randomized, double-blind, placebo-controlled, crossover trial evaluating 4 doses of umeclidinium (15.6 to 125 mcg) or placebo dosed once daily in the morning in 163 subjects with COPD. A dose ordering was observed, with the 62.5- and 125-mcg doses demonstrating larger improvements in FEV1 over 24 hours compared with the lower doses of 15.6 and 31.25 mcg (Figure 2).
- The differences in trough FEV1 from baseline after 7 days for placebo and the 15.6-, 31.25-, 62.5-, and 125-mcg doses were -74 mL (95% CI: -118, -31), 38 mL (95% CI: -6, 83), 27 mL (95% CI: -18, 72), 49 mL (95% CI: 6, 93), and 109 mL (95% CI: 65, 152), respectively. Two additional dose-ranging trials in subjects with COPD demonstrated minimal additional benefit at doses above 125 mcg. The dose-ranging results supported the evaluation of 2 doses of umeclidinium, 62.5 and 125 mcg, in the confirmatory COPD trials to further assess dose response.
- Evaluations of dosing interval by comparing once- and twice-daily dosing supported selection of a once-daily dosing interval for further evaluation in the confirmatory COPD trials.
- The clinical development program for Umeclidiniumincluded 2 randomized, double-blind, placebo-controlled, parallel-group trials in subjects with COPD designed to evaluate the efficacy of Umeclidiniumon lung function. Trial 1 was a 24-week placebo-controlled trial, and Trial 2 was a 12-week placebo-controlled trial. These trials treated subjects that had a clinical diagnosis of COPD, were 40 years of age or older, had a history of smoking greater than or equal to 10 pack-years, had a post-albuterol FEV1 less than or equal to 70% of predicted normal values, had a ratio of FEV1/FVC of less than 0.7, and had a Modified Medical Research Council (mMRC) score greater than or equal to 2. Subjects in Trial 1 had a mean age of 63 years and an average smoking history of 46 pack-years, with 50% identified as current smokers. At screening, the mean post-bronchodilator percent predicted FEV1was 47% (range: 13% to 74%), the mean post-bronchodilator FEV1/FVC ratio was 0.47 (range: 0.20 to 0.74), and the mean percent reversibility was 15% (range: -35% to 109%). Baseline demographics and lung function for subjects in Trial 2 were similar to those in Trial 1.
- Trial 1 evaluated umeclidinium 62.5 mcg and placebo. The primary endpoint was change from baseline in trough (predose) FEV1 at Day 169 (defined as the mean of the FEV1 values obtained at 23 and 24 hours after the previous dose on Day 168) compared with placebo. Umeclidinium62.5 mcg demonstrated a larger increase in mean change from baseline in trough (predose) FEV1 relative to placebo (see Table 2). Similar results were obtained from Trial 2.
- In Trial 1, the mean peak FEV1 (over the first 6 hours relative to baseline) at Day 1 and at Day 168 for the group receiving umeclidinium 62.5 mcg compared with placebo was 126 and 130 mL, respectively.
- Health-related quality of life was measured using St. George’s Respiratory Questionnaire (SGRQ). Umeclidinium demonstrated an improvement in mean SGRQ total score compared with placebo treatment at Day 168: -4.69 (95% CI: -7.07,-2.31). The proportion of patients with a clinically meaningful decrease (defined as a decrease of at least 4 units from baseline) at Week 24 was greater for Umeclidinium62.5 mcg (42%; 172/410) compared with placebo (31%; 86/274).
# How Supplied
- Umeclidiniumis supplied as a disposable light grey and light green plastic inhaler containing a double-foil blister strip with 30 blisters. The inhaler is packaged in a moisture-protective foil tray with a desiccant and a peelable lid (NDC 0173-0873-10).
- Umeclidiniumis also supplied in an institutional pack of a disposable light grey and light green plastic inhaler containing a double-foil blister strip with 7 blisters. The inhaler is packaged in a moisture-protective foil tray with a desiccant and a peelable lid (NDC 0173-0873-06).
## Storage
- Store at room temperature between 68°F and 77°F (20°C and 25°C); excursions permitted from 59°F to 86°F (15°C to 30°C) [See USP Controlled Room Temperature]. Store in a dry place away from direct heat or sunlight. Keep out of reach of children.
- Umeclidiniumshould be stored inside the unopened moisture-protective foil tray and only removed from the tray immediately before initial use. Discard Umeclidinium 6 weeks after opening the foil tray or when the counter reads “0” (after all blisters have been used), whichever comes first. The inhaler is not reusable. Do not attempt to take the inhaler apart.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).
- Not for Acute Symptoms: Inform patients that Umeclidiniumis not meant to relieve acute symptoms of COPD and extra doses should not be used for that purpose. Advise them to treat acute symptoms with a rescue inhaler such as albuterol. Provide patients with such medicine and instruct them in how it should be used.
- Instruct patients to seek medical attention immediately if they experience any of the following:
- Symptoms get worse
- Need for more inhalations than usual of their rescue inhaler
- Patients should not stop therapy with Umeclidiniumwithout physician/provider guidance since symptoms may recur after discontinuation.
- Paradoxical Bronchospasm: As with other inhaled medicines, Umeclidinium can cause paradoxical bronchospasm. If paradoxical bronchospasm occurs, instruct patients to discontinue Umeclidinium
- Worsening of Narrow-Angle Glaucoma: Instruct patients to be alert for signs and symptoms of acute narrow-angle glaucoma (e.g., eye pain or discomfort, blurred vision, visual halos or colored images in association with red eyes from conjunctival congestion and corneal edema). Instruct patients to consult a physician immediately if any of these signs or symptoms develops.
- Worsening of Urinary Retention: Instruct patients to be alert for signs and symptoms of urinary retention (e.g., difficulty passing urine, painful urination). Instruct patients to consult a physician immediately if any of these signs or symptoms develops.
# Precautions with Alcohol
- Alcohol-Umeclidinium interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Incruse Ellipta
# Look-Alike Drug Names
There is limited information regarding Umeclidinium Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Umeclidinium | |
a710dde8ed8235ec905f5b9fd53adc6aa86bb8b3 | wikidoc | Urotensin-II | Urotensin-II
Urotensin-II (U-II) is a peptide ligand that is the strongest known vasoconstrictor. Because of the involvement of the UII system in multiple biological systems such as the cardiovascular, nervous, endocrine, and renal, it represents a promising target for the development of new drugs.
In humans, Urotensin-2 is encoded by the UTS2 gene.
# Discovery
U-II was initially isolated from the neurosecretory system of the Goby fish (Gillichthys mirabilis). For many years it was thought that U-II does not exhibit significant effects in mammalian systems; a view quickly overturned when it was demonstrated that Goby U-II produces slow relaxation of mouse anococcygeus muscle, in addition to contraction of rat artery segments. In 1998, the genes for Pre-pro U-II were found in mammals proving that the peptide U-II did exist in mammals.
# Structure
The U-II gene is located on chromosome 1p36. U-II peptide length varies between species due to the specific cleaving sites located at different spots depending on the species. In humans U-II length is 11 amino acids. The peptide sequence that is needed for biological function for both U-II and urotensin II-Related Peptide (URP) is known as the core. It is hexapeptide (-CYS-TYR-LYS-TRP-PHE-CYS-), and is connected at the two ends by a disulfide bond. Also just like URP the amino terminus can be modified without any loss in pharmacological activity suggesting that it is not needed for activation of the receptor. Unlike URP, U-II has an acidic amino acid (Glutamic or Aspartic) that precedes the core sequence. While the amino acid isn’t necessary for the activation of urotensin II receptor the fact that it is conserved in different species suggests that it has a biological function that has not been discovered.
# Receptor
U-II is an agonist for the urotensin-II receptor which is a G protein-coupled receptor that primarily activates the alpha subunit Gαq11. It activates PKC which then activates PLC which increases the intercellular calcium concentration. It is found in many peripheral tissues, blood vessels, and also the brainstem cholinergic neurons of the laterodorsal tegmental (LDT) and the pedunculopontine tegmental nuclei (PPT). It is also found in rat astrocytes.
# Tissue localization
Pre-pro U-II in both humans and rats are primarily expressed in the motorneurons of the brainstem and spinal cord although it is also found in small amounts in other parts of the brain as well including the frontal lobe and the medulla oblongata. In humans U-II mRNA is also found in other peripheral tissues such as the heart, kidneys, adrenal gland, placenta, spleen, and thymus.
# Function
## Central nervous system
When injected intracerebroventricularly (icv) U-II causes an increase in the corticotropin releasing factor by activating the hypothalamic paraventricular neurons. This leads to increased plasma levels of adrenocorticotropic hormones and adrenaline. Rats and mice exhibit many stress related behaviors when injected with U-II which were tested by the elevated plus maze which measures anxiety-like effects,and the hole-board test which measures head dipping which is also an anxiety-like behavior.
U-II when injected icv in rats also leads to cardiovascular responses including raising mean arterial pressure (MAP) and causing tachycardia. When the arcuate nucleus, and the paraventricular nucleus, two different areas of the brain which are known to control blood pressure were injected with U-II simultaneously they caused an increase in blood pressure. When the two areas were injected separately it was discovered that U-II affected the excitatory neurons in the paraventricular nucleus and the inhibitory neurons of the arcuate nucleus.
U-II when injected icv in both rats and mice also stimulates locomotion in familiar environments. This experiment was also tested in rainbow trout (Oncorhynchus mykiss) where a stimulatory effect was also observed..
Depression-like behavior was also observed when U-II was injected in the brain by using the forced swim test and the tail suspension test which are used to compare molecules that are thought to cause anti-depressive-like effects.
Orexigenic behavior which is increased appetite and thirst were also observed after icv injection of U-II in rats.
## Peripheral tissue effects
U-II has a variety of effects on different tissues. In blood vessels it can cause contraction. In rat pancreas U-II inhibits insulin secretion. It also affects the kidneys including sodium transport, lipid and glucose metabolism, and natriuretic effects. Its has been linked to cardiac fibrosis and hypertrophy, heart failure, renal dysfunction, and diabetes. | Urotensin-II
Urotensin-II (U-II) is a peptide ligand that is the strongest known vasoconstrictor.[1] Because of the involvement of the UII system in multiple biological systems such as the cardiovascular, nervous, endocrine, and renal,[2][3][4] it represents a promising target for the development of new drugs.[5]
In humans, Urotensin-2 is encoded by the UTS2 gene.[6][7][8]
# Discovery
U-II was initially isolated from the neurosecretory system of the Goby fish (Gillichthys mirabilis).[9] For many years it was thought that U-II does not exhibit significant effects in mammalian systems; a view quickly overturned when it was demonstrated that Goby U-II produces slow relaxation of mouse anococcygeus muscle, in addition to contraction of rat artery segments. In 1998, the genes for Pre-pro U-II were found in mammals proving that the peptide U-II did exist in mammals.[10]
# Structure
The U-II gene is located on chromosome 1p36.[11] U-II peptide length varies between species due to the specific cleaving sites located at different spots depending on the species. In humans U-II length is 11 amino acids. The peptide sequence that is needed for biological function for both U-II and urotensin II-Related Peptide (URP) is known as the core. It is hexapeptide (-CYS-TYR-LYS-TRP-PHE-CYS-), and is connected at the two ends by a disulfide bond. Also just like URP the amino terminus can be modified without any loss in pharmacological activity suggesting that it is not needed for activation of the receptor. Unlike URP, U-II has an acidic amino acid (Glutamic or Aspartic) that precedes the core sequence. While the amino acid isn’t necessary for the activation of urotensin II receptor the fact that it is conserved in different species suggests that it has a biological function that has not been discovered.[10]
# Receptor
U-II is an agonist for the urotensin-II receptor which is a G protein-coupled receptor that primarily activates the alpha subunit Gαq11. It activates PKC which then activates PLC which increases the intercellular calcium concentration. It is found in many peripheral tissues, blood vessels, and also the brainstem cholinergic neurons of the laterodorsal tegmental (LDT) and the pedunculopontine tegmental nuclei (PPT).[12] It is also found in rat astrocytes.[13]
# Tissue localization
Pre-pro U-II in both humans and rats are primarily expressed in the motorneurons of the brainstem and spinal cord although it is also found in small amounts in other parts of the brain as well including the frontal lobe and the medulla oblongata. In humans U-II mRNA is also found in other peripheral tissues such as the heart, kidneys, adrenal gland, placenta, spleen, and thymus.[11]
# Function
## Central nervous system
When injected intracerebroventricularly (icv) U-II causes an increase in the corticotropin releasing factor by activating the hypothalamic paraventricular neurons. This leads to increased plasma levels of adrenocorticotropic hormones and adrenaline. Rats and mice exhibit many stress related behaviors when injected with U-II which were tested by the elevated plus maze which measures anxiety-like effects,and the hole-board test which measures head dipping which is also an anxiety-like behavior.[14]
U-II when injected icv in rats also leads to cardiovascular responses including raising mean arterial pressure (MAP) and causing tachycardia. When the arcuate nucleus, and the paraventricular nucleus, two different areas of the brain which are known to control blood pressure were injected with U-II simultaneously they caused an increase in blood pressure. When the two areas were injected separately it was discovered that U-II affected the excitatory neurons in the paraventricular nucleus and the inhibitory neurons of the arcuate nucleus.[14]
U-II when injected icv in both rats and mice also stimulates locomotion in familiar environments. This experiment was also tested in rainbow trout (Oncorhynchus mykiss) where a stimulatory effect was also observed..
Depression-like behavior was also observed when U-II was injected in the brain by using the forced swim test and the tail suspension test which are used to compare molecules that are thought to cause anti-depressive-like effects.
Orexigenic behavior which is increased appetite and thirst were also observed after icv injection of U-II in rats.[14]
## Peripheral tissue effects
U-II has a variety of effects on different tissues. In blood vessels it can cause contraction. In rat pancreas U-II inhibits insulin secretion. It also affects the kidneys including sodium transport, lipid and glucose metabolism, and natriuretic effects. Its has been linked to cardiac fibrosis and hypertrophy, heart failure, renal dysfunction, and diabetes.[14] | https://www.wikidoc.org/index.php/Urotensin-II | |
4ee16fbb75db27b6459733e46e23fcc5287384a7 | wikidoc | VA-HIT Trial | VA-HIT Trial
# Objective
To determine if the reduction in major CHD events (MI and CHD deaths) with gemfibrozil could be attributed to changes in major plasma lipid levels.
# Methods
VA-HIT (Veterans Affairs HDL Intervention Trial) trial is a multicentered, randomized, double-blinded, placebo-controlled trial wherein 2531 patients with CAD along with LDL levels ≤140 mg/dL (mean 111 mg/dL) and HDL ≤40 mg/dL (mean 32 mg/dL) were randomly assigned to treatment with gemfibrozil (1200mg) or placebo. The median follow-up was 5.1 years.
# Results
## Results At One Year
- Mean HDL-C level was higher by 6% in the group treated with gemfibrozil.
- Mean TG concentration was lower by 31% in the group treated with gemfibrozil.
- Mean total cholesterol was 4% lower in the group treated with gemfibrozil.
## Results At Five Year
- The combined primary end point of cardiac death and non-fatal myocardial infarction occurred in 17.3% versus 21.7% in the group receiving gemfibrozil and the placebo group respectively.
- There was a risk reduction of 22% in the primary outcome (p=.0006) and 24% risk reduction in the combined endpoint of stroke, MI, and CHD death
- Acute coronary events were reduced by 11% with gemfibrozil for every 5 mg/dL rise in HDL-C, but the reduction was independent of changes in LDL-C and triglyceride levels.
# Conclusion
Low HDL-C levels strongly and independently predict the occurrence of coronary events. Gemfibrozil reduced the rate of coronary events by raising HDL-C and lowering triglycerides without lowering LDL-C. | VA-HIT Trial
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Click here to download slides for VA-HIT Trial.
# Objective
To determine if the reduction in major CHD events (MI and CHD deaths) with gemfibrozil could be attributed to changes in major plasma lipid levels.
# Methods
VA-HIT (Veterans Affairs HDL Intervention Trial) trial is a multicentered, randomized, double-blinded, placebo-controlled trial wherein 2531 patients with CAD along with LDL levels ≤140 mg/dL (mean 111 mg/dL) and HDL ≤40 mg/dL (mean 32 mg/dL) were randomly assigned to treatment with gemfibrozil (1200mg) or placebo. The median follow-up was 5.1 years.
# Results
## Results At One Year
- Mean HDL-C level was higher by 6% in the group treated with gemfibrozil.
- Mean TG concentration was lower by 31% in the group treated with gemfibrozil.
- Mean total cholesterol was 4% lower in the group treated with gemfibrozil.
## Results At Five Year
- The combined primary end point of cardiac death and non-fatal myocardial infarction occurred in 17.3% versus 21.7% in the group receiving gemfibrozil and the placebo group respectively.
- There was a risk reduction of 22% in the primary outcome (p=.0006) and 24% risk reduction in the combined endpoint of stroke, MI, and CHD death
- Acute coronary events were reduced by 11% with gemfibrozil for every 5 mg/dL rise in HDL-C, but the reduction was independent of changes in LDL-C and triglyceride levels.
# Conclusion
Low HDL-C levels strongly and independently predict the occurrence of coronary events. Gemfibrozil reduced the rate of coronary events by raising HDL-C and lowering triglycerides without lowering LDL-C.[1][2][3][4][5] | https://www.wikidoc.org/index.php/VA-HIT_Trial | |
bc2b7ba8367e483e03ef6fb1ecf9f2f1f4d81b05 | wikidoc | VAPRED Study | VAPRED Study
# Official Title
Study of Predictive Echo Doppler Score and D-dimer Level in Evaluation of the Thromboembolic Event Recurrence After Anticoagulant Treatment Cessation
# Objective
The purpose of this trial is to perform a prospective multicentric study to determine predictive ED score and D-dimer level in the evaluation of the thromboembolic event recurrence after anticoagulant treatment cessation
# Sponsor
University Hospital, Grenoble
# Timeline
The previous information was derived from ClinicalTrials.gov on 09/25/2013 using the identification number NCT00860106 .
# Study Description
The previous information was derived from ClinicalTrials.gov on 09/25/2013 using the identification number NCT00860106 .
# Eligibility Criteria
## Inclusion Criteria
- >18 and <80 years old
- First or second treated proximal VTE event (+/- Pulmonary embolism)
- Signed informed consent
## Exclusion Criteria
- Active cancer or currently treated
- Previous VTE>2
- Long term anticoagulant treatment for VTE diseases
- Long term anticoagulant treatment for other diseases
- Pregnancy, parturient or breast feeding
- Person deprived of freedom by judicial or administrative decision
- Consent unsigned
# Outcomes
## Primary Outcomes
VTE event recurrence
## Secondary Outcomes
Not provided
# Publications
## Results
## Conclusion | VAPRED Study
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Official Title
Study of Predictive Echo Doppler Score and D-dimer Level in Evaluation of the Thromboembolic Event Recurrence After Anticoagulant Treatment Cessation
# Objective
The purpose of this trial is to perform a prospective multicentric study to determine predictive ED score and D-dimer level in the evaluation of the thromboembolic event recurrence after anticoagulant treatment cessation
# Sponsor
University Hospital, Grenoble
# Timeline
The previous information was derived from ClinicalTrials.gov on 09/25/2013 using the identification number NCT00860106 .
# Study Description
The previous information was derived from ClinicalTrials.gov on 09/25/2013 using the identification number NCT00860106 .
# Eligibility Criteria
## Inclusion Criteria
- >18 and <80 years old
- First or second treated proximal VTE event (+/- Pulmonary embolism)
- Signed informed consent
## Exclusion Criteria
- Active cancer or currently treated
- Previous VTE>2
- Long term anticoagulant treatment for VTE diseases
- Long term anticoagulant treatment for other diseases
- Pregnancy, parturient or breast feeding
- Person deprived of freedom by judicial or administrative decision
- Consent unsigned
# Outcomes
## Primary Outcomes
VTE event recurrence [ Time Frame: 0-2 years ] [ Designated as safety issue: Yes ]
## Secondary Outcomes
Not provided
# Publications
## Results
## Conclusion | https://www.wikidoc.org/index.php/VAPRED_Study | |
f99412baa0bbe2fb46955b36b9b30438eb9bb299 | wikidoc | Vaginal ring | Vaginal ring
Vaginal rings (also known as intravaginal rings, or V-Rings) are 'doughnut-shaped' polymeric drug delivery devices designed to provide controlled release of drugs to the vagina over extended periods of time. Several vaginal ring products are currently available, including:
- Estring - a low-dose estradiol-releasing ring, manufactured from silicone elastomer, for the treatment of vaginal atrophy.
- Femring - a low-dose estradiol-acetate releasing ring, manufactured from silicone elastomer, for the relief of hot flashes and vaginal atrophy associated with menopause.
- NuvaRing - a low-dose contraceptive vaginal ring, manufactured from poly(ethylene-co-vinyl acetate), and releasing etonogestrel (a progesterone) ethinyl estradiol (an estrogen).
A number of vaginal ring products are also in development.
# Methods of use
General - Vaginal rings are easily inserted and removed. Vaginal walls hold them in place. Although their exact location within the vagina is not critical for clinical efficacy, rings commonly reside next to the cervix. Rings are typically left in place during intercourse, and most couples report no interference or discomfort. In many cases, neither partner feels the presence of the ring.
Rings can be removed prior to intercourse, but in the case of the contraceptive Nuvaring only for one to three hours in order to maintain efficacy of birth control.
- Femring - Femring is inserted into the vagina and left in place for three months, after which it is removed and replaced with a fresh ring.
- Nuvaring - Nuvaring is inserted into the vagina and left in place for three weeks, after which it is removed for a 'ring-free' week to allow menstruation to occur.
# Vaginal ring updates
Vaginal ring technology is currently being developed for the controlled release of microbicides and vaccines for the prevention of HIV infection.
Issues have been raised about the biodegradability of the product given the recent concern about pollution and use of plastics, especially of the poly(ethylene-co-vinyl+) archetypes. | Vaginal ring
Vaginal rings (also known as intravaginal rings, or V-Rings) are 'doughnut-shaped' polymeric drug delivery devices designed to provide controlled release of drugs to the vagina over extended periods of time. Several vaginal ring products are currently available, including:
- Estring - a low-dose estradiol-releasing ring, manufactured from silicone elastomer, for the treatment of vaginal atrophy.
- Femring - a low-dose estradiol-acetate releasing ring, manufactured from silicone elastomer, for the relief of hot flashes and vaginal atrophy associated with menopause.
- NuvaRing - a low-dose contraceptive vaginal ring, manufactured from poly(ethylene-co-vinyl acetate), and releasing etonogestrel (a progesterone) ethinyl estradiol (an estrogen).
A number of vaginal ring products are also in development.
# Methods of use
General - Vaginal rings are easily inserted and removed. Vaginal walls hold them in place. Although their exact location within the vagina is not critical for clinical efficacy, rings commonly reside next to the cervix. Rings are typically left in place during intercourse, and most couples report no interference or discomfort. In many cases, neither partner feels the presence of the ring.
[1]
Rings can be removed prior to intercourse, but in the case of the contraceptive Nuvaring only for one to three hours in order to maintain efficacy of birth control.
- Femring - Femring is inserted into the vagina and left in place for three months, after which it is removed and replaced with a fresh ring.
- Nuvaring - Nuvaring is inserted into the vagina and left in place for three weeks, after which it is removed for a 'ring-free' week to allow menstruation to occur.
# Vaginal ring updates
Vaginal ring technology is currently being developed for the controlled release of microbicides and vaccines for the prevention of HIV infection.[citation needed]
Issues have been raised about the biodegradability of the product given the recent concern about pollution and use of plastics, especially of the poly(ethylene-co-vinyl+) archetypes.[citation needed] | https://www.wikidoc.org/index.php/Vaginal_ring | |
5a08bc0d12fc70bd2a3c201cf2b392c8130a641a | wikidoc | Valaciclovir | Valaciclovir
Synonyms / Brand Names: Valaciclovir Hcl, Valaciclovir Hydrochloride, Valacyclover Hydrochloric, Valacyclover Hydrochloride, Valacyclovir Hydrochloride, Valacyclovir, Valtrex, Zelitrex
# Dosing and Administration
The recommended dosage of Valaciclovir for the treatment of herpes zoster is 1 gram orally 3 times daily for 7 days. Therapy should be initiated at the earliest sign or symptom of herpes zoster and is most effective when started within 48 hours of the onset of zoster rash. No data are available on efficacy of treatment started greater than 72 hours after rash onset.
See Instructions for Administration for further dosing and administration information.
FDA Package Insert Resources
Indications, Contraindications, Side Effects, Drug Interactions, etc.
Calculate Creatine Clearance
On line calculator of your patients Cr Cl by a variety of formulas.
Convert pounds to Kilograms
On line calculator of your patients weight in pounds to Kg for dosing estimates.
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Patient Resources
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International Resources
en Español
# FDA Package Insert Resources
Indications
Contraindications
Side Effects
Drug Interactions
Precautions
Overdose
Instructions for Administration
How Supplied
Pharmacokinetics and Molecular Data
FDA label
FDA on Valaciclovir
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# Publication Resources
Most Recent Articles on Valaciclovir
Review Articles on Valaciclovir
Articles on Valaciclovir in N Eng J Med, Lancet, BMJ
WikiDoc State of the Art Review
Textbook Information on Valaciclovir
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# Trial Resources
Ongoing Trials with Valaciclovir at Clinical Trials.gov
Trial Results with Valaciclovir
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# Guidelines & Evidence Based Medicine Resources
US National Guidelines Clearinghouse on Valaciclovir
Cochrane Collaboration on Valaciclovir
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# Media Resources
Powerpoint Slides on Valaciclovir
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# Patient Resources
Patient Information from National Library of Medicine
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# International Resources
Valaciclovir en Español
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Adapted from the FDA Package Insert. | Valaciclovir
Synonyms / Brand Names: Valaciclovir Hcl, Valaciclovir Hydrochloride, Valacyclover Hydrochloric, Valacyclover Hydrochloride, Valacyclovir Hydrochloride, Valacyclovir, Valtrex, Zelitrex
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Dosing and Administration
The recommended dosage of Valaciclovir for the treatment of herpes zoster is 1 gram orally 3 times daily for 7 days. Therapy should be initiated at the earliest sign or symptom of herpes zoster and is most effective when started within 48 hours of the onset of zoster rash. No data are available on efficacy of treatment started greater than 72 hours after rash onset.
See Instructions for Administration for further dosing and administration information.
FDA Package Insert Resources
Indications, Contraindications, Side Effects, Drug Interactions, etc.
Calculate Creatine Clearance
On line calculator of your patients Cr Cl by a variety of formulas.
Convert pounds to Kilograms
On line calculator of your patients weight in pounds to Kg for dosing estimates.
Publication Resources
Recent articles, WikiDoc State of the Art Review, Textbook Information
Trial Resources
Ongoing Trials, Trial Results
Guidelines & Evidence Based Medicine Resources
US National Guidelines, Cochrane Collaboration, etc.
Media Resources
Slides, Video, Images, MP3, Podcasts, etc.
Patient Resources
Discussion Groups, Handouts, Blogs, News, etc.
International Resources
en Español
# FDA Package Insert Resources
Indications
Contraindications
Side Effects
Drug Interactions
Precautions
Overdose
Instructions for Administration
How Supplied
Pharmacokinetics and Molecular Data
FDA label
FDA on Valaciclovir
Return to top
# Publication Resources
Most Recent Articles on Valaciclovir
Review Articles on Valaciclovir
Articles on Valaciclovir in N Eng J Med, Lancet, BMJ
WikiDoc State of the Art Review
Textbook Information on Valaciclovir
Return to top
# Trial Resources
Ongoing Trials with Valaciclovir at Clinical Trials.gov
Trial Results with Valaciclovir
Return to top
# Guidelines & Evidence Based Medicine Resources
US National Guidelines Clearinghouse on Valaciclovir
Cochrane Collaboration on Valaciclovir
Cost Effectiveness of Valaciclovir
Return to top
# Media Resources
Powerpoint Slides on Valaciclovir
Images of Valaciclovir
Podcasts & MP3s on Valaciclovir
Videos on Valaciclovir
Return to top
# Patient Resources
Patient Information from National Library of Medicine
Patient Resources on Valaciclovir
Discussion Groups on Valaciclovir
Patient Handouts on Valaciclovir
Blogs on Valaciclovir
Valaciclovir in the News
Valaciclovir in the Marketplace
Return to top
# International Resources
Valaciclovir en Español
Return to top
Adapted from the FDA Package Insert. | https://www.wikidoc.org/index.php/Valaciclovir | |
3ab3fdb6e5e732e2131e7c865b97cfb1f346fbf4 | wikidoc | Valacyclovir | Valacyclovir
# 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
Valacyclovir is a nucleoside analogue DNA polymerase inhibitor that is FDA approved for the treatment of cold sores (herpes labialis), genital herpes, and herpes zoster. Common adverse reactions include headache, nausea, and abdominal pain.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- The recommended dosage of valacyclovir hydrochloride for treatment of cold sores is 2 grams twice daily for 1 day taken 12 hours apart. Therapy should be initiated at the earliest symptom of a cold sore (e.g., tingling, itching, or burning).
- Initial Episode: The recommended dosage of valacyclovir hydrochloride for treatment of initial genital herpes is 1 gram twice daily for 10 days. Therapy was most effective when administered within 48 hours of the onset of signs and symptoms.
- Recurrent Episodes: The recommended dosage of valacyclovir hydrochloride for treatment of recurrent genital herpes is 500 mg twice daily for 3 days. Initiate treatment at the first sign or symptom of an episode.
- Suppressive Therapy: The recommended dosage of valacyclovir hydrochloride for chronic suppressive therapy of recurrent genital herpes is 1 gram once daily in patients with normal immune function. In patients with a history of 9 or fewer recurrences per year, an alternative dose is 500 mg once daily.
- In HIV-infected patients with a CD4+ cell count ≥100 cells/mm3, the recommended dosage of valacyclovir hydrochloride for chronic suppressive therapy of recurrent genital herpes is 500 mg twice daily.
- Reduction of Transmission: The recommended dosage of valacyclovir hydrochloride for reduction of transmission of genital herpes in patients with a history of 9 or fewer recurrences per year is 500 mg once daily for the source partner.
- The recommended dosage of valacyclovir hydrochloride for treatment of herpes zoster is 1 gram 3 times daily for 7 days. Therapy should be initiated at the earliest sign or symptom of herpes zoster and is most effective when started within 48 hours of the onset of rash.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Valacyclovir in adult patients.
### Non–Guideline-Supported Use
- Oral valacyclovir 1 g 3 times a day.
- Prophylaxis with valacyclovir 2000 mg orally 4 times daily for 18 weeks after bone marrow transplantation.
- Valacyclovir for 5 to 14 days.
- Oral valacyclovir for 5 to 10 days.
- 14-day course of valacyclovir 500 mg orally twice daily.
- 7-day oral regimen of valacyclovir 1 g 3 times daily.
- Valacyclovir is a recommended option for uncomplicated chickenpox in adults with HIV.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- The recommended dosage of valacyclovir hydrochloride for the treatment of cold sores in pediatric patients ≥12 years of age is 2 grams twice daily for 1 day taken 12 hours apart. Therapy should be initiated at the earliest symptom of a cold sore (e.g., tingling, itching, or burning).
- The recommended dosage of valacyclovir hydrochloride for treatment of chickenpox in immunocompetent pediatric patients 2 to <18 years of age is 20 mg/kg administered 3 times daily for 5 days. The total dose should not exceed 1 gram 3 times daily. Therapy should be initiated at the earliest sign or symptom.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Valacyclovir in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Valacyclovir in pediatric patients.
# Contraindications
- Valacyclovir hydrochloride is contraindicated in patients who have had a demonstrated clinically significant hypersensitivity reaction (e.g., anaphylaxis) to valacyclovir, acyclovir, or any component of the formulation.
# Warnings
### Precautions
- Thrombotic Thrombocytopenic Purpura/Hemolytic Uremic Syndrome (TTP/HUS)
- TTP/HUS, in some cases resulting in death, has occurred in patients with advanced HIV disease and also in allogeneic bone marrow transplant and renal transplant recipients participating in clinical trials of Valacyclovir hydrochloride at doses of 8 grams per day. Treatment with Valacyclovir hydrochloride should be stopped immediately if clinical signs, symptoms, and laboratory abnormalities consistent with TTP/HUS occur.
- Acute Renal Failure
- Cases of acute renal failure have been reported in:
Elderly patients with or without reduced renal function. Caution should be exercised when administering valacyclovir hydrochloride to geriatric patients, and dosage reduction is recommended for those with impaired renal function.
Patients with underlying renal disease who received higher than recommended doses of valacyclovir hydrochloride for their level of renal function. Dosage reduction is recommended when administering valacyclovir hydrochloride to patients with renal impairment.
Patients receiving other nephrotoxic drugs. Caution should be exercised when administering valacyclovir hydrochloride to patients receiving potentially nephrotoxic drugs.
Patients without adequate hydration. Precipitation of acyclovir in renal tubules may occur when the solubility (2.5 mg/mL) is exceeded in the intratubular fluid. Adequate hydration should be maintained for all patients.
- Elderly patients with or without reduced renal function. Caution should be exercised when administering valacyclovir hydrochloride to geriatric patients, and dosage reduction is recommended for those with impaired renal function.
- Patients with underlying renal disease who received higher than recommended doses of valacyclovir hydrochloride for their level of renal function. Dosage reduction is recommended when administering valacyclovir hydrochloride to patients with renal impairment.
- Patients receiving other nephrotoxic drugs. Caution should be exercised when administering valacyclovir hydrochloride to patients receiving potentially nephrotoxic drugs.
- Patients without adequate hydration. Precipitation of acyclovir in renal tubules may occur when the solubility (2.5 mg/mL) is exceeded in the intratubular fluid. Adequate hydration should be maintained for all patients.
- In the event of acute renal failure and anuria, the patient may benefit from hemodialysis until renal function is restored.
- Central Nervous System Effects
- Central nervous system adverse reactions, including agitation, hallucinations, confusion, delirium, seizures, and encephalopathy, have been reported in both adult and pediatric patients with or without reduced renal function and in patients with underlying renal disease who received higher than recommended doses of valacyclovir hydrochloride for their level of renal function. Elderly patients are more likely to have central nervous system adverse reactions. Valacyclovir hydrochloride should be discontinued if central nervous system adverse reactions occur.
# 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 with rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- Cold Sores (Herpes Labialis): In clinical studies for the treatment of cold sores, the adverse reactions reported by patients receiving valacyclovir hydrochloride 2 grams twice daily (n = 609) or placebo (n = 609) for 1 day, respectively, included headache (14%, 10%) and dizziness (2%, 1%). The frequencies of abnormal ALT (>2 x ULN) were 1.8% for patients receiving valacyclovir hydrochloride compared with 0.8% for placebo. Other laboratory abnormalities (hemoglobin, white blood cells, alkaline phosphatase, and serum creatinine) occurred with similar frequencies in the 2 groups.
- Genital Herpes: Initial Episode: In a clinical study for the treatment of initial episodes of genital herpes, the adverse reactions reported by ≥5% of patients receiving valacyclovir hydrochloride 1 gram twice daily for 10 days (n = 318) or oral acyclovir 200 mg 5 times daily for 10 days (n = 318), respectively, included headache (13%, 10%) and nausea (6%, 6%). For the incidence of laboratory abnormalities see Table 2.
- Recurrent Episodes: In 3 clinical studies for the episodic treatment of recurrent genital herpes, the adverse reactions reported by ≥5% of patients receiving valacyclovir hydrochloride 500 mg twice daily for 3 days (n = 402), valacyclovir hydrochloride 500 mg twice daily for 5 days (n = 1,136) or placebo (n = 259), respectively, included headache (16%, 11%, 14%) and nausea (5%, 4%, 5%).
- For the incidence of laboratory abnormalities see Table 2.
- Suppressive Therapy: Suppression of Recurrent Genital Herpes in Immunocompetent Adults: In a clinical study for the suppression of recurrent genital herpes infections, the adverse reactions reported by patients receiving valacyclovir hydrochloride 1 gram once daily (n = 269), valacyclovir hydrochloride 500 mg once daily (n = 266), or placebo (n = 134), respectively, included headache (35%, 38%, 34%), nausea (11%, 11%, 8%), abdominal pain (11%, 9%, 6%), dysmenorrhea (8%, 5%, 4%), depression (7%, 5%, 5%), arthralgia (6%, 5%, 4%), vomiting (3%, 3%, 2%), and dizziness (4%, 2%, 1%). For the incidence of laboratory abnormalities see Table 2.
- Suppression of Recurrent Genital Herpes in HIV-Infected Patients: In HIV-infected patients, frequently reported adverse reactions for valacyclovir hydrochloride (500 mg twice daily; n = 194, median days on therapy = 172) and placebo (n = 99, median days on therapy = 59), respectively, included headache (13%, 8%), fatigue (8%, 5%), and rash (8%, 1%). Post-randomization laboratory abnormalities that were reported more frequently in valacyclovir subjects versus placebo included elevated alkaline phosphatase (4%, 2%), elevated ALT (14%, 10%), elevated AST (16%, 11%), decreased neutrophil counts (18%, 10%), and decreased platelet counts (3%, 0%), respectively.
- Reduction of Transmission: In a clinical study for the reduction of transmission of genital herpes, the adverse reactions reported by patients receiving valacyclovir hydrochloride 500 mg once daily (n = 743) or placebo once daily (n = 741), respectively, included headache (29%, 26%), nasopharyngitis (16%, 15%), and upper respiratory tract infection (9%, 10%).
- Herpes Zoster: In 2 clinical studies for the treatment of herpes zoster, the adverse reactions reported by patients receiving valacyclovir hydrochloride 1 gram 3 times daily for 7 to 14 days (n = 967) or placebo (n = 195), respectively, included nausea (15%, 8%), headache (14%, 12%), vomiting (6%, 3%), dizziness (3%, 2%), and abdominal pain (3%, 2%). For the incidence of laboratory abnormalities see Table 2.
- The safety profile of valacyclovir hydrochloride has been studied in 177 pediatric patients 1 month to <18 years of age. Sixty-five of these pediatric patients, 12 to <18 years of age, received oral tablets for 1 to 2 days for treatment of cold sores. The remaining 112 pediatric patients, 1 month to <12 years of age, participated in 3 pharmacokinetic and safety studies and received valacyclovir oral suspension. Fifty-one of these 112 pediatric patients received oral suspension for 3 to 6 days. The frequency, intensity, and nature of clinical adverse reactions and laboratory abnormalities were similar to those seen in adults.
- Pediatric Patients 12 to <18 Years of Age (Cold Sores): In clinical studies for the treatment of cold sores, the adverse reactions reported by adolescent patients receiving valacyclovir hydrochloride 2 grams twice daily for 1 day, or valacyclovir hydrochloride 2 grams twice daily for 1 day followed by 1 gram twice daily for 1 day (n = 65, across both dosing groups), or placebo (n = 30), respectively, included headache (17%, 3%) and nausea (8%, 0%).
- Pediatric Patients 1 Month to <12 Years of Age: Adverse events reported in more than 1 subject across the 3 pharmacokinetic and safety studies in children 1 month to <12 years of age were diarrhea (5%), pyrexia (4%), dehydration (2%), herpes simplex (2%), and rhinorrhea (2%). No clinically meaningful changes in laboratory values were observed.
## Postmarketing Experience
- In addition to adverse events reported from clinical trials, the following events have been identified during postmarketing use of valacyclovir hydrochloride. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to valacyclovir hydrochloride.
Facial edema, hypertension, tachycardia.
Acute hypersensitivity reactions including anaphylaxis, angioedema, dyspnea, pruritus, rash, and urticaria.
Aggressive behavior; agitation; ataxia; coma; confusion; decreased consciousness; dysarthria; encephalopathy; mania; and psychosis, including auditory and visual hallucinations, seizures, tremors.
Visual abnormalities.
Diarrhea.
Liver enzyme abnormalities, hepatitis.
Renal failure, renal pain (may be associated with renal failure).
Thrombocytopenia, aplastic anemia, leukocytoclastic vasculitis, TTP/HUS.
Erythema multiforme, rashes including photosensitivity, alopecia.
# Drug Interactions
- No clinically significant drug-drug or drug-food interactions with valacyclovir hydrochloride are known.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category B
- There are no adequate and well-controlled studies of valacyclovir hydrochloride or acyclovir in pregnant women. Based on prospective pregnancy registry data on 749 pregnancies, the overall rate of birth defects in infants exposed to acyclovir in-utero appears similar to the rate for infants in the general population. valacyclovir hydrochloride should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- A prospective epidemiologic registry of acyclovir use during pregnancy was established in 1984 and completed in April 1999. There were 749 pregnancies followed in women exposed to systemic acyclovir during the first trimester of pregnancy resulting in 756 outcomes. The occurrence rate of birth defects approximates that found in the general population. However, the small size of the registry is insufficient to evaluate the risk for less common defects or to permit reliable or definitive conclusions regarding the safety of acyclovir in pregnant women and their developing fetuses.
- Animal reproduction studies performed at oral doses that provided up to 10 and 7 times the human plasma levels during the period of major organogenesis in rats and rabbits, respectively, revealed no evidence of teratogenicity.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Valacyclovir in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Valacyclovir during labor and delivery.
### Nursing Mothers
- Following oral administration of a 500 mg dose of valacyclovir hydrochloride to 5 nursing mothers, peak acyclovir concentrations (Cmax) in breast milk ranged from 0.5 to 2.3 times (median 1.4) the corresponding maternal acyclovir serum concentrations. The acyclovir breast milk AUC ranged from 1.4 to 2.6 times (median 2.2) maternal serum AUC. A 500 mg maternal dosage of valacyclovir hydrochloride twice daily would provide a nursing infant with an oral acyclovir dosage of approximately 0.6 mg/kg/day. This would result in less than 2% of the exposure obtained after administration of a standard neonatal dose of 30 mg/kg/day of intravenous acyclovir to the nursing infant. Unchanged valacyclovir was not detected in maternal serum, breast milk, or infant urine. Caution should be exercised when valacyclovir hydrochloride is administered to a nursing woman.
### Pediatric Use
- Valacyclovir hydrochloride is indicated for treatment of cold sores in pediatric patients ≥12 years of age and for treatment of chickenpox in pediatric patients 2 to <18 years of age.
- The use of valacyclovir hydrochloride for treatment of cold sores is based on 2 double-blind, placebo-controlled clinical trials in healthy adults and adolescents (≥12 years of age) with a history of recurrent cold sores.
- The use of valacyclovir hydrochloride for treatment of chickenpox in pediatric patients 2 to <18 years of age is based on single-dose pharmacokinetic and multiple-dose safety data from an open-label trial with valacyclovir and supported by efficacy and safety data from 3 randomized, double-blind, placebo-controlled trials evaluating oral acyclovir in pediatric patients with chickenpox.
- The efficacy and safety of valacyclovir have not been established in pediatric patients:
- <12 years of age with cold sores
- <18 years of age with genital herpes
- <18 years of age with herpes zoster
- <2 years of age with chickenpox
- for suppressive therapy following neonatal HSV infection.
- The pharmacokinetic profile and safety of valacyclovir oral suspension in children <12 years of age were studied in 3 open-label studies. No efficacy evaluations were conducted in any of the 3 studies.
- Study 1 was a single-dose pharmacokinetic, multiple-dose safety study in 27 pediatric patients 1 to <12 years of age with clinically suspected varicella-zoster virus (VZV) infection.
- Study 2 was a single-dose pharmacokinetic and safety study in pediatric patients 1 month to <6 years of age who had an active herpes virus infection or who were at risk for herpes virus infection. Fifty-seven subjects were enrolled and received a single dose of 25 mg/kg valacyclovir oral suspension. In infants and children 3 months to <6 years of age, this dose provided comparable systemic acyclovir exposures to that from a 1 gram dose of valacyclovir in adults (historical data). In infants 1 month to <3 months of age, mean acyclovir exposures resulting from a 25 mg/kg dose were higher (Cmax: ↑30%, AUC: ↑60%) than acyclovir exposures following a 1 gram dose of valacyclovir in adults. Acyclovir is not approved for suppressive therapy in infants and children following neonatal HSV infections; therefore valacyclovir is not recommended for this indication because efficacy cannot be extrapolated from acyclovir.
- Study 3 was a single-dose pharmacokinetic, multiple-dose safety study in 28 pediatric patients 1 to <12 years of age with clinically suspected HSV infection. None of the children enrolled in this study had genital herpes. Each subject was dosed with valacyclovir oral suspension, 10 mg/kg twice daily for 3 to 5 days. Acyclovir systemic exposures in pediatric patients following valacyclovir oral suspension were compared with historical acyclovir systemic exposures in immunocompetent adults receiving the solid oral dosage form of valacyclovir or acyclovir for the treatment of recurrent genital herpes. The mean projected daily acyclovir systemic exposures in pediatric patients across all age-groups (1 to <12 years of age) were lower (Cmax: ↓20%, AUC: ↓33%) compared with the acyclovir systemic exposures in adults receiving valacyclovir 500 mg twice daily, but were higher (daily AUC: ↑16%) than systemic exposures in adults receiving acyclovir 200 mg 5 times daily. Insufficient data are available to support valacyclovir for the treatment of recurrent genital herpes in this age-group because clinical information on recurrent genital herpes in young children is limited; therefore, extrapolating efficacy data from adults to this population is not possible. Moreover, valacyclovir has not been studied in children 1 to <12 years of age with recurrent genital herpes.
### Geriatic Use
- Of the total number of subjects in clinical studies of valacyclovir hydrochloride, 906 were 65 and over, and 352 were 75 and over. In a clinical study of herpes zoster, the duration of pain after healing (post-herpetic neuralgia) was longer in patients 65 and older compared with younger adults. Elderly patients are more likely to have reduced renal function and require dose reduction. Elderly patients are also more likely to have renal or CNS adverse events.
### Gender
There is no FDA guidance on the use of Valacyclovir with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Valacyclovir with respect to specific racial populations.
### Renal Impairment
- Dosage reduction is recommended when administering Valacyclovir hydrochloride to patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Valacyclovir in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Valacyclovir in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Valacyclovir in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Valacyclovir in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Valacyclovir in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Caution should be exercised to prevent inadvertent overdose. Precipitation of acyclovir in renal tubules may occur when the solubility (2.5 mg/mL) is exceeded in the intratubular fluid.
### Management
- In the event of acute renal failure and anuria, the patient may benefit from hemodialysis until renal function is restored.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Valacyclovir in the drug label.
# Pharmacology
## Mechanism of Action
- Valacyclovir is a nucleoside analogue DNA polymerase inhibitor. Valacyclovir hydrochloride is rapidly converted to acyclovir which has demonstrated antiviral activity against HSV types 1 (HSV-1) and 2 (HSV-2) and VZV both in cell culture and in vivo.
- The inhibitory activity of acyclovir is highly selective due to its affinity for the enzyme thymidine kinase (TK) encoded by HSV and VZV. This viral enzyme converts acyclovir into acyclovir monophosphate, a nucleotide analogue. The monophosphate is further converted into diphosphate by cellular guanylate kinase and into triphosphate by a number of cellular enzymes. In biochemical assays, acyclovir triphosphate inhibits replication of herpes viral DNA. This is accomplished in 3 ways: 1) competitive inhibition of viral DNA polymerase, 2) incorporation and termination of the growing viral DNA chain, and 3) inactivation of the viral DNA polymerase. The greater antiviral activity of acyclovir against HSV compared with VZV is due to its more efficient phosphorylation by the viral TK.
## Structure
- Valacyclovir hydrochloride USP is the hydrochloride salt of the L-valyl ester of the antiviral drug acyclovir.
- Valacyclovir tablets, USP are for oral administration. Each tablet contains valacyclovir hydrochloride USP equivalent to 500 mg or 1 gram valacyclovir and the inactive ingredients croscarmellose sodium, FD&C Blue #2, hydrogenated castor oil, hypromellose, polyethylene glycol, polysorbate 80, starch (corn), and titanium dioxide.
- The chemical name of valacyclovir hydrochloride is L-valine, 2-ethyl ester, monohydrochloride. It has the following structural formula:
- Valacyclovir hydrochloride USP is a white to off-white powder with the molecular formula C13H20N6O4HCl and a molecular weight of 360.80. The maximum solubility in water at 25°C is 174 mg/mL. The pkas for valacyclovir hydrochloride are 1.90, 7.47, and 9.43.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Valacyclovir in the drug label.
## Pharmacokinetics
- The pharmacokinetics of valacyclovir and acyclovir after oral administration of valacyclovir hydrochloride have been investigated in 14 volunteer studies involving 283 adults and in 3 studies involving 112 pediatric subjects from 1 month to <12 years of age.
- Pharmacokinetics in Adults: Absorption and Bioavailability: After oral administration, valacyclovir hydrochloride is rapidly absorbed from the gastrointestinal tract and nearly completely converted to acyclovir and L-valine by first-pass intestinal and/or hepatic metabolism.
- The absolute bioavailability of acyclovir after administration of valacyclovir hydrochloride is 54.5% ± 9.1% as determined following a 1 gram oral dose of valacyclovir hydrochloride and a 350 mg intravenous acyclovir dose to 12 healthy volunteers. Acyclovir bioavailability from the administration of valacyclovir hydrochloride is not altered by administration with food (30 minutes after an 873 Kcal breakfast, which included 51 grams of fat).
- Acyclovir pharmacokinetic parameter estimates following administration of valacyclovir hydrochloride to healthy adult volunteers are presented in Table 3. There was a less than dose-proportional increase in acyclovir maximum concentration (Cmax) and area under the acyclovir concentration-time curve (AUC) after single-dose and multiple-dose administration (4 times daily) of valacyclovir hydrochloride from doses between 250 mg to 1 gram.
- There is no accumulation of acyclovir after the administration of valacyclovir at the recommended dosage regimens in adults with normal renal function.
- Distribution
- The binding of valacyclovir to human plasma proteins ranges from 13.5% to 17.9%. The binding of acyclovir to human plasma proteins ranges from 9% to 33%.
- Metabolism
- Valacyclovir is converted to acyclovir and L-valine by first-pass intestinal and/or hepatic metabolism. Acyclovir is converted to a small extent to inactive metabolites by aldehyde oxidase and by alcohol and aldehyde dehydrogenase. Neither valacyclovir nor acyclovir is metabolized by cytochrome P450 enzymes. Plasma concentrations of unconverted valacyclovir are low and transient, generally becoming non-quantifiable by 3 hours after administration. Peak plasma valacyclovir concentrations are generally less than 0.5 mcg/mL at all doses. After single-dose administration of 1 gram of valacyclovir hydrochloride, average plasma valacyclovir concentrations observed were 0.5, 0.4, and 0.8 mcg/mL in patients with hepatic dysfunction, renal insufficiency, and in healthy volunteers who received concomitant cimetidine and probenecid, respectively.
- Elimination
- The pharmacokinetic disposition of acyclovir delivered by valacyclovir is consistent with previous experience from intravenous and oral acyclovir. Following the oral administration of a single 1 gram dose of radiolabeled valacyclovir to 4 healthy subjects, 46% and 47% of administered radioactivity was recovered in urine and feces, respectively, over 96 hours. Acyclovir accounted for 89% of the radioactivity excreted in the urine. Renal clearance of acyclovir following the administration of a single 1 gram dose of valacyclovir hydrochloride to 12 healthy volunteers was approximately 255 ± 86 mL/min which represents 42% of total acyclovir apparent plasma clearance.
- The plasma elimination half-life of acyclovir typically averaged 2.5 to 3.3 hours in all studies of valacyclovir hydrochloride in volunteers with normal renal function.
- Specific Populations
- Renal Impairment: Reduction in dosage is recommended in patients with renal impairment.
- Following administration of valacyclovir hydrochloride to volunteers with ESRD, the average acyclovir half-life is approximately 14 hours. During hemodialysis, the acyclovir half-life is approximately 4 hours. Approximately one third of acyclovir in the body is removed by dialysis during a 4-hour hemodialysis session. Apparent plasma clearance of acyclovir in dialysis patients was 86.3 ± 21.3 mL/min/1.73 m2 compared with 679.16 ± 162.76 mL/min/1.73 m2 in healthy volunteers.
- Hepatic Impairment
- Administration of valacyclovir hydrochloride to patients with moderate (biopsy-proven cirrhosis) or severe (with and without ascites and biopsy-proven cirrhosis) liver disease indicated that the rate but not the extent of conversion of valacyclovir to acyclovir is reduced, and the acyclovir half-life is not affected. Dosage modification is not recommended for patients with cirrhosis.
- HIV Disease
- In 9 patients with HIV disease and CD4+ cell counts <150 cells/mm3 who received valacyclovir hydrochloride at a dosage of 1 gram 4 times daily for 30 days, the pharmacokinetics of valacyclovir and acyclovir were not different from that observed in healthy volunteers.
- Geriatrics
- After single-dose administration of 1 gram of valacyclovir hydrochloride in healthy geriatric volunteers, the half-life of acyclovir was 3.11 ± 0.51 hours, compared with 2.91 ± 0.63 hours in healthy younger adult volunteers. The pharmacokinetics of acyclovir following single- and multiple-dose oral administration of valacyclovir hydrochloride in geriatric volunteers varied with renal function. Dose reduction may be required in geriatric patients, depending on the underlying renal status of the patient.
- Pediatrics
- Acyclovir pharmacokinetics have been evaluated in a total of 98 pediatric patients (1 month to <12 years of age) following administration of the first dose of an extemporaneous oral suspension of valacyclovir. Acyclovir pharmacokinetic parameter estimates following a 20 mg/kg dose are provided in Table 4.
- Drug Interactions
- When valacyclovir hydrochloride is coadministered with antacids, cimetidine and/or probenicid, digoxin, or thiazide diuretics in patients with normal renal function, the effects are not considered to be of clinical significance (see below). Therefore, when valacyclovir hydrochloride is coadministered with these drugs in patients with normal renal function, no dosage adjustment is recommended.
- Antacids
- The pharmacokinetics of acyclovir after a single dose of valacyclovir hydrochloride (1 gram) were unchanged by coadministration of a single dose of antacids (Al3+ or Mg++).
- Cimetidine
- Acyclovir Cmax and AUC following a single dose of valacyclovir hydrochloride (1 gram) increased by 8% and 32%, respectively, after a single dose of cimetidine (800 mg).
- Cimetidine Plus Probenecid
- Acyclovir Cmax and AUC following a single dose of valacyclovir hydrochloride (1 gram) increased by 30% and 78%, respectively, after a combination of cimetidine and probenecid, primarily due to a reduction in renal clearance of acyclovir.
- Digoxin
- The pharmacokinetics of digoxin were not affected by coadministration of valacyclovir hydrochloride 1 gram 3 times daily, and the pharmacokinetics of acyclovir after a single dose of valacyclovir hydrochloride (1 gram) was unchanged by coadministration of digoxin (2 doses of 0.75 mg).
- Probenecid
- Acyclovir Cmax and AUC following a single dose of valacyclovir hydrochloride (1 gram) increased by 22% and 49%, respectively, after probenecid (1 gram).
- Thiazide Diuretics
- The pharmacokinetics of acyclovir after a single dose of valacyclovir hydrochloride (1 gram) were unchanged by coadministration of multiple doses of thiazide diuretics.
### Microbiology
- Antiviral Activities
- The quantitative relationship between the cell culture susceptibility of herpes viruses to antivirals and the clinical response to therapy has not been established in humans, and virus sensitivity testing has not been standardized. Sensitivity testing results, expressed as the concentration of drug required to inhibit by 50% the growth of virus in cell culture (EC50), vary greatly depending upon a number of factors. Using plaque-reduction assays, the EC50 values against herpes simplex virus isolates range from 0.09 to 60 μM (0.02 to 13.5 mcg/mL) for HSV-1 and from 0.04 to 44 μM (0.01 to 9.9 mcg/mL) for HSV-2. The EC50 values for acyclovir against most laboratory strains and clinical isolates of VZV range from 0.53 to 48 μM (0.12 to 10.8 mcg/mL). Acyclovir also demonstrates activity against the Oka vaccine strain of VZV with a mean EC50 of 6 μM (1.35 mcg/mL).
- Resistance
- Resistance of HSV and VZV to acyclovir can result from qualitative and quantitative changes in the viral TK and/or DNA polymerase. Clinical isolates of VZV with reduced susceptibility to acyclovir have been recovered from patients with AIDS. In these cases, TK-deficient mutants of VZV have been recovered.
- Resistance of HSV and VZV to acyclovir occurs by the same mechanisms. While most of the acyclovir-resistant mutants isolated thus far from immunocompromised patients have been found to be TK-deficient mutants, other mutants involving the viral TK gene (TK partial and TK altered) and DNA polymerase have also been isolated. TK-negative mutants may cause severe disease in immunocompromised patients. The possibility of viral resistance to valacyclovir (and therefore, to acyclovir) should be considered in patients who show poor clinical response during therapy.
## Nonclinical Toxicology
- The data presented below include references to the steady-state acyclovir AUC observed in humans treated with 1 gram valacyclovir hydrochloride given orally 3 times a day to treat herpes zoster. Plasma drug concentrations in animal studies are expressed as multiples of human exposure to acyclovir.
- Valacyclovir was noncarcinogenic in lifetime carcinogenicity bioassays at single daily doses (gavage) of valacyclovir giving plasma acyclovir concentrations equivalent to human levels in the mouse bioassay and 1.4 to 2.3 times human levels in the rat bioassay. There was no significant difference in the incidence of tumors between treated and control animals, nor did valacyclovir shorten the latency of tumors.
- Valacyclovir was tested in 5 genetic toxicity assays. An Ames assay was negative in the absence or presence of metabolic activation. Also negative were an in vitro cytogenetic study with human lymphocytes and a rat cytogenetic study.
- In the mouse lymphoma assay, valacyclovir was not mutagenic in the absence of metabolic activation. In the presence of metabolic activation (76% to 88% conversion to acyclovir), valacyclovir was mutagenic.
- Valacyclovir was mutagenic in a mouse micronucleus assay.
- Valacyclovir did not impair fertility or reproduction in rats at 6 times human plasma levels.
# Clinical Studies
### Cold Sores (Herpes Labialis)
- Two double-blind, placebo-controlled clinical trials were conducted in 1,856 healthy adults and adolescents (≥12 years old) with a history of recurrent cold sores. Patients self-initiated therapy at the earliest symptoms and prior to any signs of a cold sore. The majority of patients initiated treatment within 2 hours of onset of symptoms. Patients were randomized to valacyclovir hydrochloride 2 grams twice daily on Day 1 followed by placebo on Day 2, valacyclovir hydrochloride 2 grams twice daily on Day 1 followed by 1 gram twice daily on Day 2, or placebo on Days 1 and 2.
- The mean duration of cold sore episodes was about 1 day shorter in treated subjects as compared with placebo. The 2 day regimen did not offer additional benefit over the 1-day regimen.
- No significant difference was observed between subjects receiving valacyclovir hydrochloride or placebo in the prevention of progression of cold sore lesions beyond the papular stage.
### Genital Herpes Infections
- Initial Episode: Six hundred forty-three immunocompetent adults with first-episode genital herpes who presented within 72 hours of symptom onset were randomized in a double-blind trial to receive 10 days of valacyclovir hydrochloride 1 gram twice daily (n = 323) or oral acyclovir 200 mg 5 times a day (n = 320). For both treatment groups: the median time to lesion healing was 9 days, the median time to cessation of pain was 5 days, the median time to cessation of viral shedding was 3 days.
- Recurrent Episodes: Three double-blind trials (2 of them placebo-controlled) in immunocompetent adults with recurrent genital herpes were conducted. Patients self-initiated therapy within 24 hours of the first sign or symptom of a recurrent genital herpes episode.
- In 1 study, patients were randomized to receive 5 days of treatment with either valacyclovir hydrochloride 500 mg twice daily (n = 360) or placebo (n = 259). The median time to lesion healing was 4 days in the group receiving valacyclovir hydrochloride 500 mg versus 6 days in the placebo group, and the median time to cessation of viral shedding in patients with at least 1 positive culture (42% of the overall study population) was 2 days in the group receiving valacyclovir hydrochloride 500 mg versus 4 days in the placebo group. The median time to cessation of pain was 3 days in the group receiving valacyclovir hydrochloride 500 mg versus 4 days in the placebo group. Results supporting efficacy were replicated in a second trial.
- In a third study, patients were randomized to receive valacyclovir hydrochloride 500 mg twice daily for 5 days (n = 398) or valacyclovir hydrochloride 500 mg twice daily for 3 days (and matching placebo twice daily for 2 additional days) (n = 402). The median time to lesion healing was about 4½ days in both treatment groups. The median time to cessation of pain was about 3 days in both treatment groups.
- Suppressive Therapy: Two clinical studies were conducted, one in immunocompetent adults and one in HIV-infected adults.
- A double-blind, 12-month, placebo- and active-controlled study enrolled immunocompetent adults with a history of 6 or more recurrences per year. Outcomes for the overall study population are shown in Table 5.
- Subjects with 9 or fewer recurrences per year showed comparable results with valacyclovir hydrochloride 500 mg once daily.
- In a second study, 293 HIV-infected adults on stable antiretroviral therapy with a history of 4 or more recurrences of ano-genital herpes per year were randomized to receive either valacyclovir hydrochloride 500 mg twice daily (n = 194) or matching placebo (n = 99) for 6 months. The median duration of recurrent genital herpes in enrolled subjects was 8 years, and the median number of recurrences in the year prior to enrollment was 5. Overall, the median prestudy HIV-1 RNA was 2.6 log10 copies/mL. Among patients who received valacyclovir hydrochloride, the prestudy median CD4+ cell count was 336 cells/mm3; 11% had <100 cells/mm3, 16% had 100 to 199 cells/mm3, 42% had 200 to 499 cells/mm3, and 31% had ≥500 cells/mm3. Outcomes for the overall study population are shown in Table 6.
- Reduction of Transmission of Genital Herpes: A double-blind, placebo-controlled study to assess transmission of genital herpes was conducted in 1,484 monogamous, heterosexual, immunocompetent adult couples. The couples were discordant for HSV-2 infection. The source partner had a history of 9 or fewer genital herpes episodes per year. Both partners were counseled on safer sex practices and were advised to use condoms throughout the study period. Source partners were randomized to treatment with either valacyclovir hydrochloride 500 mg once daily or placebo once daily for 8 months. The primary efficacy endpoint was symptomatic acquisition of HSV-2 in susceptible partners. Overall HSV-2 acquisition was defined as symptomatic HSV-2 acquisition and/or HSV-2 seroconversion in susceptible partners. The efficacy results are summarized in Table 7.
### Herpes Zoster
- Two randomized double-blind clinical trials in immunocompetent adults with localized herpes zoster were conducted. Valacyclovir hydrochloride was compared with placebo in patients less than 50 years of age, and with oral acyclovir in patients greater than 50 years of age. All patients were treated within 72 hours of appearance of zoster rash. In patients less than 50 years of age, the median time to cessation of new lesion formation was 2 days for those treated with valacyclovir hydrochloride compared with 3 days for those treated with placebo. In patients greater than 50 years of age, the median time to cessation of new lesions was 3 days in patients treated with either valacyclovir hydrochloride or oral acyclovir. In patients less than 50 years of age, no difference was found with respect to the duration of pain after healing (post-herpetic neuralgia) between the recipients of valacyclovir hydrochloride and placebo. In patients greater than 50 years of age, among the 83% who reported pain after healing (post-herpetic neuralgia), the median duration of pain after healing in days was: 40 , 43 , and 59 for 7-day valacyclovir hydrochloride, 14-day valacyclovir hydrochloride, and 7-day oral acyclovir, respectively.
### Chickenpox
- The use of valacyclovir hydrochloride for treatment of chickenpox in pediatric patients 2 to <18 years of age is based on single-dose pharmacokinetic and multiple-dose safety data from an open-label trial with valacyclovir and supported by safety and extrapolated efficacy data from 3 randomized, double-blind, placebo-controlled trials evaluating oral acyclovir in pediatric patients.
- The single-dose pharmacokinetic and multiple-dose safety study enrolled 27 pediatric patients 1 to <12 years of age with clinically suspected VZV infection. Each subject was dosed with valacyclovir oral suspension, 20 mg/kg 3 times daily for 5 days. Acyclovir systemic exposures in pediatric patients following valacyclovir oral suspension were compared with historical acyclovir systemic exposures in immunocompetent adults receiving the solid oral dosage form of valacyclovir or acyclovir for the treatment of herpes zoster. The mean projected daily acyclovir exposures in pediatric patients across all age-groups (1 to <12 years of age) were lower (Cmax: ↓13%, AUC: ↓30%) than the mean daily historical exposures in adults receiving valacyclovir 1 gram 3 times daily, but were higher (daily AUC: ↑50%) than the mean daily historical exposures in adults receiving acyclovir 800 mg 5 times daily. The projected daily exposures in pediatric patients were greater (daily AUC approximately 100% greater) than the exposures seen in immunocompetent pediatric patients receiving acyclovir 20 mg/kg 4 times daily for the treatment of chickenpox. Based on the pharmacokinetic and safety data from this study and the safety and extrapolated efficacy data from the acyclovir studies, oral valacyclovir 20 mg/kg 3 times a day for 5 days (not to exceed 1 gram 3 times daily) is recommended for the treatment of chickenpox in pediatric patients 2 to <18 years of age. Because the efficacy and safety of acyclovir for the treatment of chickenpox in children <2 years of age have not been established, efficacy data cannot be extrapolated to support valacyclovir treatment in children <2 years of age with chickenpox. Valacyclovir is also not recommended for the treatment of herpes zoster in children because safety data up to 7 days' duration are not available.
# How Supplied
- Valacyclovir tablets, USP (blue, film-coated, capsule-shaped, biconvex tablets) containing valacyclovir hydrochloride equivalent to 500 mg valacyclovir and debossed with "CIPLA" on one side and "153" on the other side.
- Bottle of 30 (NDC 69097-153-02).
- Bottle of 90 (NDC 69097-153-05).
- Bottle of 500 (NDC 69097-153-12).
- Valacyclovir tablets, USP (blue, film-coated, capsule-shaped, biconvex tablets), with a partial scorebar on both sides) containing valacyclovir hydrochloride equivalent to 1 gram valacyclovir and debossed with "CIPLA"on one side and "154" on the other side.
- Bottle of 30 (NDC 69097-154-02).
- Bottle of 90 (NDC 69097-154-05).
- Bottle of 500 (NDC 69097-154-12).
- Storage
- Store at 20°C to 25°C (68°F to 77°F). Dispense in a well-closed container as defined in the USP.
## Storage
There is limited information regarding Valacyclovir Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Importance of Adequate Hydration
- Patients should be advised to maintain adequate hydration.
- Cold Sores (Herpes Labialis)
- Patients should be advised to initiate treatment at the earliest symptom of a cold sore (e.g., tingling, itching, or burning). There are no data on the effectiveness of treatment initiated after the development of clinical signs of a cold sore (e.g., papule, vesicle, or ulcer). Patients should be instructed that treatment for cold sores should not exceed 1 day (2 doses) and that their doses should be taken about 12 hours apart. Patients should be informed that valacyclovir hydrochloride is not a cure for cold sores.
- Genital Herpes
- Patients should be informed that valacyclovir hydrochloride is not a cure for genital herpes. Because genital herpes is a sexually transmitted disease, patients should avoid contact with lesions or intercourse when lesions and/or symptoms are present to avoid infecting partners. Genital herpes is frequently transmitted in the absence of symptoms through asymptomatic viral shedding. Therefore, patients should be counseled to use safer sex practices in combination with suppressive therapy with valacyclovir hydrochloride. Sex partners of infected persons should be advised that they might be infected even if they have no symptoms. Type-specific serologic testing of asymptomatic partners of persons with genital herpes can determine whether risk for HSV-2 acquisition exists.
- Valacyclovir hydrochloride has not been shown to reduce transmission of sexually transmitted infections other than HSV-2.
- If medical management of a genital herpes recurrence is indicated, patients should be advised to initiate therapy at the first sign or symptom of an episode.
- There are no data on the effectiveness of treatment initiated more than 72 hours after the onset of signs and symptoms of a first episode of genital herpes or more than 24 hours after the onset of signs and symptoms of a recurrent episode.
- There are no data on the safety or effectiveness of chronic suppressive therapy of more than 1 year's duration in otherwise healthy patients. There are no data on the safety or effectiveness of chronic suppressive therapy of more than 6 months' duration in HIV-infected patients.
- Herpes Zoster
- There are no data on treatment initiated more than 72 hours after onset of the zoster rash. Patients should be advised to initiate treatment as soon as possible after a diagnosis of herpes zoster.
- Chickenpox
- Patients should be advised to initiate treatment at the earliest sign or symptom of chickenpox.
# Precautions with Alcohol
- Alcohol-Valacyclovir interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- VALACYCLOVIR HYDROCHLORIDE®
# Look-Alike Drug Names
- Valtrex® — Keflex®
- valacyclovir® — valganciclovir®
- Valtrex® — Valcyte®
# Drug Shortage Status
# Price | Valacyclovir
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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# Overview
Valacyclovir is a nucleoside analogue DNA polymerase inhibitor that is FDA approved for the treatment of cold sores (herpes labialis), genital herpes, and herpes zoster. Common adverse reactions include headache, nausea, and abdominal pain.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- The recommended dosage of valacyclovir hydrochloride for treatment of cold sores is 2 grams twice daily for 1 day taken 12 hours apart. Therapy should be initiated at the earliest symptom of a cold sore (e.g., tingling, itching, or burning).
- Initial Episode: The recommended dosage of valacyclovir hydrochloride for treatment of initial genital herpes is 1 gram twice daily for 10 days. Therapy was most effective when administered within 48 hours of the onset of signs and symptoms.
- Recurrent Episodes: The recommended dosage of valacyclovir hydrochloride for treatment of recurrent genital herpes is 500 mg twice daily for 3 days. Initiate treatment at the first sign or symptom of an episode.
- Suppressive Therapy: The recommended dosage of valacyclovir hydrochloride for chronic suppressive therapy of recurrent genital herpes is 1 gram once daily in patients with normal immune function. In patients with a history of 9 or fewer recurrences per year, an alternative dose is 500 mg once daily.
- In HIV-infected patients with a CD4+ cell count ≥100 cells/mm3, the recommended dosage of valacyclovir hydrochloride for chronic suppressive therapy of recurrent genital herpes is 500 mg twice daily.
- Reduction of Transmission: The recommended dosage of valacyclovir hydrochloride for reduction of transmission of genital herpes in patients with a history of 9 or fewer recurrences per year is 500 mg once daily for the source partner.
- The recommended dosage of valacyclovir hydrochloride for treatment of herpes zoster is 1 gram 3 times daily for 7 days. Therapy should be initiated at the earliest sign or symptom of herpes zoster and is most effective when started within 48 hours of the onset of rash.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Valacyclovir in adult patients.
### Non–Guideline-Supported Use
- Oral valacyclovir 1 g 3 times a day.[1]
- Prophylaxis with valacyclovir 2000 mg orally 4 times daily for 18 weeks after bone marrow transplantation.
- Valacyclovir for 5 to 14 days.[2]
- Oral valacyclovir for 5 to 10 days.[2]
- 14-day course of valacyclovir 500 mg orally twice daily.
- 7-day oral regimen of valacyclovir 1 g 3 times daily.[3]
- Valacyclovir is a recommended option for uncomplicated chickenpox in adults with HIV.[2]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- The recommended dosage of valacyclovir hydrochloride for the treatment of cold sores in pediatric patients ≥12 years of age is 2 grams twice daily for 1 day taken 12 hours apart. Therapy should be initiated at the earliest symptom of a cold sore (e.g., tingling, itching, or burning).
- The recommended dosage of valacyclovir hydrochloride for treatment of chickenpox in immunocompetent pediatric patients 2 to <18 years of age is 20 mg/kg administered 3 times daily for 5 days. The total dose should not exceed 1 gram 3 times daily. Therapy should be initiated at the earliest sign or symptom.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Valacyclovir in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Valacyclovir in pediatric patients.
# Contraindications
- Valacyclovir hydrochloride is contraindicated in patients who have had a demonstrated clinically significant hypersensitivity reaction (e.g., anaphylaxis) to valacyclovir, acyclovir, or any component of the formulation.
# Warnings
### Precautions
- Thrombotic Thrombocytopenic Purpura/Hemolytic Uremic Syndrome (TTP/HUS)
- TTP/HUS, in some cases resulting in death, has occurred in patients with advanced HIV disease and also in allogeneic bone marrow transplant and renal transplant recipients participating in clinical trials of Valacyclovir hydrochloride at doses of 8 grams per day. Treatment with Valacyclovir hydrochloride should be stopped immediately if clinical signs, symptoms, and laboratory abnormalities consistent with TTP/HUS occur.
- Acute Renal Failure
- Cases of acute renal failure have been reported in:
Elderly patients with or without reduced renal function. Caution should be exercised when administering valacyclovir hydrochloride to geriatric patients, and dosage reduction is recommended for those with impaired renal function.
Patients with underlying renal disease who received higher than recommended doses of valacyclovir hydrochloride for their level of renal function. Dosage reduction is recommended when administering valacyclovir hydrochloride to patients with renal impairment.
Patients receiving other nephrotoxic drugs. Caution should be exercised when administering valacyclovir hydrochloride to patients receiving potentially nephrotoxic drugs.
Patients without adequate hydration. Precipitation of acyclovir in renal tubules may occur when the solubility (2.5 mg/mL) is exceeded in the intratubular fluid. Adequate hydration should be maintained for all patients.
- Elderly patients with or without reduced renal function. Caution should be exercised when administering valacyclovir hydrochloride to geriatric patients, and dosage reduction is recommended for those with impaired renal function.
- Patients with underlying renal disease who received higher than recommended doses of valacyclovir hydrochloride for their level of renal function. Dosage reduction is recommended when administering valacyclovir hydrochloride to patients with renal impairment.
- Patients receiving other nephrotoxic drugs. Caution should be exercised when administering valacyclovir hydrochloride to patients receiving potentially nephrotoxic drugs.
- Patients without adequate hydration. Precipitation of acyclovir in renal tubules may occur when the solubility (2.5 mg/mL) is exceeded in the intratubular fluid. Adequate hydration should be maintained for all patients.
- In the event of acute renal failure and anuria, the patient may benefit from hemodialysis until renal function is restored.
- Central Nervous System Effects
- Central nervous system adverse reactions, including agitation, hallucinations, confusion, delirium, seizures, and encephalopathy, have been reported in both adult and pediatric patients with or without reduced renal function and in patients with underlying renal disease who received higher than recommended doses of valacyclovir hydrochloride for their level of renal function. Elderly patients are more likely to have central nervous system adverse reactions. Valacyclovir hydrochloride should be discontinued if central nervous system adverse reactions occur.
# 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 with rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- Cold Sores (Herpes Labialis): In clinical studies for the treatment of cold sores, the adverse reactions reported by patients receiving valacyclovir hydrochloride 2 grams twice daily (n = 609) or placebo (n = 609) for 1 day, respectively, included headache (14%, 10%) and dizziness (2%, 1%). The frequencies of abnormal ALT (>2 x ULN) were 1.8% for patients receiving valacyclovir hydrochloride compared with 0.8% for placebo. Other laboratory abnormalities (hemoglobin, white blood cells, alkaline phosphatase, and serum creatinine) occurred with similar frequencies in the 2 groups.
- Genital Herpes: Initial Episode: In a clinical study for the treatment of initial episodes of genital herpes, the adverse reactions reported by ≥5% of patients receiving valacyclovir hydrochloride 1 gram twice daily for 10 days (n = 318) or oral acyclovir 200 mg 5 times daily for 10 days (n = 318), respectively, included headache (13%, 10%) and nausea (6%, 6%). For the incidence of laboratory abnormalities see Table 2.
- Recurrent Episodes: In 3 clinical studies for the episodic treatment of recurrent genital herpes, the adverse reactions reported by ≥5% of patients receiving valacyclovir hydrochloride 500 mg twice daily for 3 days (n = 402), valacyclovir hydrochloride 500 mg twice daily for 5 days (n = 1,136) or placebo (n = 259), respectively, included headache (16%, 11%, 14%) and nausea (5%, 4%, 5%).
- For the incidence of laboratory abnormalities see Table 2.
- Suppressive Therapy: Suppression of Recurrent Genital Herpes in Immunocompetent Adults: In a clinical study for the suppression of recurrent genital herpes infections, the adverse reactions reported by patients receiving valacyclovir hydrochloride 1 gram once daily (n = 269), valacyclovir hydrochloride 500 mg once daily (n = 266), or placebo (n = 134), respectively, included headache (35%, 38%, 34%), nausea (11%, 11%, 8%), abdominal pain (11%, 9%, 6%), dysmenorrhea (8%, 5%, 4%), depression (7%, 5%, 5%), arthralgia (6%, 5%, 4%), vomiting (3%, 3%, 2%), and dizziness (4%, 2%, 1%). For the incidence of laboratory abnormalities see Table 2.
- Suppression of Recurrent Genital Herpes in HIV-Infected Patients: In HIV-infected patients, frequently reported adverse reactions for valacyclovir hydrochloride (500 mg twice daily; n = 194, median days on therapy = 172) and placebo (n = 99, median days on therapy = 59), respectively, included headache (13%, 8%), fatigue (8%, 5%), and rash (8%, 1%). Post-randomization laboratory abnormalities that were reported more frequently in valacyclovir subjects versus placebo included elevated alkaline phosphatase (4%, 2%), elevated ALT (14%, 10%), elevated AST (16%, 11%), decreased neutrophil counts (18%, 10%), and decreased platelet counts (3%, 0%), respectively.
- Reduction of Transmission: In a clinical study for the reduction of transmission of genital herpes, the adverse reactions reported by patients receiving valacyclovir hydrochloride 500 mg once daily (n = 743) or placebo once daily (n = 741), respectively, included headache (29%, 26%), nasopharyngitis (16%, 15%), and upper respiratory tract infection (9%, 10%).
- Herpes Zoster: In 2 clinical studies for the treatment of herpes zoster, the adverse reactions reported by patients receiving valacyclovir hydrochloride 1 gram 3 times daily for 7 to 14 days (n = 967) or placebo (n = 195), respectively, included nausea (15%, 8%), headache (14%, 12%), vomiting (6%, 3%), dizziness (3%, 2%), and abdominal pain (3%, 2%). For the incidence of laboratory abnormalities see Table 2.
- The safety profile of valacyclovir hydrochloride has been studied in 177 pediatric patients 1 month to <18 years of age. Sixty-five of these pediatric patients, 12 to <18 years of age, received oral tablets for 1 to 2 days for treatment of cold sores. The remaining 112 pediatric patients, 1 month to <12 years of age, participated in 3 pharmacokinetic and safety studies and received valacyclovir oral suspension. Fifty-one of these 112 pediatric patients received oral suspension for 3 to 6 days. The frequency, intensity, and nature of clinical adverse reactions and laboratory abnormalities were similar to those seen in adults.
- Pediatric Patients 12 to <18 Years of Age (Cold Sores): In clinical studies for the treatment of cold sores, the adverse reactions reported by adolescent patients receiving valacyclovir hydrochloride 2 grams twice daily for 1 day, or valacyclovir hydrochloride 2 grams twice daily for 1 day followed by 1 gram twice daily for 1 day (n = 65, across both dosing groups), or placebo (n = 30), respectively, included headache (17%, 3%) and nausea (8%, 0%).
- Pediatric Patients 1 Month to <12 Years of Age: Adverse events reported in more than 1 subject across the 3 pharmacokinetic and safety studies in children 1 month to <12 years of age were diarrhea (5%), pyrexia (4%), dehydration (2%), herpes simplex (2%), and rhinorrhea (2%). No clinically meaningful changes in laboratory values were observed.
## Postmarketing Experience
- In addition to adverse events reported from clinical trials, the following events have been identified during postmarketing use of valacyclovir hydrochloride. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to valacyclovir hydrochloride.
Facial edema, hypertension, tachycardia.
Acute hypersensitivity reactions including anaphylaxis, angioedema, dyspnea, pruritus, rash, and urticaria.
Aggressive behavior; agitation; ataxia; coma; confusion; decreased consciousness; dysarthria; encephalopathy; mania; and psychosis, including auditory and visual hallucinations, seizures, tremors.
Visual abnormalities.
Diarrhea.
Liver enzyme abnormalities, hepatitis.
Renal failure, renal pain (may be associated with renal failure).
Thrombocytopenia, aplastic anemia, leukocytoclastic vasculitis, TTP/HUS.
Erythema multiforme, rashes including photosensitivity, alopecia.
# Drug Interactions
- No clinically significant drug-drug or drug-food interactions with valacyclovir hydrochloride are known.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category B
- There are no adequate and well-controlled studies of valacyclovir hydrochloride or acyclovir in pregnant women. Based on prospective pregnancy registry data on 749 pregnancies, the overall rate of birth defects in infants exposed to acyclovir in-utero appears similar to the rate for infants in the general population. valacyclovir hydrochloride should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- A prospective epidemiologic registry of acyclovir use during pregnancy was established in 1984 and completed in April 1999. There were 749 pregnancies followed in women exposed to systemic acyclovir during the first trimester of pregnancy resulting in 756 outcomes. The occurrence rate of birth defects approximates that found in the general population. However, the small size of the registry is insufficient to evaluate the risk for less common defects or to permit reliable or definitive conclusions regarding the safety of acyclovir in pregnant women and their developing fetuses.
- Animal reproduction studies performed at oral doses that provided up to 10 and 7 times the human plasma levels during the period of major organogenesis in rats and rabbits, respectively, revealed no evidence of teratogenicity.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Valacyclovir in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Valacyclovir during labor and delivery.
### Nursing Mothers
- Following oral administration of a 500 mg dose of valacyclovir hydrochloride to 5 nursing mothers, peak acyclovir concentrations (Cmax) in breast milk ranged from 0.5 to 2.3 times (median 1.4) the corresponding maternal acyclovir serum concentrations. The acyclovir breast milk AUC ranged from 1.4 to 2.6 times (median 2.2) maternal serum AUC. A 500 mg maternal dosage of valacyclovir hydrochloride twice daily would provide a nursing infant with an oral acyclovir dosage of approximately 0.6 mg/kg/day. This would result in less than 2% of the exposure obtained after administration of a standard neonatal dose of 30 mg/kg/day of intravenous acyclovir to the nursing infant. Unchanged valacyclovir was not detected in maternal serum, breast milk, or infant urine. Caution should be exercised when valacyclovir hydrochloride is administered to a nursing woman.
### Pediatric Use
- Valacyclovir hydrochloride is indicated for treatment of cold sores in pediatric patients ≥12 years of age and for treatment of chickenpox in pediatric patients 2 to <18 years of age.
- The use of valacyclovir hydrochloride for treatment of cold sores is based on 2 double-blind, placebo-controlled clinical trials in healthy adults and adolescents (≥12 years of age) with a history of recurrent cold sores.
- The use of valacyclovir hydrochloride for treatment of chickenpox in pediatric patients 2 to <18 years of age is based on single-dose pharmacokinetic and multiple-dose safety data from an open-label trial with valacyclovir and supported by efficacy and safety data from 3 randomized, double-blind, placebo-controlled trials evaluating oral acyclovir in pediatric patients with chickenpox.
- The efficacy and safety of valacyclovir have not been established in pediatric patients:
- <12 years of age with cold sores
- <18 years of age with genital herpes
- <18 years of age with herpes zoster
- <2 years of age with chickenpox
- for suppressive therapy following neonatal HSV infection.
- The pharmacokinetic profile and safety of valacyclovir oral suspension in children <12 years of age were studied in 3 open-label studies. No efficacy evaluations were conducted in any of the 3 studies.
- Study 1 was a single-dose pharmacokinetic, multiple-dose safety study in 27 pediatric patients 1 to <12 years of age with clinically suspected varicella-zoster virus (VZV) infection.
- Study 2 was a single-dose pharmacokinetic and safety study in pediatric patients 1 month to <6 years of age who had an active herpes virus infection or who were at risk for herpes virus infection. Fifty-seven subjects were enrolled and received a single dose of 25 mg/kg valacyclovir oral suspension. In infants and children 3 months to <6 years of age, this dose provided comparable systemic acyclovir exposures to that from a 1 gram dose of valacyclovir in adults (historical data). In infants 1 month to <3 months of age, mean acyclovir exposures resulting from a 25 mg/kg dose were higher (Cmax: ↑30%, AUC: ↑60%) than acyclovir exposures following a 1 gram dose of valacyclovir in adults. Acyclovir is not approved for suppressive therapy in infants and children following neonatal HSV infections; therefore valacyclovir is not recommended for this indication because efficacy cannot be extrapolated from acyclovir.
- Study 3 was a single-dose pharmacokinetic, multiple-dose safety study in 28 pediatric patients 1 to <12 years of age with clinically suspected HSV infection. None of the children enrolled in this study had genital herpes. Each subject was dosed with valacyclovir oral suspension, 10 mg/kg twice daily for 3 to 5 days. Acyclovir systemic exposures in pediatric patients following valacyclovir oral suspension were compared with historical acyclovir systemic exposures in immunocompetent adults receiving the solid oral dosage form of valacyclovir or acyclovir for the treatment of recurrent genital herpes. The mean projected daily acyclovir systemic exposures in pediatric patients across all age-groups (1 to <12 years of age) were lower (Cmax: ↓20%, AUC: ↓33%) compared with the acyclovir systemic exposures in adults receiving valacyclovir 500 mg twice daily, but were higher (daily AUC: ↑16%) than systemic exposures in adults receiving acyclovir 200 mg 5 times daily. Insufficient data are available to support valacyclovir for the treatment of recurrent genital herpes in this age-group because clinical information on recurrent genital herpes in young children is limited; therefore, extrapolating efficacy data from adults to this population is not possible. Moreover, valacyclovir has not been studied in children 1 to <12 years of age with recurrent genital herpes.
### Geriatic Use
- Of the total number of subjects in clinical studies of valacyclovir hydrochloride, 906 were 65 and over, and 352 were 75 and over. In a clinical study of herpes zoster, the duration of pain after healing (post-herpetic neuralgia) was longer in patients 65 and older compared with younger adults. Elderly patients are more likely to have reduced renal function and require dose reduction. Elderly patients are also more likely to have renal or CNS adverse events.
### Gender
There is no FDA guidance on the use of Valacyclovir with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Valacyclovir with respect to specific racial populations.
### Renal Impairment
- Dosage reduction is recommended when administering Valacyclovir hydrochloride to patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Valacyclovir in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Valacyclovir in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Valacyclovir in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Valacyclovir in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Valacyclovir in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Caution should be exercised to prevent inadvertent overdose. Precipitation of acyclovir in renal tubules may occur when the solubility (2.5 mg/mL) is exceeded in the intratubular fluid.
### Management
- In the event of acute renal failure and anuria, the patient may benefit from hemodialysis until renal function is restored.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Valacyclovir in the drug label.
# Pharmacology
## Mechanism of Action
- Valacyclovir is a nucleoside analogue DNA polymerase inhibitor. Valacyclovir hydrochloride is rapidly converted to acyclovir which has demonstrated antiviral activity against HSV types 1 (HSV-1) and 2 (HSV-2) and VZV both in cell culture and in vivo.
- The inhibitory activity of acyclovir is highly selective due to its affinity for the enzyme thymidine kinase (TK) encoded by HSV and VZV. This viral enzyme converts acyclovir into acyclovir monophosphate, a nucleotide analogue. The monophosphate is further converted into diphosphate by cellular guanylate kinase and into triphosphate by a number of cellular enzymes. In biochemical assays, acyclovir triphosphate inhibits replication of herpes viral DNA. This is accomplished in 3 ways: 1) competitive inhibition of viral DNA polymerase, 2) incorporation and termination of the growing viral DNA chain, and 3) inactivation of the viral DNA polymerase. The greater antiviral activity of acyclovir against HSV compared with VZV is due to its more efficient phosphorylation by the viral TK.
## Structure
- Valacyclovir hydrochloride USP is the hydrochloride salt of the L-valyl ester of the antiviral drug acyclovir.
- Valacyclovir tablets, USP are for oral administration. Each tablet contains valacyclovir hydrochloride USP equivalent to 500 mg or 1 gram valacyclovir and the inactive ingredients croscarmellose sodium, FD&C Blue #2, hydrogenated castor oil, hypromellose, polyethylene glycol, polysorbate 80, starch (corn), and titanium dioxide.
- The chemical name of valacyclovir hydrochloride is L-valine, 2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl ester, monohydrochloride. It has the following structural formula:
- Valacyclovir hydrochloride USP is a white to off-white powder with the molecular formula C13H20N6O4•HCl and a molecular weight of 360.80. The maximum solubility in water at 25°C is 174 mg/mL. The pkas for valacyclovir hydrochloride are 1.90, 7.47, and 9.43.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Valacyclovir in the drug label.
## Pharmacokinetics
- The pharmacokinetics of valacyclovir and acyclovir after oral administration of valacyclovir hydrochloride have been investigated in 14 volunteer studies involving 283 adults and in 3 studies involving 112 pediatric subjects from 1 month to <12 years of age.
- Pharmacokinetics in Adults: Absorption and Bioavailability: After oral administration, valacyclovir hydrochloride is rapidly absorbed from the gastrointestinal tract and nearly completely converted to acyclovir and L-valine by first-pass intestinal and/or hepatic metabolism.
- The absolute bioavailability of acyclovir after administration of valacyclovir hydrochloride is 54.5% ± 9.1% as determined following a 1 gram oral dose of valacyclovir hydrochloride and a 350 mg intravenous acyclovir dose to 12 healthy volunteers. Acyclovir bioavailability from the administration of valacyclovir hydrochloride is not altered by administration with food (30 minutes after an 873 Kcal breakfast, which included 51 grams of fat).
- Acyclovir pharmacokinetic parameter estimates following administration of valacyclovir hydrochloride to healthy adult volunteers are presented in Table 3. There was a less than dose-proportional increase in acyclovir maximum concentration (Cmax) and area under the acyclovir concentration-time curve (AUC) after single-dose and multiple-dose administration (4 times daily) of valacyclovir hydrochloride from doses between 250 mg to 1 gram.
- There is no accumulation of acyclovir after the administration of valacyclovir at the recommended dosage regimens in adults with normal renal function.
- Distribution
- The binding of valacyclovir to human plasma proteins ranges from 13.5% to 17.9%. The binding of acyclovir to human plasma proteins ranges from 9% to 33%.
- Metabolism
- Valacyclovir is converted to acyclovir and L-valine by first-pass intestinal and/or hepatic metabolism. Acyclovir is converted to a small extent to inactive metabolites by aldehyde oxidase and by alcohol and aldehyde dehydrogenase. Neither valacyclovir nor acyclovir is metabolized by cytochrome P450 enzymes. Plasma concentrations of unconverted valacyclovir are low and transient, generally becoming non-quantifiable by 3 hours after administration. Peak plasma valacyclovir concentrations are generally less than 0.5 mcg/mL at all doses. After single-dose administration of 1 gram of valacyclovir hydrochloride, average plasma valacyclovir concentrations observed were 0.5, 0.4, and 0.8 mcg/mL in patients with hepatic dysfunction, renal insufficiency, and in healthy volunteers who received concomitant cimetidine and probenecid, respectively.
- Elimination
- The pharmacokinetic disposition of acyclovir delivered by valacyclovir is consistent with previous experience from intravenous and oral acyclovir. Following the oral administration of a single 1 gram dose of radiolabeled valacyclovir to 4 healthy subjects, 46% and 47% of administered radioactivity was recovered in urine and feces, respectively, over 96 hours. Acyclovir accounted for 89% of the radioactivity excreted in the urine. Renal clearance of acyclovir following the administration of a single 1 gram dose of valacyclovir hydrochloride to 12 healthy volunteers was approximately 255 ± 86 mL/min which represents 42% of total acyclovir apparent plasma clearance.
- The plasma elimination half-life of acyclovir typically averaged 2.5 to 3.3 hours in all studies of valacyclovir hydrochloride in volunteers with normal renal function.
- Specific Populations
- Renal Impairment: Reduction in dosage is recommended in patients with renal impairment.
- Following administration of valacyclovir hydrochloride to volunteers with ESRD, the average acyclovir half-life is approximately 14 hours. During hemodialysis, the acyclovir half-life is approximately 4 hours. Approximately one third of acyclovir in the body is removed by dialysis during a 4-hour hemodialysis session. Apparent plasma clearance of acyclovir in dialysis patients was 86.3 ± 21.3 mL/min/1.73 m2 compared with 679.16 ± 162.76 mL/min/1.73 m2 in healthy volunteers.
- Hepatic Impairment
- Administration of valacyclovir hydrochloride to patients with moderate (biopsy-proven cirrhosis) or severe (with and without ascites and biopsy-proven cirrhosis) liver disease indicated that the rate but not the extent of conversion of valacyclovir to acyclovir is reduced, and the acyclovir half-life is not affected. Dosage modification is not recommended for patients with cirrhosis.
- HIV Disease
- In 9 patients with HIV disease and CD4+ cell counts <150 cells/mm3 who received valacyclovir hydrochloride at a dosage of 1 gram 4 times daily for 30 days, the pharmacokinetics of valacyclovir and acyclovir were not different from that observed in healthy volunteers.
- Geriatrics
- After single-dose administration of 1 gram of valacyclovir hydrochloride in healthy geriatric volunteers, the half-life of acyclovir was 3.11 ± 0.51 hours, compared with 2.91 ± 0.63 hours in healthy younger adult volunteers. The pharmacokinetics of acyclovir following single- and multiple-dose oral administration of valacyclovir hydrochloride in geriatric volunteers varied with renal function. Dose reduction may be required in geriatric patients, depending on the underlying renal status of the patient.
- Pediatrics
- Acyclovir pharmacokinetics have been evaluated in a total of 98 pediatric patients (1 month to <12 years of age) following administration of the first dose of an extemporaneous oral suspension of valacyclovir. Acyclovir pharmacokinetic parameter estimates following a 20 mg/kg dose are provided in Table 4.
- Drug Interactions
- When valacyclovir hydrochloride is coadministered with antacids, cimetidine and/or probenicid, digoxin, or thiazide diuretics in patients with normal renal function, the effects are not considered to be of clinical significance (see below). Therefore, when valacyclovir hydrochloride is coadministered with these drugs in patients with normal renal function, no dosage adjustment is recommended.
- Antacids
- The pharmacokinetics of acyclovir after a single dose of valacyclovir hydrochloride (1 gram) were unchanged by coadministration of a single dose of antacids (Al3+ or Mg++).
- Cimetidine
- Acyclovir Cmax and AUC following a single dose of valacyclovir hydrochloride (1 gram) increased by 8% and 32%, respectively, after a single dose of cimetidine (800 mg).
- Cimetidine Plus Probenecid
- Acyclovir Cmax and AUC following a single dose of valacyclovir hydrochloride (1 gram) increased by 30% and 78%, respectively, after a combination of cimetidine and probenecid, primarily due to a reduction in renal clearance of acyclovir.
- Digoxin
- The pharmacokinetics of digoxin were not affected by coadministration of valacyclovir hydrochloride 1 gram 3 times daily, and the pharmacokinetics of acyclovir after a single dose of valacyclovir hydrochloride (1 gram) was unchanged by coadministration of digoxin (2 doses of 0.75 mg).
- Probenecid
- Acyclovir Cmax and AUC following a single dose of valacyclovir hydrochloride (1 gram) increased by 22% and 49%, respectively, after probenecid (1 gram).
- Thiazide Diuretics
- The pharmacokinetics of acyclovir after a single dose of valacyclovir hydrochloride (1 gram) were unchanged by coadministration of multiple doses of thiazide diuretics.
### Microbiology
- Antiviral Activities
- The quantitative relationship between the cell culture susceptibility of herpes viruses to antivirals and the clinical response to therapy has not been established in humans, and virus sensitivity testing has not been standardized. Sensitivity testing results, expressed as the concentration of drug required to inhibit by 50% the growth of virus in cell culture (EC50), vary greatly depending upon a number of factors. Using plaque-reduction assays, the EC50 values against herpes simplex virus isolates range from 0.09 to 60 μM (0.02 to 13.5 mcg/mL) for HSV-1 and from 0.04 to 44 μM (0.01 to 9.9 mcg/mL) for HSV-2. The EC50 values for acyclovir against most laboratory strains and clinical isolates of VZV range from 0.53 to 48 μM (0.12 to 10.8 mcg/mL). Acyclovir also demonstrates activity against the Oka vaccine strain of VZV with a mean EC50 of 6 μM (1.35 mcg/mL).
- Resistance
- Resistance of HSV and VZV to acyclovir can result from qualitative and quantitative changes in the viral TK and/or DNA polymerase. Clinical isolates of VZV with reduced susceptibility to acyclovir have been recovered from patients with AIDS. In these cases, TK-deficient mutants of VZV have been recovered.
- Resistance of HSV and VZV to acyclovir occurs by the same mechanisms. While most of the acyclovir-resistant mutants isolated thus far from immunocompromised patients have been found to be TK-deficient mutants, other mutants involving the viral TK gene (TK partial and TK altered) and DNA polymerase have also been isolated. TK-negative mutants may cause severe disease in immunocompromised patients. The possibility of viral resistance to valacyclovir (and therefore, to acyclovir) should be considered in patients who show poor clinical response during therapy.
## Nonclinical Toxicology
- The data presented below include references to the steady-state acyclovir AUC observed in humans treated with 1 gram valacyclovir hydrochloride given orally 3 times a day to treat herpes zoster. Plasma drug concentrations in animal studies are expressed as multiples of human exposure to acyclovir.
- Valacyclovir was noncarcinogenic in lifetime carcinogenicity bioassays at single daily doses (gavage) of valacyclovir giving plasma acyclovir concentrations equivalent to human levels in the mouse bioassay and 1.4 to 2.3 times human levels in the rat bioassay. There was no significant difference in the incidence of tumors between treated and control animals, nor did valacyclovir shorten the latency of tumors.
- Valacyclovir was tested in 5 genetic toxicity assays. An Ames assay was negative in the absence or presence of metabolic activation. Also negative were an in vitro cytogenetic study with human lymphocytes and a rat cytogenetic study.
- In the mouse lymphoma assay, valacyclovir was not mutagenic in the absence of metabolic activation. In the presence of metabolic activation (76% to 88% conversion to acyclovir), valacyclovir was mutagenic.
- Valacyclovir was mutagenic in a mouse micronucleus assay.
- Valacyclovir did not impair fertility or reproduction in rats at 6 times human plasma levels.
# Clinical Studies
### Cold Sores (Herpes Labialis)
- Two double-blind, placebo-controlled clinical trials were conducted in 1,856 healthy adults and adolescents (≥12 years old) with a history of recurrent cold sores. Patients self-initiated therapy at the earliest symptoms and prior to any signs of a cold sore. The majority of patients initiated treatment within 2 hours of onset of symptoms. Patients were randomized to valacyclovir hydrochloride 2 grams twice daily on Day 1 followed by placebo on Day 2, valacyclovir hydrochloride 2 grams twice daily on Day 1 followed by 1 gram twice daily on Day 2, or placebo on Days 1 and 2.
- The mean duration of cold sore episodes was about 1 day shorter in treated subjects as compared with placebo. The 2 day regimen did not offer additional benefit over the 1-day regimen.
- No significant difference was observed between subjects receiving valacyclovir hydrochloride or placebo in the prevention of progression of cold sore lesions beyond the papular stage.
### Genital Herpes Infections
- Initial Episode: Six hundred forty-three immunocompetent adults with first-episode genital herpes who presented within 72 hours of symptom onset were randomized in a double-blind trial to receive 10 days of valacyclovir hydrochloride 1 gram twice daily (n = 323) or oral acyclovir 200 mg 5 times a day (n = 320). For both treatment groups: the median time to lesion healing was 9 days, the median time to cessation of pain was 5 days, the median time to cessation of viral shedding was 3 days.
- Recurrent Episodes: Three double-blind trials (2 of them placebo-controlled) in immunocompetent adults with recurrent genital herpes were conducted. Patients self-initiated therapy within 24 hours of the first sign or symptom of a recurrent genital herpes episode.
- In 1 study, patients were randomized to receive 5 days of treatment with either valacyclovir hydrochloride 500 mg twice daily (n = 360) or placebo (n = 259). The median time to lesion healing was 4 days in the group receiving valacyclovir hydrochloride 500 mg versus 6 days in the placebo group, and the median time to cessation of viral shedding in patients with at least 1 positive culture (42% of the overall study population) was 2 days in the group receiving valacyclovir hydrochloride 500 mg versus 4 days in the placebo group. The median time to cessation of pain was 3 days in the group receiving valacyclovir hydrochloride 500 mg versus 4 days in the placebo group. Results supporting efficacy were replicated in a second trial.
- In a third study, patients were randomized to receive valacyclovir hydrochloride 500 mg twice daily for 5 days (n = 398) or valacyclovir hydrochloride 500 mg twice daily for 3 days (and matching placebo twice daily for 2 additional days) (n = 402). The median time to lesion healing was about 4½ days in both treatment groups. The median time to cessation of pain was about 3 days in both treatment groups.
- Suppressive Therapy: Two clinical studies were conducted, one in immunocompetent adults and one in HIV-infected adults.
- A double-blind, 12-month, placebo- and active-controlled study enrolled immunocompetent adults with a history of 6 or more recurrences per year. Outcomes for the overall study population are shown in Table 5.
- Subjects with 9 or fewer recurrences per year showed comparable results with valacyclovir hydrochloride 500 mg once daily.
- In a second study, 293 HIV-infected adults on stable antiretroviral therapy with a history of 4 or more recurrences of ano-genital herpes per year were randomized to receive either valacyclovir hydrochloride 500 mg twice daily (n = 194) or matching placebo (n = 99) for 6 months. The median duration of recurrent genital herpes in enrolled subjects was 8 years, and the median number of recurrences in the year prior to enrollment was 5. Overall, the median prestudy HIV-1 RNA was 2.6 log10 copies/mL. Among patients who received valacyclovir hydrochloride, the prestudy median CD4+ cell count was 336 cells/mm3; 11% had <100 cells/mm3, 16% had 100 to 199 cells/mm3, 42% had 200 to 499 cells/mm3, and 31% had ≥500 cells/mm3. Outcomes for the overall study population are shown in Table 6.
- Reduction of Transmission of Genital Herpes: A double-blind, placebo-controlled study to assess transmission of genital herpes was conducted in 1,484 monogamous, heterosexual, immunocompetent adult couples. The couples were discordant for HSV-2 infection. The source partner had a history of 9 or fewer genital herpes episodes per year. Both partners were counseled on safer sex practices and were advised to use condoms throughout the study period. Source partners were randomized to treatment with either valacyclovir hydrochloride 500 mg once daily or placebo once daily for 8 months. The primary efficacy endpoint was symptomatic acquisition of HSV-2 in susceptible partners. Overall HSV-2 acquisition was defined as symptomatic HSV-2 acquisition and/or HSV-2 seroconversion in susceptible partners. The efficacy results are summarized in Table 7.
### Herpes Zoster
- Two randomized double-blind clinical trials in immunocompetent adults with localized herpes zoster were conducted. Valacyclovir hydrochloride was compared with placebo in patients less than 50 years of age, and with oral acyclovir in patients greater than 50 years of age. All patients were treated within 72 hours of appearance of zoster rash. In patients less than 50 years of age, the median time to cessation of new lesion formation was 2 days for those treated with valacyclovir hydrochloride compared with 3 days for those treated with placebo. In patients greater than 50 years of age, the median time to cessation of new lesions was 3 days in patients treated with either valacyclovir hydrochloride or oral acyclovir. In patients less than 50 years of age, no difference was found with respect to the duration of pain after healing (post-herpetic neuralgia) between the recipients of valacyclovir hydrochloride and placebo. In patients greater than 50 years of age, among the 83% who reported pain after healing (post-herpetic neuralgia), the median duration of pain after healing [95% confidence interval] in days was: 40 [31, 51], 43 [36, 55], and 59 [41, 77] for 7-day valacyclovir hydrochloride, 14-day valacyclovir hydrochloride, and 7-day oral acyclovir, respectively.
### Chickenpox
- The use of valacyclovir hydrochloride for treatment of chickenpox in pediatric patients 2 to <18 years of age is based on single-dose pharmacokinetic and multiple-dose safety data from an open-label trial with valacyclovir and supported by safety and extrapolated efficacy data from 3 randomized, double-blind, placebo-controlled trials evaluating oral acyclovir in pediatric patients.
- The single-dose pharmacokinetic and multiple-dose safety study enrolled 27 pediatric patients 1 to <12 years of age with clinically suspected VZV infection. Each subject was dosed with valacyclovir oral suspension, 20 mg/kg 3 times daily for 5 days. Acyclovir systemic exposures in pediatric patients following valacyclovir oral suspension were compared with historical acyclovir systemic exposures in immunocompetent adults receiving the solid oral dosage form of valacyclovir or acyclovir for the treatment of herpes zoster. The mean projected daily acyclovir exposures in pediatric patients across all age-groups (1 to <12 years of age) were lower (Cmax: ↓13%, AUC: ↓30%) than the mean daily historical exposures in adults receiving valacyclovir 1 gram 3 times daily, but were higher (daily AUC: ↑50%) than the mean daily historical exposures in adults receiving acyclovir 800 mg 5 times daily. The projected daily exposures in pediatric patients were greater (daily AUC approximately 100% greater) than the exposures seen in immunocompetent pediatric patients receiving acyclovir 20 mg/kg 4 times daily for the treatment of chickenpox. Based on the pharmacokinetic and safety data from this study and the safety and extrapolated efficacy data from the acyclovir studies, oral valacyclovir 20 mg/kg 3 times a day for 5 days (not to exceed 1 gram 3 times daily) is recommended for the treatment of chickenpox in pediatric patients 2 to <18 years of age. Because the efficacy and safety of acyclovir for the treatment of chickenpox in children <2 years of age have not been established, efficacy data cannot be extrapolated to support valacyclovir treatment in children <2 years of age with chickenpox. Valacyclovir is also not recommended for the treatment of herpes zoster in children because safety data up to 7 days' duration are not available.
# How Supplied
- Valacyclovir tablets, USP (blue, film-coated, capsule-shaped, biconvex tablets) containing valacyclovir hydrochloride equivalent to 500 mg valacyclovir and debossed with "CIPLA" on one side and "153" on the other side.
- Bottle of 30 (NDC 69097-153-02).
- Bottle of 90 (NDC 69097-153-05).
- Bottle of 500 (NDC 69097-153-12).
- Valacyclovir tablets, USP (blue, film-coated, capsule-shaped, biconvex tablets), with a partial scorebar on both sides) containing valacyclovir hydrochloride equivalent to 1 gram valacyclovir and debossed with "CIPLA"on one side and "154" on the other side.
- Bottle of 30 (NDC 69097-154-02).
- Bottle of 90 (NDC 69097-154-05).
- Bottle of 500 (NDC 69097-154-12).
- Storage
- Store at 20°C to 25°C (68°F to 77°F). Dispense in a well-closed container as defined in the USP.
## Storage
There is limited information regarding Valacyclovir Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Importance of Adequate Hydration
- Patients should be advised to maintain adequate hydration.
- Cold Sores (Herpes Labialis)
- Patients should be advised to initiate treatment at the earliest symptom of a cold sore (e.g., tingling, itching, or burning). There are no data on the effectiveness of treatment initiated after the development of clinical signs of a cold sore (e.g., papule, vesicle, or ulcer). Patients should be instructed that treatment for cold sores should not exceed 1 day (2 doses) and that their doses should be taken about 12 hours apart. Patients should be informed that valacyclovir hydrochloride is not a cure for cold sores.
- Genital Herpes
- Patients should be informed that valacyclovir hydrochloride is not a cure for genital herpes. Because genital herpes is a sexually transmitted disease, patients should avoid contact with lesions or intercourse when lesions and/or symptoms are present to avoid infecting partners. Genital herpes is frequently transmitted in the absence of symptoms through asymptomatic viral shedding. Therefore, patients should be counseled to use safer sex practices in combination with suppressive therapy with valacyclovir hydrochloride. Sex partners of infected persons should be advised that they might be infected even if they have no symptoms. Type-specific serologic testing of asymptomatic partners of persons with genital herpes can determine whether risk for HSV-2 acquisition exists.
- Valacyclovir hydrochloride has not been shown to reduce transmission of sexually transmitted infections other than HSV-2.
- If medical management of a genital herpes recurrence is indicated, patients should be advised to initiate therapy at the first sign or symptom of an episode.
- There are no data on the effectiveness of treatment initiated more than 72 hours after the onset of signs and symptoms of a first episode of genital herpes or more than 24 hours after the onset of signs and symptoms of a recurrent episode.
- There are no data on the safety or effectiveness of chronic suppressive therapy of more than 1 year's duration in otherwise healthy patients. There are no data on the safety or effectiveness of chronic suppressive therapy of more than 6 months' duration in HIV-infected patients.
- Herpes Zoster
- There are no data on treatment initiated more than 72 hours after onset of the zoster rash. Patients should be advised to initiate treatment as soon as possible after a diagnosis of herpes zoster.
- Chickenpox
- Patients should be advised to initiate treatment at the earliest sign or symptom of chickenpox.
# Precautions with Alcohol
- Alcohol-Valacyclovir interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- VALACYCLOVIR HYDROCHLORIDE®[4]
# Look-Alike Drug Names
- Valtrex® — Keflex®[5]
- valacyclovir® — valganciclovir®[5]
- Valtrex® — Valcyte®[5]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Valacyclovir | |
72400febdbc30a669fcb2cc039bf78fa28f1dd61 | wikidoc | Valnoctamide | Valnoctamide
# Overview
Valnoctamide (INN, USAN) has been used in France as an sedative-hypnotic since 1964. It is a structural isomer of valpromide, a valproic acid prodrug; unlike valpromide, however, valnoctamide is not transformed into its homologous acid, valnoctic acid, in vivo.
# Indications
In addition to being a sedative, valnoctamide has been investigated for use in epilepsy since 1969 and was still being investigated in 2000 and 2003.
It was studied for neuropathic pain in 2005 by Winkler et al, with good results: it had minimal effects on motor coordination and alertness at effective doses, and appeared to be equally effective as gabapentin.
RH Belmaker, Yuly Bersudsky and Alex Mishory started a clinical trial of valnoctamide for prophylaxis of mania in lieu of the much more teratogenic valproic acid or its salts.
# Side effects
The side effects of valnoctamide are mostly minor and include somnolence and the slight motor impairments mentioned above.
# Interactions
Valnoctamide is known to increase through inhibition of epoxide hydrolase the serum levels of carbamazepine-10,11-epoxide, the active metabolite of carbamazepine, sometimes to toxic levels.
# Chemistry
Valnoctamide is a racemic compound with four stereoisomers, all of which were shown to be more effective than valproic acid in animal models of epilepsy and one of which ((2S,3S)-valnoctamide) was considered to be a good candidate by
Isoherranen, et al for an anticonvulsant in August of 2003.
# Notes and references
- ↑ Haj-Yehia, Abdullah (1988). "Pharmacokinetics of a valpromide isomer, valnoctamide, in dogs". Journal of Pharmaceutical Science. 77 (10): 831–4. PMID 3148708. Unknown parameter |coauthors= ignored (help); Unknown parameter |month= ignored (help).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}
- ↑ Template:Fr icon HARL, F. M. (1964). "". La Presse Médicale. 72: 753-4. PMID 14119722. Unknown parameter |month= ignored (help)
- ↑ Haj-Yehia, Abdullah (1989). "Structure-pharmacokinetic relationships in a series of valpromide derivatives with antiepileptic activity". Pharmaceutical Research. 6 (8): 683–9. PMID 2510141. Unknown parameter |coauthors= ignored (help); Unknown parameter |month= ignored (help)
- ↑ Template:Pt icon Mattos Nda, S. (1969). "". Hospital (Rio J). 75 (5): 1701–4. PMID 5306499. Unknown parameter |month= ignored (help)
- ↑ Lindekens (2000). "In vivo study of the effect of valpromide and valnoctamide in the pilocarpine rat model of focal epilepsy". Pharmaceutical Research. 17 (11): 1408–13. PMID 11205735. Text " Hilde " ignored (help); Unknown parameter |coauthors= ignored (help); Unknown parameter |month= ignored (help)
- ↑ Winkler, Ilan (2005). "Efficacy of antiepileptic isomers of valproic acid and valpromide in a rat model of neuropathic pain". British Journal of Pharmacology. PMID 15997234. Unknown parameter |coauthors= ignored (help); Unknown parameter |month= ignored (help)
- ↑ RH Belmaker, Yuly Bersudsky, Alex Mishory and Beersheva Mental Health Center (2005). "Valnoctamide in Mania". ClinicalTrials.gov. United States National Institutes of Health. Unknown parameter |accessyear= ignored (|access-date= suggested) (help); Unknown parameter |accessdaymonth= ignored (help)CS1 maint: Multiple names: authors list (link)
- ↑ VALNOCTAMIDE Biam French.
- ↑ Pisani F, Fazio A, Artesi C, Oteri G, Spina E, Tomson T, Perucca E. "Impairment of carbamazepine-10, 11-epoxide elimination by valnoctamide, a valpromide isomer, in healthy subjects." British Journal of Clinical Pharmacology. 1992 Jul;34(1):85-7. PMID 1352988
- ↑ Isoherranen, Nina (2003). "Pharmacokinetic-pharmacodynamic relationships of (2S,3S)-valnoctamide and its stereoisomer (2R,3S)-valnoctamide in rodent models of epilepsy". Pharmaceutical Research. 8 (8): 1293–301. PMID 12948028. Unknown parameter |coauthors= ignored (help); Unknown parameter |month= ignored (help) | Valnoctamide
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Valnoctamide (INN, USAN) has been used in France as an sedative-hypnotic since 1964.[2] It is a structural isomer of valpromide, a valproic acid prodrug; unlike valpromide, however, valnoctamide is not transformed into its homologous acid, valnoctic acid, in vivo.[3]
# Indications
In addition to being a sedative, valnoctamide has been investigated for use in epilepsy since 1969[4] and was still being investigated in 2000[5] and 2003.
It was studied for neuropathic pain in 2005 by Winkler et al, with good results: it had minimal effects on motor coordination and alertness at effective doses, and appeared to be equally effective as gabapentin.[6]
RH Belmaker, Yuly Bersudsky and Alex Mishory started a clinical trial of valnoctamide for prophylaxis of mania in lieu of the much more teratogenic valproic acid or its salts.[7]
# Side effects
The side effects of valnoctamide are mostly minor and include somnolence[8] and the slight motor impairments mentioned above.
# Interactions
Valnoctamide is known to increase through inhibition of epoxide hydrolase the serum levels of carbamazepine-10,11-epoxide, the active metabolite of carbamazepine, sometimes to toxic levels.[9]
# Chemistry
Valnoctamide is a racemic compound with four stereoisomers, all of which were shown to be more effective than valproic acid in animal models of epilepsy and one of which ((2S,3S)-valnoctamide) was considered to be a good candidate by
Isoherranen, et al for an anticonvulsant in August of 2003.[10]
# Notes and references
- ↑ Haj-Yehia, Abdullah (1988). "Pharmacokinetics of a valpromide isomer, valnoctamide, in dogs". Journal of Pharmaceutical Science. 77 (10): 831–4. PMID 3148708. Unknown parameter |coauthors= ignored (help); Unknown parameter |month= ignored (help).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}
- ↑ Template:Fr icon HARL, F. M. (1964). "[CLINICAL STUDY OF VALNOCTAMIDE ON 70 NEUROPSYCHIATRIC CLINIC PATIENTS UNDERGOING AMBULATORY TREATMENT.]". La Presse Médicale. 72: 753-4. PMID 14119722. Unknown parameter |month= ignored (help)
- ↑ Haj-Yehia, Abdullah (1989). "Structure-pharmacokinetic relationships in a series of valpromide derivatives with antiepileptic activity". Pharmaceutical Research. 6 (8): 683–9. PMID 2510141. Unknown parameter |coauthors= ignored (help); Unknown parameter |month= ignored (help)
- ↑ Template:Pt icon Mattos Nda, S. (1969). "[Use of Valnoctamide (nirvanil) in oligophrenic erethics and epileptics.]". Hospital (Rio J). 75 (5): 1701–4. PMID 5306499. Unknown parameter |month= ignored (help)
- ↑ Lindekens (2000). "In vivo study of the effect of valpromide and valnoctamide in the pilocarpine rat model of focal epilepsy". Pharmaceutical Research. 17 (11): 1408–13. PMID 11205735. Text " Hilde " ignored (help); Unknown parameter |coauthors= ignored (help); Unknown parameter |month= ignored (help)
- ↑ Winkler, Ilan (2005). "Efficacy of antiepileptic isomers of valproic acid and valpromide in a rat model of neuropathic pain". British Journal of Pharmacology. PMID 15997234. Unknown parameter |coauthors= ignored (help); Unknown parameter |month= ignored (help)
- ↑ RH Belmaker, Yuly Bersudsky, Alex Mishory and Beersheva Mental Health Center (2005). "Valnoctamide in Mania". ClinicalTrials.gov. United States National Institutes of Health. Unknown parameter |accessyear= ignored (|access-date= suggested) (help); Unknown parameter |accessdaymonth= ignored (help)CS1 maint: Multiple names: authors list (link)
- ↑ VALNOCTAMIDE Biam French.
- ↑ Pisani F, Fazio A, Artesi C, Oteri G, Spina E, Tomson T, Perucca E. "Impairment of carbamazepine-10, 11-epoxide elimination by valnoctamide, a valpromide isomer, in healthy subjects." British Journal of Clinical Pharmacology. 1992 Jul;34(1):85-7. PMID 1352988
- ↑ Isoherranen, Nina (2003). "Pharmacokinetic-pharmacodynamic relationships of (2S,3S)-valnoctamide and its stereoisomer (2R,3S)-valnoctamide in rodent models of epilepsy". Pharmaceutical Research. 8 (8): 1293–301. PMID 12948028. Unknown parameter |coauthors= ignored (help); Unknown parameter |month= ignored (help)
# External links
Template:Anticonvulsants
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Valnoctamide | |
c2c4c7033cef98aa275477f9b38c0c5cdba2a68b | wikidoc | Vasa praevia | Vasa praevia
# Overview
Vasa praevia (vasa previa AE) is an obstetric complication defined as "fetal vessels crossing or running in close proximity to the inner cervical os. These vessels course within the membranes (unsupported by the umbilical cord or placental tissue) and are at risk of rupture when the supporting membranes rupture."
# Etiology & Pathogenesis
Vasa previa is present when fetal vessels traverse the fetal membranes over the internal cervical os. These vessels may be from either a velamentous insertion of the umbilical cord or may be joining an accessory (succenturiate) placental lobe to the main disk of the placenta. If these fetal vessels rupture the bleeding is from the fetoplacental circulation, and fetal exsanguination will rapidly occur, leading to fetal death.
# Risk Factors
Vasa previa is seen more commonly with velamentous insertion of the umbilical cord, accessory placental lobes, and multiple gestation.
# Diagnosis
- This is rarely confirmed before delivery but may be suspected when antenatal sono-gram with color-flow Doppler reveals a vessel crossing the membranes over the internal cervical os.
- The diagnosis is usually confirmed after delivery on examination of the placenta and fetal membranes.
- Most often the foetus is already dead when the diagnosis is made; because the blood loss (say 300ml) constitutes a major bulk of blood volume of the foetus (80-100ml/kg i.e. 300ml approx for a 3kg foetus).
# Treatment
Treatment immediately with an emergency cesarean delivery is usually indicated.
### Contraindicated medications
Vasa praevia is considered an absolute contraindication to the use of the following medications:
- Oxytocin | Vasa praevia
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-In-Chief: Cafer Zorkun M.D., PhD.
# Overview
Vasa praevia (vasa previa AE) is an obstetric complication defined as "fetal vessels crossing or running in close proximity to the inner cervical os. These vessels course within the membranes (unsupported by the umbilical cord or placental tissue) and are at risk of rupture when the supporting membranes rupture."[1]
# Etiology & Pathogenesis
Vasa previa is present when fetal vessels traverse the fetal membranes over the internal cervical os. These vessels may be from either a velamentous insertion of the umbilical cord or may be joining an accessory (succenturiate) placental lobe to the main disk of the placenta. If these fetal vessels rupture the bleeding is from the fetoplacental circulation, and fetal exsanguination will rapidly occur, leading to fetal death.
# Risk Factors
Vasa previa is seen more commonly with velamentous insertion of the umbilical cord, accessory placental lobes, and multiple gestation.
# Diagnosis
- This is rarely confirmed before delivery but may be suspected when antenatal sono-gram with color-flow Doppler reveals a vessel crossing the membranes over the internal cervical os.[2][3]
- The diagnosis is usually confirmed after delivery on examination of the placenta and fetal membranes.
- Most often the foetus is already dead when the diagnosis is made; because the blood loss (say 300ml) constitutes a major bulk of blood volume of the foetus (80-100ml/kg i.e. 300ml approx for a 3kg foetus).
# Treatment
Treatment immediately with an emergency cesarean delivery is usually indicated.[4][5]
### Contraindicated medications
Vasa praevia is considered an absolute contraindication to the use of the following medications:
- Oxytocin | https://www.wikidoc.org/index.php/Vasa_praevia | |
9c5de75c4c0cda619c768cd4f97cb906cdde4f57 | wikidoc | Vat Yellow 4 | Vat Yellow 4
# Overview
Vat Yellow 4, also known as Golden Yellow GK, dibenzochrysenedione, dibenzpyrenequinone, Tyrian Yellow I-GOK, and C.I. 59100, is a yellow synthetic anthraquinone vat dye. Chemically it is dibenzochrysene-7,14-dione, or 3,4:8,9-dibenzopyrene-5,10-dione, or C24H12O2. It has the appearance of a viscous orange liquid.
Vat Yellow 4 is used mostly as a dye for textiles and paper.
Together with benzanthrone, it is used in some older pyrotechnic compositions for green and yellow colored smokes.
Vat Yellow 4 is a Group 3 carcinogen according to the IARC, as the evidence of its carcinogenity to humans is inadequate. | Vat Yellow 4
# Overview
Vat Yellow 4, also known as Golden Yellow GK, dibenzochrysenedione, dibenzpyrenequinone, Tyrian Yellow I-GOK, and C.I. 59100, is a yellow synthetic anthraquinone vat dye. Chemically it is dibenzo[b,def]chrysene-7,14-dione, or 3,4:8,9-dibenzopyrene-5,10-dione, or C24H12O2. It has the appearance of a viscous orange liquid.
Vat Yellow 4 is used mostly as a dye for textiles and paper.
Together with benzanthrone, it is used in some older pyrotechnic compositions for green and yellow colored smokes.
Vat Yellow 4 is a Group 3 carcinogen according to the IARC, as the evidence of its carcinogenity to humans is inadequate.
Template:SMILESCAS
# External links
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Vat_Yellow_4 | |
81c526751474cb3ea30975bb58bef84bddfe6326 | wikidoc | Velvet grass | Velvet grass
# Overview
Holcus lanatus, known as Yorkshire Fog or velvet grass, is a perennial grass. The specific epithet lanatus is Latin for 'woolly' which describes the plant's hairy texture.
In parts of northern Europe the grass is a common native grass species and a hardy pasture grass. Yorkshire Fog, tufted grass and meadow soft grass are the common names used. In North America, where it is an invasive species, the names are velvet grass or common velvet grass.
# Characteristics and hybrids
Holcus lanatus has velvety grey-green leaves. The shoots are round. The base of the shoots are white with pink stripes or veins - these are used in identification and are known by certain ecologists as 'stripey pyjamas'. The inflorescence is robust and often tinged purple. It produces a large amount of seed and is a rapid coloniser of disturbed ground. It prefers wetter ground, often seen around drainage ditches. The ligule is 1-4mm long, blunt and hairy.
Holcus lanatus can also be told apart from H. mollis by its beardless nodes on the culm; the absence of rhizomes; the awn of the upper lemma becoming hooked when dry and not projecting beyond the tips of the glumes.
It spreads vegetatively by developing new shoots and roots at its nodes. Plants form a blanket of runners on the soil surface. Semi-prostrate rosettes of shoots called 'mops' may form at the end of the runners. These mops root readily in contact with moist soil.
A male sterile hybrid with Holcus mollis exists with 2n = 21 chromosomes. Hybrids tend to resemble H. lanatus in their morphology.
# Invasive species and habitat preferences
In a European survey of weed seed contamination in cereal seed in 1970, Holcus lanatus was found in 1% of samples. All of this was home saved seed. H. lanatus is an indicator of poor soil, too low stocking or poor drainage. It is tolerant of ranges of soil pH, but grows best between pH 5.0 and 7.5; exhibits climatic tolerance over a wide altitude range; severe frosts kill H. lanatus under certain conditions; and it does not survive trampling and puddling. It can be controlled in some European locations by increasing available potassium and phosphorus, increasing stocking rate and improved drainage. This is not effective in North America.
## Noxious weed
Holcus lanatus is a significant pest weed in Australia, as it is a winter growing C3 grass and survives droughts and hot summers as seed. It is distasteful to stock unless young and not much else is available. The flowers are wind pollinated and out-crossing predominates. The seeds start to become viable 5 to 9 days after flowering and are completely viable after 20 days. Seeds are shed from June to early autumn. Seed numbers per panicle range from 100 to 380. The average seed number per plant ranges from 177,000 to 240,000 depending on time of emergence.
## Invasive species
In North America, Holcus lanatus is an invasive species in native grasslands and disrupts other ecosystem also. In Yosemite National Park it is one of nine priority noxious weeds to control for habitat restoration and regenerating native plant balances. H. lanatus forms a dense stand that can exclude other plants and may reduce or eliminate native Poacea species and other Genrera diversity.
# Insect foodplant status
Holcus lanatus in its natural habitat is a food source for the Speckled Wood, Wall and especially Small Skipper butterflies. It is rarely utilized by the Essex Skipper. In its native range it may occur in plant associations such as the Juncus subnodulosus–Cirsium palustre fen-meadow habitat. | Velvet grass
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Holcus lanatus, known as Yorkshire Fog or velvet grass, is a perennial grass. The specific epithet lanatus is Latin for 'woolly' which describes the plant's hairy texture.
In parts of northern Europe the grass is a common native grass species and a hardy pasture grass. Yorkshire Fog, tufted grass and meadow soft grass are the common names used. In North America, where it is an invasive species,[1] the names are velvet grass or common velvet grass.[2][3]
# Characteristics and hybrids
Holcus lanatus has velvety grey-green leaves. The shoots are round. The base of the shoots are white with pink stripes or veins - these are used in identification and are known by certain ecologists as 'stripey pyjamas'. The inflorescence is robust and often tinged purple. It produces a large amount of seed and is a rapid coloniser of disturbed ground. It prefers wetter ground, often seen around drainage ditches. The ligule is 1-4mm long, blunt and hairy.[4]
Holcus lanatus can also be told apart from H. mollis by its beardless nodes on the culm; the absence of rhizomes; the awn of the upper lemma becoming hooked when dry and not projecting beyond the tips of the glumes.[2]
It spreads vegetatively by developing new shoots and roots at its nodes. Plants form a blanket of runners on the soil surface. Semi-prostrate rosettes of shoots called 'mops' may form at the end of the runners. These mops root readily in contact with moist soil.[3]
A male sterile hybrid with Holcus mollis exists with 2n = 21 chromosomes.[5] Hybrids tend to resemble H. lanatus in their morphology.[6]
# Invasive species and habitat preferences
In a European survey of weed seed contamination in cereal seed in 1970, Holcus lanatus was found in 1% of samples. All of this was home saved seed.[citation needed] H. lanatus is an indicator of poor soil, too low stocking or poor drainage. It is tolerant of ranges of soil pH, but grows best between pH 5.0 and 7.5; exhibits climatic tolerance over a wide altitude range; severe frosts kill H. lanatus under certain conditions; and it does not survive trampling and puddling. It can be controlled in some European locations by increasing available potassium and phosphorus, increasing stocking rate and improved drainage. This is not effective in North America.[3]
## Noxious weed
Holcus lanatus is a significant pest weed in Australia, as it is a winter growing C3 grass and survives droughts and hot summers as seed. It is distasteful to stock unless young and not much else is available. The flowers are wind pollinated and out-crossing predominates. The seeds start to become viable 5 to 9 days after flowering and are completely viable after 20 days. Seeds are shed from June to early autumn. Seed numbers per panicle range from 100 to 380. The average seed number per plant ranges from 177,000 to 240,000 depending on time of emergence.[3]
## Invasive species
In North America, Holcus lanatus is an invasive species in native grasslands and disrupts other ecosystem also. In Yosemite National Park it is one of nine priority noxious weeds to control for habitat restoration and regenerating native plant balances.[7] H. lanatus forms a dense stand that can exclude other plants and may reduce or eliminate native Poacea species and other Genrera diversity.
# Insect foodplant status
Holcus lanatus in its natural habitat is a food source for the Speckled Wood, Wall and especially Small Skipper butterflies. It is rarely utilized by the Essex Skipper. In its native range it may occur in plant associations such as the Juncus subnodulosus–Cirsium palustre fen-meadow habitat. | https://www.wikidoc.org/index.php/Velvet_grass | |
5d606e408192b5d7cbf3d801cd4afd928866e276 | wikidoc | Venous ulcer | Venous ulcer
# Overview
Chronic venous ulcers are formed due to the deformed venous valves causing back flow of the blood and stasis of the venous blood. Management of venous ulcers include education, elevation, elastic compression and evaluation. Antibiotic therapy are reserved for the ulcers with secondary infection.
# Venous Ulcers
Venous ulcers are wounds that are thought to occur due to improper functioning of valves in the veins usually of the legs. They are the major cause of chronic wounds, occurring in 70% to 90% of chronic wound cases.
# Pathophysiology
The exact etiology of venous ulcers is not certain, but they are thought to arise when venous valves that exist to prevent backflow of blood do not function properly, causing the pressure in veins to increase. The body needs the pressure gradient between arteries and veins in order for the heart to pump blood forward through arteries and into veins. When venous hypertension exists, arteries no longer have significantly higher pressure than veins, blood is not pumped as effectively into or out of the area, and it pools.
Venous hypertension may also stretch veins and allow blood proteins to leak into the extravascular space, isolating extracellular matrix (ECM) molecules and growth factors, preventing them from helping to heal the wound. Leakage of fibrinogen from veins as well as deficiencies in fibrinolysis may also cause fibrin to build up around the vessels, preventing oxygen and nutrients from reaching cells. Venous insufficiency may also cause white blood cells (leukocytes) to accumulate in small blood vessels, releasing inflammatory factors and reactive oxygen species (ROS, free radicals) and further contributing to chronic wound formation. Buildup of white blood cells in small blood vessels may also plug the vessels, further contributing to ischemia. This blockage of blood vessels by leukocytes may be responsible for the "no reflow phenomenon," in which ischemic tissue is never fully reperfused. Allowing blood to flow back into the limb, for example by elevating it, is necessary but also contributes to reperfusion injury. Other comorbidities may also be the root cause of venous ulcers.
# Treatment
Venous ulcers are costly to treat, and there is a significant chance that they will reoccur after healing; one study found that up to 48% of venous ulcers had recurred by the fifth year after healing.
## Ulcerated Skin: Venous/Arterial Insufficiency; Pressure With Secondary Infection (Infected Decubiti) Treatment
- Ulcerated skin: venous/arterial insufficiency; pressure with secondary infection (infected decubiti) treatment
- Preferred regimen (1): Imipenem 0.5 g IV q6h (OR Meropenem 1 g IV q24h OR Doripenem 500 mg IV q8h)
- Preferred regimen (2): Ticarcillin-Clavulanate 3.1 g IV q8h
- Preferred regimen (3): Piperacillin-Tazobactam 3.375 g IV q6h
- Preferred regimen (4): Ertapenem 1 g IV q24h
- Alternative regimen (1): Ciprofloxacin 500 mg PO bid OR Levofloxacin PO 500 mg qd AND Metronidazole 500 mg PO qid
- Alternative regimen (2): Cefepime 2 g IV q12h OR Ceftazidime 2 g IV q8h AND Metronidazole 500 mg PO qid
- Note (1): If gram positive cocci on gram stain add Vancomycin.
- Note (2): If the ulcer is inflamed, treat with parenteral antibiotics with no topical treatment.
- Note (3): If the ulcer is not clinically inflamed, consider debridement, removal of foreign body, reduce the pressure for weight bearing limbs and leg elevation.
- Note (4): If not inflamed, healing improved on air bed, protein supplement, radiant heat and electric stimulation.
- Note (5): Avoid chlorhexidine and povidone iodine as it may harm the granulation tissue.
## Bisgaard regimen
Most venous ulcers respond to a regimen called Bisgaard regimen for treating ulcers. Best remembered as a mnemonic 4E's - education, elevation, elastic compression and evaluation.
## Compression therapy
Non-elastic, ambulatory, below knee (BK) compression aggressively counters the impact of reflux on venous pump failure. Compression therapy is used for venous leg ulcers and can decrease blood vessel diameter and pressure, which increases their effectiveness, preventing blood from flowing backwards. Compression is also used to increase release of inflammatory cytokines, lower the amount of fluid leaking from capillaries and therefore prevent swelling, and prevent clotting by decreasing activation of thrombin and increasing that of plasmin.
Compression is applied using elastic bandages or boots specifically designed for the purpose. It is not clear whether non-elastic systems are better than a multilayer elastic system. Patients should wear as much compression as is comfortable. The type of dressing applied beneath the compression does not seem to matter, and hydrocolloid is not better than simple low adherent dressings.
## Pentoxifylline
A meta-analysis of randomized controlled trials by the Cochrane Collaboration found that "Pentoxifylline is an effective adjunct to compression bandaging for treating venous ulcers and may be effective in the absence of compression".
## Artificial skin
Artificial skin, made of collagen and cultured skin cells, is also used to cover venous ulcers and excrete growth factors to help them heal. A meta-analysis of randomized controlled trials by the Cochrane Collaboration concluded "Bilayer artificial skin, used in conjunction with compression bandaging, increases the chance of healing a venous ulcer compared with compression and a simple dressing".
## Surgical correction of superficial venous reflux
A randomized controlled trial found that surgery "reduces the recurrence of ulcers at four years and results in a greater proportion of ulcer free time".
# See Also
- Bedsore
- Peripheral arterial disease | Venous ulcer
Template:WikiDoc Cardiology News
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Chronic venous ulcers are formed due to the deformed venous valves causing back flow of the blood and stasis of the venous blood. Management of venous ulcers include education, elevation, elastic compression and evaluation. Antibiotic therapy are reserved for the ulcers with secondary infection.
# Venous Ulcers
Venous ulcers are wounds that are thought to occur due to improper functioning of valves in the veins usually of the legs. They are the major cause of chronic wounds, occurring in 70% to 90% of chronic wound cases.[1]
# Pathophysiology
The exact etiology of venous ulcers is not certain, but they are thought to arise when venous valves that exist to prevent backflow of blood do not function properly, causing the pressure in veins to increase.[2][3][4][5] The body needs the pressure gradient between arteries and veins in order for the heart to pump blood forward through arteries and into veins. When venous hypertension exists, arteries no longer have significantly higher pressure than veins, blood is not pumped as effectively into or out of the area,[2][3][4][5] and it pools.
Venous hypertension may also stretch veins and allow blood proteins to leak into the extravascular space, isolating extracellular matrix (ECM) molecules and growth factors, preventing them from helping to heal the wound.[2][5] Leakage of fibrinogen from veins as well as deficiencies in fibrinolysis may also cause fibrin to build up around the vessels, preventing oxygen and nutrients from reaching cells.[2] Venous insufficiency may also cause white blood cells (leukocytes) to accumulate in small blood vessels, releasing inflammatory factors and reactive oxygen species (ROS, free radicals) and further contributing to chronic wound formation.[2][5] Buildup of white blood cells in small blood vessels may also plug the vessels, further contributing to ischemia.[6] This blockage of blood vessels by leukocytes may be responsible for the "no reflow phenomenon," in which ischemic tissue is never fully reperfused.[6] Allowing blood to flow back into the limb, for example by elevating it, is necessary but also contributes to reperfusion injury.[3] Other comorbidities may also be the root cause of venous ulcers.[4]
# Treatment
Venous ulcers are costly to treat, and there is a significant chance that they will reoccur after healing;[1][2] one study found that up to 48% of venous ulcers had recurred by the fifth year after healing.
## Ulcerated Skin: Venous/Arterial Insufficiency; Pressure With Secondary Infection (Infected Decubiti) Treatment
- Ulcerated skin: venous/arterial insufficiency; pressure with secondary infection (infected decubiti) treatment[7]
- Preferred regimen (1): Imipenem 0.5 g IV q6h (OR Meropenem 1 g IV q24h OR Doripenem 500 mg IV q8h)
- Preferred regimen (2): Ticarcillin-Clavulanate 3.1 g IV q8h
- Preferred regimen (3): Piperacillin-Tazobactam 3.375 g IV q6h
- Preferred regimen (4): Ertapenem 1 g IV q24h
- Alternative regimen (1): Ciprofloxacin 500 mg PO bid OR Levofloxacin PO 500 mg qd AND Metronidazole 500 mg PO qid
- Alternative regimen (2): Cefepime 2 g IV q12h OR Ceftazidime 2 g IV q8h AND Metronidazole 500 mg PO qid
- Note (1): If gram positive cocci on gram stain add Vancomycin.
- Note (2): If the ulcer is inflamed, treat with parenteral antibiotics with no topical treatment.
- Note (3): If the ulcer is not clinically inflamed, consider debridement, removal of foreign body, reduce the pressure for weight bearing limbs and leg elevation.
- Note (4): If not inflamed, healing improved on air bed, protein supplement, radiant heat and electric stimulation.
- Note (5): Avoid chlorhexidine and povidone iodine as it may harm the granulation tissue.
## Bisgaard regimen
Most venous ulcers respond to a regimen called Bisgaard regimen for treating ulcers.[citation needed] Best remembered as a mnemonic 4E's - education, elevation, elastic compression and evaluation.
## Compression therapy
Non-elastic, ambulatory, below knee (BK) compression aggressively counters the impact of reflux on venous pump failure.[8] Compression therapy is used for venous leg ulcers and can decrease blood vessel diameter and pressure, which increases their effectiveness, preventing blood from flowing backwards.[2] Compression is also used [2][9] to increase release of inflammatory cytokines, lower the amount of fluid leaking from capillaries and therefore prevent swelling, and prevent clotting by decreasing activation of thrombin and increasing that of plasmin.[1]
Compression is applied using elastic bandages or boots specifically designed for the purpose. It is not clear whether non-elastic systems are better than a multilayer elastic system. Patients should wear as much compression as is comfortable. [10] The type of dressing applied beneath the compression does not seem to matter, and hydrocolloid is not better than simple low adherent dressings.[11][12]
## Pentoxifylline
A meta-analysis of randomized controlled trials by the Cochrane Collaboration found that "Pentoxifylline is an effective adjunct to compression bandaging for treating venous ulcers and may be effective in the absence of compression".[13]
## Artificial skin
Artificial skin, made of collagen and cultured skin cells, is also used to cover venous ulcers and excrete growth factors to help them heal.[14] A meta-analysis of randomized controlled trials by the Cochrane Collaboration concluded "Bilayer artificial skin, used in conjunction with compression bandaging, increases the chance of healing a venous ulcer compared with compression and a simple dressing".[15]
## Surgical correction of superficial venous reflux
A randomized controlled trial found that surgery "reduces the recurrence of ulcers at four years and results in a greater proportion of ulcer free time".[16]
# See Also
- Bedsore
- Peripheral arterial disease | https://www.wikidoc.org/index.php/Venous_ulcer | |
cd2540600184624473d2d414c14f73eda4bedfb8 | wikidoc | Victor Babeş | Victor Babeş
Victor Babeş (July 4, 1854—October 19, 1926) was a Romanian physician, biologist, and one of the earliest bacteriologists. He made early and significant contributions to the study of rabies, leprosy, diphtheria, tuberculosis, and other infectious diseases.
The Babeş-Bolyai University in Cluj-Napoca and the Victor Babeş University of Medicine and Pharmacy in Timisoara bears his name.
# Biography
Born in Vienna (at the time, the capital of the Austrian Empire) to an ethnic Romanian family from the Banat, he studied in Budapest, then in Vienna, where he received his doctorate in Science. Attracted by the discoveries of Louis Pasteur, he left for Paris, and worked first in Pasteur's laboratory, and then with Victor André Cornil.
In 1885 he discovered a parasitic sporozoan of the ticks, named Babesia (of the genus Babesiidae), and which causes a rare and severe disease called babesiosis. In the same year, he published the first treaty of bacteriology in the world, Bacteria and their role in the histopathology of infectious diseases, which he co-authored with Cornil.
Babeş' scientific endeavours were wide-ranging. He was the first to demonstrate the presence of tuberculous bacilli in the urine of infected patients. He also discovered cellular inclusions in rabies-infected nerve cells. Of diagnostic value, they were to be named after him (Babeş-Negri bodies).
Babeş was one of the founders of serum therapy, and was the first to introduce rabies vaccination to Romania. His work also had a strong influence upon veterinary medicine, especially concerning prophylaxis and serum medication.
He became a professor of Pathology and Bacteriology at the Carol Davila University of Medicine and Pharmacy in Bucharest. He was also a member of the Romanian Academy (in 1893), of the Paris Académie Nationale de Médecine, and an officer of the French Légion d'honneur.
His nephew, Aurel Babeş, was also a physician, who discovered a screening test for cervical cancer.
# Eponyms
- Babeş-Ernst bodies: metachromatic inclusions in the cytoplasm of gram-positive bacteria such as diphtheria
- Babeş-Negri bodies: inclusions in rabies-infected nervous cells
- Babesia: parasites of the genus Hemosporidiae
# Selected published works
- Über Poliomyelitis anterior, 1877
- Ueber die selbständige combinirte Seiten- und Hinterstrangsclerose des Rückenmarks, Archiv für pathologische Anatomie und Physiologie und für klinische Medicin, Berlin, 1876
- Ueber einen im menschlichen Peritoneum gefundenen Nematoden, Archiv für pathologische Anatomie und Physiologie und für klinische Medicin, Berlin, volume LXXXI
- Studien über Safraninfärbung, 1881
- Bakterien des rothen Schweisses, 1881
- Eine experimentelle Studie über den Einfluss des Nervensystems auf die pathologischen Veränderungen der Haut, with Arthur von Irsay, Vierteljahresschrift für Dermatologie
- Les bactéries et leur rôle dans l’anatomie et l’histologie pathologiques des maladies infectieuses, Written with Victor André Cornil, 1 volume and Atlas, Paris, F. Alcan, 1885
- Über isoliert färbbare Antheile von Bakterien, Zeitschrift für Hygiene, Leipzig, 1889, 5: 173-190
- Observations sur la morve, Archives de médecine experimentale et d’anatomie pathologique, 1891, 3:619-645
- Atlas der pathologischen Histologie des Nervensystems, with Georges Marinesco and Paul Oscar Blocq, Berlin, Hirschwald, 1892
- Untersuchungen über Koch's Kommabacillus, Archiv für pathologische Anatomie und Physiologie und für klinische Medicin, Berlin
- Untersuchungen über den Leprabazillus und über die Histologie der Lepra, Berlin, 1898
- Beobachtungen über Riesenzellen, Stuttgart, 1905
- Über die Notwendigkeit der AbVerfahrens der Wutbehandlungänderung des Pasteur'schen, Zeitschrift für Hygiene und Infektionskrankheiten, Leipzig, 1908, 58:401-412.
de:Victor Babeş
gl:Victor Babeş
hu:Victor Babeş | Victor Babeş
Victor Babeş (July 4, 1854—October 19, 1926) was a Romanian physician, biologist, and one of the earliest bacteriologists. He made early and significant contributions to the study of rabies, leprosy, diphtheria, tuberculosis, and other infectious diseases.
The Babeş-Bolyai University in Cluj-Napoca and the Victor Babeş University of Medicine and Pharmacy in Timisoara bears his name.
# Biography
Born in Vienna (at the time, the capital of the Austrian Empire) to an ethnic Romanian family from the Banat, he studied in Budapest, then in Vienna, where he received his doctorate in Science. Attracted by the discoveries of Louis Pasteur, he left for Paris, and worked first in Pasteur's laboratory, and then with Victor André Cornil.
In 1885 he discovered a parasitic sporozoan of the ticks, named Babesia (of the genus Babesiidae), and which causes a rare and severe disease called babesiosis. In the same year, he published the first treaty of bacteriology in the world, Bacteria and their role in the histopathology of infectious diseases, which he co-authored with Cornil.
Babeş' scientific endeavours were wide-ranging. He was the first to demonstrate the presence of tuberculous bacilli in the urine of infected patients. He also discovered cellular inclusions in rabies-infected nerve cells. Of diagnostic value, they were to be named after him (Babeş-Negri bodies).
Babeş was one of the founders of serum therapy, and was the first to introduce rabies vaccination to Romania. His work also had a strong influence upon veterinary medicine, especially concerning prophylaxis and serum medication.
He became a professor of Pathology and Bacteriology at the Carol Davila University of Medicine and Pharmacy in Bucharest. He was also a member of the Romanian Academy (in 1893), of the Paris Académie Nationale de Médecine, and an officer of the French Légion d'honneur.
His nephew, Aurel Babeş, was also a physician, who discovered a screening test for cervical cancer.
# Eponyms
- Babeş-Ernst bodies: metachromatic inclusions in the cytoplasm of gram-positive bacteria such as diphtheria
- Babeş-Negri bodies: inclusions in rabies-infected nervous cells
- Babesia: parasites of the genus Hemosporidiae
# Selected published works
- Über Poliomyelitis anterior, 1877
- Ueber die selbständige combinirte Seiten- und Hinterstrangsclerose des Rückenmarks, [Virchows] Archiv für pathologische Anatomie und Physiologie und für klinische Medicin, Berlin, 1876
- Ueber einen im menschlichen Peritoneum gefundenen Nematoden, [Virchows] Archiv für pathologische Anatomie und Physiologie und für klinische Medicin, Berlin, volume LXXXI
- Studien über Safraninfärbung, 1881
- Bakterien des rothen Schweisses, 1881
- Eine experimentelle Studie über den Einfluss des Nervensystems auf die pathologischen Veränderungen der Haut, with Arthur von Irsay, Vierteljahresschrift für Dermatologie
- Les bactéries et leur rôle dans l’anatomie et l’histologie pathologiques des maladies infectieuses, Written with Victor André Cornil, 1 volume and Atlas, Paris, F. Alcan, 1885
- Über isoliert färbbare Antheile von Bakterien, Zeitschrift für Hygiene, Leipzig, 1889, 5: 173-190
- Observations sur la morve, Archives de médecine experimentale et d’anatomie pathologique, 1891, 3:619-645
- Atlas der pathologischen Histologie des Nervensystems, with Georges Marinesco and Paul Oscar Blocq, Berlin, Hirschwald, 1892
- Untersuchungen über Koch's Kommabacillus, [Virchows] Archiv für pathologische Anatomie und Physiologie und für klinische Medicin, Berlin
- Untersuchungen über den Leprabazillus und über die Histologie der Lepra, Berlin, 1898
- Beobachtungen über Riesenzellen, Stuttgart, 1905
- Über die Notwendigkeit der AbVerfahrens der Wutbehandlungänderung des Pasteur'schen, Zeitschrift für Hygiene und Infektionskrankheiten, Leipzig, 1908, 58:401-412.
de:Victor Babeş
gl:Victor Babeş
hu:Victor Babeş
Template:WH
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Victor_Babe%C5%9F | |
20651545971b7e501b571ee598597d989ad6a062 | wikidoc | Vildagliptin | Vildagliptin
# Overview
Vildagliptin, previously identified as LAF237, is a new oral anti-hyperglycemic agent (anti-diabetic drug) of the new dipeptidyl peptidase-4 (DPP-4) inhibitor class of drugs. Vildagliptin inhibits the inactivation of GLP-1 and GIP by DPP-4, allowing GLP-1 and GIP to potentiate the secretion of insulin in the beta cells and suppress glucaon release by the alpha cells of the islets of Langerhans in the pancreas.
It is currently in clinical trials and has been shown to reduce hyperglycemia in type 2 diabetes mellitus.
Vildagliptin has been submitted to the U.S. Food and Drug Administration for approval, and will be marketed as Galvus by Novartis. The Food and Drug Administration demanded additional clinical data before it can approve vildagliptin including extra evidence that skin lesions and kidney impairment seen during an early study on animals have not occurred in human trials. Vildagliptin is currently approved for use in the European Union, although it is not yet marketed. The recent finding of liver toxicity problems among clinical trial patients could delay the European debut of this drug.
Dipeptidyl peptidase-4's role in blood glucose regulation is thought to be through inactivation of GIP and GLP-1. | Vildagliptin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Vildagliptin, previously identified as LAF237, is a new oral anti-hyperglycemic agent (anti-diabetic drug) of the new dipeptidyl peptidase-4 (DPP-4) inhibitor class of drugs. Vildagliptin inhibits the inactivation of GLP-1 and GIP by DPP-4, allowing GLP-1 and GIP to potentiate the secretion of insulin in the beta cells and suppress glucaon release by the alpha cells of the islets of Langerhans in the pancreas.
It is currently in clinical trials and has been shown to reduce hyperglycemia in type 2 diabetes mellitus.[1]
Vildagliptin has been submitted to the U.S. Food and Drug Administration for approval, and will be marketed as Galvus by Novartis. The Food and Drug Administration demanded additional clinical data before it can approve vildagliptin including extra evidence that skin lesions and kidney impairment seen during an early study on animals have not occurred in human trials. Vildagliptin is currently approved for use in the European Union, although it is not yet marketed. The recent finding of liver toxicity problems among clinical trial patients[2] could delay the European debut of this drug.
Dipeptidyl peptidase-4's role in blood glucose regulation is thought to be through inactivation of GIP[3] and GLP-1.[1][3] | https://www.wikidoc.org/index.php/Vildagliptin | |
44eace91ef2d8790819184ed8a72faf4e4facb72 | wikidoc | Viral vector | Viral vector
# Overview
Viral vectors are a tool commonly used by molecular biologists to deliver genetic material into cells. This process can be performed inside a living organism (in vivo) or in cell culture (in vitro). Viruses have evolved specialized molecular mechanisms to efficiently transport their genomes inside the cells they infect. Delivery of genes by a virus is termed transduction and the infected cells are described as transduced. Molecular biologists first harnessed this machinery in the 1970s. Paul Berg used a modified SV40 virus containing DNA from the bacteriophage lambda to infect monkey kidney cells maintained in culture.
Key properties of a viral vector
Viral vectors are tailored to their specific applications but generally share a few key properties.
- Safety. Although viral vectors are occasionally created from pathogenic viruses, they are modified in such a way as to minimize the risk of handling them. This usually involves the deletion of a part of the viral genome critical for viral replication. Such a virus can efficiently infect cells but, once the infection has taken place, requires a helper virus to provide the missing proteins for production of new virions.
- Low toxicity. The viral vector should have a minimal effect on the physiology of the cell it infects.
- Stability. Some viruses are genetically unstable and can rapidly rearrange their genomes. This is detrimental to predictability and reproducibility of the work conducted using a viral vector and is avoided in their design.
- Cell type specificity. Most viral vectors are engineered to infect as wide a range of cell types as possible. However, sometimes the opposite is preferred. The viral receptor can be modified to target the virus to a specific kind of cell.
# Applications
## Basic research
Viral vectors were originally developed as an alternative to transfection of naked DNA for molecular genetic experiments. Compared to traditional methods such as calcium phosphate precipitation, transduction can ensure that nearly 100% of cells are infected without severely affecting cell viability. Furthermore, some viruses integrate into the cell genome facilitating stable expression. However, transfection is still the method of choice for many applications as construction of a viral vector is a much more laborious process.
Protein coding genes can be expressed using viral vectors, commonly to study the function of the particular protein. Viral vectors, especially retroviruses, stably expressing marker genes such as GFP are widely used to permanently label cells to track them and their progeny, for example in xenotransplantation experiments, when cells infected in vitro are implanted into a host animal.
Genes inserted into the vector can encode shRNAs and siRNAs used to efficiently block or silence production of a specific protein. Such knock-down experiments are much quicker and cheaper to carry out than gene knockout. But as the silencing is sometimes non-specific and has off-target effects on other genes, it provides less reliable results.
## Gene therapy
In the future gene therapy may provide a way to cure genetic disorders, such as severe combined immunodeficiency or cystic fibrosis. Several gene therapy trials have used viruses to deliver 'good' genes to the cells of the patient's body. There have been a huge number of laboratory successes with gene therapy. However, several problems of viral gene therapy must be overcome before it gains widespread use. Immune response to viruses not only impedes the delivery of genes to target cells but can cause severe complications for the patient. In one of the early gene therapy trials in 1999 this led to the death of Jesse Gelsinger, who was treated using an adenoviral vector.
Some viral vectors, for instance lentiviruses, insert their genomes at a seemingly random location on one of the host chromosomes, which can disturb the function of cellular genes and lead to cancer. In a severe combined immunodeficiency retroviral gene therapy trial conducted in 2002, two of the patients developed leukemia as a consequence of the treatment. Adeno-associated virus-based vectors are much safer in this respect as they always integrate at the same site in the human genome.
## Vaccines
Viruses expressing pathogen proteins are currently being developed as vaccines against these pathogens, based on the same rationale as DNA vaccines. T-lymphocytes recognize cells infected with intracellular parasites based on the foreign proteins produced within the cell. T cell immunity is crucial for protection against viral infections and such diseases as malaria. A viral vaccine induces expression of pathogen proteins within host cells similarly to the Sabin Polio vaccine and other attenuated vaccines. However, since viral vaccines contain only a small fraction of pathogen genes, they are much safer and sporadic infection by the pathogen is impossible. Adenoviruses are being actively developed as vaccines.
# Types of viral vectors
## Retroviruses
Retroviruses are the one of mainstays of current gene therapy approaches. The recombinant retroviruses such as the Moloney murine leukemia virus have the ability to integrate into the host genome in a stable fashion. They contain a reverse transcriptase which allows integration into the host genome. They have been used in a number of FDA-approved clinical trials such as the SCID-X1 trial. The primary drawback to use of retroviruses such as the Moloney retrovirus involves the requirement for cells to be actively dividing for transduction. As a result, cells such as neurons are very resistant to infection and transduction by retroviruses. There is a concern for insertional mutagensis due to the integration into the host genome which can lead to cancer or leukemia.
## Lentiviruses
Lentiviruses are a subclass of Retroviruses. They are widely adapted as vectors thanks to their ability integrate into the genome of non-dividing as well as dividing cells. The viral genome in the form of RNA is reverse-transcribed when the virus enters the cell to produce DNA, which is then inserted into the genome at a random position by the viral integrase enzyme. The vector, now called a provirus, remains in the genome and is passed on to the progeny of the cell when it divides. The site of integration is unpredictable, which can pose a problem. The provirus can disturb the function of cellular genes and lead to activation of oncogenes promoting the development of cancer, which raises concerns for possible applications of lentiviruses in gene therapy.
For safety reasons lentiviral vectors never carry the genes required for their replication. To produce a lentivirus, several plasmids are transfected into a so-called packaging cell line, commonly HEK 293. One or more plasmids, generally referred to as packaging plasmids, encode the virion proteins, such as the capsid and the reverse transcriptase. Another plasmid contains the genetic material to be delivered by the vector. It is transcribed to produce the single-stranded RNA viral genome and is marked by the presence of the ψ (psi) sequence. This sequence is used to package the genome into the virion.
## Adenoviruses
As opposed to lentiviruses, adenoviral DNA does not integrate into the genome and is not replicated during cell division. This limits their use in basic research, although adenoviral vectors are occasionally used in in vitro experiments. Their primary applications are in gene therapy and vaccination. Since humans commonly come in contact with adenoviruses, which cause respiratory, gastrointestinal and eye infections, they trigger a rapid immune response with potentially dangerous consequences. To overcome this problem scientists are currently investigating adenoviruses to which humans do not have immunity.
## Adeno-associated viruses
## Nanoengineered Substances
Substances such as Ormosil have been successfully used as a DNA vector. | Viral vector
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Viral vectors are a tool commonly used by molecular biologists to deliver genetic material into cells. This process can be performed inside a living organism (in vivo) or in cell culture (in vitro). Viruses have evolved specialized molecular mechanisms to efficiently transport their genomes inside the cells they infect. Delivery of genes by a virus is termed transduction and the infected cells are described as transduced. Molecular biologists first harnessed this machinery in the 1970s. Paul Berg used a modified SV40 virus containing DNA from the bacteriophage lambda to infect monkey kidney cells maintained in culture.[1]
Key properties of a viral vector
Viral vectors are tailored to their specific applications but generally share a few key properties.
- Safety. Although viral vectors are occasionally created from pathogenic viruses, they are modified in such a way as to minimize the risk of handling them. This usually involves the deletion of a part of the viral genome critical for viral replication. Such a virus can efficiently infect cells but, once the infection has taken place, requires a helper virus to provide the missing proteins for production of new virions.
- Low toxicity. The viral vector should have a minimal effect on the physiology of the cell it infects.
- Stability. Some viruses are genetically unstable and can rapidly rearrange their genomes. This is detrimental to predictability and reproducibility of the work conducted using a viral vector and is avoided in their design.
- Cell type specificity. Most viral vectors are engineered to infect as wide a range of cell types as possible. However, sometimes the opposite is preferred. The viral receptor can be modified to target the virus to a specific kind of cell.
# Applications
## Basic research
Viral vectors were originally developed as an alternative to transfection of naked DNA for molecular genetic experiments. Compared to traditional methods such as calcium phosphate precipitation, transduction can ensure that nearly 100% of cells are infected without severely affecting cell viability. Furthermore, some viruses integrate into the cell genome facilitating stable expression. However, transfection is still the method of choice for many applications as construction of a viral vector is a much more laborious process.
Protein coding genes can be expressed using viral vectors, commonly to study the function of the particular protein. Viral vectors, especially retroviruses, stably expressing marker genes such as GFP are widely used to permanently label cells to track them and their progeny, for example in xenotransplantation experiments, when cells infected in vitro are implanted into a host animal.
Genes inserted into the vector can encode shRNAs and siRNAs used to efficiently block or silence production of a specific protein. Such knock-down experiments are much quicker and cheaper to carry out than gene knockout. But as the silencing is sometimes non-specific and has off-target effects on other genes, it provides less reliable results.
## Gene therapy
In the future gene therapy may provide a way to cure genetic disorders, such as severe combined immunodeficiency or cystic fibrosis. Several gene therapy trials have used viruses to deliver 'good' genes to the cells of the patient's body. There have been a huge number of laboratory successes with gene therapy. However, several problems of viral gene therapy must be overcome before it gains widespread use. Immune response to viruses not only impedes the delivery of genes to target cells but can cause severe complications for the patient. In one of the early gene therapy trials in 1999 this led to the death of Jesse Gelsinger, who was treated using an adenoviral vector.[2]
Some viral vectors, for instance lentiviruses, insert their genomes at a seemingly random location on one of the host chromosomes, which can disturb the function of cellular genes and lead to cancer. In a severe combined immunodeficiency retroviral gene therapy trial conducted in 2002, two of the patients developed leukemia as a consequence of the treatment.[3] Adeno-associated virus-based vectors are much safer in this respect as they always integrate at the same site in the human genome.
## Vaccines
Viruses expressing pathogen proteins are currently being developed as vaccines against these pathogens, based on the same rationale as DNA vaccines. T-lymphocytes recognize cells infected with intracellular parasites based on the foreign proteins produced within the cell. T cell immunity is crucial for protection against viral infections and such diseases as malaria. A viral vaccine induces expression of pathogen proteins within host cells similarly to the Sabin Polio vaccine and other attenuated vaccines. However, since viral vaccines contain only a small fraction of pathogen genes, they are much safer and sporadic infection by the pathogen is impossible. Adenoviruses are being actively developed as vaccines.
# Types of viral vectors
## Retroviruses
Retroviruses are the one of mainstays of current gene therapy approaches. The recombinant retroviruses such as the Moloney murine leukemia virus have the ability to integrate into the host genome in a stable fashion. They contain a reverse transcriptase which allows integration into the host genome. They have been used in a number of FDA-approved clinical trials such as the SCID-X1 trial.[4] The primary drawback to use of retroviruses such as the Moloney retrovirus involves the requirement for cells to be actively dividing for transduction. As a result, cells such as neurons are very resistant to infection and transduction by retroviruses. There is a concern for insertional mutagensis due to the integration into the host genome which can lead to cancer or leukemia.
## Lentiviruses
Lentiviruses are a subclass of Retroviruses. They are widely adapted as vectors thanks to their ability integrate into the genome of non-dividing as well as dividing cells. The viral genome in the form of RNA is reverse-transcribed when the virus enters the cell to produce DNA, which is then inserted into the genome at a random position by the viral integrase enzyme. The vector, now called a provirus, remains in the genome and is passed on to the progeny of the cell when it divides. The site of integration is unpredictable, which can pose a problem. The provirus can disturb the function of cellular genes and lead to activation of oncogenes promoting the development of cancer, which raises concerns for possible applications of lentiviruses in gene therapy.
For safety reasons lentiviral vectors never carry the genes required for their replication. To produce a lentivirus, several plasmids are transfected into a so-called packaging cell line, commonly HEK 293. One or more plasmids, generally referred to as packaging plasmids, encode the virion proteins, such as the capsid and the reverse transcriptase. Another plasmid contains the genetic material to be delivered by the vector. It is transcribed to produce the single-stranded RNA viral genome and is marked by the presence of the ψ (psi) sequence. This sequence is used to package the genome into the virion.
## Adenoviruses
As opposed to lentiviruses, adenoviral DNA does not integrate into the genome and is not replicated during cell division. This limits their use in basic research, although adenoviral vectors are occasionally used in in vitro experiments. Their primary applications are in gene therapy and vaccination. Since humans commonly come in contact with adenoviruses, which cause respiratory, gastrointestinal and eye infections, they trigger a rapid immune response with potentially dangerous consequences.[2] To overcome this problem scientists are currently investigating adenoviruses to which humans do not have immunity.
## Adeno-associated viruses
## Nanoengineered Substances
Substances such as Ormosil have been successfully used as a DNA vector. | https://www.wikidoc.org/index.php/Viral_vector | |
769d99a0f77bd0ed2bbf354fec989a8cec5f1c46 | wikidoc | Visceral fat | Visceral fat
# Overview
Visceral fat, also known as inner organ fat, is located inside the peritoneal cavity, packed in between internal organs, as opposed to subcutaneous fat which is found underneath the skin and intramuscular fat which is found interspersed in skeletal muscle. An excess of visceral fat leads to the "pot belly" or "beer belly" effect, in which the abdomen protrudes excessively. This body type is also known as "apple" shaped, as opposed to "pear" shape, in which fat is deposited on the hips and buttocks. Visceral fat is composed of several adipose depots including mesenteric, epididymal white adipose tissue (EWAT) and perirenal depots. Visceral fat accumulation is associated with increased risk of heart disease and type 2 diabetes.
de:Viszeralfett
# Measuring Visceral Fat
Visceral fat can be estimated per area, manually or using a BIA or bioelectrical impedance analysis diagnostic machine or using a CT or computed tomography scan at the umbilical level.
The VFA using BIA can be expressed as:
VFA=a0+a1Vo'Wc
where a0 and a1 are constants, Vo' is the voltage measured at the flank and Wc is the waist circumference.
The voltage occurring at the flank to the flow between the umbilicus and the back becomes larger as the visceral fat can be different even with subjects with the same Wc because the resistance of intra abdominal fat is greater than the resistance of fat free mass.
# Risk Factors
Visceral fat has been associated with more risk factor syndromes than the BMI or body mass index which is the result of the equation of diving the weight over the height squared.
Scientists have proved that it is possible to be thin on the outside and have inner organ fat | Visceral fat
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Dayana Davidis, M.D. [2]
# Overview
Visceral fat, also known as inner organ fat, is located inside the peritoneal cavity, packed in between internal organs, as opposed to subcutaneous fat which is found underneath the skin and intramuscular fat which is found interspersed in skeletal muscle. An excess of visceral fat leads to the "pot belly" or "beer belly" effect, in which the abdomen protrudes excessively. This body type is also known as "apple" shaped, as opposed to "pear" shape, in which fat is deposited on the hips and buttocks. Visceral fat is composed of several adipose depots including mesenteric, epididymal white adipose tissue (EWAT) and perirenal depots. Visceral fat accumulation is associated with increased risk of heart disease and type 2 diabetes.
de:Viszeralfett
Template:WikiDoc Sources
# Measuring Visceral Fat
Visceral fat can be estimated per area, manually or using a BIA or bioelectrical impedance analysis diagnostic machine or using a CT or computed tomography scan at the umbilical level.
The VFA using BIA can be expressed as:
VFA=a0+a1Vo'Wc
where a0 and a1 are constants, Vo' is the voltage measured at the flank and Wc is the waist circumference.
The voltage occurring at the flank to the flow between the umbilicus and the back becomes larger as the visceral fat can be different even with subjects with the same Wc because the resistance of intra abdominal fat is greater than the resistance of fat free mass.
# Risk Factors
Visceral fat has been associated with more risk factor syndromes than the BMI or body mass index which is the result of the equation of diving the weight over the height squared.
Scientists have proved that it is possible to be thin on the outside and have inner organ fat | https://www.wikidoc.org/index.php/Visceral_fat | |
0ebf5e58b85179dcb98d306aa3f6d7616f08946d | wikidoc | Viscum album | Viscum album
Viscum album is a species of mistletoe, the species originally so-named, and also known as European Mistletoe or Common Mistletoe to distinguish it from other related species. It is native to Europe, and western and southern Asia.
It is a hemi-parasitic shrub, which grows on the stems of other trees. It has stems 30-100 cm long with dichotomous branching. The leaves are in opposite pairs, strap-shaped, entire, leathery textured, 2-8 cm long and 0.8-2.5 cm broad, yellowish-green in colour. Usually dioecious, the flowers are inconspicuous, yellowish-green, 2-3 mm diameter. The fruit is a white or yellow berry containing several seeds embedded in the very sticky, glutinous fruit pulp.
Up to four subspecies are commonly accepted (Flora Europaea, Flora of China, Bean 1980, Blamey & Grey-Wilson 1989), and two others sometimes so. They differ in fruit colour, leaf shape and size, and most obviously in the host trees utilised.
- Viscum album subsp. abietis (Wiesb.) Abromeit. Central Europe. Fruit white; leaves up to 8 cm. On Abies.
- Viscum album subsp. album. Europe, southwestern Asia east to Nepal. Fruit white; leaves 3-5 cm. On Malus, Populus, Tilia, and less often on numerous other species, including (rarely) Quercus.
- Viscum album subsp. austriacum (Wiesb.) Vollmann. Fruit yellow; leaves 2-4 cm. Central Europe. On Larix, Pinus, Picea.
- Viscum album subsp. meridianum (Danser) D.G.Long. Southeastern Asia. Fruit yellow; leaves 3-5 cm. On Acer, Carpinus, Juglans, Prunus, Sorbus.
- Viscum album subsp. creticum Böhling et al. has recently been described from eastern Crete (Böhling et al. 2002). Fruit white; leaves short. On Pinus brutia.
- Viscum album subsp. coloratum Kom. is treated by the Flora of China as a distinct species Viscum coloratum (Kom) Nakai.
# Mythology and symbolism
It has always attracted interest and has been surrounded by a number of myths and legends. In some countries it plays a part in Christmas festivities. It also features in the popular Asterix comic books, where mistletoe collected from oaks was considered to have special qualities.
- Fruit of subsp. album, Poland
Fruit of subsp. album, Poland
- Plant of subsp. austriacum on Pinus sylvestris, Poland
Plant of subsp. austriacum on Pinus sylvestris, Poland
- 19th century illustration by Köhler
19th century illustration by Köhler
- File:VIscum album fruit kz.jpg | Viscum album
Viscum album is a species of mistletoe, the species originally so-named, and also known as European Mistletoe or Common Mistletoe to distinguish it from other related species. It is native to Europe, and western and southern Asia.
It is a hemi-parasitic shrub, which grows on the stems of other trees. It has stems 30-100 cm long with dichotomous branching. The leaves are in opposite pairs, strap-shaped, entire, leathery textured, 2-8 cm long and 0.8-2.5 cm broad, yellowish-green in colour. Usually dioecious, the flowers are inconspicuous, yellowish-green, 2-3 mm diameter. The fruit is a white or yellow berry containing several seeds embedded in the very sticky, glutinous fruit pulp.
Up to four subspecies are commonly accepted (Flora Europaea, Flora of China, Bean 1980, Blamey & Grey-Wilson 1989), and two others sometimes so. They differ in fruit colour, leaf shape and size, and most obviously in the host trees utilised.
- Viscum album subsp. abietis (Wiesb.) Abromeit. Central Europe. Fruit white; leaves up to 8 cm. On Abies.
- Viscum album subsp. album. Europe, southwestern Asia east to Nepal. Fruit white; leaves 3-5 cm. On Malus, Populus, Tilia, and less often on numerous other species, including (rarely) Quercus.
- Viscum album subsp. austriacum (Wiesb.) Vollmann. Fruit yellow; leaves 2-4 cm. Central Europe. On Larix, Pinus, Picea.
- Viscum album subsp. meridianum (Danser) D.G.Long. Southeastern Asia. Fruit yellow; leaves 3-5 cm. On Acer, Carpinus, Juglans, Prunus, Sorbus.
- Viscum album subsp. creticum Böhling et al. has recently been described from eastern Crete (Böhling et al. 2002). Fruit white; leaves short. On Pinus brutia.
- Viscum album subsp. coloratum Kom. is treated by the Flora of China as a distinct species Viscum coloratum (Kom) Nakai.
## Mythology and symbolism
It has always attracted interest and has been surrounded by a number of myths and legends. In some countries it plays a part in Christmas festivities. It also features in the popular Asterix comic books, where mistletoe collected from oaks was considered to have special qualities.
- Fruit of subsp. album, Poland
Fruit of subsp. album, Poland
- Plant of subsp. austriacum on Pinus sylvestris, Poland
Plant of subsp. austriacum on Pinus sylvestris, Poland
- 19th century illustration by Köhler
19th century illustration by Köhler
- File:VIscum album fruit kz.jpg | https://www.wikidoc.org/index.php/Viscum_album | |
48432380535e4c1ed0c450b8cc5c7f68601eb8f9 | wikidoc | Vitellogenin | Vitellogenin
Vitellogenin (Vg) (from latin vitellus = yolk and gener = to produce) is a synonymous term for the gene and the expressed protein. The molecule is classified as a glyco-lipo-protein, having properties of a sugar, fat and protein.
Vitellogenin is an egg yolk precursor protein expressed in female fish, dormant in male fish and female insects. In the presence of estrogenic endocrine disruptive chemicals (EDCs), males can express the Vg gene in a dose dependent manner. The use of Vg gene expression in male fish can be used as a molecular marker of exposure to estrogenic EDCs.
# Vitellogenin and honey bees
Honey bees deposit vitellogenin in fat bodies in their abdomen and heads. The fat bodies apparently acts as a food storage reservoir. The glycolipoprotein vitellogenin has additional functionality as it acts as an antioxidant to prolong Queen bee and forager lifespan as well as a hormone that affects future foraging behavior.
The health of a honey bee colony is dependent upon the vitellogenin reserves of the nurse bees - the foragers have low levels of vitellogenin. As expendable laborers the foragers are fed just enough protein to keep them working their risky task of collecting nectar and pollen. Vitellogenin is important during the nest stage and thus for worker division of labor. A nurse bees vitellogenin titer that developed in the first four days after emergence, affects its subsequent age to begin foraging and whether it preferentially forages for nectar or pollen. If young workers are short on food their first days of life, they tend to begin foraging early and preferentially for nectar. If they are moderately fed, they forage at normal age preferentially for nectar. If they are abundantly fed, immediately after emergence, their vitellogenin titer is high and they begin foraging later in life, preferentially collecting pollen, which is the only available protein source for honey bees.
## Vitellogenin and juvenile hormone feedback loop
Vitellogenin is part of a regulatory feedback loop that enables vitellogenin and juvenile hormone to mutually suppress each other. Vitellogenin and juvenile hormone work antagonistically in the honey bee to regulate their development and behavior. Suppression of one leads to high titers of the other. It is likely that the balance between vitellogenin and juvenile hormone levels is also involved in swarming behavior.
Juvenile hormone levels drop pre-swarming and it is expected that vitellogenin levels would therefore rise. Swarming bees would want to pack along as much vitellogenin as possible to extend their lifespan and to be able to quickly build a new nest. | Vitellogenin
Vitellogenin (Vg) (from latin vitellus = yolk and gener = to produce) is a synonymous term for the gene and the expressed protein. The molecule is classified as a glyco-lipo-protein, having properties of a sugar, fat and protein.
Vitellogenin is an egg yolk precursor protein expressed in female fish, dormant in male fish and female insects. In the presence of estrogenic endocrine disruptive chemicals (EDCs), males can express the Vg gene in a dose dependent manner. The use of Vg gene expression in male fish can be used as a molecular marker of exposure to estrogenic EDCs.
# Vitellogenin and honey bees
Honey bees deposit vitellogenin in fat bodies in their abdomen and heads. The fat bodies apparently acts as a food storage reservoir. The glycolipoprotein vitellogenin has additional functionality as it acts as an antioxidant to prolong Queen bee and forager lifespan as well as a hormone that affects future foraging behavior. [1]
The health of a honey bee colony is dependent upon the vitellogenin reserves of the nurse bees - the foragers have low levels of vitellogenin. As expendable laborers the foragers are fed just enough protein to keep them working their risky task of collecting nectar and pollen. Vitellogenin is important during the nest stage and thus for worker division of labor. A nurse bees vitellogenin titer that developed in the first four days after emergence, affects its subsequent age to begin foraging and whether it preferentially forages for nectar or pollen. If young workers are short on food their first days of life, they tend to begin foraging early and preferentially for nectar. If they are moderately fed, they forage at normal age preferentially for nectar. If they are abundantly fed, immediately after emergence, their vitellogenin titer is high and they begin foraging later in life, preferentially collecting pollen, which is the only available protein source for honey bees.
## Vitellogenin and juvenile hormone feedback loop
Vitellogenin is part of a regulatory feedback loop that enables vitellogenin and juvenile hormone to mutually suppress each other. Vitellogenin and juvenile hormone work antagonistically in the honey bee to regulate their development and behavior. Suppression of one leads to high titers of the other. [2] It is likely that the balance between vitellogenin and juvenile hormone levels is also involved in swarming behavior. [3]
Juvenile hormone levels drop pre-swarming and it is expected that vitellogenin levels would therefore rise. Swarming bees would want to pack along as much vitellogenin as possible to extend their lifespan and to be able to quickly build a new nest. | https://www.wikidoc.org/index.php/Vitellogenin | |
6b3a69d39c500fc90716d0a039d93c54443e49a4 | wikidoc | Voltage drop | Voltage drop
Voltage drop is the reduction in voltage in an electrical circuit between the source and load. In electrical wiring national and local electrical codes may set guidelines for maximum voltage drop allowed in a circuit, to ensure reasonable efficiency of distribution and proper operation of electrical equipment (the maximum permitted voltage drop varies from one country to another).
Voltage drop may be neglected when the impedance of the interconnecting conductors is small relative to the other components of the circuit.
For example, an electric space heater may very well have a resistance of ten ohms, and the wires which supply it may have a resistance of 0.2 ohms, about 2% of the total circuit resistance. This means that 2% of the supplied voltage is actually being lost by the wire itself.
Excessive voltage drop will result in unsatisfactory operation of electrical equipment, and represents energy wasted in the wiring system. Voltage drop can also cause damage to electrical motors.
In electronic design and power transmission, various techniques are used to compensate for the effect of voltage drop on long circuits or where voltage levels must be accurately maintained. The simplest way to reduce voltage drop is to increase the diameter of the cable between the source and the load which lowers the overall resistance.
# Voltage drop in direct current circuits
A current flowing through the non-zero resistance of a practical conductor necessarily produces a voltage across that conductor. The dc resistance of the conductor depends upon the conductor's length, cross-sectional area, type of material, and temperature.
If the voltage between the conductor and a fixed reference point is measured at many points along the conductor, the measured voltage will decrease gradually toward the load. As the current passes through a longer and longer conductor, more and more of the voltage is "lost" (unavailable to the load), due to the voltage drop developed across the resistance of the conductor. In this diagram the voltage drop along the conductor is represented by the shaded area. The local voltages along the line decrease gradually from the source to the load. If the load current increases, the voltage drop in the supply conductor also increases. This arrangement reproduces the famous Ohm's experiment.
A principle known as Kirchoff's Law states that in any circuit, the sum of the voltage drops across each component of the circuit is equal to the supply voltage.
# Voltage drop in alternating current circuits
In alternating current circuits, additional opposition to current flow occurs due to the interaction between electric and magnetic fields and the current within the conductor; this opposition is called "impedance". The impedance in an alternating current circuit depends on the spacing and dimensions of the conductors, the frequency of the current, and the magnetic permeability of the conductor and its surroundings.
The voltage drop in an AC circuit is the product of the current and the impedance (Z) of the circuit. Electrical impedance, like resistance, is expressed in ohms. Electrical impedance is the vector sum of electrical resistance, capacitive reactance, and inductive reactance. The voltage drop occurring in an alternating current circuit is the product of the current and impedance of the circuit. It is expressed by the formula E = I Z, analogous to Ohm's law for direct current circuits.
# Voltage drop in household wiring
Most circuits in a house do not have enough current or length to produce a high voltage drop. In the case of very long circuits, for example, connecting a home to a separate building on the same property, it may be necessary to increase the size of conductors over the minimum requirement for the circuit current rating. Heavily-loaded circuits may also require a cable size increase to meet voltage drop requirements in wiring regulations.
Wiring codes or regulations set an upper limit to the allowable voltage drop in a branch circuit. In the United States, the 2005 National Electrical Code (NEC) recommends no more than a 5% voltage drop at the outlet.. The Canadian electrical code requires no more than 5% drop between service entrance and point of use. UK regulations limit voltage drop to 4% of supply voltage. Following changes to the BS7671:2008 on consumers' installation, the following will become in force on 1st July 2008:
Voltage drop of a branch circuit is readily calculated, or less accurately it can be measured by observing the voltage before and after applying a load to the circuit. Excessive voltage drop on a residential branch circuit may be a sign of insufficiently sized wiring or of other faults within the wiring system, such as high resistance connections.
# Using higher voltages
Over long distances, larger conductors become expensive, and it is preferable to redesign the circuit to operate at a higher voltage. Doubling the voltage halves the current required to deliver the same amount of power, halving the voltage drop, and an additional doubling in efficiency is realized because that drop is a smaller fraction of the total voltage.
This is the motivation for commercial high voltage electrical power distribution, and for the use of the +12V power supply rail for high-power loads in modern personal computers. | Voltage drop
Voltage drop is the reduction in voltage in an electrical circuit between the source and load. In electrical wiring national and local electrical codes may set guidelines for maximum voltage drop allowed in a circuit, to ensure reasonable efficiency of distribution and proper operation of electrical equipment (the maximum permitted voltage drop varies from one country to another)[1].
Voltage drop may be neglected when the impedance of the interconnecting conductors is small relative to the other components of the circuit.
For example, an electric space heater may very well have a resistance of ten ohms, and the wires which supply it may have a resistance of 0.2 ohms, about 2% of the total circuit resistance. This means that 2% of the supplied voltage is actually being lost by the wire itself.
Excessive voltage drop will result in unsatisfactory operation of electrical equipment, and represents energy wasted in the wiring system. Voltage drop can also cause damage to electrical motors.
In electronic design and power transmission, various techniques are used to compensate for the effect of voltage drop on long circuits or where voltage levels must be accurately maintained. The simplest way to reduce voltage drop is to increase the diameter of the cable between the source and the load which lowers the overall resistance.
# Voltage drop in direct current circuits
A current flowing through the non-zero resistance of a practical conductor necessarily produces a voltage across that conductor. The dc resistance of the conductor depends upon the conductor's length, cross-sectional area, type of material, and temperature.
If the voltage between the conductor and a fixed reference point is measured at many points along the conductor, the measured voltage will decrease gradually toward the load. As the current passes through a longer and longer conductor, more and more of the voltage is "lost" (unavailable to the load), due to the voltage drop developed across the resistance of the conductor. In this diagram the voltage drop along the conductor is represented by the shaded area. The local voltages along the line decrease gradually from the source to the load. If the load current increases, the voltage drop in the supply conductor also increases. This arrangement reproduces the famous Ohm's experiment[1].
A principle known as Kirchoff's Law states that in any circuit, the sum of the voltage drops across each component of the circuit is equal to the supply voltage.
# Voltage drop in alternating current circuits
In alternating current circuits, additional opposition to current flow occurs due to the interaction between electric and magnetic fields and the current within the conductor; this opposition is called "impedance". The impedance in an alternating current circuit depends on the spacing and dimensions of the conductors, the frequency of the current, and the magnetic permeability of the conductor and its surroundings.
The voltage drop in an AC circuit is the product of the current and the impedance (Z) of the circuit. Electrical impedance, like resistance, is expressed in ohms. Electrical impedance is the vector sum of electrical resistance, capacitive reactance, and inductive reactance. The voltage drop occurring in an alternating current circuit is the product of the current and impedance of the circuit. It is expressed by the formula <math>E = I Z</math>, analogous to Ohm's law for direct current circuits.
# Voltage drop in household wiring
Most circuits in a house do not have enough current or length to produce a high voltage drop. In the case of very long circuits, for example, connecting a home to a separate building on the same property, it may be necessary to increase the size of conductors over the minimum requirement for the circuit current rating. Heavily-loaded circuits may also require a cable size increase to meet voltage drop requirements in wiring regulations.
Wiring codes or regulations set an upper limit to the allowable voltage drop in a branch circuit. In the United States, the 2005 National Electrical Code (NEC) recommends no more than a 5% voltage drop at the outlet.[2]. The Canadian electrical code requires no more than 5% drop between service entrance and point of use. [3] UK regulations limit voltage drop to 4% of supply voltage. Following changes to the BS7671:2008 on consumers' installation, the following will become in force on 1st July 2008:
Voltage drop of a branch circuit is readily calculated, or less accurately it can be measured by observing the voltage before and after applying a load to the circuit. Excessive voltage drop on a residential branch circuit may be a sign of insufficiently sized wiring or of other faults within the wiring system, such as high resistance connections.
# Using higher voltages
Over long distances, larger conductors become expensive, and it is preferable to redesign the circuit to operate at a higher voltage. Doubling the voltage halves the current required to deliver the same amount of power, halving the voltage drop, and an additional doubling in efficiency is realized because that drop is a smaller fraction of the total voltage.
This is the motivation for commercial high voltage electrical power distribution, and for the use of the +12V power supply rail for high-power loads in modern personal computers. | https://www.wikidoc.org/index.php/Voltage_drop | |
acde3f0afb25f351c6375f97141072878c94fe25 | wikidoc | Vortioxetine | Vortioxetine
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# Black Box Warning
# Overview
Vortioxetine is an antidepressant that is FDA approved for the {{{indicationType}}} of major depressive disorder. There is a Black Box Warning for this drug as shown here. Common adverse reactions include nausea, constipation and vomiting.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- The recommended starting dose is 10 mg administered orally once daily without regard to meals. Dosage should then be increased to 20 mg/day, as tolerated, because higher doses demonstrated better treatment effects in trials conducted in the United States. The efficacy and safety of doses above 20 mg/day have not been evaluated in controlled clinical trials. A dose decrease down to 5 mg/day may be considered for patients who do not tolerate higher doses.
- Maintenance/Continuation/Extended Treatment
- It is generally agreed that acute episodes of major depression should be followed by several months or longer of sustained pharmacologic therapy. A maintenance study of BRINTELLIX demonstrated that BRINTELLIX decreased the risk of recurrence of depressive episodes compared to placebo.
- Discontinuing Treatment
- Although BRINTELLIX can be abruptly discontinued, in placebo-controlled trials patients experienced transient adverse reactions such as headache and muscle tension following abrupt discontinuation of BRINTELLIX 15 mg/day or 20 mg/day. To avoid these adverse reactions, it is recommended that the dose be decreased to 10 mg/day for one week before full discontinuation of BRINTELLIX 15 mg/day or 20 mg/day.
- Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders
- At least 14 days should elapse between discontinuation of a MAOI intended to treat psychiatric disorders and initiation of therapy with BRINTELLIX to avoid the risk of Serotonin Syndrome. Conversely, at least 21 days should be allowed after stopping BRINTELLIX before starting an MAOI intended to treat psychiatric disorders.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Vortioxetine in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Vortioxetine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Vortioxetine in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Vortioxetine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Vortioxetine in pediatric patients.
# Contraindications
- Hypersensitivity to vortioxetine or any components of the formulation. Angioedema has been reported in patients treated with BRINTELLIX.
- The use of MAOIs intended to treat psychiatric disorders with BRINTELLIX or within 21 days of stopping treatment with BRINTELLIX is contraindicated because of an increased risk of serotonin syndrome. The use of BRINTELLIX within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated.
- Starting BRINTELLIX in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome.
# Warnings
### Precautions
- Clinical Worsening and Suicide Risk
- 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 studies of antidepressant drugs (selective serotonin reuptake inhibitors and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with 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 trend toward reduction with antidepressants compared to placebo in adults aged 65 and older.
- The pooled analyses of placebo-controlled studies in children and adolescents with MDD, obsessive-compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term studies of nine antidepressant drugs in over 4,400 patients. The pooled analyses of placebo-controlled studies in adults with MDD or other psychiatric disorders included a total of 295 short-term studies (median duration of two 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 1.
- No suicides occurred in any of the pediatric studies. There were suicides in the adult studies, 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 studies 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 MDD 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 MDD 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.
- Screening Patients for Bipolar Disorder
- A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled studies) 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, 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. It should be noted that BRINTELLIX is not approved for use in treating bipolar depression.
- Serotonin Syndrome
- The development of a potentially life-threatening serotonin syndrome has been reported with serotonergic antidepressants including BRINTELLIX, when used alone but more often when used concomitantly with other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John’s Wort), and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
- Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome.
- The concomitant use of BRINTELLIX with MAOIs intended to treat psychiatric disorders is contraindicated. BRINTELLIX should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with a MAOI such as linezolid or intravenous methylene blue in a patient taking BRINTELLIX. BRINTELLIX should be discontinued before initiating treatment with the MAOI.
- If concomitant use of BRINTELLIX with other serotonergic drugs, including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John’s Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.
- Treatment with BRINTELLIX and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.
- Abnormal Bleeding
- The use of drugs that interfere with serotonin reuptake inhibition, including BRINTELLIX, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin, and other anticoagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to drugs that inhibit serotonin reuptake have ranged from ecchymosis, hematoma, epistaxis, and petechiae to life-threatening hemorrhages.
- Patients should be cautioned about the increased risk of bleeding when BRINTELLIX is coadministered with NSAIDs, aspirin, or other drugs that affect coagulation or bleeding.
- Activation of Mania/Hypomania
- Symptoms of mania/hypomania were reported in <0.1% of patients treated with BRINTELLIX in pre-marketing clinical studies. Activation of mania/hypomania has been reported in a small proportion of patients with major affective disorder who were treated with other antidepressants. As with all antidepressants, use BRINTELLIX cautiously in patients with a history or family history of bipolar disorder, mania, or hypomania.
- Angle Closure Glaucoma
- Angle Closure Glaucoma: The pupillary dilation that occurs following use of many antidepressant drugs, including BRINTELLIX, may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.
- Hyponatremia
- Hyponatremia has occurred as a result of treatment with serotonergic drugs. In many cases, hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). One case with serum sodium lower than 110 mmol/L was reported in a subject treated with BRINTELLIX in a pre-marketing clinical study. Elderly patients may be at greater risk of developing hyponatremia with a serotonergic antidepressant. Also, patients taking diuretics or who are otherwise volume-depleted can be at greater risk. Discontinuation of BRINTELLIX in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which can lead to falls. More severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death.
# 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 studies of another drug and may not reflect the rates observed in clinical practice.
- Patient Exposure
- BRINTELLIX was evaluated for safety in 4746 patients (18 years to 88 years of age) diagnosed with MDD who participated in pre-marketing clinical studies; 2616 of those patients were exposed to BRINTELLIX in 6 to 8 week, placebo-controlled studies at doses ranging from 5 mg to 20 mg once daily and 204 patients were exposed to BRINTELLIX in a 24 week to 64 week placebo-controlled maintenance study at doses of 5 mg to 10 mg once daily. Patients from the 6 to 8 week studies continued into 12‑month open-label studies. A total of 2586 patients were exposed to at least one dose of BRINTELLIX in open-label studies, 1727 were exposed to BRINTELLIX for six months and 885 were exposed for at least one year.
- Adverse Reactions Reported as Reasons for Discontinuation of Treatment
- In pooled 6 to 8 week placebo-controlled studies the incidence of patients who received BRINTELLIX 5 mg/day, 10 mg/day, 15 mg/day and 20 mg/day and discontinued treatment because of an adverse reaction was 5%, 6%, 8% and 8%, respectively, compared to 4% of placebo-treated patients. Nausea was the most common adverse reaction reported as a reason for discontinuation.
- Common Adverse Reactions in Placebo-Controlled MDD Studies
- The most commonly observed adverse reactions in MDD patients treated with BRINTELLIX in 6 to 8 week placebo-controlled studies (incidence ≥5% and at least twice the rate of placebo) were nausea, constipation and vomiting.
- Table 2 shows the incidence of common adverse reactions that occurred in ≥2% of MDD patients treated with any BRINTELLIX dose and at least 2% more frequently than in placebo-treated patients in the 6 to 8 week placebo-controlled studies.
- Nausea
- Nausea was the most common adverse reaction and its frequency was dose-related (Table 2). It was usually considered mild or moderate in intensity and the median duration was 2 weeks. Nausea was more common in females than males. Nausea most commonly occurred in the first week of BRINTELLIX treatment with 15 to 20% of patients experiencing nausea after 1 to 2 days of treatment. Approximately 10% of patients taking BRINTELLIX 10 mg/day to 20 mg/day had nausea at the end of the 6 to 8 week placebo-controlled studies.
- Sexual Dysfunction
- Difficulties in sexual desire, sexual performance and sexual satisfaction often occur as manifestations of psychiatric disorders, but they may also be consequences of pharmacologic treatment.
- In the MDD 6 to 8 week controlled trials of BRINTELLIX, voluntarily reported adverse reactions related to sexual dysfunction were captured as individual event terms. These event terms have been aggregated and the overall incidence was as follows. In male patients the overall incidence was 3%, 4%, 4%, 5% in BRINTELLIX 5 mg/day, 10 mg/day, 15 mg/day, 20 mg/day, respectively, compared to 2% in placebo. In female patients, the overall incidence was <1%, 1%, <1%, 2% in BRINTELLIX 5 mg/day, 10 mg/day, 15 mg/day, 20 mg/day, respectively, compared to <1% in placebo.
- Because voluntarily reported adverse sexual reactions are known to be underreported, in part because patients and physicians may be reluctant to discuss them, the Arizona Sexual Experiences Scale (ASEX), a validated measure designed to identify sexual side effects, was used prospectively in seven placebo-controlled trials. The ASEX scale includes five questions that pertain to the following aspects of sexual function: 1) sex drive, 2) ease of arousal, 3) ability to achieve erection (men) or lubrication (women), 4) ease of reaching orgasm, and 5) orgasm satisfaction.
- The presence or absence of sexual dysfunction among patients entering clinical studies was based on their ASEX scores. For patients without sexual dysfunction at baseline (approximately 1/3 of the population across all treatment groups in each study), Table 3 shows the incidence of patients that developed treatment-emergent sexual dysfunction when treated with BRINTELLIX or placebo in any fixed dose group. Physicians should routinely inquire about possible sexual side effects.
- Adverse Reactions Following Abrupt Discontinuation of BRINTELLIX Treatment
- Discontinuation symptoms have been prospectively evaluated in patients taking BRINTELLIX 10 mg/day, 15 mg/day, and 20 mg/day using the Discontinuation-Emergent Signs and Symptoms (DESS) scale in clinical trials. Some patients experienced discontinuation symptoms such as headache, muscle tension, mood swings, sudden outbursts of anger, dizziness, and runny nose in the first week of abrupt discontinuation of BRINTELLIX 15 mg/day and 20 mg/day.
- Laboratory Tests
- BRINTELLIX has not been associated with any clinically important changes in laboratory test parameters in serum chemistry (except sodium), hematology and urinalysis as measured in the 6 to 8 week placebo-controlled studies. Hyponatremia has been reported with the treatment of BRINTELLIX. In the 6-month, double-blind, placebo-controlled phase of a long-term study in patients who had responded to BRINTELLIX during the initial 12-week, open-label phase, there were no clinically important changes in lab test parameters between BRINTELLIX and placebo-treated patients.
- Weight
- BRINTELLIX had no significant effect on body weight as measured by the mean change from baseline in the 6 to 8 week placebo-controlled studies. In the 6-month, double-blind, placebo-controlled phase of a long-term study in patients who had responded to BRINTELLIX during the initial 12-week, open-label phase, there was no significant effect on body weight between BRINTELLIX and placebo-treated patients.
- Vital Signs
- BRINTELLIX has not been associated with any clinically significant effects on vital signs, including systolic and diastolic blood pressure and heart rate, as measured in placebo-controlled studies.
- Other Adverse Reactions Observed in Clinical Studies
- The following listing does not include reactions: 1) already listed in previous tables or elsewhere in labeling, 2) for which a drug cause was remote, 3) which were so general as to be uninformative, 4) which were not considered to have significant clinical implications, or 5) which occurred at a rate equal to or less than placebo.
Vertigo
Dyspepsia
Dysgeusia
Flushing
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Vortioxetine in the drug label.
# Drug Interactions
- Monoamine Oxidase Inhibitors
- Adverse reactions, some of which are serious or fatal, can develop in patients who use MAOIs or who have recently been discontinued from an MAOI and started on a serotonergic antidepressant(s) or who have recently had SSRI or SNRI therapy discontinued prior to initiation of an MAOI.
- Serotonergic Drugs
- Based on the mechanism of action of BRINTELLIX and the potential for serotonin toxicity, serotonin syndrome may occur when BRINTELLIX is coadministered with other drugs that may affect the serotonergic neurotransmitter systems (e.g., SSRIs, SNRIs, triptans, buspirone, tramadol, and tryptophan products etc.). Closely monitor symptoms of serotonin syndrome if BRINTELLIX is co-administered with other serotonergic drugs. Treatment with BRINTELLIX and any concomitant serotonergic agents should be discontinued immediately if serotonin syndrome occurs.
- Other CNS Active Agents
- No clinically relevant effect was observed on steady state lithium exposure following coadministration with multiple daily doses of BRINTELLIX. Multiple doses of BRINTELLIX did not affect the pharmacokinetics or pharmacodynamics (composite cognitive score) of diazepam. A clinical study has shown that BRINTELLIX (single dose of 20 or 40 mg) did not increase the impairment of mental and motor skills caused by alcohol (single dose of 0.6 g/kg). Details on the potential pharmacokinetic interactions between BRINTELLIX and bupropion can be found in Section 7.3.
- Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin)
- Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of case-control and cohort design have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. These studies have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs and SNRIs are coadministered with warfarin.
- Following coadministration of stable doses of warfarin (1 to 10 mg/day) with multiple daily doses of BRINTELLIX, no significant effects were observed in INR, prothrombin values or total warfarin (protein bound plus free drug) pharmacokinetics for both R- and S-warfarin. Coadministration of aspirin 150 mg/day with multiple daily doses of BRINTELLIX had no significant inhibitory effect on platelet aggregation or pharmacokinetics of aspirin and salicylic acid. Patients receiving other drugs that interfere with hemostasis should be carefully monitored when BRINTELLIX is initiated or discontinued.
- Potential for Other Drugs to Affect BRINTELLIX
- Reduce BRINTELLIX dose by half when a strong CYP2D6 inhibitor (e.g., bupropion, fluoxetine, paroxetine, quinidine) is coadministered. Consider increasing the BRINTELLIX dose when a strong CYP inducer (e.g., rifampicin, carbamazepine, phenytoin) is coadministered. The maximum dose is not recommended to exceed three times the original dose (Figure 1).
- Potential for BRINTELLIX to Affect Other Drugs
- No dose adjustment for the comedications is needed when BRINTELLIX is coadministered with a substrate of CYP1A2 (e.g., duloxetine), CYP2A6, CYP2B6 (e.g., bupropion), CYP2C8 (e.g., repaglinide), CYP2C9 (e.g., S-warfarin), CYP2C19 (e.g., diazepam), CYP2D6 (e.g., venlafaxine), CYP3A4/5 (e.g., budesonide), and P-gp (e.g., digoxin). In addition, no dose adjustment for lithium, aspirin, and warfarin is necessary.
- Vortioxetine and its metabolites are unlikely to inhibit the following CYP enzymes and transporter based on in vitro data: CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, and P-gp. As such, no clinically relevant interactions with drugs metabolized by these CYP enzymes would be expected.
- In addition, vortioxetine did not induce CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP3A4/5 in an in vitro study in cultured human hepatocytes. Chronic administration of BRINTELLIX is unlikely to induce the metabolism of drugs metabolized by these CYP isoforms. Furthermore, in a series of clinical drug interaction studies, coadministration of BRINTELLIX with substrates for CYP2B6 (e.g., bupropion), CYP2C9 (e.g., warfarin), and CYP2C19 (e.g., diazepam), had no clinical meaningful effect on the pharmacokinetics of these substrates (Figure 2).
- Because vortioxetine is highly bound to plasma protein, coadministration of BRINTELLIX with another drug that is highly protein bound may increase free concentrations of the other drug. However, in a clinical study with coadministration of BRINTELLIX (10 mg/day) and warfarin (1 mg/day to 10 mg/day), a highly protein-bound drug, no significant change in INR was observed.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- Risk Summary
- There are no adequate and well-controlled studies of BRINTELLIX in pregnant women. Vortioxetine caused developmental delays when administered during pregnancy to rats and rabbits at doses 15 and 10 times the maximum recommended human dose (MRHD) of 20 mg, respectively. Developmental delays were also seen after birth in rats at doses 20 times the MRHD of vortioxetine given during pregnancy and through lactation. There were no teratogenic effects in rats or rabbits at doses up to 77 and 58 times, the MRHD of vortioxetine, respectively, given during organogenesis. The incidence of malformations in human pregnancies has not been established for BRINTELLIX. All human pregnancies, regardless of drug exposure, have a background rate of 2 to 4% for major malformations, and 15 to 20% for pregnancy loss. BRINTELLIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Clinical Considerations
- Neonates exposed to SSRIs or SNRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability and constant crying. These features are consistent with either a direct toxic effect of these classes of drugs or possibly, a drug discontinuation syndrome. It should be noted that in some cases, the clinical picture is consistent with serotonin syndrome. When treating a pregnant woman with BRINTELLIX during the third trimester, the physician should carefully consider the potential risks and benefits of treatment.
- Neonates exposed to SSRIs in pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in one to two per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. Several recent epidemiologic studies suggest a positive statistical association between SSRI use in pregnancy and PPHN. Other studies do not show a significant statistical association.
- A prospective longitudinal study was conducted of 201 pregnant women with a history of major depression, who were either on antidepressants or had received antidepressants less than 12 weeks prior to their last menstrual period, and were in remission. Women who discontinued antidepressant medication during pregnancy showed a significant increase in relapse of their major depression compared to those women who remained on antidepressant medication throughout pregnancy. When treating a pregnant woman with BRINTELLIX, the physician should carefully consider both the potential risks of taking a serotonergic antidepressant, along with the established benefits of treating depression with an antidepressant.
- Animal Data
- In pregnant rats and rabbits, no teratogenic effects were seen when vortioxetine was given during the period of organogenesis at oral doses up to 160 and 60 mg/kg/day, respectively. These doses are 77 and 58 times, in rats and rabbits, respectively, the maximum recommended human dose (MRHD) of 20 mg on a mg/m2 basis. Developmental delay, seen as decreased fetal body weight and delayed ossification, occurred in rats and rabbits at doses equal to and greater than 30 and 10 mg/kg (15 and 10 times the MRHD, respectively) in the presence of maternal toxicity (decreased food consumption and decreased body weight gain). When vortioxetine was administered to pregnant rats at oral doses up to 120 mg/kg (58 times the MRHD) throughout pregnancy and lactation, the number of live-born pups was decreased and early postnatal pup mortality was increased at 40 and 120 mg/kg. Additionally, pup weights were decreased at birth to weaning at 120 mg/kg and development (specifically eye opening) was slightly delayed at 40 and 120 mg/kg. These effects were not seen at 10 mg/kg (5 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 Vortioxetine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Vortioxetine during labor and delivery.
### Nursing Mothers
- It is not known whether vortioxetine is present in human milk. Vortioxetine is present in the milk of lactating rats. Because many drugs are present in human milk and because of the potential for serious adverse reactions in nursing infants from BRINTELLIX, 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
- Clinical studies on the use of BRINTELLIX in pediatric patients have not been conducted; therefore, the safety and effectiveness of BRINTELLIX in the pediatric population have not been established.
### Geriatic Use
- No dose adjustment is recommended on the basis of age (Figure 3). Results from a single-dose pharmacokinetic study in elderly (>65 years old) vs. young (24 to 45 years old) subjects demonstrated that the pharmacokinetics were generally similar between the two age groups.
- Of the 2616 subjects in clinical studies of BRINTELLIX, 11% (286) were 65 and over, which included subjects from a placebo-controlled study specifically in elderly patients. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients.
- Serotonergic antidepressants have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event.
### Gender
There is no FDA guidance on the use of Vortioxetine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Vortioxetine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Vortioxetine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Vortioxetine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Vortioxetine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Vortioxetine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Vortioxetine in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Vortioxetine in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- There is limited clinical trial experience regarding human overdosage with BRINTELLIX. In pre-marketing clinical studies, cases of overdose were limited to patients who accidentally or intentionally consumed up to a maximum dose of 40 mg of BRINTELLIX. The maximum single dose tested was 75 mg in men. Ingestion of BRINTELLIX in the dose range of 40 to 75 mg was associated with increased rates of nausea, dizziness, diarrhea, abdominal discomfort, generalized pruritus, somnolence, and flushing.
### Management
- No specific antidotes for BRINTELLIX are known. In managing over dosage, consider the possibility of multiple drug involvement. In case of overdose, call Poison Control Center at 1-800-222-1222 for latest recommendations.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Vortioxetine in the drug label.
# Pharmacology
## Mechanism of Action
- The mechanism of the antidepressant effect of vortioxetine is not fully understood, but is thought to be related to its enhancement of serotonergic activity in the CNS through inhibition of the reuptake of serotonin (5-HT). It also has several other activities including 5-HT3 receptor antagonism and 5-HT1A receptor agonism. The contribution of these activities to vortioxetine’s antidepressant effect has not been established.
## Structure
- BRINTELLIX is an immediate-release tablet for oral administration that contains the beta (β) polymorph of vortioxetine hydrobromide (HBr), an antidepressant. Vortioxetine HBr is known chemically as 1--piperazine, hydrobromide. The empirical formula is C18 H22 N2 S, HBr with a molecular weight of 379.36 g/mol. The structural formula is:
- Vortioxetine HBr is a white to very slightly beige powder that is slightly soluble in water.
- Each BRINTELLIX tablet contains 6.355 mg, 12.71 mg, 19.065 mg, or 25.42 mg of vortioxetine HBr equivalent to 5 mg, 10 mg, 15 mg, or 20 mg of vortioxetine, respectively. The inactive ingredients in BRINTELLIX tablets include mannitol, microcrystalline cellulose, hydroxypropyl cellulose, sodium starch glycolate, magnesium stearate and film coating which consists of hypromellose, titanium dioxide, polyethylene glycol 400, iron oxide red (5 mg, 15 mg, and 20 mg) and iron oxide yellow (10 mg and 15 mg).
## Pharmacodynamics
- Vortioxetine binds with high affinity to the human serotonin transporter (Ki=1.6 nM), but not to the norepinephrine (Ki=113 nM) or dopamine (Ki>1000 nM) transporters. Vortioxetine potently and selectively inhibits reuptake of serotonin (IC50=5.4 nM). Vortioxetine binds to 5-HT3 (Ki=3.7 nM), 5-HT1A (Ki=15 nM), 5-HT7 (Ki=19 nM), 5-HT1D (Ki=54 nM), and 5-HT1B (Ki=33 nM), receptors and is a 5-HT3, 5-HT1D, and 5-HT7 receptor antagonist, 5-HT1B receptor partial agonist, and 5-HT1A receptor agonist.
- In humans, the mean 5-HT transporter occupancy, based on the results from 2 clinical PET studies using 5-HTT ligands (-MADAM or -DASB), was approximately 50% at 5 mg/day, 65% at 10 mg/day and approximately 80% at 20 mg/day in the regions of interest.
- Effect on Cardiac Repolarization
- The effect of vortioxetine 10 mg and 40 mg administered once daily on QTc interval was evaluated in a randomized, double-blind, placebo-, and active-controlled (moxifloxacin 400 mg), four-treatment-arm parallel study in 340 male subjects. In the study the upper bound of the one-sided 95% confidence interval for the QTc was below 10 ms, the threshold for regulatory concern. The oral dose of 40 mg is sufficient to assess the effect of metabolic inhibition.
- Effect on Driving Performance
- In a clinical study in healthy subjects, BRINTELLIX did not impair driving performance, or have adverse psychomotor or cognitive effects following single and multiple doses of 10 mg/day. Because any psychoactive drug may impair judgment, thinking, or motor skills, however, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that BRINTELLIX therapy does not affect their ability to engage in such activities.
## Pharmacokinetics
- Vortioxetine pharmacological activity is due to the parent drug. The pharmacokinetics of vortioxetine (2.5 mg to 60 mg) are linear and dose-proportional when vortioxetine is administered once daily. The mean terminal half-life is approximately 66 hours, and steady-state plasma concentrations are typically achieved within two weeks of dosing.
- Absorption
- The maximal plasma vortioxetine concentration (Cmax) after dosing is reached within 7 to 11 hours postdose (Tmax). Steady-state mean Cmax values were 9, 18, and 33 ng/mL following doses of 5, 10, and 20 mg/day. Absolute bioavailability is 75%. No effect of food on the pharmacokinetics was observed.
- Distribution
- The apparent volume of distribution of vortioxetine is approximately 2600 L, indicating extensive extravascular distribution. The plasma protein binding of vortioxetine in humans is 98%, independent of plasma concentrations. No apparent difference in the plasma protein binding between healthy subjects and subjects with hepatic (mild, moderate) or renal (mild, moderate, severe, ESRD) impairment is observed.
- Metabolism and Elimination
- Vortioxetine is extensively metabolized primarily through oxidation via cytochrome P450 isozymes CYP2D6, CYP3A4/5, CYP2C19, CYP2C9, CYP2A6, CYP2C8 and CYP2B6 and subsequent glucuronic acid conjugation. CYP2D6 is the primary enzyme catalyzing the metabolism of vortioxetine to its major, pharmacologically inactive, carboxylic acid metabolite, and poor metabolizers of CYP2D6 have approximately twice the vortioxetine plasma concentration of extensive metabolizers.
- Following a single oral dose of -labeled vortioxetine, approximately 59% and 26% of the administered radioactivity was recovered in the urine and feces, respectively as metabolites. Negligible amounts of unchanged vortioxetine were excreted in the urine up to 48 hours. The presence of hepatic (mild or moderate) or renal impairment (mild, moderate, severe and ESRD) did not affect the apparent clearance of vortioxetine.
## Nonclinical Toxicology
- Carcinogenesis
- Carcinogenicity studies were conducted in which CD-1 mice and Wistar rats were given oral doses of vortioxetine up to 50 and 100 mg/kg/day for male and female mice, respectively, and 40 and 80 mg/kg/day for male and female rats, respectively, for 2 years. The doses in the two species were approximately 12, 24, 20, and 39 times, respectively, the maximum recommended human dose (MRHD) of 20 mg on a mg/m2 basis.
- In rats, the incidence of benign polypoid adenomas of the rectum was statistically significantly increased in females at doses 39 times the MRHD, but not at 15 times the MRHD. These were considered related to inflammation and hyperplasia and possibly caused by an interaction with a vehicle component of the formulation used for the study. The finding did not occur in male rats at 20 times the MRHD.
- In mice, vortioxetine was not carcinogenic in males or females at doses up to 12 and 24 times, respectively, the MRHD.
- Mutagenicity
- Vortioxetine was not genotoxic in the in vitro bacterial reverse mutation assay (Ames test), an in vitro chromosome aberration assay in cultured human lymphocytes, and an in vivo rat bone marrow micronucleus assay.
- Impairment of Fertility
- Treatment of rats with vortioxetine at doses up to 120 mg/kg/day had no effect on male or female fertility, which is 58 times the maximum recommended human dose (MRHD) of 20 mg on a mg/m2 basis.
# Clinical Studies
- The efficacy of BRINTELLIX in treatment for MDD was established in six 6 to 8 week randomized, double-blind, placebo-controlled, fixed-dose studies (including one study in the elderly) and one maintenance study in adult inpatients and outpatients who met the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) criteria for MDD.
- Adults (aged 18 years to 75 years)
- The efficacy of BRINTELLIX in patients aged 18 years to 75 years was demonstrated in five 6 to 8 week, placebo-controlled studies (Studies 1 to 5 in Table 4). In these studies, patients were randomized to BRINTELLIX 5 mg, 10 mg, 15 mg or 20 mg or placebo once daily. For patients who were randomized to BRINTELLIX 15 mg/day or 20 mg/day, the final doses were titrated up from 10 mg/day after the first week.
- The primary efficacy measures were the Hamilton Depression Scale (HAMD-24) total score in Study 2 and the Montgomery-Asberg Depression Rating Scale (MADRS) total score in all other studies. In each of these studies, at least one dose group of BRINTELLIX was superior to placebo in improvement of depressive symptoms as measured by mean change from baseline to endpoint visit on the primary efficacy measurement (see Table 4). Subgroup analysis by age, gender or race did not suggest any clear evidence of differential responsiveness. Two studies of the 5 mg dose in the U.S. (not represented in Table 4) failed to show effectiveness.
- Elderly Study (aged 64 years to 88 years)
- The efficacy of BRINTELLIX for the treatment of MDD was also demonstrated in a randomized, double-blind, placebo-controlled, fixed-dose study of BRINTELLIX in elderly patients (aged 64 years to 88 years) with MDD (Study 6 in Table 4). Patients meeting the diagnostic criteria for recurrent MDD with at least one previous major depressive episode before the age of 60 years and without comorbid cognitive impairment (Mini Mental State Examination score <24) received BRINTELLIX 5 mg or placebo.
- Time Course of Treatment Response
- In the 6 to 8 week placebo-controlled studies, an effect of BRINTELLIX based on the primary efficacy measure was generally observed starting at Week 2 and increased in subsequent weeks with the full antidepressant effect of BRINTELLIX generally not seen until Study Week 4 or later. Figure 4 depicts time course of response in U.S. based on the primary efficacy measure (MADRS) in Study 5.
- Maintenance Study
- In a non-US maintenance study (Study 7 in Figure 6), 639 patients meeting DSM-IV-TR criteria for MDD received flexible doses of BRINTELLIX (5 mg or 10 mg) once daily during an initial 12 week open-label treatment phase; the dose of BRINTELLIX was fixed during Weeks 8 to 12. Three hundred ninety six (396) patients who were in remission (MADRS total score ≤10 at both Weeks 10 and 12) after open-label treatment were randomly assigned to continuation of a fixed dose of BRINTELLIX at the final dose they responded to (about 75% of patients were on 10 mg/day) during the open-label phase or to placebo for 24 to 64 weeks. Approximately 61% of randomized patients satisfied remission criterion (MADRS total score ≤10) for at least 4 weeks (since Week 8), and 15% for at least 8 weeks (since Week 4). Patients on BRINTELLIX experienced a statistically significantly longer time to have recurrence of depressive episodes than did patients on placebo. Recurrence of depressive episode was defined as a MADRS total score ≥22 or lack of efficacy as judged by the investigator.
# How Supplied
- BRINTELLIX tablets are available as follows:
- Storage: Store at 77°F (25°C); excursions permitted to 59°F to 86°F (15°C to 30°C).
## Storage
There is limited information regarding Vortioxetine Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise patients and their caregivers about the benefits and risks associated with treatment with BRINTELLIX and counsel them in its appropriate use. Advise patients and their caregivers to read the Medication Guide and assist them in understanding its contents. The complete text of the Medication Guide is reprinted at the end of this document.
- Suicide Risk
- Advise patients and caregivers to look for the emergence of suicidal ideation and behavior, especially early during treatment and when the dose is adjusted up or down.
- Discontinuation of Treatment
- Patients who are on BRINTELLIX 15 mg/day or 20 mg/day may experience headache, muscle tension, mood swings, sudden outburst of anger, dizziness and runny nose if they abruptly stop their medicine. Advise patients not stopping BRINTELLIX without talking to their healthcare provider.
- Concomitant Medication
- Advise patients to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter medications because of a potential for interactions. Instruct patients not to take BRINTELLIX with an MAOI or within 14 days of stopping an MAOI and to allow 21 days after stopping BRINTELLIX before starting an MAOI.
- Serotonin Syndrome
- Caution patients about the risk of serotonin syndrome, particularly with the concomitant use of BRINTELLIX and triptans, tricyclic antidepressants, fentanyl, Lithium, tramadol, tryptophan supplements, and St. John’s Wort supplements.
- Abnormal Bleeding
- Caution patients about the increased risk of abnormal bleeding when BRINTELLIX is given with NSAIDs, aspirin, warfarin, or other drugs that affect coagulation.
- Activation of Mania/Hypomania
- Advise patients and their caregivers to look for signs of activation of mania/hypomania.
- Angle Closure Glaucoma
- Patients should be advised that taking BRINTELLIX can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible.
- Hyponatremia
- Advise patients that if they are treated with diuretics, or are otherwise volume depleted, or are elderly, they may be at greater risk of developing hyponatremia while taking BRINTELLIX.
- Nausea
- Advise patients that nausea is the most common adverse reaction, and is dose related. Nausea commonly occurs within the first week of treatment, then decreases in frequency but can persist in some patients.
- Alcohol
- A clinical study has shown that BRINTELLIX (single dose of 20 or 40 mg/day) did not increase the impairment of mental and motor skills caused by alcohol.
- Allergic Reactions
- Advise patients to notify their healthcare provider if they develop an allergic reaction such as rash, hives, swelling, or difficulty breathing.
- Pregnancy
- Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during therapy with BRINTELLIX.
- Nursing Mothers
- Advise patients to notify their healthcare provider if they are breast-feeding an infant and would like to continue or start BRINTELLIX.
# Precautions with Alcohol
- Alcohol-Vortioxetine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- BRINTELLIX®
# Look-Alike Drug Names
There is limited information regarding Vortioxetine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Vortioxetine
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
Vortioxetine is an antidepressant that is FDA approved for the {{{indicationType}}} of major depressive disorder. There is a Black Box Warning for this drug as shown here. Common adverse reactions include nausea, constipation and vomiting.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- The recommended starting dose is 10 mg administered orally once daily without regard to meals. Dosage should then be increased to 20 mg/day, as tolerated, because higher doses demonstrated better treatment effects in trials conducted in the United States. The efficacy and safety of doses above 20 mg/day have not been evaluated in controlled clinical trials. A dose decrease down to 5 mg/day may be considered for patients who do not tolerate higher doses.
- Maintenance/Continuation/Extended Treatment
- It is generally agreed that acute episodes of major depression should be followed by several months or longer of sustained pharmacologic therapy. A maintenance study of BRINTELLIX demonstrated that BRINTELLIX decreased the risk of recurrence of depressive episodes compared to placebo.
- Discontinuing Treatment
- Although BRINTELLIX can be abruptly discontinued, in placebo-controlled trials patients experienced transient adverse reactions such as headache and muscle tension following abrupt discontinuation of BRINTELLIX 15 mg/day or 20 mg/day. To avoid these adverse reactions, it is recommended that the dose be decreased to 10 mg/day for one week before full discontinuation of BRINTELLIX 15 mg/day or 20 mg/day.
- Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders
- At least 14 days should elapse between discontinuation of a MAOI intended to treat psychiatric disorders and initiation of therapy with BRINTELLIX to avoid the risk of Serotonin Syndrome. Conversely, at least 21 days should be allowed after stopping BRINTELLIX before starting an MAOI intended to treat psychiatric disorders.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Vortioxetine in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Vortioxetine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Vortioxetine in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Vortioxetine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Vortioxetine in pediatric patients.
# Contraindications
- Hypersensitivity to vortioxetine or any components of the formulation. Angioedema has been reported in patients treated with BRINTELLIX.
- The use of MAOIs intended to treat psychiatric disorders with BRINTELLIX or within 21 days of stopping treatment with BRINTELLIX is contraindicated because of an increased risk of serotonin syndrome. The use of BRINTELLIX within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated.
- Starting BRINTELLIX in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome.
# Warnings
### Precautions
- Clinical Worsening and Suicide Risk
- 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 studies of antidepressant drugs (selective serotonin reuptake inhibitors [SSRIs] and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with 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 trend toward reduction with antidepressants compared to placebo in adults aged 65 and older.
- The pooled analyses of placebo-controlled studies in children and adolescents with MDD, obsessive-compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term studies of nine antidepressant drugs in over 4,400 patients. The pooled analyses of placebo-controlled studies in adults with MDD or other psychiatric disorders included a total of 295 short-term studies (median duration of two 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 1.
- No suicides occurred in any of the pediatric studies. There were suicides in the adult studies, 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 studies 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 MDD 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 MDD 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.
- Screening Patients for Bipolar Disorder
- A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled studies) 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, 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. It should be noted that BRINTELLIX is not approved for use in treating bipolar depression.
- Serotonin Syndrome
- The development of a potentially life-threatening serotonin syndrome has been reported with serotonergic antidepressants including BRINTELLIX, when used alone but more often when used concomitantly with other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John’s Wort), and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
- Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome.
- The concomitant use of BRINTELLIX with MAOIs intended to treat psychiatric disorders is contraindicated. BRINTELLIX should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with a MAOI such as linezolid or intravenous methylene blue in a patient taking BRINTELLIX. BRINTELLIX should be discontinued before initiating treatment with the MAOI.
- If concomitant use of BRINTELLIX with other serotonergic drugs, including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John’s Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.
- Treatment with BRINTELLIX and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.
- Abnormal Bleeding
- The use of drugs that interfere with serotonin reuptake inhibition, including BRINTELLIX, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin, and other anticoagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to drugs that inhibit serotonin reuptake have ranged from ecchymosis, hematoma, epistaxis, and petechiae to life-threatening hemorrhages.
- Patients should be cautioned about the increased risk of bleeding when BRINTELLIX is coadministered with NSAIDs, aspirin, or other drugs that affect coagulation or bleeding.
- Activation of Mania/Hypomania
- Symptoms of mania/hypomania were reported in <0.1% of patients treated with BRINTELLIX in pre-marketing clinical studies. Activation of mania/hypomania has been reported in a small proportion of patients with major affective disorder who were treated with other antidepressants. As with all antidepressants, use BRINTELLIX cautiously in patients with a history or family history of bipolar disorder, mania, or hypomania.
- Angle Closure Glaucoma
- Angle Closure Glaucoma: The pupillary dilation that occurs following use of many antidepressant drugs, including BRINTELLIX, may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.
- Hyponatremia
- Hyponatremia has occurred as a result of treatment with serotonergic drugs. In many cases, hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). One case with serum sodium lower than 110 mmol/L was reported in a subject treated with BRINTELLIX in a pre-marketing clinical study. Elderly patients may be at greater risk of developing hyponatremia with a serotonergic antidepressant. Also, patients taking diuretics or who are otherwise volume-depleted can be at greater risk. Discontinuation of BRINTELLIX in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which can lead to falls. More severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death.
# 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 studies of another drug and may not reflect the rates observed in clinical practice.
- Patient Exposure
- BRINTELLIX was evaluated for safety in 4746 patients (18 years to 88 years of age) diagnosed with MDD who participated in pre-marketing clinical studies; 2616 of those patients were exposed to BRINTELLIX in 6 to 8 week, placebo-controlled studies at doses ranging from 5 mg to 20 mg once daily and 204 patients were exposed to BRINTELLIX in a 24 week to 64 week placebo-controlled maintenance study at doses of 5 mg to 10 mg once daily. Patients from the 6 to 8 week studies continued into 12‑month open-label studies. A total of 2586 patients were exposed to at least one dose of BRINTELLIX in open-label studies, 1727 were exposed to BRINTELLIX for six months and 885 were exposed for at least one year.
- Adverse Reactions Reported as Reasons for Discontinuation of Treatment
- In pooled 6 to 8 week placebo-controlled studies the incidence of patients who received BRINTELLIX 5 mg/day, 10 mg/day, 15 mg/day and 20 mg/day and discontinued treatment because of an adverse reaction was 5%, 6%, 8% and 8%, respectively, compared to 4% of placebo-treated patients. Nausea was the most common adverse reaction reported as a reason for discontinuation.
- Common Adverse Reactions in Placebo-Controlled MDD Studies
- The most commonly observed adverse reactions in MDD patients treated with BRINTELLIX in 6 to 8 week placebo-controlled studies (incidence ≥5% and at least twice the rate of placebo) were nausea, constipation and vomiting.
- Table 2 shows the incidence of common adverse reactions that occurred in ≥2% of MDD patients treated with any BRINTELLIX dose and at least 2% more frequently than in placebo-treated patients in the 6 to 8 week placebo-controlled studies.
- Nausea
- Nausea was the most common adverse reaction and its frequency was dose-related (Table 2). It was usually considered mild or moderate in intensity and the median duration was 2 weeks. Nausea was more common in females than males. Nausea most commonly occurred in the first week of BRINTELLIX treatment with 15 to 20% of patients experiencing nausea after 1 to 2 days of treatment. Approximately 10% of patients taking BRINTELLIX 10 mg/day to 20 mg/day had nausea at the end of the 6 to 8 week placebo-controlled studies.
- Sexual Dysfunction
- Difficulties in sexual desire, sexual performance and sexual satisfaction often occur as manifestations of psychiatric disorders, but they may also be consequences of pharmacologic treatment.
- In the MDD 6 to 8 week controlled trials of BRINTELLIX, voluntarily reported adverse reactions related to sexual dysfunction were captured as individual event terms. These event terms have been aggregated and the overall incidence was as follows. In male patients the overall incidence was 3%, 4%, 4%, 5% in BRINTELLIX 5 mg/day, 10 mg/day, 15 mg/day, 20 mg/day, respectively, compared to 2% in placebo. In female patients, the overall incidence was <1%, 1%, <1%, 2% in BRINTELLIX 5 mg/day, 10 mg/day, 15 mg/day, 20 mg/day, respectively, compared to <1% in placebo.
- Because voluntarily reported adverse sexual reactions are known to be underreported, in part because patients and physicians may be reluctant to discuss them, the Arizona Sexual Experiences Scale (ASEX), a validated measure designed to identify sexual side effects, was used prospectively in seven placebo-controlled trials. The ASEX scale includes five questions that pertain to the following aspects of sexual function: 1) sex drive, 2) ease of arousal, 3) ability to achieve erection (men) or lubrication (women), 4) ease of reaching orgasm, and 5) orgasm satisfaction.
- The presence or absence of sexual dysfunction among patients entering clinical studies was based on their ASEX scores. For patients without sexual dysfunction at baseline (approximately 1/3 of the population across all treatment groups in each study), Table 3 shows the incidence of patients that developed treatment-emergent sexual dysfunction when treated with BRINTELLIX or placebo in any fixed dose group. Physicians should routinely inquire about possible sexual side effects.
- Adverse Reactions Following Abrupt Discontinuation of BRINTELLIX Treatment
- Discontinuation symptoms have been prospectively evaluated in patients taking BRINTELLIX 10 mg/day, 15 mg/day, and 20 mg/day using the Discontinuation-Emergent Signs and Symptoms (DESS) scale in clinical trials. Some patients experienced discontinuation symptoms such as headache, muscle tension, mood swings, sudden outbursts of anger, dizziness, and runny nose in the first week of abrupt discontinuation of BRINTELLIX 15 mg/day and 20 mg/day.
- Laboratory Tests
- BRINTELLIX has not been associated with any clinically important changes in laboratory test parameters in serum chemistry (except sodium), hematology and urinalysis as measured in the 6 to 8 week placebo-controlled studies. Hyponatremia has been reported with the treatment of BRINTELLIX. In the 6-month, double-blind, placebo-controlled phase of a long-term study in patients who had responded to BRINTELLIX during the initial 12-week, open-label phase, there were no clinically important changes in lab test parameters between BRINTELLIX and placebo-treated patients.
- Weight
- BRINTELLIX had no significant effect on body weight as measured by the mean change from baseline in the 6 to 8 week placebo-controlled studies. In the 6-month, double-blind, placebo-controlled phase of a long-term study in patients who had responded to BRINTELLIX during the initial 12-week, open-label phase, there was no significant effect on body weight between BRINTELLIX and placebo-treated patients.
- Vital Signs
- BRINTELLIX has not been associated with any clinically significant effects on vital signs, including systolic and diastolic blood pressure and heart rate, as measured in placebo-controlled studies.
- Other Adverse Reactions Observed in Clinical Studies
- The following listing does not include reactions: 1) already listed in previous tables or elsewhere in labeling, 2) for which a drug cause was remote, 3) which were so general as to be uninformative, 4) which were not considered to have significant clinical implications, or 5) which occurred at a rate equal to or less than placebo.
Vertigo
Dyspepsia
Dysgeusia
Flushing
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Vortioxetine in the drug label.
# Drug Interactions
- Monoamine Oxidase Inhibitors
- Adverse reactions, some of which are serious or fatal, can develop in patients who use MAOIs or who have recently been discontinued from an MAOI and started on a serotonergic antidepressant(s) or who have recently had SSRI or SNRI therapy discontinued prior to initiation of an MAOI.
- Serotonergic Drugs
- Based on the mechanism of action of BRINTELLIX and the potential for serotonin toxicity, serotonin syndrome may occur when BRINTELLIX is coadministered with other drugs that may affect the serotonergic neurotransmitter systems (e.g., SSRIs, SNRIs, triptans, buspirone, tramadol, and tryptophan products etc.). Closely monitor symptoms of serotonin syndrome if BRINTELLIX is co-administered with other serotonergic drugs. Treatment with BRINTELLIX and any concomitant serotonergic agents should be discontinued immediately if serotonin syndrome occurs.
- Other CNS Active Agents
- No clinically relevant effect was observed on steady state lithium exposure following coadministration with multiple daily doses of BRINTELLIX. Multiple doses of BRINTELLIX did not affect the pharmacokinetics or pharmacodynamics (composite cognitive score) of diazepam. A clinical study has shown that BRINTELLIX (single dose of 20 or 40 mg) did not increase the impairment of mental and motor skills caused by alcohol (single dose of 0.6 g/kg). Details on the potential pharmacokinetic interactions between BRINTELLIX and bupropion can be found in Section 7.3.
- Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin)
- Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of case-control and cohort design have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. These studies have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs and SNRIs are coadministered with warfarin.
- Following coadministration of stable doses of warfarin (1 to 10 mg/day) with multiple daily doses of BRINTELLIX, no significant effects were observed in INR, prothrombin values or total warfarin (protein bound plus free drug) pharmacokinetics for both R- and S-warfarin. Coadministration of aspirin 150 mg/day with multiple daily doses of BRINTELLIX had no significant inhibitory effect on platelet aggregation or pharmacokinetics of aspirin and salicylic acid. Patients receiving other drugs that interfere with hemostasis should be carefully monitored when BRINTELLIX is initiated or discontinued.
- Potential for Other Drugs to Affect BRINTELLIX
- Reduce BRINTELLIX dose by half when a strong CYP2D6 inhibitor (e.g., bupropion, fluoxetine, paroxetine, quinidine) is coadministered. Consider increasing the BRINTELLIX dose when a strong CYP inducer (e.g., rifampicin, carbamazepine, phenytoin) is coadministered. The maximum dose is not recommended to exceed three times the original dose (Figure 1).
- Potential for BRINTELLIX to Affect Other Drugs
- No dose adjustment for the comedications is needed when BRINTELLIX is coadministered with a substrate of CYP1A2 (e.g., duloxetine), CYP2A6, CYP2B6 (e.g., bupropion), CYP2C8 (e.g., repaglinide), CYP2C9 (e.g., S-warfarin), CYP2C19 (e.g., diazepam), CYP2D6 (e.g., venlafaxine), CYP3A4/5 (e.g., budesonide), and P-gp (e.g., digoxin). In addition, no dose adjustment for lithium, aspirin, and warfarin is necessary.
- Vortioxetine and its metabolites are unlikely to inhibit the following CYP enzymes and transporter based on in vitro data: CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, and P-gp. As such, no clinically relevant interactions with drugs metabolized by these CYP enzymes would be expected.
- In addition, vortioxetine did not induce CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP3A4/5 in an in vitro study in cultured human hepatocytes. Chronic administration of BRINTELLIX is unlikely to induce the metabolism of drugs metabolized by these CYP isoforms. Furthermore, in a series of clinical drug interaction studies, coadministration of BRINTELLIX with substrates for CYP2B6 (e.g., bupropion), CYP2C9 (e.g., warfarin), and CYP2C19 (e.g., diazepam), had no clinical meaningful effect on the pharmacokinetics of these substrates (Figure 2).
- Because vortioxetine is highly bound to plasma protein, coadministration of BRINTELLIX with another drug that is highly protein bound may increase free concentrations of the other drug. However, in a clinical study with coadministration of BRINTELLIX (10 mg/day) and warfarin (1 mg/day to 10 mg/day), a highly protein-bound drug, no significant change in INR was observed.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- Risk Summary
- There are no adequate and well-controlled studies of BRINTELLIX in pregnant women. Vortioxetine caused developmental delays when administered during pregnancy to rats and rabbits at doses 15 and 10 times the maximum recommended human dose (MRHD) of 20 mg, respectively. Developmental delays were also seen after birth in rats at doses 20 times the MRHD of vortioxetine given during pregnancy and through lactation. There were no teratogenic effects in rats or rabbits at doses up to 77 and 58 times, the MRHD of vortioxetine, respectively, given during organogenesis. The incidence of malformations in human pregnancies has not been established for BRINTELLIX. All human pregnancies, regardless of drug exposure, have a background rate of 2 to 4% for major malformations, and 15 to 20% for pregnancy loss. BRINTELLIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Clinical Considerations
- Neonates exposed to SSRIs or SNRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability and constant crying. These features are consistent with either a direct toxic effect of these classes of drugs or possibly, a drug discontinuation syndrome. It should be noted that in some cases, the clinical picture is consistent with serotonin syndrome. When treating a pregnant woman with BRINTELLIX during the third trimester, the physician should carefully consider the potential risks and benefits of treatment.
- Neonates exposed to SSRIs in pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in one to two per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. Several recent epidemiologic studies suggest a positive statistical association between SSRI use in pregnancy and PPHN. Other studies do not show a significant statistical association.
- A prospective longitudinal study was conducted of 201 pregnant women with a history of major depression, who were either on antidepressants or had received antidepressants less than 12 weeks prior to their last menstrual period, and were in remission. Women who discontinued antidepressant medication during pregnancy showed a significant increase in relapse of their major depression compared to those women who remained on antidepressant medication throughout pregnancy. When treating a pregnant woman with BRINTELLIX, the physician should carefully consider both the potential risks of taking a serotonergic antidepressant, along with the established benefits of treating depression with an antidepressant.
- Animal Data
- In pregnant rats and rabbits, no teratogenic effects were seen when vortioxetine was given during the period of organogenesis at oral doses up to 160 and 60 mg/kg/day, respectively. These doses are 77 and 58 times, in rats and rabbits, respectively, the maximum recommended human dose (MRHD) of 20 mg on a mg/m2 basis. Developmental delay, seen as decreased fetal body weight and delayed ossification, occurred in rats and rabbits at doses equal to and greater than 30 and 10 mg/kg (15 and 10 times the MRHD, respectively) in the presence of maternal toxicity (decreased food consumption and decreased body weight gain). When vortioxetine was administered to pregnant rats at oral doses up to 120 mg/kg (58 times the MRHD) throughout pregnancy and lactation, the number of live-born pups was decreased and early postnatal pup mortality was increased at 40 and 120 mg/kg. Additionally, pup weights were decreased at birth to weaning at 120 mg/kg and development (specifically eye opening) was slightly delayed at 40 and 120 mg/kg. These effects were not seen at 10 mg/kg (5 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 Vortioxetine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Vortioxetine during labor and delivery.
### Nursing Mothers
- It is not known whether vortioxetine is present in human milk. Vortioxetine is present in the milk of lactating rats. Because many drugs are present in human milk and because of the potential for serious adverse reactions in nursing infants from BRINTELLIX, 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
- Clinical studies on the use of BRINTELLIX in pediatric patients have not been conducted; therefore, the safety and effectiveness of BRINTELLIX in the pediatric population have not been established.
### Geriatic Use
- No dose adjustment is recommended on the basis of age (Figure 3). Results from a single-dose pharmacokinetic study in elderly (>65 years old) vs. young (24 to 45 years old) subjects demonstrated that the pharmacokinetics were generally similar between the two age groups.
- Of the 2616 subjects in clinical studies of BRINTELLIX, 11% (286) were 65 and over, which included subjects from a placebo-controlled study specifically in elderly patients. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients.
- Serotonergic antidepressants have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event.
### Gender
There is no FDA guidance on the use of Vortioxetine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Vortioxetine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Vortioxetine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Vortioxetine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Vortioxetine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Vortioxetine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Vortioxetine in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Vortioxetine in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- There is limited clinical trial experience regarding human overdosage with BRINTELLIX. In pre-marketing clinical studies, cases of overdose were limited to patients who accidentally or intentionally consumed up to a maximum dose of 40 mg of BRINTELLIX. The maximum single dose tested was 75 mg in men. Ingestion of BRINTELLIX in the dose range of 40 to 75 mg was associated with increased rates of nausea, dizziness, diarrhea, abdominal discomfort, generalized pruritus, somnolence, and flushing.
### Management
- No specific antidotes for BRINTELLIX are known. In managing over dosage, consider the possibility of multiple drug involvement. In case of overdose, call Poison Control Center at 1-800-222-1222 for latest recommendations.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Vortioxetine in the drug label.
# Pharmacology
## Mechanism of Action
- The mechanism of the antidepressant effect of vortioxetine is not fully understood, but is thought to be related to its enhancement of serotonergic activity in the CNS through inhibition of the reuptake of serotonin (5-HT). It also has several other activities including 5-HT3 receptor antagonism and 5-HT1A receptor agonism. The contribution of these activities to vortioxetine’s antidepressant effect has not been established.
## Structure
- BRINTELLIX is an immediate-release tablet for oral administration that contains the beta (β) polymorph of vortioxetine hydrobromide (HBr), an antidepressant. Vortioxetine HBr is known chemically as 1-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]-piperazine, hydrobromide. The empirical formula is C18 H22 N2 S, HBr with a molecular weight of 379.36 g/mol. The structural formula is:
- Vortioxetine HBr is a white to very slightly beige powder that is slightly soluble in water.
- Each BRINTELLIX tablet contains 6.355 mg, 12.71 mg, 19.065 mg, or 25.42 mg of vortioxetine HBr equivalent to 5 mg, 10 mg, 15 mg, or 20 mg of vortioxetine, respectively. The inactive ingredients in BRINTELLIX tablets include mannitol, microcrystalline cellulose, hydroxypropyl cellulose, sodium starch glycolate, magnesium stearate and film coating which consists of hypromellose, titanium dioxide, polyethylene glycol 400, iron oxide red (5 mg, 15 mg, and 20 mg) and iron oxide yellow (10 mg and 15 mg).
## Pharmacodynamics
- Vortioxetine binds with high affinity to the human serotonin transporter (Ki=1.6 nM), but not to the norepinephrine (Ki=113 nM) or dopamine (Ki>1000 nM) transporters. Vortioxetine potently and selectively inhibits reuptake of serotonin (IC50=5.4 nM). Vortioxetine binds to 5-HT3 (Ki=3.7 nM), 5-HT1A (Ki=15 nM), 5-HT7 (Ki=19 nM), 5-HT1D (Ki=54 nM), and 5-HT1B (Ki=33 nM), receptors and is a 5-HT3, 5-HT1D, and 5-HT7 receptor antagonist, 5-HT1B receptor partial agonist, and 5-HT1A receptor agonist.
- In humans, the mean 5-HT transporter occupancy, based on the results from 2 clinical PET studies using 5-HTT ligands ([11C]-MADAM or [11C]-DASB), was approximately 50% at 5 mg/day, 65% at 10 mg/day and approximately 80% at 20 mg/day in the regions of interest.
- Effect on Cardiac Repolarization
- The effect of vortioxetine 10 mg and 40 mg administered once daily on QTc interval was evaluated in a randomized, double-blind, placebo-, and active-controlled (moxifloxacin 400 mg), four-treatment-arm parallel study in 340 male subjects. In the study the upper bound of the one-sided 95% confidence interval for the QTc was below 10 ms, the threshold for regulatory concern. The oral dose of 40 mg is sufficient to assess the effect of metabolic inhibition.
- Effect on Driving Performance
- In a clinical study in healthy subjects, BRINTELLIX did not impair driving performance, or have adverse psychomotor or cognitive effects following single and multiple doses of 10 mg/day. Because any psychoactive drug may impair judgment, thinking, or motor skills, however, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that BRINTELLIX therapy does not affect their ability to engage in such activities.
## Pharmacokinetics
- Vortioxetine pharmacological activity is due to the parent drug. The pharmacokinetics of vortioxetine (2.5 mg to 60 mg) are linear and dose-proportional when vortioxetine is administered once daily. The mean terminal half-life is approximately 66 hours, and steady-state plasma concentrations are typically achieved within two weeks of dosing.
- Absorption
- The maximal plasma vortioxetine concentration (Cmax) after dosing is reached within 7 to 11 hours postdose (Tmax). Steady-state mean Cmax values were 9, 18, and 33 ng/mL following doses of 5, 10, and 20 mg/day. Absolute bioavailability is 75%. No effect of food on the pharmacokinetics was observed.
- Distribution
- The apparent volume of distribution of vortioxetine is approximately 2600 L, indicating extensive extravascular distribution. The plasma protein binding of vortioxetine in humans is 98%, independent of plasma concentrations. No apparent difference in the plasma protein binding between healthy subjects and subjects with hepatic (mild, moderate) or renal (mild, moderate, severe, ESRD) impairment is observed.
- Metabolism and Elimination
- Vortioxetine is extensively metabolized primarily through oxidation via cytochrome P450 isozymes CYP2D6, CYP3A4/5, CYP2C19, CYP2C9, CYP2A6, CYP2C8 and CYP2B6 and subsequent glucuronic acid conjugation. CYP2D6 is the primary enzyme catalyzing the metabolism of vortioxetine to its major, pharmacologically inactive, carboxylic acid metabolite, and poor metabolizers of CYP2D6 have approximately twice the vortioxetine plasma concentration of extensive metabolizers.
- Following a single oral dose of [14C]-labeled vortioxetine, approximately 59% and 26% of the administered radioactivity was recovered in the urine and feces, respectively as metabolites. Negligible amounts of unchanged vortioxetine were excreted in the urine up to 48 hours. The presence of hepatic (mild or moderate) or renal impairment (mild, moderate, severe and ESRD) did not affect the apparent clearance of vortioxetine.
## Nonclinical Toxicology
- Carcinogenesis
- Carcinogenicity studies were conducted in which CD-1 mice and Wistar rats were given oral doses of vortioxetine up to 50 and 100 mg/kg/day for male and female mice, respectively, and 40 and 80 mg/kg/day for male and female rats, respectively, for 2 years. The doses in the two species were approximately 12, 24, 20, and 39 times, respectively, the maximum recommended human dose (MRHD) of 20 mg on a mg/m2 basis.
- In rats, the incidence of benign polypoid adenomas of the rectum was statistically significantly increased in females at doses 39 times the MRHD, but not at 15 times the MRHD. These were considered related to inflammation and hyperplasia and possibly caused by an interaction with a vehicle component of the formulation used for the study. The finding did not occur in male rats at 20 times the MRHD.
- In mice, vortioxetine was not carcinogenic in males or females at doses up to 12 and 24 times, respectively, the MRHD.
- Mutagenicity
- Vortioxetine was not genotoxic in the in vitro bacterial reverse mutation assay (Ames test), an in vitro chromosome aberration assay in cultured human lymphocytes, and an in vivo rat bone marrow micronucleus assay.
- Impairment of Fertility
- Treatment of rats with vortioxetine at doses up to 120 mg/kg/day had no effect on male or female fertility, which is 58 times the maximum recommended human dose (MRHD) of 20 mg on a mg/m2 basis.
# Clinical Studies
- The efficacy of BRINTELLIX in treatment for MDD was established in six 6 to 8 week randomized, double-blind, placebo-controlled, fixed-dose studies (including one study in the elderly) and one maintenance study in adult inpatients and outpatients who met the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) criteria for MDD.
- Adults (aged 18 years to 75 years)
- The efficacy of BRINTELLIX in patients aged 18 years to 75 years was demonstrated in five 6 to 8 week, placebo-controlled studies (Studies 1 to 5 in Table 4). In these studies, patients were randomized to BRINTELLIX 5 mg, 10 mg, 15 mg or 20 mg or placebo once daily. For patients who were randomized to BRINTELLIX 15 mg/day or 20 mg/day, the final doses were titrated up from 10 mg/day after the first week.
- The primary efficacy measures were the Hamilton Depression Scale (HAMD-24) total score in Study 2 and the Montgomery-Asberg Depression Rating Scale (MADRS) total score in all other studies. In each of these studies, at least one dose group of BRINTELLIX was superior to placebo in improvement of depressive symptoms as measured by mean change from baseline to endpoint visit on the primary efficacy measurement (see Table 4). Subgroup analysis by age, gender or race did not suggest any clear evidence of differential responsiveness. Two studies of the 5 mg dose in the U.S. (not represented in Table 4) failed to show effectiveness.
- Elderly Study (aged 64 years to 88 years)
- The efficacy of BRINTELLIX for the treatment of MDD was also demonstrated in a randomized, double-blind, placebo-controlled, fixed-dose study of BRINTELLIX in elderly patients (aged 64 years to 88 years) with MDD (Study 6 in Table 4). Patients meeting the diagnostic criteria for recurrent MDD with at least one previous major depressive episode before the age of 60 years and without comorbid cognitive impairment (Mini Mental State Examination score <24) received BRINTELLIX 5 mg or placebo.
- Time Course of Treatment Response
- In the 6 to 8 week placebo-controlled studies, an effect of BRINTELLIX based on the primary efficacy measure was generally observed starting at Week 2 and increased in subsequent weeks with the full antidepressant effect of BRINTELLIX generally not seen until Study Week 4 or later. Figure 4 depicts time course of response in U.S. based on the primary efficacy measure (MADRS) in Study 5.
- Maintenance Study
- In a non-US maintenance study (Study 7 in Figure 6), 639 patients meeting DSM-IV-TR criteria for MDD received flexible doses of BRINTELLIX (5 mg or 10 mg) once daily during an initial 12 week open-label treatment phase; the dose of BRINTELLIX was fixed during Weeks 8 to 12. Three hundred ninety six (396) patients who were in remission (MADRS total score ≤10 at both Weeks 10 and 12) after open-label treatment were randomly assigned to continuation of a fixed dose of BRINTELLIX at the final dose they responded to (about 75% of patients were on 10 mg/day) during the open-label phase or to placebo for 24 to 64 weeks. Approximately 61% of randomized patients satisfied remission criterion (MADRS total score ≤10) for at least 4 weeks (since Week 8), and 15% for at least 8 weeks (since Week 4). Patients on BRINTELLIX experienced a statistically significantly longer time to have recurrence of depressive episodes than did patients on placebo. Recurrence of depressive episode was defined as a MADRS total score ≥22 or lack of efficacy as judged by the investigator.
# How Supplied
- BRINTELLIX tablets are available as follows:
- Storage: Store at 77°F (25°C); excursions permitted to 59°F to 86°F (15°C to 30°C).
## Storage
There is limited information regarding Vortioxetine Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise patients and their caregivers about the benefits and risks associated with treatment with BRINTELLIX and counsel them in its appropriate use. Advise patients and their caregivers to read the Medication Guide and assist them in understanding its contents. The complete text of the Medication Guide is reprinted at the end of this document.
- Suicide Risk
- Advise patients and caregivers to look for the emergence of suicidal ideation and behavior, especially early during treatment and when the dose is adjusted up or down.
- Discontinuation of Treatment
- Patients who are on BRINTELLIX 15 mg/day or 20 mg/day may experience headache, muscle tension, mood swings, sudden outburst of anger, dizziness and runny nose if they abruptly stop their medicine. Advise patients not stopping BRINTELLIX without talking to their healthcare provider.
- Concomitant Medication
- Advise patients to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter medications because of a potential for interactions. Instruct patients not to take BRINTELLIX with an MAOI or within 14 days of stopping an MAOI and to allow 21 days after stopping BRINTELLIX before starting an MAOI.
- Serotonin Syndrome
- Caution patients about the risk of serotonin syndrome, particularly with the concomitant use of BRINTELLIX and triptans, tricyclic antidepressants, fentanyl, Lithium, tramadol, tryptophan supplements, and St. John’s Wort supplements.
- Abnormal Bleeding
- Caution patients about the increased risk of abnormal bleeding when BRINTELLIX is given with NSAIDs, aspirin, warfarin, or other drugs that affect coagulation.
- Activation of Mania/Hypomania
- Advise patients and their caregivers to look for signs of activation of mania/hypomania.
- Angle Closure Glaucoma
- Patients should be advised that taking BRINTELLIX can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible.
- Hyponatremia
- Advise patients that if they are treated with diuretics, or are otherwise volume depleted, or are elderly, they may be at greater risk of developing hyponatremia while taking BRINTELLIX.
- Nausea
- Advise patients that nausea is the most common adverse reaction, and is dose related. Nausea commonly occurs within the first week of treatment, then decreases in frequency but can persist in some patients.
- Alcohol
- A clinical study has shown that BRINTELLIX (single dose of 20 or 40 mg/day) did not increase the impairment of mental and motor skills caused by alcohol.
- Allergic Reactions
- Advise patients to notify their healthcare provider if they develop an allergic reaction such as rash, hives, swelling, or difficulty breathing.
- Pregnancy
- Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during therapy with BRINTELLIX.
- Nursing Mothers
- Advise patients to notify their healthcare provider if they are breast-feeding an infant and would like to continue or start BRINTELLIX.
# Precautions with Alcohol
- Alcohol-Vortioxetine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- BRINTELLIX®[1]
# Look-Alike Drug Names
There is limited information regarding Vortioxetine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Vortioxetine | |
5490ee51aa419a9a879334ddd6a2b1f2d14e505e | wikidoc | WIN 55,212-2 | WIN 55,212-2
WIN 55,212-2 is a drug described as an aminoalkylindole derivative, that produces effects similar to those of Cannabinoid derivatives such as THC but has an entirely different chemical structure.
WIN 55,212-2 is a potent cannabinoid receptor agonist which has been found to be a potent analgesic in a rat model of neuropathic pain. It activates p42 and p44 MAP kinase via receptor-mediated signaling.
WIN55,212-2, along side HU-210 and JWH-133, are implicated in preventing the inflammation caused by Amyloid beta proteins involved in Alzheimer's Disease, in addition to preventing cognitive impairment and loss of neuronal markers. This antiinflamatory action is induced through the agonization of cannabinoid receptors which prevents microglial activation that elicits the inflammation. Additionally, cannabinoids completely abolish neurotoxicity related to microglia activation in rat models.
WIN55212-2 is a weaker partial agonist than THC, but with higher affinity to the CB1 receptor. This means that the threshold dose for onset of effects is smaller than that of THC, but the maximum effects attainable are not as strong as those of THC, meaning that WIN55212-2 could potentially be used as a legal cannabis substitute drug, for instance as an alternative to medical marijuana. WIN55212-2 produces cannabis-like effects in humans within the oral dosage range of 1 to 3 miligrams however the effects are described as milder and shorter lasting when compared to THC. | WIN 55,212-2
WIN 55,212-2 is a drug described as an aminoalkylindole derivative, that produces effects similar to those of Cannabinoid derivatives such as THC but has an entirely different chemical structure.[1][2][3]
WIN 55,212-2 is a potent cannabinoid receptor agonist [4] which has been found to be a potent analgesic[5] in a rat model of neuropathic pain[6]. It activates p42 and p44 MAP kinase via receptor-mediated signaling[7].
WIN55,212-2, along side HU-210 and JWH-133, are implicated in preventing the inflammation caused by Amyloid beta proteins involved in Alzheimer's Disease, in addition to preventing cognitive impairment and loss of neuronal markers. This antiinflamatory action is induced through the agonization of cannabinoid receptors which prevents microglial activation that elicits the inflammation. Additionally, cannabinoids completely abolish neurotoxicity related to microglia activation in rat models.
WIN55212-2 is a weaker partial agonist than THC, but with higher affinity to the CB1 receptor. [8] This means that the threshold dose for onset of effects is smaller than that of THC, but the maximum effects attainable are not as strong as those of THC, meaning that WIN55212-2 could potentially be used as a legal cannabis substitute drug, for instance as an alternative to medical marijuana. WIN55212-2 produces cannabis-like effects in humans within the oral dosage range of 1 to 3 miligrams however the effects are described as milder and shorter lasting when compared to THC[citation needed].
# External links
- Biomol Win 55,212-2 Data Sheet
- The cannabinoid WIN 55,212-2 inhibits transient receptor potential vanilloid 1 (TRPV1) and evokes peripheral antihyperalgesia via calcineurin. 2006 Jul 18; Template:PubMed
- JNeurosci.orgPrevention of Alzheimer's Disease Pathology by Cannabinoids: Neuroprotection Mediated by Blockade of Microglial Activation
- New Scientist: Hope for cannabis-based drug for Alzheimer's | https://www.wikidoc.org/index.php/WIN_55,212-2 | |
e86bc63674ea9f1a6d7b100c240616905ef0bfd9 | wikidoc | Walter Reppe | Walter Reppe
Walter Julius Reppe (b. 29 July 1892 in Göringen, d. 26 July 1969 in Heidelberg) was a German chemist. He is notable for his contributions to the chemistry of acetylene.
# Education and career
Walter Reppe began his study of the natural sciences University of Jena in 1911. Interrupted by the First World War, he obtained his doctorate in Munich in 1920.
In 1921, Reppe worked for BASF's main laboratory. From 1923, he worked on the catalytic dehydration of formamide to prussic acid in the indigo laboratory, developing this procedure for industrial use. In 1924, he left research for 10 years, only resuming it in 1934.
# Acetylene chemistry
Reppe began his interest in acetylene in 1928. Acetylene is a gas which can take part in many chemical reactions. However, it was explosive and accidents often occurred. Because of this danger, small quantities of acetylene were used at a time, and always without high pressures. In fact, it was forbidden to compress acetylene over 1.5 bar at BASF.
Reactions at such low pressures did not correspond at all to the traditions at BASF, and one could expect no useful process engineering results. Reppe commented in 1949 retrospectively: "therefore the necessity resulted to break with all delivered opinions and to study first of all the acetylene decay with consideration of the most diverse test conditions of reason on, in order to determine suitable safety precautions, one safe working also in the industrial yardstick made possible." To work with acetylene safely, Reppe designed special test tubes, the so-called "Reppe glasses" — stainless steel spheres with screw-type cap, which permitted high pressure experiments. The efforts ended finally with a large number of interconnected reactions, known as Reppe chemistry.
# Reppe chemistry
The high pressure reactions catalysed by heavy metal acetylides, especially copper acetylide, or metal carbonyls is called Reppe Chemistry. Reactions can be classified into four large classes:
- The vinylization according to the equation:
File:Reppe-chemnistry-vinylization.png
- Preparing ethynyldiols from aldehydes according to the equation:
File:Reppe-chemistry-endiol.png
- Reactions with carbon monoxide:
File:Reppe-chemistry-carbonmonoxide-01.png
File:Reppe-chemistry-carbonmonoxide-02.png
This simple synthesis was used to prepare acrylic acid derivatives for the production of acrylic glass.
- The cyclic polymerization
File:Reppe-chemistry-benzene.png
File:Reppe-chemistry-cyclooctatetraene.png
This reaction provided an unusual route to benzene and especially to cyclooctatetraene, which was difficult to prepare otherwise.
Products from these four reaction types proved to be versatile intermediates in the syntheses of lacquers, adhesives, foam materials, textile fibers, and pharmaceuticals could now be produced.
# Post-war
After the Second World War, Reppe led the research of BASF from 1949 up to his retirement in 1957. From 1952 to 1966, he also sat on the supervisory board. He was also a professor at the University of Mainz and TH Darmstadt from 1951 and 1952 respectively. Together with Otto Bayer and Karl Ziegler he received the Werner-von-Siemens-Ring in 1960 for expanding the scientific knowledge on and for the technical development of new synthetic high-molecular materials.
# Legacy
Most of the industrial processes that were developed by Reppe and coworkers have been superseded, largely because acetylenes are expensive, high energy species relative to alkenes which are more cheaply produced. Together with his contemporaries Otto Roelen, Karl Ziegler, Hans Tropsch, and Franz Joseph Emil Fischer, Reppe was a leader in demonstrating the utility of metal-catalyzed reactions in large scale synthesis of organic compounds. The economic benefits demonstrated by this research motivated the eventual flowering of organometallic chemistry and its close connection to industry.
# Publications
- Neue Entwicklungen auf dem Gebiet der Chemie des Acetylen und Kohlenoxyds (New developments in the area of the chemistry acetylene and carbon monoxide). Springer Berlin, Göttingen, Heidelberg. 1949. 184 pages.
- Reppe, W.; Schlichting, O.; Klager, K.; Toepel, T. (1948). "Cyclisierende Polymerisation von Acetylen I Über Cyclooctatetraen". Justus Liebigs Ann. Chem.: 1–93.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}
- Reppe, W.; Schlichting, O.; Meister, H. (1948). "Cyclisierende Polymerisation von Acetylen II Über die Kohlenwasserstoffe C10H10 C12H12 Azulen". Justus Liebigs Ann. Chem.: 93–104.CS1 maint: Multiple names: authors list (link)
- Reppe, W.; Schweckendiek W. J (1948). "Cyclisierende Polymerisation von Acetylen III Benzol, Benzolderivate und hydroaromatische Verbindungen". Justus Liebigs Ann. Chem.: 104–116.CS1 maint: Multiple names: authors list (link) | Walter Reppe
Template:Infobox Scientist
Walter Julius Reppe (b. 29 July 1892 in Göringen, d. 26 July 1969 in Heidelberg) was a German chemist. He is notable for his contributions to the chemistry of acetylene.
# Education and career
Walter Reppe began his study of the natural sciences University of Jena in 1911. Interrupted by the First World War, he obtained his doctorate in Munich in 1920.
In 1921, Reppe worked for BASF's main laboratory. From 1923, he worked on the catalytic dehydration of formamide to prussic acid in the indigo laboratory, developing this procedure for industrial use. In 1924, he left research for 10 years, only resuming it in 1934.
# Acetylene chemistry
Reppe began his interest in acetylene in 1928. Acetylene is a gas which can take part in many chemical reactions. However, it was explosive and accidents often occurred. Because of this danger, small quantities of acetylene were used at a time, and always without high pressures. In fact, it was forbidden to compress acetylene over 1.5 bar at BASF.
Reactions at such low pressures did not correspond at all to the traditions at BASF, and one could expect no useful process engineering results. Reppe commented in 1949 retrospectively: "therefore the necessity resulted to break with all delivered opinions and to study first of all the acetylene decay with consideration of the most diverse test conditions of reason on, in order to determine suitable safety precautions, one safe working also in the industrial yardstick made possible."[citation needed] To work with acetylene safely, Reppe designed special test tubes, the so-called "Reppe glasses" — stainless steel spheres with screw-type cap, which permitted high pressure experiments. The efforts ended finally with a large number of interconnected reactions, known as Reppe chemistry.
# Reppe chemistry
The high pressure reactions catalysed by heavy metal acetylides, especially copper acetylide, or metal carbonyls is called Reppe Chemistry. Reactions can be classified into four large classes:
- The vinylization according to the equation:
File:Reppe-chemnistry-vinylization.png
- Preparing ethynyldiols from aldehydes according to the equation:
File:Reppe-chemistry-endiol.png
- Reactions with carbon monoxide:
File:Reppe-chemistry-carbonmonoxide-01.png
File:Reppe-chemistry-carbonmonoxide-02.png
This simple synthesis was used to prepare acrylic acid derivatives for the production of acrylic glass.
- The cyclic polymerization
File:Reppe-chemistry-benzene.png
File:Reppe-chemistry-cyclooctatetraene.png
This reaction provided an unusual route to benzene and especially to cyclooctatetraene, which was difficult to prepare otherwise.
Products from these four reaction types proved to be versatile intermediates in the syntheses of lacquers, adhesives, foam materials, textile fibers, and pharmaceuticals could now be produced.
# Post-war
After the Second World War, Reppe led the research of BASF from 1949 up to his retirement in 1957. From 1952 to 1966, he also sat on the supervisory board. He was also a professor at the University of Mainz and TH Darmstadt from 1951 and 1952 respectively. Together with Otto Bayer and Karl Ziegler he received the Werner-von-Siemens-Ring in 1960 for expanding the scientific knowledge on and for the technical development of new synthetic high-molecular materials.
# Legacy
Most of the industrial processes that were developed by Reppe and coworkers have been superseded, largely because acetylenes are expensive, high energy species relative to alkenes which are more cheaply produced. Together with his contemporaries Otto Roelen, Karl Ziegler, Hans Tropsch, and Franz Joseph Emil Fischer, Reppe was a leader in demonstrating the utility of metal-catalyzed reactions in large scale synthesis of organic compounds. The economic benefits demonstrated by this research motivated the eventual flowering of organometallic chemistry and its close connection to industry.
# Publications
- Neue Entwicklungen auf dem Gebiet der Chemie des Acetylen und Kohlenoxyds (New developments in the area of the chemistry acetylene and carbon monoxide). Springer Berlin, Göttingen, Heidelberg. 1949. 184 pages.
- Reppe, W.; Schlichting, O.; Klager, K.; Toepel, T. (1948). "Cyclisierende Polymerisation von Acetylen I Über Cyclooctatetraen". Justus Liebigs Ann. Chem.: 1–93.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}
- Reppe, W.; Schlichting, O.; Meister, H. (1948). "Cyclisierende Polymerisation von Acetylen II Über die Kohlenwasserstoffe C10H10 C12H12 Azulen". Justus Liebigs Ann. Chem.: 93–104.CS1 maint: Multiple names: authors list (link)
- Reppe, W.; Schweckendiek W. J (1948). "Cyclisierende Polymerisation von Acetylen III Benzol, Benzolderivate und hydroaromatische Verbindungen". Justus Liebigs Ann. Chem.: 104–116.CS1 maint: Multiple names: authors list (link) | https://www.wikidoc.org/index.php/Walter_Reppe | |
f5ca1c255953b8d46862130c6c7ab4bbc0b1f9de | wikidoc | Water crisis | Water crisis
The water crisis is the status of the world’s water resources relative to human demand as of the 1970s and to the current time. The term "water crisis" has been applied to the worldwide water situation by the United Nations and other world organizations. The major aspects of the water crisis are overall scarcity of usable water and water pollution.
The Earth has a finite supply of fresh water, stored in aquifers, surface waters and the atmosphere. Sometimes oceans are mistaken for available water, but the amount of energy needed to convert saline water to potable water is prohibitive today, explaining why only a very small fraction of the world's water supply derives from desalination.
There are several principal manifestations of the water crisis.
- Inadequate access to safe drinking water for about 1.1 billion people
- Groundwater overdrafting leading to diminished agricultural yields
- Overuse and pollution of water resources harming biodiversity
- Regional conflicts over scarce water resources sometimes resulting in warfare
Waterborne diseases and the absence of sanitary domestic water is the leading cause of death worldwide and may account for up to 80 percent of human sickness.
Historically the manifestations of the water crisis have been less pronounced, but 20th century levels of human overpopulation have revealed the limited quantity of fresh water. Drought dramatizes the underlying tenuous balance of safe water supply, but it is the imprudent actions of humans that have rendered the human population vulnerable to the devastation of major droughts.
# Health impacts of the water crisis
Not only are there 1.1 billion without adequate drinking water, but the United Nations acknowledges 2.6 billion people are without adequate water for sanitation (e.g. wastewater disposal). The issues are coupled, since, without water for sewage disposal, cross-contamination of drinking water by untreated sewage is the chief adverse outcome of inadequate safe water supply. Consequently disease and significant deaths arise from people using contaminated water supplies; these effects are particularly pronounced for children in underdeveloped countries, where 3900 children per day die of diarrhea alone.
While these deaths are generally considered preventable, the situation is considerably more complex, since the Earth is beyond its carrying capacity with respect to available fresh water. Often technology is advanced as a panacea, but the costs of technology presently exclude a number of countries from availing themselves of these solutions. If lesser developed countries acquire more wealth, partial mitigation will occur, but sustainable solutions must involve each region in balancing population to water resource and in managing water resources more optimally. In any case the finite nature of the water resource must be acknowledged if the world is to achieve a better balance.
# Damage to biodiversity
Vegetation and wildlife are fundamentally dependent upon adequate freshwater resources. Marshes, bogs and riparian zones are more obviously dependent upon sustainable water supply, but forests and other upland ecosystems are equally at risk of significant productivity changes as water availability is diminished. In the case of wetlands, considerable area has been simply taken from wildlife use to feed and house the expanding human population. But other areas have suffered reduced productivity from gradual diminishing of freshwater inflow, as upstream sources are diverted for human use. In seven states of the U.S. over 80 percent of all historic wetlands were filled by the 1980s, when Congress acted to create a “no net loss” of wetlands.
In Europe extensive loss of wetlands has also occurred with resulting loss of biodiversity. For example many bogs in Scotland have been drained or developed through human population expansion. One example is the Portlethen Moss in Aberdeenshire, that has been over half lost, and a number of species which inhabited this moss are no longer present such as the Great Crested Newt.
On Madagascar’s central highland plateau, a massive transformation occurred that eliminated virtually all the heavily forested vegetation in the period 1970 to 2000. The slash and burn agriculture eliminated about ten percent of the total country’s native biomass and converted it to a barren wasteland. These effects were from overpopulation and the necessity to feed poor indigenous peoples, but the adverse effects included widspread gully erosion that in turn produced heavily silted rivers that “run red” decades after the deforestation. This eliminated a large amount of usable fresh water and also destroyed much of the riverine ecosystems of several large west-flowing rivers. Several fish species have been driven to the edge of extinction and some coral reef formations in the Indian Ocean are effectively lost.
# Regional conflicts
There are approximately 260 different river systems worldwide, where conflicts exist crossing national boundaries. While Helsinki Rules help to interpret intrinsic water rights among countries, there are some conflicts so bitter or so related to basic survival that strife and even warfare are inevitable. In many cases water use disputes are merely an added dimension to underlying border tensions founded on other bases.
The Tigris-Euphrates River System is one example where differing national interests and withdrawal rights have been in conflict. The countries of Iran, Iraq and Syria each present valid claims of certain water use, but the total demands on the riverine system surpass the physical constraints of water availability. As early as 1974 Iraq massed troops on the Syrian border and threatened to destroy Syria’s al-Thawra dam on the Euphrates.
In 1992 Hungary and Czechoslovakia took a dispute over Danube River water diversions and dam construction to the International Court of Justice. This case represents a minority of disputes where logic and jurisprudence may be the path of dispute resolution. Other conflicts involving North and South Korea, Israel and Palestine, Egypt and Ethiopia, may prove more difficult tests of negotiation.
# Overview of regions suffering crisis impacts
There are many other countries of the world that are severely impacted with regard to human health and inadequate drinking water. The following is a partial list of some of the countries with significant populations (numerical population of affected population listed) whose only consumption is of contaminated water:
- Sudan 12.3 million
- Iran 5.6 million
- Venezuela 5.0 million
- Syria 3.8 million
- Zimbabwe 2.7 million
- Tunisia 2.1 million
- Cuba 1.2 million
According to the California Department of Water Resources, if more supplies aren’t found by 2020, region will face a shortfall nearly as great as the amount consumed today. Los Angeles is a coastal desert able to support at most 1 million people on its own water; the Los Angeles basin now is the core of a megacity that spans 220 miles (350 km) from Santa Barbara to the Mexican border. The region’s population is expected to reach 22 million by 2020. The population of California continues to grow by more than a half million a year and is expected to reach 48 million in 2030. But water shortage is likely to surface well before then.
Water deficits, which are already spurring heavy grain imports in numerous smaller countries, may soon do the same in larger countries, such as China or India. The water tables are falling in scores of countries (including Northern China, the US, and India) due to widespread overpumping using powerful diesel and electric pumps. Other countries affected include Pakistan, Iran, and Mexico. This will eventually lead to water scarcity and cutbacks in grain harvest. Even with the overpumping of its aquifers, China is developing a grain deficit. When this happens, it will almost certainly drive grain prices upward. Most of the 3 billion people projected to be added worldwide by mid-century will be born in countries already experiencing water shortages. Unless population growth can be slowed quickly by investing heavily in female literacy and family planning services, there may not be a humane solution to the emerging world water shortage.
After China and India, there is a second tier of smaller countries with large water deficits — Algeria, Egypt, Iran, Mexico, and Pakistan. Four of these already import a large share of their grain. Only Pakistan remains self-sufficient. But with a population expanding by 4 million a year, it will also likely soon turn to the world market for grain.
According to a UN climate report, the Himalayan glaciers that are the sources of Asia's biggest rivers - Ganges, Indus, Brahmaputra, Yangtze, Mekong, Salween and Yellow - could disappear by 2035 as temperatures rise. Approximately 2.4 billion people live in the drainage basin of the Himalayan rivers. India, China, Pakistan, Bangladesh, Nepal and Myanmar could experience floods followed by droughts in coming decades. In India alone, the Ganges provides water for drinking and farming for more than 500 million people.
# Outlook
Year 2025 forecasts state that two thirds of the world population will be without safe drinking water and basic sanitation services. Construction of wastewater treatment plants and reduction of groundwater overdrafting appear to be obvious solutions to the worldwide problem; however, a deeper look reveals more fundamental issues in play. Wastewater treatment is highly capital intensive, restricting access to this technology in some regions; furthermore the rapid increase in population of many countries makes this a race that is difficult to win. As if those factors are not daunting enough, one must consider the enormous costs and skill sets involved to maintain wastewater treatment plants even if they are successfully developed.
Reduction in groundwater overdrafting is usually politically very unpopular and has major economic impacts to farmers; moreover, this strategy will necessarily reduce crop output, which is something the world can ill afford, given the population level at present.
At more realistic levels, developing countries can strive to achieve primary wastewater treatment or secure septic systems, and carefully analyse wastewater outfall design to miminise impacts to drinking water and to ecosystems. Developed countries can not only share technology better, including cost-effective wastewater and water treatment systems but also in hydrological transport modeling. At the individual level, people in developed countries can look inward and reduce overconsumption, which further strains worldwide water consumption. Both developed and developing countries can increase protection of ecosytems, especially wetlands and riparian zones. These measures will not only conserve biota, but also render more effective the natural water cycle flushing and transport that make water systems more healthy for humans.
# Desalination
As new technological innovations continue to reduce the capital cost of desalination, more countries are building desalination plants as a small element in addressing their water crises , .
- Israel desalinizes water for a cost of 53 cents per cubic meter .
- Singapore desalinizes water for 49 cents per cubic meter .
- China and India, the world's two most populous countries, are turning to desalination to provide a small part of their water needs , .
- In 2007 Pakistan announced plans to use desalination .
- Australia uses desalination .
- In 2007 Bermuda signed a contract to purchase a desalination plant .
- Desalination allows Dubai to have year round indoor skiing in the middle of the desert .
- In the United States, California, Arizona, Texas, and Florida use desalination for a very small part of their water supply , , .
Nuclear power is one way to provide the energy for desalination. , , , .
Cheaper alternatives to million-dollar desalianation projects are water filters, such as reverse osmosis water processors and vapaires. These are often more viable when shortage of funds is an obstacle. | Water crisis
The water crisis is the status of the world’s water resources relative to human demand as of the 1970s and to the current time.[1] The term "water crisis" has been applied to the worldwide water situation by the United Nations and other world organizations.[2][3] The major aspects of the water crisis are overall scarcity of usable water and water pollution.
The Earth has a finite supply of fresh water, stored in aquifers, surface waters and the atmosphere. Sometimes oceans are mistaken for available water, but the amount of energy needed to convert saline water to potable water is prohibitive today, explaining why only a very small fraction of the world's water supply derives from desalination[4].
There are several principal manifestations of the water crisis.
- Inadequate access to safe drinking water for about 1.1 billion people
- Groundwater overdrafting leading to diminished agricultural yields
- Overuse and pollution of water resources harming biodiversity
- Regional conflicts over scarce water resources sometimes resulting in warfare
Waterborne diseases and the absence of sanitary domestic water is the leading cause of death worldwide and may account for up to 80 percent of human sickness.[5]
Historically the manifestations of the water crisis have been less pronounced, but 20th century levels of human overpopulation have revealed the limited quantity of fresh water. Drought dramatizes the underlying tenuous balance of safe water supply, but it is the imprudent actions of humans that have rendered the human population vulnerable to the devastation of major droughts.
# Health impacts of the water crisis
Not only are there 1.1 billion without adequate drinking water, but the United Nations acknowledges 2.6 billion people are without adequate water for sanitation (e.g. wastewater disposal). The issues are coupled, since, without water for sewage disposal, cross-contamination of drinking water by untreated sewage is the chief adverse outcome of inadequate safe water supply. Consequently disease and significant deaths arise from people using contaminated water supplies; these effects are particularly pronounced for children in underdeveloped countries, where 3900 children per day die of diarrhea alone[6].
While these deaths are generally considered preventable, the situation is considerably more complex, since the Earth is beyond its carrying capacity with respect to available fresh water[7]. Often technology is advanced as a panacea, but the costs of technology presently exclude a number of countries from availing themselves of these solutions. If lesser developed countries acquire more wealth, partial mitigation will occur, but sustainable solutions must involve each region in balancing population to water resource and in managing water resources more optimally. In any case the finite nature of the water resource must be acknowledged if the world is to achieve a better balance.
# Damage to biodiversity
Vegetation and wildlife are fundamentally dependent upon adequate freshwater resources. Marshes, bogs and riparian zones are more obviously dependent upon sustainable water supply, but forests and other upland ecosystems are equally at risk of significant productivity changes as water availability is diminished. In the case of wetlands, considerable area has been simply taken from wildlife use to feed and house the expanding human population. But other areas have suffered reduced productivity from gradual diminishing of freshwater inflow, as upstream sources are diverted for human use. In seven states of the U.S. over 80 percent of all historic wetlands were filled[8] by the 1980s, when Congress acted to create a “no net loss” of wetlands.
In Europe extensive loss of wetlands has also occurred with resulting loss of biodiversity. For example many bogs in Scotland have been drained or developed through human population expansion. One example is the Portlethen Moss in Aberdeenshire, that has been over half lost, and a number of species which inhabited this moss are no longer present such as the Great Crested Newt.
On Madagascar’s central highland plateau, a massive transformation occurred that eliminated virtually all the heavily forested vegetation in the period 1970 to 2000. The slash and burn agriculture eliminated about ten percent of the total country’s native biomass and converted it to a barren wasteland. These effects were from overpopulation and the necessity to feed poor indigenous peoples, but the adverse effects included widspread gully erosion that in turn produced heavily silted rivers that “run red” decades after the deforestation. This eliminated a large amount of usable fresh water and also destroyed much of the riverine ecosystems of several large west-flowing rivers. Several fish species have been driven to the edge of extinction and some coral reef formations in the Indian Ocean are effectively lost.
# Regional conflicts
There are approximately 260 different river systems worldwide, where conflicts exist crossing national boundaries. While Helsinki Rules help to interpret intrinsic water rights among countries, there are some conflicts so bitter or so related to basic survival that strife and even warfare are inevitable. In many cases water use disputes are merely an added dimension to underlying border tensions founded on other bases.
The Tigris-Euphrates River System is one example where differing national interests and withdrawal rights have been in conflict. The countries of Iran, Iraq and Syria each present valid claims of certain water use, but the total demands on the riverine system surpass the physical constraints of water availability.[9] As early as 1974 Iraq massed troops on the Syrian border and threatened to destroy Syria’s al-Thawra dam on the Euphrates.[10]
In 1992 Hungary and Czechoslovakia took a dispute over Danube River water diversions and dam construction to the International Court of Justice. This case represents a minority of disputes where logic and jurisprudence may be the path of dispute resolution. Other conflicts involving North and South Korea, Israel and Palestine, Egypt and Ethiopia, may prove more difficult tests of negotiation.
# Overview of regions suffering crisis impacts
There are many other countries of the world that are severely impacted with regard to human health and inadequate drinking water. The following is a partial list of some of the countries with significant populations (numerical population of affected population listed) whose only consumption is of contaminated water[1]:
- Sudan 12.3 million
- Iran 5.6 million
- Venezuela 5.0 million
- Syria 3.8 million
- Zimbabwe 2.7 million
- Tunisia 2.1 million
- Cuba 1.2 million
According to the California Department of Water Resources, if more supplies aren’t found by 2020, region will face a shortfall nearly as great as the amount consumed today.[11] Los Angeles is a coastal desert able to support at most 1 million people on its own water; the Los Angeles basin now is the core of a megacity that spans 220 miles (350 km) from Santa Barbara to the Mexican border. The region’s population is expected to reach 22 million by 2020. The population of California continues to grow by more than a half million a year and is expected to reach 48 million in 2030. But water shortage is likely to surface well before then.[12]
Water deficits, which are already spurring heavy grain imports in numerous smaller countries, may soon do the same in larger countries, such as China or India.[13] The water tables are falling in scores of countries (including Northern China, the US, and India) due to widespread overpumping using powerful diesel and electric pumps. Other countries affected include Pakistan, Iran, and Mexico. This will eventually lead to water scarcity and cutbacks in grain harvest. Even with the overpumping of its aquifers, China is developing a grain deficit. When this happens, it will almost certainly drive grain prices upward. Most of the 3 billion people projected to be added worldwide by mid-century will be born in countries already experiencing water shortages. Unless population growth can be slowed quickly by investing heavily in female literacy and family planning services, there may not be a humane solution to the emerging world water shortage.[14][15][16]
After China and India, there is a second tier of smaller countries with large water deficits — Algeria, Egypt, Iran, Mexico, and Pakistan. Four of these already import a large share of their grain. Only Pakistan remains self-sufficient. But with a population expanding by 4 million a year, it will also likely soon turn to the world market for grain.[17]
According to a UN climate report, the Himalayan glaciers that are the sources of Asia's biggest rivers - Ganges, Indus, Brahmaputra, Yangtze, Mekong, Salween and Yellow - could disappear by 2035 as temperatures rise.[18] Approximately 2.4 billion people live in the drainage basin of the Himalayan rivers.[19] India, China, Pakistan, Bangladesh, Nepal and Myanmar could experience floods followed by droughts in coming decades. In India alone, the Ganges provides water for drinking and farming for more than 500 million people.[20][21][22]
# Outlook
Year 2025 forecasts state that two thirds of the world population will be without safe drinking water and basic sanitation services. Construction of wastewater treatment plants and reduction of groundwater overdrafting appear to be obvious solutions to the worldwide problem; however, a deeper look reveals more fundamental issues in play. Wastewater treatment is highly capital intensive, restricting access to this technology in some regions; furthermore the rapid increase in population of many countries makes this a race that is difficult to win. As if those factors are not daunting enough, one must consider the enormous costs and skill sets involved to maintain wastewater treatment plants even if they are successfully developed.
Reduction in groundwater overdrafting is usually politically very unpopular and has major economic impacts to farmers; moreover, this strategy will necessarily reduce crop output, which is something the world can ill afford, given the population level at present.
At more realistic levels, developing countries can strive to achieve primary wastewater treatment or secure septic systems, and carefully analyse wastewater outfall design to miminise impacts to drinking water and to ecosystems. Developed countries can not only share technology better, including cost-effective wastewater and water treatment systems but also in hydrological transport modeling. At the individual level, people in developed countries can look inward and reduce overconsumption, which further strains worldwide water consumption. Both developed and developing countries can increase protection of ecosytems, especially wetlands and riparian zones. These measures will not only conserve biota, but also render more effective the natural water cycle flushing and transport that make water systems more healthy for humans.
# Desalination
As new technological innovations continue to reduce the capital cost of desalination, more countries are building desalination plants as a small element in addressing their water crises [2], [3].
- Israel desalinizes water for a cost of 53 cents per cubic meter [4].
- Singapore desalinizes water for 49 cents per cubic meter [5].
- China and India, the world's two most populous countries, are turning to desalination to provide a small part of their water needs [6], [7].
- In 2007 Pakistan announced plans to use desalination [8].
- Australia uses desalination [9].
- In 2007 Bermuda signed a contract to purchase a desalination plant [10].
- Desalination allows Dubai to have year round indoor skiing in the middle of the desert [11].
- In the United States, California, Arizona, Texas, and Florida use desalination for a very small part of their water supply [12], [13], [14].
Nuclear power is one way to provide the energy for desalination. [15], [16], [17], [18].
Cheaper alternatives to million-dollar desalianation projects are water filters, such as reverse osmosis water processors and vapaires. These are often more viable when shortage of funds is an obstacle. | https://www.wikidoc.org/index.php/Water_crisis | |
59467f8ef581a5a3ef3e43ead2c9659b5a5f86f5 | wikidoc | Water memory | Water memory
Water memory is a scientifically unsupported speculation that water is capable of retaining a memory of particles once dissolved in it, even after being diluted so much that the chance of even one molecule remaining in the quantity being used is minuscule. Shaking the water at each stage of a serial dilution is claimed to be necessary for an effect to occur. The concept was proposed by Jacques Benveniste to explain the alleged therapeutic powers of homeopathic remedies, which are prepared by serially diluting aqueous solutions to such a high degree that even a single molecule of the original solute is highly unlikely to remain in each final preparation. Benveniste sought to prove this as the basic foundation of homeopathy, by conducting an experiment to be published "independently of homeopathic interests" in a major journal. However, while some studies, including Benveniste's, have claimed such an effect, double-blind repetitions of the experiments involved have failed to reproduce the results, and the concept is not accepted by the scientific community.
# The Nature controversy
The most prominent advocate of this idea was the French immunologist Jacques Benveniste. His team, at the French National Institute of Health and Medical Research (INSERM), diluted a solution of human antibodies to such a degree that there was no likelihood that a single molecule remained, but said that when human basophils were exposed to the solution, they responded by releasing a chemical substance as they would have if they had encountered the original antibody (part of the allergic reaction). The effect supposedly only worked when the solution was shaken violently. Benveniste claimed "It's like agitating a car key in the river, going miles downstream, extracting a few drops of water, and then starting one's car with the water."
At the time, Benveniste offered no explanation of how the effect might work.
Benveniste sent the research to the science journal Nature for publication. There was concern on the part of Nature's editorial oversight board that the material, if published, would lend credibility to homeopathic practitioners even if the effects eventually proved untrue. There was equal concern that the research was simply wrong, given the changes that it would demand of the known laws of physics and chemistry. The editor of Nature, John Maddox, stated that, "Our minds were not so much closed as unready to change our whole view of how science is constructed." But rejecting the paper on any objective grounds was deemed unsupportable; there were no known mistakes within the methodology that were apparent at the time.
In the end, a compromise was reached. The paper was published in Nature Vol. 333 on 30 June 1988, but it was accompanied with an editorial by Maddox that noted "There are good and particular reasons why prudent people should, for the time being, suspend judgment" and described some of the fundamental laws of chemistry and physics which it would violate, if shown to be true. Additionally, Maddox demanded that the experiments be re-run under the supervision of a hand-picked group of what became known as "ghostbusters", including Maddox, famed magician-cum-paranormal researcher James Randi, and Walter Stewart, a physicist and free-lance debunker at the U.S. National Institutes of Health.
The team travelled to Benveniste's lab and the experiments were re-run. In the first series the original experimental procedure was carried out as it had been when the paper was first submitted for publication. The experiments were successful, matching the published data quite closely. However, Maddox noted that during the procedure the experimenters were aware of which test tubes originally contained the antibodies and which did not. A second experimental series was started with Maddox and his team in charge of the double-blinding; notebooks were photographed, the lab videotaped, and vials juggled and secretly coded. Randi went so far as to wrap the labels in tinfoil, seal them in an envelope, and then stick them on the ceiling so Benveniste and his colleagues could not read them. Although everyone was confident that the outcome would be the same, reportedly including the Maddox-led team, the effect immediately disappeared.
Nature published a follow-up report in the very next issue: "We conclude that there is no substantial basis for the claim that antiIgE at high dilution (by factors as great as 10120) retains its biological effectiveness, and that the hypothesis that water can be imprinted with the memory of past solutes is as unnecessary as it is fanciful." Nevertheless, there was no suggestion of fraud; Maddox and his team initially speculated that someone in the lab "was playing a trick on Benveniste," but later concluded, "We believe the laboratory has fostered and then cherished a delusion about the interpretation of its data." Maddox also pointed out that two of Benveniste's researchers were being paid for by the French homeopathic company Boiron.
In a response letter published in the same issue of the journal, Benveniste lashed out at Maddox and complained about the "ordeal" he endured at the hands of the Nature team, comparing it to "Salem witchhunts or McCarthy-like prosecutions." In both the Nature response and a following Quirks and Quarks episode, Benveniste especially complained about Stewart, who he stated acted as if they were all frauds and treated them with disdain, complaining about his "typical know-it-all attitude". In his Nature letter, Benveniste also implied that Randi was attempting to hoodwink the experimental run by doing magic tricks, "distracting the technician in charge of its supervision!" He was more apologetic on Quirks and Quarks, re-phrasing his mention of Randi to imply that he had kept the team amused with his tricks and that his presence was generally welcomed. He also pointed out that although it was true two of his team-members were being paid for by a homeopathic company, the same company had paid for Maddox's team's hotel bill.
Maddox was unapologetic, stating "I'm sorry we didn't find something more interesting." On the same Quirks and Quarks show he dismissed Benveniste's complaints, stating that the possibility that the results would be used by the homeopathy community demanded an immediate re-test. In failing, the tests demonstrated that the initial results were likely due to the experimenter effect. He also pointed out that the entire test procedure that Benveniste later complained about was one that had been agreed upon in advance by all parties. It was only when the test then failed that Benveniste claimed it was not appropriate.
The debate continued in the letters section of Nature for several issues, until eventually being ended by the editorial board. It continued in the French press for some time. For all of the arguing over the retests, it has done nothing to stop what Maddox worried about; even in the light of their failure they are still used to claim that the experiments "prove" that homeopathy works. One of Benveniste's co-authors on the Nature paper, Francis Beauvais, later stated that while unblinded experimental trials usually yielded "correct" results (i.e. ultradiluted samples were biologically active, controls were not), "the results of blinded samples were almost always at random and did not fit the expected results: some 'controls' were active and some 'active' samples were without effect on the biological system."
# More recent experiments
Third-party attempts at replication of the Benveniste experiment have produced mixed results. Nature published a paper describing number of follow-up experiments that failed to find a similar effect in 1993 and an independent study published in Experientia in 1992 showed no effect. However, an international team led by Professor Madeleine Ennis of Queen's University of Belfast claimed to have succeeded. Randi then forwarded the $1 million challenge to the BBC Horizon program to prove the "water memory" theory following Ennis' experimental procedure. In response, experiments were conducted with the Vice-President of the Royal Society, Professor John Enderby, overseeing the proceedings. The challenge ended with the Horizon team failing to prove the memory of water. For a piece on homeopathy, the ABC program 20/20 also attempted, unsuccessfully, to reproduce Ennis's results.
Benveniste claimed in a 1997 paper that the memory effect could be transmitted over phone lines. This culminated in two additional papers in 1999 and another on remote-transmission in 2000. This work has never been accepted by the rest of the scientific community, and an investigation into the subject by the American Department of Defence failed to find any effect.
Research published in 2005 on hydrogen bond network dynamics in water showed that "liquid water essentially loses the memory of persistent correlations in its structure" within fifty femtoseconds. | Water memory
Water memory is a scientifically unsupported speculation that water is capable of retaining a memory of particles once dissolved in it, even after being diluted so much that the chance of even one molecule remaining in the quantity being used is minuscule.[1][2] Shaking the water at each stage of a serial dilution is claimed to be necessary for an effect to occur.[3] The concept was proposed by Jacques Benveniste to explain the alleged therapeutic powers of homeopathic remedies, which are prepared by serially diluting aqueous solutions to such a high degree that even a single molecule of the original solute is highly unlikely to remain in each final preparation. Benveniste sought to prove this as the basic foundation of homeopathy, by conducting an experiment to be published "independently of homeopathic interests" in a major journal.[4] However, while some studies, including Benveniste's, have claimed such an effect, double-blind repetitions of the experiments involved have failed to reproduce the results, and the concept is not accepted by the scientific community.[5]
# The Nature controversy
The most prominent advocate of this idea was the French immunologist Jacques Benveniste.[4] His team, at the French National Institute of Health and Medical Research (INSERM), diluted a solution of human antibodies to such a degree that there was no likelihood that a single molecule remained, but said that when human basophils were exposed to the solution, they responded by releasing a chemical substance as they would have if they had encountered the original antibody (part of the allergic reaction). The effect supposedly only worked when the solution was shaken violently. Benveniste claimed "It's like agitating a car key in the river, going miles downstream, extracting a few drops of water, and then starting one's car with the water."
[6] At the time, Benveniste offered no explanation of how the effect might work.
Benveniste sent the research to the science journal Nature for publication. There was concern on the part of Nature's editorial oversight board that the material, if published, would lend credibility to homeopathic practitioners even if the effects eventually proved untrue. There was equal concern that the research was simply wrong, given the changes that it would demand of the known laws of physics and chemistry. The editor of Nature, John Maddox, stated that, "Our minds were not so much closed as unready to change our whole view of how science is constructed."[6] But rejecting the paper on any objective grounds was deemed unsupportable; there were no known mistakes within the methodology that were apparent at the time.
In the end, a compromise was reached. The paper was published in Nature Vol. 333 on 30 June 1988,[3] but it was accompanied with an editorial by Maddox that noted "There are good and particular reasons why prudent people should, for the time being, suspend judgment" and described some of the fundamental laws of chemistry and physics which it would violate, if shown to be true.[1] Additionally, Maddox demanded that the experiments be re-run under the supervision of a hand-picked group of what became known as "ghostbusters", including Maddox, famed magician-cum-paranormal researcher James Randi, and Walter Stewart, a physicist and free-lance debunker at the U.S. National Institutes of Health.
The team travelled to Benveniste's lab and the experiments were re-run. In the first series the original experimental procedure was carried out as it had been when the paper was first submitted for publication. The experiments were successful, matching the published data quite closely. However, Maddox noted that during the procedure the experimenters were aware of which test tubes originally contained the antibodies and which did not. A second experimental series was started with Maddox and his team in charge of the double-blinding; notebooks were photographed, the lab videotaped, and vials juggled and secretly coded. Randi went so far as to wrap the labels in tinfoil, seal them in an envelope, and then stick them on the ceiling so Benveniste and his colleagues could not read them. Although everyone was confident that the outcome would be the same, reportedly including the Maddox-led team, the effect immediately disappeared.
Nature published a follow-up report in the very next issue[7]: "We conclude that there is no substantial basis for the claim that antiIgE at high dilution (by factors as great as 10120) retains its biological effectiveness, and that the hypothesis that water can be imprinted with the memory of past solutes is as unnecessary as it is fanciful." Nevertheless, there was no suggestion of fraud; Maddox and his team initially speculated that someone in the lab "was playing a trick on Benveniste,"[6] but later concluded, "We believe the laboratory has fostered and then cherished a delusion about the interpretation of its data." Maddox also pointed out that two of Benveniste's researchers were being paid for by the French homeopathic company Boiron.
In a response letter published in the same issue of the journal, Benveniste lashed out at Maddox and complained about the "ordeal" he endured at the hands of the Nature team, comparing it to "Salem witchhunts or McCarthy-like prosecutions."[8] In both the Nature response and a following Quirks and Quarks episode, Benveniste especially complained about Stewart, who he stated acted as if they were all frauds and treated them with disdain, complaining about his "typical know-it-all attitude". In his Nature letter, Benveniste also implied that Randi was attempting to hoodwink the experimental run by doing magic tricks, "distracting the technician in charge of its supervision!" He was more apologetic on Quirks and Quarks, re-phrasing his mention of Randi to imply that he had kept the team amused with his tricks and that his presence was generally welcomed. He also pointed out that although it was true two of his team-members were being paid for by a homeopathic company, the same company had paid for Maddox's team's hotel bill.
Maddox was unapologetic, stating "I'm sorry we didn't find something more interesting." On the same Quirks and Quarks show he dismissed Benveniste's complaints, stating that the possibility that the results would be used by the homeopathy community demanded an immediate re-test. In failing, the tests demonstrated that the initial results were likely due to the experimenter effect. He also pointed out that the entire test procedure that Benveniste later complained about was one that had been agreed upon in advance by all parties. It was only when the test then failed that Benveniste claimed it was not appropriate.
The debate continued in the letters section of Nature for several issues, until eventually being ended by the editorial board. It continued in the French press for some time.[9] For all of the arguing over the retests, it has done nothing to stop what Maddox worried about; even in the light of their failure they are still used to claim that the experiments "prove" that homeopathy works.[10] One of Benveniste's co-authors on the Nature paper, Francis Beauvais, later stated that while unblinded experimental trials usually yielded "correct" results (i.e. ultradiluted samples were biologically active, controls were not), "the results of blinded samples were almost always at random and did not fit the expected results: some 'controls' were active and some 'active' samples were without effect on the biological system."[11]
# More recent experiments
Third-party attempts at replication of the Benveniste experiment have produced mixed results. Nature published a paper describing number of follow-up experiments that failed to find a similar effect in 1993[12] and an independent study published in Experientia in 1992 showed no effect.[13] However, an international team led by Professor Madeleine Ennis of Queen's University of Belfast claimed to have succeeded.[14] Randi then forwarded the $1 million challenge to the BBC Horizon program to prove the "water memory" theory following Ennis' experimental procedure. In response, experiments were conducted with the Vice-President of the Royal Society, Professor John Enderby, overseeing the proceedings. The challenge ended with the Horizon team failing to prove the memory of water.[15] For a piece on homeopathy, the ABC program 20/20 also attempted, unsuccessfully, to reproduce Ennis's results.[16]
Benveniste claimed in a 1997 paper that the memory effect could be transmitted over phone lines.[17] This culminated in two additional papers in 1999[18] and another on remote-transmission in 2000.[19] This work has never been accepted by the rest of the scientific community, and an investigation into the subject by the American Department of Defence failed to find any effect.[20]
Research published in 2005 on hydrogen bond network dynamics in water showed that "liquid water essentially loses the memory of persistent correlations in its structure" within fifty femtoseconds.[21] | https://www.wikidoc.org/index.php/Water_memory | |
59decd16777299f4cfdad33a9ef2c7d5ee85af26 | wikidoc | Water supply | Water supply
Water supply is the process of self-provision or provision by third parties of water of various qualities to different users. This article is so far limited to public water supply. It is expected to also cover industrial self-supply of water.
Irrigation is covered separately.
# Global access to water supply
In 2004 about 3.5 billion people worldwide (54% of the global population) had access to piped water supply through house connections. Another 1.3 billion (20%) had access to safe water through other means than house connections, including standpipes, "water kiosks", protected springs and protected wells. Finally, more than 1 billion people (16%) did not have access to safe water, meaning that they have to revert to unprotected wells or springs, canals, lakes or rivers to fetch water.
# Water and public health
Both an adequate amount of water and adequate water quality are essential for public health and hygiene. Waterborne diseases are among the leading causes of morbidity and mortality in low- and middle-income countries, frequently called developing countries. For example, an estimated 900 million people suffer (and approximately 2 million die) from water-related diarrhoeal illnesses each year. At least 17 percent of the total burden of human diseases in many developing countries can be attributed to diarrhea and infestations by intestinal worms. The most common waterborne or waterwashed diseases are diarrhea, typhoid and cholera. Another example is trachoma, an infectious disease of the eye, which results in many cases of blindness in developing countries, which is associated with poor water supply, poor sanitation and failure to adequately process human excrement.
Sometimes, due to actual or suspected contamination by pathogens a boil water advisory, known as a Boiling water order in the UK, may be invoked.
The World Health Organization has defined around 20 liter per capita per day as basic access, which implies high health concerns, and 100 liter per capita per day as optimal access, associated with low health concerns.
# Technical overview of water supply
Water supply systems get water from a variety of locations, including groundwater (aquifers), surface water (lakes and rivers), conservation and the sea through desalination. The water is then, in most cases, purified, disinfected through chlorination and sometimes fluoridated. Treated water then either flows by gravity or is pumped to reservoirs, which can be elevated such as water towers or on the ground (for indicators related to the efficiency of drinking water distribution see non-revenue water). Once water is used, wastewater is typically discharged in a sewer system and treated in a wastewater treatment plant before being discharged into a river, lake or the sea or reused for landscaping, irrigation or industrial use (see also sanitation).
# Service quality
Many of the 3.5 billion people having access to piped water receive a poor or very poor quality of service, especially in developing countries where about 80% of the world population lives. Water supply service quality has many dimensions: continuity; water quality; pressure; and the degree of responsiveness of service providers to customer complaints.
## Continuity of supply
Continuity of water supply is taken for granted in most developed countries, but is a severe problem in many developing countries, where sometimes water is only provided for a few hours every day or a few days a week. It is estimated that about half of the population of developing countries receives water on an intermittent basis.
## Water quality
Drinking water quality has a micro-biological and a physico-chemical dimension. There are thousands of parameters of water quality. In public water supply systems water should, at a minimum, be disinfected - previously through chlorination, now using ultra violet light - or it may need to undergo treatment, especially in the case of surface water. For more details please see the separate entries on water quality, water treatment and drinking water.
## Water pressure
Water pressures vary in different locations of a distribution system. Water mains below the street may operate at higher pressures, with a pressure reducer located at each point where the water enters a building or a house. In poorly managed systems, water pressure can be so low as to result only in a trickle of water or so high that it leads to damage to plumbing fixtures and waste of water. Pressure in an urban water system is typically maintained either by a pressurized water tank serving an urban area, by pumping the water up into a tower and relying on gravity to maintain a constant pressure in the system or solely by pumps at the water treatment plant and repeater pumping stations.
Typical UK pressures are 4-5 bar for an urban supply. However, some people can get over 8bars. A single iron main pipe may cross a deep valley, it will have the same nominal pressure, however each consumer will get a bit more or less because of the hydrostatic pressure (about 1 bar /10m height). So people at the bottom of a 100-foot hill will get about 3 bars more than those at the top.
The effective pressure also varies because of the supply resistance even for the same static pressure. An urban consumer may have 5 metres of 1/2" lead pipe running from the iron main, so the kitchen tap flow will be fairly unrestricted, so high flow. A rural consumer may have a kilometre of rusted and limed 3/4" iron pipe so their kitchen tap flow will be small.
For this reason the traditional UK domestic water system has a header/storage tank in the attic. Water can dribble into this tank through a 1/2" lead pipe, plus ball valve, and then supply the house on 22 or 28 mm pipes. Gravity water has a small pressure (say 1/4 bar in the bathroom) but needs wide pipes allow higher flows. This is fine for baths and toilets but is frequently inadequate for showers. People install shower booster pumps to increase the pressure. For this reason urban houses are increasingly using mains pressure boilers (combies) which take a long time to fill a bath but suit the high back pressure of a shower.
# Comparing the performance of water and sanitation service providers
Comparing the performance of water and sanitation service providers (utilities) is needed, because the sector offers limited scope for direct competition (natural monopoly). Firms operating in competitive markets are under constant pressure to out perform each other. Water utilities are often sheltered from this pressure, and it frequently shows: some utilities are on a sustained improvement track, but many others keep falling further behind best practice. Benchmarking the performance of utilities allows to simulate competition, establish realistic targets for improvement and create pressure to catch up with better utilities. Information on benchmarks for water and sanitation utilities is provided by the International Benchmarking Network for Water and Sanitation Utilities.
# Institutional responsibility and governance
A great variety of institutions have responsibilities in water supply. A basic distinction is between institutions responsible for policy and regulation on the one hand; and institutions in charge of providing services on the other hand.
## Policy and regulation
Water supply policies and regulation are usually defined by one or several Ministries, in consultation with the legislative branch. In the United States the EPA, whose administrator reports directly to the President, is responsible for water and sanitation policy and standard setting within the executive branch. In other countries responsibility for sector policy is entrusted to a Ministry of Environment (such as in Mexico and Colombia), to a Ministry of Health (such as in Panama, Honduras and Uruguay), a Ministry of Public Works (such as in Ecuador and Haiti), a Ministry of Economy (such as in German states) or a Ministry of Energy (such as in Iran). A few countries, such as Jordan and Bolivia, even have a Ministry of Water. Often several Ministries share responsibilities for water supply. In the European Union, important policy functions have been entrusted to the supranational level. Policy and regulatory functions include the setting of tariff rules and the approval of tariff increases; setting, monitoring and enforcing norms for quality of service and environmental protection; benchmarking the performance of service providers; and reforms in the structure of institutions responsible for service provision. The distinction between policy functions and regulatory functions is not always clear-cut. In some countries they are both entrusted to Ministries, but in others regulatory functions are entrusted to agencies that are separate from Ministries.
### Regulatory agencies
Dozens of countries around the world have established regulatory agencies for infrastructure services, including often water supply and sanitation, in order to better protect consumers and to improve efficiency. Regulatory agencies can be entrusted with a variety of responsibilities, including in particular the approval of tariff increases and the management of sector information systems, including benchmarking systems. Sometimes they also have a mandate to settle complaints by consumers that have not been dealt with satisfactorily by service providers. These specialized entities are expected to be more competent and objective in regulating service providers than departments of government Ministries. Regulatory agencies are supposed to be autonomous from the executive branch of government, but in many countries have often not been able to exercise a great degree of autonomy. In the United States regulatory agencies for utilities have existed for almost a century at the level of states, and in Canada at the level of provinces. In both countries they cover several infrastructure sectors. In many US states they are called Public Utility Commissions. For England and Wales, a regulatory agency for water (OFWAT) was created as part of the privatization of the water industry in 1989. In many developing countries, water regulatory agencies were created during the 1990s in parallel with efforts at increasing private sector participation. (for more details on regulatory agencies in Latin America, for example, please see Water and sanitation in Latin America and the regional association of water regulatory agencies ADERASA )
Many countries do not have regulatory agencies for water. In these countries service providers are regulated directly by local government, or the national government. This is, for example, the case in the countries of continental Europe, in China and India.
For more information on utility regulation in the water sector see the body of knowledge on utility regulation and the World Bank's knowledge base on the same topic at
## Service provision
Water supply service providers, which are often utilities, differ from each other in terms of their geographical coverage relative to administrative boundaries; their sectoral coverage; their ownership structure; and their governance arrangements.
### Geographical coverage
Many water utilities provide services in a single city, town or municipality. However, in many countries municipalities have associated in regional or inter-municipal or multi-jurisdictional utilities to benefit from economies of scale. In the United States these can take the form of special-purpose districts which may have independent taxing authority. An example of a multi-jurisdictional water utility in the United States is WASA, a utility serving Washington, DC and various localities in the state of Maryland. Multi-jurisdictional utilities are also common in Germany, where they are known as "Zweckverbaende", in France and in Italy. In some federal countries there are water service providers covering most or all cities and towns in an entire state, such as in all states of Brazil and some states in Mexico (see Water supply and sanitation in Mexico). In England and Wales water supply and sewerage is supplied almost entirely through ten regional companies. Some smaller countries, especially developed countries, have established service providers that cover the entire country or at least most of its cities and major towns. Such national service providers are especially prevalent in West Africa and Central America, but also exist, for example, in Tunisia, Jordan and Uruguay (see also water supply and sanitation in Uruguay). In rural areas, where about half the world population lives, water services are often not provided by utilities, but by community-based organizations which usually cover one or sometimes several villages.
### Sector coverage
Some water utilities provide only water supply services, while sewerage is under the responsibility of a different entity. This is for example the case in Tunisia. However, in most cases water utilities also provide sewer and wastewater treatment services. In some cities or countries utilities also distribute electricity. In a few cases such multi-utilities also collect solid waste and provide local telephone services. An example of such an integrated utility can be found in the Colombian city of Medellín. Utilities that provide water, sanitation and electricity can be found in Frankfurt, Germany (Mainova), in Casablanca, Morocco and in Gabon in West Africa. Multi-utilities provide certain benefits such as common billing and the option to cross-subsidize water services with revenues from electricity sales, if permitted by law.
### Ownership and governance arrangements
Water supply providers can be either public, private, mixed or cooperative. Most urban water supply services around the world are provided by public entities.
An estimated 10 percent of urban water supply is provided by private or mixed public-private companies, usually under concessions, leases or management contracts. Under these arrangements the public entity that is legally responsible for service provision delegates certain or all aspects of service provision to the private service provider for a period typically ranging from 4 to 30 years. The public entity continues to own the assets. These arrangements are common in France and in Spain. Only in few parts of the world water supply systems have been completely sold to the private sector (privatization), such as in England and Wales as well as in Chile. The largest private water companies in the world are SUEZ and Veolia Environnement from France; Aguas de Barcelona from Spain; and Thames Water from the UK, all of which are engaged internationally (see links to website of these companies below).
Governance arrangements for both public and private utilities can take many forms. Governance arrangements define the relationship between the service provider, its owners, its customers and regulatory entities. They determine the financial autonomy of the service provider and thus its ability to maintain its assets, expand services, attract and retain qualified staff, and ulitmately to provide high-quality services. Key aspects of governance arrangements are the extent to which the entity in charge of providing services is insulated from arbitrary political intervention; and whether there is an explicit mandate and political will to allow the service provider to recover all or at least most of its costs through tariffs and retain these revenues. If water supply is the responsibility of a department that is integrated in the administration of a city, town or municipality, there is a risk that tariff revenues are diverted for other purposes. In some cases, there is also a risk that staff are appointed mainly on political grounds rather than based on their professional credentials. These risks are particularly high in developing countries. Municipal or inter-municipal utilities with a separate legal personality and budget as well as a certain extent of managerial autonomy can mitigate these risks.
# Tariffs
Almost all service providers in the world charge tariffs to recover part of their costs. According to estimates by the World Bank the average (mean) global water tariff is US$ 0.53 per cubic meter. In developed countries the average tariff is US$ 1.04, while it is only U$ 0.11 in the poorest developing countries. The lowest tariffs in developing countries are found in South Asia (mean of US$ 0.09/m3), while the highest are found in Latin America (US$ 0.41/m3). Few utilities do recover all their costs. According to the same World Bank study only 30% of utilities globally, and only 50% of utilities in developed countries, generate sufficient revenue to cover operation, maintenance and partial capital costs.
According to another study undertaken in 2006 by NUS Consulting, the average water and sewerage tariff in 14 mainly OECD countries excluding VAT varied between US$ 0.66 per cubic meter in the United States and the equivalent of US$ 2.25 per cubic meter in Denmark. However, it should be noted that water consumption in the US is much higher than in Europe. Therefore, residential water bills may be very similar, even if the tariff per unit of consumption tends to be higher in Europe than in the US.
A typical family on the US East Coast paid between US$30 and US$70 per month for water and sewer services in 2005.
In developing countries tariffs are usually much further from covering costs. Residential water bills for a typical consumption of 15 cubic meters per month vary between less than US$ 1 and US$ 12 per month.
Water and sanitation tariffs, which are almost always billed together, can take many different forms. Where meters are installed, tariffs are typically volumetric (per usage), sometimes combined with a small monthly fixed charge. In the absence of meters, flat or fixed rates - which are independent of actual consumption - are being charged. In developed countries, tariffs are usually the same for different categories of users and for different levels of consumption.
In developing countries, are often characterized by cross-subsidies with the intent to make water more affordable for residential low-volume users that are assumed to be poor. For example, industrial and commercial users are often charged higher tariffs than public or residential users. Also, metered users are often charged higher tariffs for higher levels of consumption (increasing-block tariffs). However, cross-subsidies between residential users do not always reach their objective. Given the overall low level of water tariffs in developing countries even at higher levels of consumption, most consumption subsidies benefit the wealthier segments of society. Also, high industrial and commercial tariffs can provide an incentive for these users to supply water from other sources than the utility (own wells, water tankers) and thus actually erode the utility's revenue base.
# Metering
Metering of water supply is usually motivated by one or several of four objectives: First, it provides an incentive to conserve water which protects water resources (environmental objective). Second, it can postpone costly system expansion and saves energy and chemical costs (economic objective). Third, it allows a utility to better locate distribution losses (technical objective). Fourth, it allows to charge for water based on use, which is perceived by many as the fairest way to allocate the costs of water supply to users. Metering is considered good practice in water supply and is widespread in developed countries, except for the United Kingdom. In developing countries it is estimated that half of all urban water supply systems are metered and the tendency is increasing.
Water meters are read by one of several methods:
- the water customer writes down the meter reading and mails in a postcard with this info to the water department;
- the water customer writes down the meter reading and uses a phone dial-in system to transfer this info to the water department;
- the water customer logs in to the website of the water supply company, enters the address, meter ID and meter readings
- a meter reader comes to the premise and enters the meter reading into a handheld computer;
- the meter reading is echoed on a display unit mounted to the outside of the premise, where a meter reader records them;
- a small radio is hooked up to the meter to automatically transmit readings to corresponding receivers in handheld computers, utility vehicles or distributed collectors
- a small computer is hooked up to the meter that can either dial out or receive automated phone calls that give the reading to a central computer system.
Most cities are increasingly installing Automatic Meter Reading (AMR) systems to prevent fraud, to lower ever-increasing labor and liability costs and to improve customer service and satisfaction.
# Costs and Financing
The cost of supplying water consists to a very large extent of fixed costs (capital costs and personnel costs) and only to a small extent of variable costs that depend on the amount of water consumed (mainly energy and chemicals). The full cost of supplying water in urban areas in developed countries is about US$1-2 per cubic meter depending on local costs and local water consumption levels. The cost of sanitation (sewerage and wastewater treatment) is another US$1-2 per cubic meter. These costs are somewhat lower in developing countries. Throughout the world, only part of these costs is usually billed to consumers, the remainder being financed through direct or indirect subsidies from local, regional or national governments (see section on tariffs).
Besides subsidies water supply investments are financed through internally generated revenues as well as through debt. Debt financing can take the form of credits from commercial Banks, credits from international financial institutions such as the World Bank and regional development banks (in the case of developing countries), and bonds (in the case of some developed countries and some upper middle-income countries).
# History of water supply
Throughout history people have devised systems to make getting and using water more convenient. Early Rome had indoor plumbing, meaning a system of aqueducts and pipes that terminated in homes and at public wells and fountains for people to use.
The technique of purification of drinking water by use of compressed liquefied chlorine gas was developed in 1910 by U.S. Army Major (later Brig. Gen.) Carl Rogers Darnall (1867-1941), Professor of Chemistry at the Army Medical School. Shortly thereafter, Major (later Col.) William J. L. Lyster (1869-1947) of the Army Medical Department used a solution of calcium hypochlorite in a linen bag to treat water. For many decades, Lyster's method remained the standard for U.S. ground forces in the field and in camps, implemented in the form of the familiar Lyster Bag (also spelled Lister Bag). Darnall's work became the basis for present day systems of municipal water purification.
# Footnotes
- ↑ IBNET
- ↑ World Bank 2006: Water, Electricity and the Poor. Who Benefits from Utility Subsidies?, p. 21 Data for 132 cities were assessed. The tariff is estimate for a consumption level of 15 cubic meters per month
- ↑ NUS Consulting 2005-2006 International Water Report & Cost Survey The study covered Denmark, Germany, the UK, Belgium, France, The Netherlands, Italy, Finland, Australia, Spain, South Africa, Sweden, Canada and the US. The methodology for assessing tariffs may be different from the methodology of the World Bank study cited above. It should be noted that the report means by "costs" average tariffs and not the costs of the utility, which can be lower or higher than average tariffs
- ↑ quoted from a comparison of 24 utilities on the US East Coast in the 2005 Annual Report of DC WASA, p. 38 The comparison refers to a consumption level of 25 cubic feet per quarter
- ↑ World Bank, op.cit., calculated from Table 2.3 on p. 21
- ↑ World Bank 2006: Water, Electricity and the Poor. Who Benefits from Utility Subsidies? | Water supply
Water supply is the process of self-provision or provision by third parties of water of various qualities to different users. This article is so far limited to public water supply. It is expected to also cover industrial self-supply of water.
Irrigation is covered separately.
# Global access to water supply
In 2004 about 3.5 billion people worldwide (54% of the global population) had access to piped water supply through house connections. Another 1.3 billion (20%) had access to safe water through other means than house connections, including standpipes, "water kiosks", protected springs and protected wells. Finally, more than 1 billion people (16%) did not have access to safe water, meaning that they have to revert to unprotected wells or springs, canals, lakes or rivers to fetch water.
# Water and public health
Both an adequate amount of water and adequate water quality are essential for public health and hygiene. Waterborne diseases are among the leading causes of morbidity and mortality in low- and middle-income countries, frequently called developing countries. For example, an estimated 900 million people suffer (and approximately 2 million die) from water-related diarrhoeal illnesses each year. At least 17 percent of the total burden of human diseases in many developing countries can be attributed to diarrhea and infestations by intestinal worms. The most common waterborne or waterwashed diseases are diarrhea, typhoid and cholera. Another example is trachoma, an infectious disease of the eye, which results in many cases of blindness in developing countries, which is associated with poor water supply, poor sanitation and failure to adequately process human excrement.
Sometimes, due to actual or suspected contamination by pathogens a boil water advisory, known as a Boiling water order in the UK, may be invoked.
The World Health Organization has defined around 20 liter per capita per day as basic access, which implies high health concerns, and 100 liter per capita per day as optimal access, associated with low health concerns. [6]
# Technical overview of water supply
Water supply systems get water from a variety of locations, including groundwater (aquifers), surface water (lakes and rivers), conservation and the sea through desalination. The water is then, in most cases, purified, disinfected through chlorination and sometimes fluoridated. Treated water then either flows by gravity or is pumped to reservoirs, which can be elevated such as water towers or on the ground (for indicators related to the efficiency of drinking water distribution see non-revenue water). Once water is used, wastewater is typically discharged in a sewer system and treated in a wastewater treatment plant before being discharged into a river, lake or the sea or reused for landscaping, irrigation or industrial use (see also sanitation).
# Service quality
Many of the 3.5 billion people having access to piped water receive a poor or very poor quality of service, especially in developing countries where about 80% of the world population lives. Water supply service quality has many dimensions: continuity; water quality; pressure; and the degree of responsiveness of service providers to customer complaints.
## Continuity of supply
Continuity of water supply is taken for granted in most developed countries, but is a severe problem in many developing countries, where sometimes water is only provided for a few hours every day or a few days a week. It is estimated that about half of the population of developing countries receives water on an intermittent basis.
## Water quality
Drinking water quality has a micro-biological and a physico-chemical dimension. There are thousands of parameters of water quality. In public water supply systems water should, at a minimum, be disinfected - previously through chlorination, now using ultra violet light - or it may need to undergo treatment, especially in the case of surface water. For more details please see the separate entries on water quality, water treatment and drinking water.
## Water pressure
Water pressures vary in different locations of a distribution system. Water mains below the street may operate at higher pressures, with a pressure reducer located at each point where the water enters a building or a house. In poorly managed systems, water pressure can be so low as to result only in a trickle of water or so high that it leads to damage to plumbing fixtures and waste of water. Pressure in an urban water system is typically maintained either by a pressurized water tank serving an urban area, by pumping the water up into a tower and relying on gravity to maintain a constant pressure in the system or solely by pumps at the water treatment plant and repeater pumping stations.
Typical UK pressures are 4-5 bar for an urban supply. However, some people can get over 8bars. A single iron main pipe may cross a deep valley, it will have the same nominal pressure, however each consumer will get a bit more or less because of the hydrostatic pressure (about 1 bar /10m height). So people at the bottom of a 100-foot hill will get about 3 bars more than those at the top.
The effective pressure also varies because of the supply resistance even for the same static pressure. An urban consumer may have 5 metres of 1/2" lead pipe running from the iron main, so the kitchen tap flow will be fairly unrestricted, so high flow. A rural consumer may have a kilometre of rusted and limed 3/4" iron pipe so their kitchen tap flow will be small.
For this reason the traditional UK domestic water system has a header/storage tank in the attic. Water can dribble into this tank through a 1/2" lead pipe, plus ball valve, and then supply the house on 22 or 28 mm pipes. Gravity water has a small pressure (say 1/4 bar in the bathroom) but needs wide pipes allow higher flows. This is fine for baths and toilets but is frequently inadequate for showers. People install shower booster pumps to increase the pressure. For this reason urban houses are increasingly using mains pressure boilers (combies) which take a long time to fill a bath but suit the high back pressure of a shower.
# Comparing the performance of water and sanitation service providers
Comparing the performance of water and sanitation service providers (utilities) is needed, because the sector offers limited scope for direct competition (natural monopoly). Firms operating in competitive markets are under constant pressure to out perform each other. Water utilities are often sheltered from this pressure, and it frequently shows: some utilities are on a sustained improvement track, but many others keep falling further behind best practice. Benchmarking the performance of utilities allows to simulate competition, establish realistic targets for improvement and create pressure to catch up with better utilities. Information on benchmarks for water and sanitation utilities is provided by the International Benchmarking Network for Water and Sanitation Utilities.[1]
# Institutional responsibility and governance
A great variety of institutions have responsibilities in water supply. A basic distinction is between institutions responsible for policy and regulation on the one hand; and institutions in charge of providing services on the other hand.
## Policy and regulation
Water supply policies and regulation are usually defined by one or several Ministries, in consultation with the legislative branch. In the United States the EPA, whose administrator reports directly to the President, is responsible for water and sanitation policy and standard setting within the executive branch. In other countries responsibility for sector policy is entrusted to a Ministry of Environment (such as in Mexico and Colombia), to a Ministry of Health (such as in Panama, Honduras and Uruguay), a Ministry of Public Works (such as in Ecuador and Haiti), a Ministry of Economy (such as in German states) or a Ministry of Energy (such as in Iran). A few countries, such as Jordan and Bolivia, even have a Ministry of Water. Often several Ministries share responsibilities for water supply. In the European Union, important policy functions have been entrusted to the supranational level. Policy and regulatory functions include the setting of tariff rules and the approval of tariff increases; setting, monitoring and enforcing norms for quality of service and environmental protection; benchmarking the performance of service providers; and reforms in the structure of institutions responsible for service provision. The distinction between policy functions and regulatory functions is not always clear-cut. In some countries they are both entrusted to Ministries, but in others regulatory functions are entrusted to agencies that are separate from Ministries.
### Regulatory agencies
Dozens of countries around the world have established regulatory agencies for infrastructure services, including often water supply and sanitation, in order to better protect consumers and to improve efficiency. Regulatory agencies can be entrusted with a variety of responsibilities, including in particular the approval of tariff increases and the management of sector information systems, including benchmarking systems. Sometimes they also have a mandate to settle complaints by consumers that have not been dealt with satisfactorily by service providers. These specialized entities are expected to be more competent and objective in regulating service providers than departments of government Ministries. Regulatory agencies are supposed to be autonomous from the executive branch of government, but in many countries have often not been able to exercise a great degree of autonomy. In the United States regulatory agencies for utilities have existed for almost a century at the level of states, and in Canada at the level of provinces. In both countries they cover several infrastructure sectors. In many US states they are called Public Utility Commissions. For England and Wales, a regulatory agency for water (OFWAT) was created as part of the privatization of the water industry in 1989. In many developing countries, water regulatory agencies were created during the 1990s in parallel with efforts at increasing private sector participation. (for more details on regulatory agencies in Latin America, for example, please see Water and sanitation in Latin America and the regional association of water regulatory agencies ADERASA [http:/www.aderasa.org])
Many countries do not have regulatory agencies for water. In these countries service providers are regulated directly by local government, or the national government. This is, for example, the case in the countries of continental Europe, in China and India.
For more information on utility regulation in the water sector see the body of knowledge on utility regulation [7] and the World Bank's knowledge base on the same topic at [8]
## Service provision
Water supply service providers, which are often utilities, differ from each other in terms of their geographical coverage relative to administrative boundaries; their sectoral coverage; their ownership structure; and their governance arrangements.
### Geographical coverage
Many water utilities provide services in a single city, town or municipality. However, in many countries municipalities have associated in regional or inter-municipal or multi-jurisdictional utilities to benefit from economies of scale. In the United States these can take the form of special-purpose districts which may have independent taxing authority. An example of a multi-jurisdictional water utility in the United States is WASA, a utility serving Washington, DC and various localities in the state of Maryland. Multi-jurisdictional utilities are also common in Germany, where they are known as "Zweckverbaende", in France and in Italy. In some federal countries there are water service providers covering most or all cities and towns in an entire state, such as in all states of Brazil and some states in Mexico (see Water supply and sanitation in Mexico). In England and Wales water supply and sewerage is supplied almost entirely through ten regional companies. Some smaller countries, especially developed countries, have established service providers that cover the entire country or at least most of its cities and major towns. Such national service providers are especially prevalent in West Africa and Central America, but also exist, for example, in Tunisia, Jordan and Uruguay (see also water supply and sanitation in Uruguay). In rural areas, where about half the world population lives, water services are often not provided by utilities, but by community-based organizations which usually cover one or sometimes several villages.
### Sector coverage
Some water utilities provide only water supply services, while sewerage is under the responsibility of a different entity. This is for example the case in Tunisia. However, in most cases water utilities also provide sewer and wastewater treatment services. In some cities or countries utilities also distribute electricity. In a few cases such multi-utilities also collect solid waste and provide local telephone services. An example of such an integrated utility can be found in the Colombian city of Medellín. Utilities that provide water, sanitation and electricity can be found in Frankfurt, Germany (Mainova), in Casablanca, Morocco and in Gabon in West Africa. Multi-utilities provide certain benefits such as common billing and the option to cross-subsidize water services with revenues from electricity sales, if permitted by law.
### Ownership and governance arrangements
Water supply providers can be either public, private, mixed or cooperative. Most urban water supply services around the world are provided by public entities.
An estimated 10 percent of urban water supply is provided by private or mixed public-private companies, usually under concessions, leases or management contracts. Under these arrangements the public entity that is legally responsible for service provision delegates certain or all aspects of service provision to the private service provider for a period typically ranging from 4 to 30 years. The public entity continues to own the assets. These arrangements are common in France and in Spain. Only in few parts of the world water supply systems have been completely sold to the private sector (privatization), such as in England and Wales as well as in Chile. The largest private water companies in the world are SUEZ and Veolia Environnement from France; Aguas de Barcelona from Spain; and Thames Water from the UK, all of which are engaged internationally (see links to website of these companies below).
Governance arrangements for both public and private utilities can take many forms. Governance arrangements define the relationship between the service provider, its owners, its customers and regulatory entities. They determine the financial autonomy of the service provider and thus its ability to maintain its assets, expand services, attract and retain qualified staff, and ulitmately to provide high-quality services. Key aspects of governance arrangements are the extent to which the entity in charge of providing services is insulated from arbitrary political intervention; and whether there is an explicit mandate and political will to allow the service provider to recover all or at least most of its costs through tariffs and retain these revenues. If water supply is the responsibility of a department that is integrated in the administration of a city, town or municipality, there is a risk that tariff revenues are diverted for other purposes. In some cases, there is also a risk that staff are appointed mainly on political grounds rather than based on their professional credentials. These risks are particularly high in developing countries. Municipal or inter-municipal utilities with a separate legal personality and budget as well as a certain extent of managerial autonomy can mitigate these risks.
# Tariffs
Almost all service providers in the world charge tariffs to recover part of their costs. According to estimates by the World Bank the average (mean) global water tariff is US$ 0.53 per cubic meter. In developed countries the average tariff is US$ 1.04, while it is only U$ 0.11 in the poorest developing countries. The lowest tariffs in developing countries are found in South Asia (mean of US$ 0.09/m3), while the highest are found in Latin America (US$ 0.41/m3).[2] Few utilities do recover all their costs. According to the same World Bank study only 30% of utilities globally, and only 50% of utilities in developed countries, generate sufficient revenue to cover operation, maintenance and partial capital costs.
According to another study undertaken in 2006 by NUS Consulting, the average water and sewerage tariff in 14 mainly OECD countries excluding VAT varied between US$ 0.66 per cubic meter in the United States and the equivalent of US$ 2.25 per cubic meter in Denmark.[3] However, it should be noted that water consumption in the US is much higher than in Europe. Therefore, residential water bills may be very similar, even if the tariff per unit of consumption tends to be higher in Europe than in the US.
A typical family on the US East Coast paid between US$30 and US$70 per month for water and sewer services in 2005.[4]
In developing countries tariffs are usually much further from covering costs. Residential water bills for a typical consumption of 15 cubic meters per month vary between less than US$ 1 and US$ 12 per month.[5]
Water and sanitation tariffs, which are almost always billed together, can take many different forms. Where meters are installed, tariffs are typically volumetric (per usage), sometimes combined with a small monthly fixed charge. In the absence of meters, flat or fixed rates - which are independent of actual consumption - are being charged. In developed countries, tariffs are usually the same for different categories of users and for different levels of consumption.
In developing countries, are often characterized by cross-subsidies with the intent to make water more affordable for residential low-volume users that are assumed to be poor. For example, industrial and commercial users are often charged higher tariffs than public or residential users. Also, metered users are often charged higher tariffs for higher levels of consumption (increasing-block tariffs). However, cross-subsidies between residential users do not always reach their objective. Given the overall low level of water tariffs in developing countries even at higher levels of consumption, most consumption subsidies benefit the wealthier segments of society.[6] Also, high industrial and commercial tariffs can provide an incentive for these users to supply water from other sources than the utility (own wells, water tankers) and thus actually erode the utility's revenue base.
# Metering
Metering of water supply is usually motivated by one or several of four objectives: First, it provides an incentive to conserve water which protects water resources (environmental objective). Second, it can postpone costly system expansion and saves energy and chemical costs (economic objective). Third, it allows a utility to better locate distribution losses (technical objective). Fourth, it allows to charge for water based on use, which is perceived by many as the fairest way to allocate the costs of water supply to users. Metering is considered good practice in water supply and is widespread in developed countries, except for the United Kingdom. In developing countries it is estimated that half of all urban water supply systems are metered and the tendency is increasing.
Water meters are read by one of several methods:
- the water customer writes down the meter reading and mails in a postcard with this info to the water department;
- the water customer writes down the meter reading and uses a phone dial-in system to transfer this info to the water department;
- the water customer logs in to the website of the water supply company, enters the address, meter ID and meter readings [9]
- a meter reader comes to the premise and enters the meter reading into a handheld computer;
- the meter reading is echoed on a display unit mounted to the outside of the premise, where a meter reader records them;
- a small radio is hooked up to the meter to automatically transmit readings to corresponding receivers in handheld computers, utility vehicles or distributed collectors
- a small computer is hooked up to the meter that can either dial out or receive automated phone calls that give the reading to a central computer system.
Most cities are increasingly installing Automatic Meter Reading (AMR) systems to prevent fraud, to lower ever-increasing labor and liability costs and to improve customer service and satisfaction.
# Costs and Financing
The cost of supplying water consists to a very large extent of fixed costs (capital costs and personnel costs) and only to a small extent of variable costs that depend on the amount of water consumed (mainly energy and chemicals). The full cost of supplying water in urban areas in developed countries is about US$1-2 per cubic meter depending on local costs and local water consumption levels. The cost of sanitation (sewerage and wastewater treatment) is another US$1-2 per cubic meter. These costs are somewhat lower in developing countries. Throughout the world, only part of these costs is usually billed to consumers, the remainder being financed through direct or indirect subsidies from local, regional or national governments (see section on tariffs).
Besides subsidies water supply investments are financed through internally generated revenues as well as through debt. Debt financing can take the form of credits from commercial Banks, credits from international financial institutions such as the World Bank and regional development banks (in the case of developing countries), and bonds (in the case of some developed countries and some upper middle-income countries).
# History of water supply
Throughout history people have devised systems to make getting and using water more convenient. Early Rome had indoor plumbing, meaning a system of aqueducts and pipes that terminated in homes and at public wells and fountains for people to use.
The technique of purification of drinking water by use of compressed liquefied chlorine gas was developed in 1910 by U.S. Army Major (later Brig. Gen.) Carl Rogers Darnall (1867-1941), Professor of Chemistry at the Army Medical School. Shortly thereafter, Major (later Col.) William J. L. Lyster (1869-1947) of the Army Medical Department used a solution of calcium hypochlorite in a linen bag to treat water. For many decades, Lyster's method remained the standard for U.S. ground forces in the field and in camps, implemented in the form of the familiar Lyster Bag (also spelled Lister Bag). Darnall's work became the basis for present day systems of municipal water purification.
Template:Sect-stub
# Footnotes
- ↑ IBNET [1]
- ↑ World Bank 2006: Water, Electricity and the Poor. Who Benefits from Utility Subsidies?, p. 21 [2] Data for 132 cities were assessed. The tariff is estimate for a consumption level of 15 cubic meters per month
- ↑ NUS Consulting 2005-2006 International Water Report & Cost Survey [3] The study covered Denmark, Germany, the UK, Belgium, France, The Netherlands, Italy, Finland, Australia, Spain, South Africa, Sweden, Canada and the US. The methodology for assessing tariffs may be different from the methodology of the World Bank study cited above. It should be noted that the report means by "costs" average tariffs and not the costs of the utility, which can be lower or higher than average tariffs
- ↑ quoted from a comparison of 24 utilities on the US East Coast in the 2005 Annual Report of DC WASA, p. 38 [4] The comparison refers to a consumption level of 25 cubic feet per quarter
- ↑ World Bank, op.cit., calculated from Table 2.3 on p. 21
- ↑ World Bank 2006: Water, Electricity and the Poor. Who Benefits from Utility Subsidies? [5] | https://www.wikidoc.org/index.php/Water_supply | |
b4324b9248508627365378bd6cc440c5fc4c3481 | wikidoc | Whey protein | Whey protein
Whey protein is the name for a collection of globular proteins that can be isolated from whey, a by-product of cheese manufactured from cow's milk. It is typically a mixture of beta-lactoglobulin (~65%), alpha-lactalbumin (~25%), and serum albumin (~8%), which are soluble in their native forms, independent of pH. Whey has the highest Biological Value (BV) of any known protein.
Whey is a lactose-free or reduced lactose protein containing a variety of nutrients and essential amino acids. Whey comprises four major protein fractions and six minor protein fractions. The major protein fractions in whey are beta-lactoglobulin, alpha-lactalbumin, bovine serum albumin and immunoglobulins. Each of these components have important disease-fighting effects. In addition, whey protein is easily digestible.
Native whey protein does not aggregate upon renneting or acidification of milk. Prolonged heat-treatment at sufficiently high temperatures and long duration will denature (i.e. partly unfold) the whey protein, triggering hydrophobic interactions with other proteins, and the formation of disulfide bonds between whey proteins and casein micelles, leading to aggregation with other milk proteins at low pH.
Whey protein can be denatured (irreversibly changed) by heat — similar to the protein in egg whites which, when cooked, permanently changes from a clear liquid to a white solid. When subjected to high heat (like the sustained high temperatures above 72 degrees Celsius (160 degrees Fahrenheit) associated with the pasteurization process) whey proteins become denatured and lose some bioactive compounds like cysteine, an amino acid that is a precursor to glutathione, an antioxidant.
Whey protein typically comes in three major forms: concentrate, isolate and hydrolysate. Whey protein concentrates contain a low level of fat and cholesterol but generally have higher levels of bioactive compounds, and carbohydrates in the form of lactose — they are 29%-89% protein by weight. Isolates are processed to remove the fat, and lactose, but are usually lower in bioactive compounds as well — they are 90%+ protein by weight. Hydrolysates are predigested, partially hydrolyzed whey proteins which consequently are more easily absorbed, but their cost is generally higher.
# Uses
Whey protein contains high levels of both essential and non-essential amino acids, and pregnant mothers are sometimes advised by their obstetricians to supplement their diets with whey protein to ensure that their developing babies get all the basic amino acids they might need.
More than other protein supplements, whey protein powder is commonly used by bodybuilders and other athletes to accelerate muscle development and aid in recovery. Some individuals with suppressed or otherwise abnormal immune systems or degenerative diseases use undenatured bioactive whey proteins to increase their antioxidant levels. Undenatured whey proteins are a good source of cysteine, a conditionally essential amino acid which is the rate limiting factor for the body's production of glutathione, an important antioxidant.
Examples of commercial whey proteins include those available in most health food stores and supermarket health sections; they typically consist of isolate/concentrate or isolate/concentrate/hydrolysate mixtures and they are usually flavored so they can be mixed with water or milk and consumed as a drink or shake. It is not always as expensive as you would think, it can be purchased cheaply from any good sports store. | Whey protein
Whey protein is the name for a collection of globular proteins that can be isolated from whey, a by-product of cheese manufactured from cow's milk. It is typically a mixture of beta-lactoglobulin (~65%), alpha-lactalbumin (~25%), and serum albumin (~8%), which are soluble in their native forms, independent of pH. Whey has the highest Biological Value (BV) of any known protein.
Whey is a lactose-free or reduced lactose protein containing a variety of nutrients and essential amino acids. Whey comprises four major protein fractions and six minor protein fractions. The major protein fractions in whey are beta-lactoglobulin, alpha-lactalbumin, bovine serum albumin and immunoglobulins. Each of these components have important disease-fighting effects. In addition, whey protein is easily digestible.
Native whey protein does not aggregate upon renneting or acidification of milk. Prolonged heat-treatment at sufficiently high temperatures and long duration will denature (i.e. partly unfold) the whey protein, triggering hydrophobic interactions with other proteins, and the formation of disulfide bonds between whey proteins and casein micelles, leading to aggregation with other milk proteins at low pH.
Whey protein can be denatured (irreversibly changed) by heat — similar to the protein in egg whites which, when cooked, permanently changes from a clear liquid to a white solid. When subjected to high heat (like the sustained high temperatures above 72 degrees Celsius (160 degrees Fahrenheit) associated with the pasteurization process) whey proteins become denatured and lose some bioactive compounds like cysteine, an amino acid that is a precursor to glutathione, an antioxidant.
Whey protein typically comes in three major forms: concentrate, isolate and hydrolysate. Whey protein concentrates contain a low level of fat and cholesterol but generally have higher levels of bioactive compounds, and carbohydrates in the form of lactose — they are 29%-89% protein by weight. Isolates are processed to remove the fat, and lactose, but are usually lower in bioactive compounds as well — they are 90%+ protein by weight. Hydrolysates are predigested, partially hydrolyzed whey proteins which consequently are more easily absorbed, but their cost is generally higher.
## Uses
Whey protein contains high levels of both essential and non-essential amino acids, and pregnant mothers are sometimes advised by their obstetricians to supplement their diets with whey protein to ensure that their developing babies get all the basic amino acids they might need.[citation needed]
More than other protein supplements, whey protein powder is commonly used by bodybuilders and other athletes to accelerate muscle development and aid in recovery. Some individuals with suppressed or otherwise abnormal immune systems or degenerative diseases use undenatured bioactive whey proteins to increase their antioxidant levels. Undenatured whey proteins are a good source of cysteine, a conditionally essential amino acid which is the rate limiting factor for the body's production of glutathione, an important antioxidant.
Examples of commercial whey proteins include those available in most health food stores and supermarket health sections; they typically consist of isolate/concentrate or isolate/concentrate/hydrolysate mixtures and they are usually flavored so they can be mixed with water or milk and consumed as a drink or shake. It is not always as expensive as you would think, it can be purchased cheaply from any good sports store. | https://www.wikidoc.org/index.php/Whey_protein | |
9a368b70e13f311e48f1184d3d1a855e42b4b443 | wikidoc | White Willow | White Willow
Salix alba, the White Willow is a willow native to Europe, and western and central Asia. It is a large deciduous tree up to 20-30 m tall. The name derives from the leaves, which are paler than most other willows, due to a covering of very fine silky white hairs, particularly on the underside. The leaves are typically 5-10 cm long and 1-1.5 cm wide. The shoots in the typical species are grey-brown to green-brown. The dioecious flowers are catkins, produced in early spring, and pollinated by bees.
A number of cultivars and hybrids of White Willow have been selected for forestry and horticulture use:
- The Cricket-bat Willow (Salix alba 'Caerulea'), often referred to simply as English Willow, is grown as a specialist timber crop in Britain, mainly for the production of cricket bats, but also for other uses where a tough, lightweight wood that does not splinter easily, is required. It is distinguished mainly by its growth form, very fast growing with a single straight stem, and also by its slightly larger leaves (10-11 cm long, 1.5-2 cm wide) with a more blue-green colour. Its origin is unknown, but it may be a hybrid between White Willow and Crack Willow (Salix fragilis).
- The Weeping Willow (Salix × sepulcralis 'Chrysocoma', syn. Salix 'Tristis') is a hybrid between White Willow and Peking Willow (Salix babylonica, syn. Salix matsudana).
- The Golden Willow (Salix alba 'Vitellina') is a cultivar grown in gardens for its shoots, which are golden yellow for 1-2 years before turning brown. It is particularly decorative in winter; the best effect is achieved by coppicing it every 2-3 years to stimulate the production of longer young shoots with better colour. Two other similar cultivars, 'Britzensis' and 'Cardinal', have orange-red shoots.
White Willows are fast-growing, but short-lived, being susceptible to several diseases, including watermark disease caused by the bacterium Erwinia salicis (named because of the characteristic 'watermark' staining in the wood) and willow anthracnose, caused by the fungus Marssonina salicicola. These diseases can be a serious problem on trees grown for timber or ornament.
# Medicinal Uses
Hippocrates wrote in the 5th century BC about a bitter powder extracted from willow bark that could ease aches and pains and reduce fevers. This remedy is also mentioned in texts from ancient Egypt, Sumer, and Assyria. Native American Indians used it for headaches, fever, sore muscles, rheumatism, and chills. The Reverend Edward Stone, a vicar from Chipping Norton in Oxfordshire England, noted in 1763 that the bark of the willow was effective in reducing a fever.
The active extract of the bark, called salicin, after the Latin name for the White Willow (Salix alba), was isolated to its crystalline form in 1828 by Henri Leroux, a French pharmacist, and Raffaele Piria, an Italian chemist, who then succeeded in separating out the acid in its pure state. Salicin, like aspirin, is a chemical derivative of salicylic acid.
- White Willow illustration
White Willow illustration
- Catkins
Catkins
- File:Salix alba(01).jpg
- All Cricket bats are made from willow
All Cricket bats are made from willow
- White Willows in winter time
White Willows in winter time
bg:Бяла върба
ca:Vimetera
da:Hvid-pil
de:Silber-Weide
it:Salix alba
lt:Baltasis gluosnis
nl:Schietwilg
sq:Shelgu i bardhë
sv:Vitpil
uk:Верба біла | White Willow
Salix alba, the White Willow is a willow native to Europe, and western and central Asia. It is a large deciduous tree up to 20-30 m tall. The name derives from the leaves, which are paler than most other willows, due to a covering of very fine silky white hairs, particularly on the underside. The leaves are typically 5-10 cm long and 1-1.5 cm wide. The shoots in the typical species are grey-brown to green-brown. The dioecious flowers are catkins, produced in early spring, and pollinated by bees.
A number of cultivars and hybrids of White Willow have been selected for forestry and horticulture use:
- The Cricket-bat Willow (Salix alba 'Caerulea'), often referred to simply as English Willow, is grown as a specialist timber crop in Britain, mainly for the production of cricket bats, but also for other uses where a tough, lightweight wood that does not splinter easily, is required. It is distinguished mainly by its growth form, very fast growing with a single straight stem, and also by its slightly larger leaves (10-11 cm long, 1.5-2 cm wide) with a more blue-green colour. Its origin is unknown, but it may be a hybrid between White Willow and Crack Willow (Salix fragilis).
- The Weeping Willow (Salix × sepulcralis 'Chrysocoma', syn. Salix 'Tristis') is a hybrid between White Willow and Peking Willow (Salix babylonica, syn. Salix matsudana).
- The Golden Willow (Salix alba 'Vitellina') is a cultivar grown in gardens for its shoots, which are golden yellow for 1-2 years before turning brown. It is particularly decorative in winter; the best effect is achieved by coppicing it every 2-3 years to stimulate the production of longer young shoots with better colour. Two other similar cultivars, 'Britzensis' and 'Cardinal', have orange-red shoots.
White Willows are fast-growing, but short-lived, being susceptible to several diseases, including watermark disease caused by the bacterium Erwinia salicis (named because of the characteristic 'watermark' staining in the wood) and willow anthracnose, caused by the fungus Marssonina salicicola. These diseases can be a serious problem on trees grown for timber or ornament.
## Medicinal Uses
Hippocrates wrote in the 5th century BC about a bitter powder extracted from willow bark that could ease aches and pains and reduce fevers.[citation needed] This remedy is also mentioned in texts from ancient Egypt, Sumer, and Assyria.[citation needed] Native American Indians used it for headaches, fever, sore muscles, rheumatism, and chills.[citation needed] The Reverend Edward Stone, a vicar from Chipping Norton in Oxfordshire England, noted in 1763 that the bark of the willow was effective in reducing a fever.[citation needed]
The active extract of the bark, called salicin, after the Latin name for the White Willow (Salix alba), was isolated to its crystalline form in 1828 by Henri Leroux, a French pharmacist, and Raffaele Piria, an Italian chemist, who then succeeded in separating out the acid in its pure state. Salicin, like aspirin, is a chemical derivative of salicylic acid.
- White Willow illustration
White Willow illustration
- Catkins
Catkins
- File:Salix alba(01).jpg
- All Cricket bats are made from willow
All Cricket bats are made from willow
- White Willows in winter time
White Willows in winter time
bg:Бяла върба
ca:Vimetera
da:Hvid-pil
de:Silber-Weide
it:Salix alba
lt:Baltasis gluosnis
nl:Schietwilg
sq:Shelgu i bardhë
sv:Vitpil
uk:Верба біла | https://www.wikidoc.org/index.php/White_Willow | |
f43e462f7461017bb26b1e0a7256ce216121a6dc | wikidoc | White matter | White matter
# Overview
White matter is one of the three main solid components of the central nervous system designated by color. The other two are gray matter and substantia nigra.
# Structure
It is composed of myelinated nerve cell processes, or axons, which connect various gray matter areas (the locations of nerve cell bodies) of the brain to each other and carry nerve impulses between neurons.
Cerebral and spinal white matter do not contain dendrites, which can only be found in gray matter along with neural cell bodies and shorter axons.
# Function
The white matter is the tissue through which messages pass between different areas of gray matter within the nervous system. Using a computer network as an analogy, the gray matter can be thought of as the actual computers themselves, whereas the white matter represents the network cables connecting the computers together. The white matter is white because of the fatty substance (myelin) that surrounds the nerve fibers (axons). This myelin is found in almost all long nerve fibers as the insulation is important for allowing the messages to pass quickly from place to place.
The brain in general (and especially a child's brain) can adapt to white matter damage by finding alternative routes which bypass the damaged areas of white matter and can therefore maintain good connections between the various areas of gray matter.
Unlike gray matter, which peaks in development in a persons twenties, the white matter continues to develop and peaks in late middle age.
# Location
White matter forms the bulk of the deep parts of the brain and the superficial parts of the spinal cord. Aggregates of grey matter such as the basal ganglia (caudate nucleus, putamen, globus pallidus, subthalamic nucleus, nucleus accumbens) and brain stem nuclei (red nucleus, substantia nigra, cranial nerve nuclei) are spread within the cerebral white matter.
The cerebellum is structured in a similar manner as the cerebrum, with a superficial mantle of cerebellar cortex, deep cerebellar white matter (called the "arbor vitae") and aggregates of grey matter surrounded by deep cerebellar white matter (dentate nucleus, globose nucleus, emboliform nucleus, and fastigial nucleus). The fluid-filled cerebral ventricles (lateral ventricles, third ventricle, cerebral aqueduct, fourth ventricle) are also located deep within the cerebral white matter.and suppl
# Types of astrocytes
In 1983, M. C. Raff et al. discovered that tissue samples originating from rat optic nerve contained two morphologically distinct types of astrocytes.
- So-called "Type 1 astrocytes" had a fibroblast appearance and resided in both gray matter and white matter.
- "Type 2 astrocytes" has a neuron-like appearance and resided in white matter alone (Sherman, Chris).
# Clinical relevance
Leukoaraiosis is "non-specific white matter changes in the brain, often seen after age 65". The prevalence of these changes is 20% among patients over age 60. These lesions are associated with a doubling of risk of dementia, stroke, and death.
Multiple Sclerosis is one of the most common disease which affects white matter. In MS lesions, the myelin shield around the axons has been destroyed by inflammation.
Changes in white matter known as amyloid plaques are associated with Alzheimer's disease and other neurodegenerative diseases. White matter injuries ("axonal shearing") may be reversible, while gray matter regeneration is less likely.
# Notes
- ↑ Leukoaraiosis. Available at
- ↑ Jump up to: 2.0 2.1 Vermeer SE, Prins ND, den Heijer T, Hofman A, Koudstaal PJ, Breteler MM (2003). "Silent brain infarcts and the risk of dementia and cognitive decline". N Engl J Med. 348 (13): 1215–22. doi:10.1056/NEJMoa022066. PMID 12660385.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}
- ↑ Jump up to: 3.0 3.1 3.2 Debette S, Markus HS (2010). "The clinical importance of white matter hyperintensities on brain magnetic resonance imaging: systematic review and meta-analysis". BMJ. 341: c3666. doi:10.1136/bmj.c3666. PMC 2910261. PMID 20660506. Review in: Evid Based Ment Health. 2011 Feb;14(1):1
- ↑ Putaala J, Kurkinen M, Tarvos V, Salonen O, Kaste M, Tatlisumak T (2009). "Silent brain infarcts and leukoaraiosis in young adults with first-ever ischemic stroke". Neurology. 72 (21): 1823–9. doi:10.1212/WNL.0b013e3181a711df. PMID 19470964.CS1 maint: Multiple names: authors list (link) | White matter
Template:Infobox Anatomy
# Overview
White matter is one of the three main solid components of the central nervous system designated by color. The other two are gray matter and substantia nigra.
# Structure
It is composed of myelinated nerve cell processes, or axons, which connect various gray matter areas (the locations of nerve cell bodies) of the brain to each other and carry nerve impulses between neurons.
Cerebral and spinal white matter do not contain dendrites, which can only be found in gray matter along with neural cell bodies and shorter axons.
# Function
The white matter is the tissue through which messages pass between different areas of gray matter within the nervous system. Using a computer network as an analogy, the gray matter can be thought of as the actual computers themselves, whereas the white matter represents the network cables connecting the computers together. The white matter is white because of the fatty substance (myelin) that surrounds the nerve fibers (axons). This myelin is found in almost all long nerve fibers as the insulation is important for allowing the messages to pass quickly from place to place.
The brain in general (and especially a child's brain) can adapt to white matter damage by finding alternative routes which bypass the damaged areas of white matter and can therefore maintain good connections between the various areas of gray matter.
Unlike gray matter, which peaks in development in a persons twenties, the white matter continues to develop and peaks in late middle age.
# Location
White matter forms the bulk of the deep parts of the brain and the superficial parts of the spinal cord. Aggregates of grey matter such as the basal ganglia (caudate nucleus, putamen, globus pallidus, subthalamic nucleus, nucleus accumbens) and brain stem nuclei (red nucleus, substantia nigra, cranial nerve nuclei) are spread within the cerebral white matter.
The cerebellum is structured in a similar manner as the cerebrum, with a superficial mantle of cerebellar cortex, deep cerebellar white matter (called the "arbor vitae") and aggregates of grey matter surrounded by deep cerebellar white matter (dentate nucleus, globose nucleus, emboliform nucleus, and fastigial nucleus). The fluid-filled cerebral ventricles (lateral ventricles, third ventricle, cerebral aqueduct, fourth ventricle) are also located deep within the cerebral white matter.and suppl
# Types of astrocytes
In 1983, M. C. Raff et al. discovered that tissue samples originating from rat optic nerve contained two morphologically distinct types of astrocytes.
- So-called "Type 1 astrocytes" had a fibroblast appearance and resided in both gray matter and white matter.
- "Type 2 astrocytes" has a neuron-like appearance and resided in white matter alone (Sherman, Chris).
# Clinical relevance
Leukoaraiosis is "non-specific white matter changes in the brain, often seen after age 65".[1] The prevalence of these changes is 20% among patients over age 60.[2] These lesions are associated with a doubling of risk of dementia[2][3], stroke[3], and death[3].
[4]
Multiple Sclerosis is one of the most common disease which affects white matter. In MS lesions, the myelin shield around the axons has been destroyed by inflammation.
Changes in white matter known as amyloid plaques are associated with Alzheimer's disease and other neurodegenerative diseases. White matter injuries ("axonal shearing") may be reversible, while gray matter regeneration is less likely.
# Notes
- ↑ Leukoaraiosis. Available at https://www.ncbi.nlm.nih.gov/mesh/?term=Leukoaraiosis
- ↑ Jump up to: 2.0 2.1 Vermeer SE, Prins ND, den Heijer T, Hofman A, Koudstaal PJ, Breteler MM (2003). "Silent brain infarcts and the risk of dementia and cognitive decline". N Engl J Med. 348 (13): 1215–22. doi:10.1056/NEJMoa022066. PMID 12660385.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}
- ↑ Jump up to: 3.0 3.1 3.2 Debette S, Markus HS (2010). "The clinical importance of white matter hyperintensities on brain magnetic resonance imaging: systematic review and meta-analysis". BMJ. 341: c3666. doi:10.1136/bmj.c3666. PMC 2910261. PMID 20660506. Review in: Evid Based Ment Health. 2011 Feb;14(1):1
- ↑ Putaala J, Kurkinen M, Tarvos V, Salonen O, Kaste M, Tatlisumak T (2009). "Silent brain infarcts and leukoaraiosis in young adults with first-ever ischemic stroke". Neurology. 72 (21): 1823–9. doi:10.1212/WNL.0b013e3181a711df. PMID 19470964.CS1 maint: Multiple names: authors list (link)
Template:Neuroanatomy-stub
# External links
- White Matter Atlas
- Template:EMedicineDictionary
Template:Spinal cord
de:Weiße Substanz
it:Sostanza bianca
nl:Witte stof
sk:Biela hmota
sv:Vit hjärnsubstans
Template:WS | https://www.wikidoc.org/index.php/White_matter | |
76e971582dd7018da417d8d8b9046c5113e89854 | wikidoc | Zinc sulfate | Zinc sulfate
# 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
Zinc sulfate is a parenteral mineral- trace mineral that is FDA approved for the prophylaxis of prophylaxis of zinc deficiency. Common adverse reactions include indigestion, nausea, vomiting.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Zinc Sulfate Injection, USP is indicated for use as a supplement to intravenous solutions given for TPN. Administration helps to maintain plasma levels and to prevent depletion of endogenous stores.
- Dosing Information
- Zinc Sulfate Injection, USP provides 1 mg zinc/mL. For metabolically stable adults receiving TPN, the suggested intravenous dosage is 2.5 to 4 mg zinc/day. An additional 2 mg zinc/day is suggested for acute catabolic states. For the stable adult with fluid loss from the small bowel, an additional 12.2 mg zinc/liter of small bowel fluid lost, or an additional 17.1 mg zinc/kg of stool or ileostomy output is recommended. Frequent monitoring of zinc blood levels is suggested for patients receiving more than the usual maintenance dosage level of zinc.
- For full term infants and children up to 5 years of age, 100 mcg zinc/kg/day is recommended. For premature infants (birth weight less than 1500 g) up to 3 kg in body weight, 300 mcg zinc/kg/day is suggested.
- Aseptic addition of Zinc Sulfate Injection, USP to the TPN solution under a laminar flow hood is recommended. Zinc is physically compatible with the electrolytes and vitamins usually present in the amino acid/dextrose solution used for TPN.
- Parenteral drug products should be inspected visually for particulate matter and discoloration, whenever solution and container permit.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Zinc sulfate in adult patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Zinc sulfate in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- There is limited information regarding FDA-Labeled Use of Zinc sulfate in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Zinc sulfate in pediatric patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Zinc sulfate in pediatric patients.
# Contraindications
There is limited information regarding Zinc sulfate Contraindications in the drug label.
# Warnings
There is limited information regarding Zinc sulfate Warnings' in the drug label.
# Adverse Reactions
## Clinical Trials Experience
- There is limited information regarding Clinical Trial Experience of Zinc sulfate in the drug label.
## Postmarketing Experience
- There is limited information regarding Postmarketing Experience of Zinc sulfate in the drug label.
# Drug Interactions
There is limited information regarding Zinc sulfate Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
- There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Zinc sulfate in women who are pregnant.
### Labor and Delivery
- There is no FDA guidance on use of Zinc sulfate during labor and delivery.
### Nursing Mothers
- There is no FDA guidance on the use of Zinc sulfate with respect to nursing mothers.
### Pediatric Use
- There is no FDA guidance on the use of Zinc sulfate with respect to pediatric patients.
### Geriatic Use
- There is no FDA guidance on the use of Zinc sulfate with respect to geriatric patients.
### Gender
- There is no FDA guidance on the use of Zinc sulfate with respect to specific gender populations.
### Race
- There is no FDA guidance on the use of Zinc sulfate with respect to specific racial populations.
### Renal Impairment
- There is no FDA guidance on the use of Zinc sulfate in patients with renal impairment.
### Hepatic Impairment
- There is no FDA guidance on the use of Zinc sulfate in patients with hepatic impairment.
### Females of Reproductive Potential and Males
- There is no FDA guidance on the use of Zinc sulfate in women of reproductive potentials and males.
### Immunocompromised Patients
- There is no FDA guidance one the use of Zinc sulfate in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Zinc Sulfate Injection, USP provides 1 mg zinc/mL. For metabolically stable adults receiving TPN, the suggested intravenous dosage is 2.5 to 4 mg zinc/day. An additional 2 mg zinc/day is suggested for acute catabolic states. For the stable adult with fluid loss from the small bowel, an additional 12.2 mg zinc/liter of small bowel fluid lost, or an additional 17.1 mg zinc/kg of stool or ileostomy output is recommended. Frequent monitoring of zinc blood levels is suggested for patients receiving more than the usual maintenance dosage level of zinc.
- For full term infants and children up to 5 years of age, 100 mcg zinc/kg/day is recommended. For premature infants (birth weight less than 1500 g) up to 3 kg in body weight, 300 mcg zinc/kg/day is suggested.
- Aseptic addition of Zinc Sulfate Injection, USP to the TPN solution under a laminar flow hood is recommended. Zinc is physically compatible with the electrolytes and vitamins usually present in the amino acid/dextrose solution used for TPN.
- Parenteral drug products should be inspected visually for particulate matter and discoloration, whenever solution and container permit.
### Monitoring
- There is limited information regarding Monitoring of Zinc sulfate in the drug label.
# IV Compatibility
- There is limited information regarding IV Compatibility of Zinc sulfate in the drug label.
# Overdosage
- Symptoms of zinc overdosage resulting from oral ingestion of zinc sulfate in large amounts (30 and 44 grams, respectively) have resulted in death. Symptoms include nausea, vomiting, dehydration, electrolyte imbalances, dizziness, abdominal pain, lethargy and incoordination. Single intravenous doses of 1 to 2 mg zinc/kg body weight have been given to adult leukemic patients without toxic manifestations. Normal plasma levels for zinc vary from approximately 88 to 112 mcg/100 mL. Plasma levels sufficient to produce symptoms of toxic manifestations in humans are not known. Calcium supplements may confer a protective effect against zinc toxicity.
# Pharmacology
## Mechanism of Action
- Zinc has been identified as a cofactor for over 70 different enzymes, including alkaline phosphatase, lactic dehydrogenase and both RNA and DNA polymerase. Zinc facilitates wound healing, helps maintain normal growth rates, normal skin hydration and the senses of taste and smell.
- Providing zinc during TPN prevents development of the following deficiency symptoms: Parakeratosis, hypogeusia, anorexia, dysosmia, geophagia, hypogonadism, growth retardation and hepatosplenomegaly. At plasma levels below 20 mcg zinc/100 mL, dermatitis followed by alopecia has been reported for TPN patients.
## Structure
- Zinc Sulfate Injection, USP is a sterile, nonpyrogenic solution intended for use as an additive to solutions for Total Parenteral Nutrition (TPN). Each mL contains Zinc Sulfate (Anhydrous) 2.46 mg, Water for Injection q.s. pH adjusted with Sulfuric Acid. It contains no preservatives. Discard any unused portion.
## Pharmacodynamics
- There is limited information regarding Pharmacodynamics of Zinc sulfate in the drug label.
## Pharmacokinetics
- There is limited information regarding Pharmacokinetics of Zinc sulfate in the drug label.
## Nonclinical Toxicology
- There is limited information regarding Nonclinical Toxicology of Zinc sulfate in the drug label.
# Clinical Studies
- There is limited information regarding Clinical Studies of Zinc sulfate in the drug label.
# How Supplied
- Zinc Sulfate Injection, USP 1 mg/mL
- NDC 0517-6110-25- 10 mL SDV- packed in a box of 25
## Storage
- Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) (See USP Controlled Room Temperature).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- There is limited information regarding Patient Counseling Information of Zinc sulfate in the drug label.
# Precautions with Alcohol
- Alcohol-Zinc sulfate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
M2 Zinc 50,
Zn Plus Protein.
# Look-Alike Drug Names
- A® — B®
# Drug Shortage Status
# Price | Zinc sulfate
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Deepika Beereddy, MBBS [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
Zinc sulfate is a parenteral mineral- trace mineral that is FDA approved for the prophylaxis of prophylaxis of zinc deficiency. Common adverse reactions include indigestion, nausea, vomiting.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Zinc Sulfate Injection, USP is indicated for use as a supplement to intravenous solutions given for TPN. Administration helps to maintain plasma levels and to prevent depletion of endogenous stores.
- Dosing Information
- Zinc Sulfate Injection, USP provides 1 mg zinc/mL. For metabolically stable adults receiving TPN, the suggested intravenous dosage is 2.5 to 4 mg zinc/day. An additional 2 mg zinc/day is suggested for acute catabolic states. For the stable adult with fluid loss from the small bowel, an additional 12.2 mg zinc/liter of small bowel fluid lost, or an additional 17.1 mg zinc/kg of stool or ileostomy output is recommended. Frequent monitoring of zinc blood levels is suggested for patients receiving more than the usual maintenance dosage level of zinc.
- For full term infants and children up to 5 years of age, 100 mcg zinc/kg/day is recommended. For premature infants (birth weight less than 1500 g) up to 3 kg in body weight, 300 mcg zinc/kg/day is suggested.
- Aseptic addition of Zinc Sulfate Injection, USP to the TPN solution under a laminar flow hood is recommended. Zinc is physically compatible with the electrolytes and vitamins usually present in the amino acid/dextrose solution used for TPN.
- Parenteral drug products should be inspected visually for particulate matter and discoloration, whenever solution and container permit.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Zinc sulfate in adult patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Zinc sulfate in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- There is limited information regarding FDA-Labeled Use of Zinc sulfate in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Zinc sulfate in pediatric patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Zinc sulfate in pediatric patients.
# Contraindications
There is limited information regarding Zinc sulfate Contraindications in the drug label.
# Warnings
There is limited information regarding Zinc sulfate Warnings' in the drug label.
# Adverse Reactions
## Clinical Trials Experience
- There is limited information regarding Clinical Trial Experience of Zinc sulfate in the drug label.
## Postmarketing Experience
- There is limited information regarding Postmarketing Experience of Zinc sulfate in the drug label.
# Drug Interactions
There is limited information regarding Zinc sulfate Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
- There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Zinc sulfate in women who are pregnant.
### Labor and Delivery
- There is no FDA guidance on use of Zinc sulfate during labor and delivery.
### Nursing Mothers
- There is no FDA guidance on the use of Zinc sulfate with respect to nursing mothers.
### Pediatric Use
- There is no FDA guidance on the use of Zinc sulfate with respect to pediatric patients.
### Geriatic Use
- There is no FDA guidance on the use of Zinc sulfate with respect to geriatric patients.
### Gender
- There is no FDA guidance on the use of Zinc sulfate with respect to specific gender populations.
### Race
- There is no FDA guidance on the use of Zinc sulfate with respect to specific racial populations.
### Renal Impairment
- There is no FDA guidance on the use of Zinc sulfate in patients with renal impairment.
### Hepatic Impairment
- There is no FDA guidance on the use of Zinc sulfate in patients with hepatic impairment.
### Females of Reproductive Potential and Males
- There is no FDA guidance on the use of Zinc sulfate in women of reproductive potentials and males.
### Immunocompromised Patients
- There is no FDA guidance one the use of Zinc sulfate in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Zinc Sulfate Injection, USP provides 1 mg zinc/mL. For metabolically stable adults receiving TPN, the suggested intravenous dosage is 2.5 to 4 mg zinc/day. An additional 2 mg zinc/day is suggested for acute catabolic states. For the stable adult with fluid loss from the small bowel, an additional 12.2 mg zinc/liter of small bowel fluid lost, or an additional 17.1 mg zinc/kg of stool or ileostomy output is recommended. Frequent monitoring of zinc blood levels is suggested for patients receiving more than the usual maintenance dosage level of zinc.
- For full term infants and children up to 5 years of age, 100 mcg zinc/kg/day is recommended. For premature infants (birth weight less than 1500 g) up to 3 kg in body weight, 300 mcg zinc/kg/day is suggested.
- Aseptic addition of Zinc Sulfate Injection, USP to the TPN solution under a laminar flow hood is recommended. Zinc is physically compatible with the electrolytes and vitamins usually present in the amino acid/dextrose solution used for TPN.
- Parenteral drug products should be inspected visually for particulate matter and discoloration, whenever solution and container permit.
### Monitoring
- There is limited information regarding Monitoring of Zinc sulfate in the drug label.
# IV Compatibility
- There is limited information regarding IV Compatibility of Zinc sulfate in the drug label.
# Overdosage
- Symptoms of zinc overdosage resulting from oral ingestion of zinc sulfate in large amounts (30 and 44 grams, respectively) have resulted in death. Symptoms include nausea, vomiting, dehydration, electrolyte imbalances, dizziness, abdominal pain, lethargy and incoordination. Single intravenous doses of 1 to 2 mg zinc/kg body weight have been given to adult leukemic patients without toxic manifestations. Normal plasma levels for zinc vary from approximately 88 to 112 mcg/100 mL. Plasma levels sufficient to produce symptoms of toxic manifestations in humans are not known. Calcium supplements may confer a protective effect against zinc toxicity.
# Pharmacology
## Mechanism of Action
- Zinc has been identified as a cofactor for over 70 different enzymes, including alkaline phosphatase, lactic dehydrogenase and both RNA and DNA polymerase. Zinc facilitates wound healing, helps maintain normal growth rates, normal skin hydration and the senses of taste and smell.
- Providing zinc during TPN prevents development of the following deficiency symptoms: Parakeratosis, hypogeusia, anorexia, dysosmia, geophagia, hypogonadism, growth retardation and hepatosplenomegaly. At plasma levels below 20 mcg zinc/100 mL, dermatitis followed by alopecia has been reported for TPN patients.
## Structure
- Zinc Sulfate Injection, USP is a sterile, nonpyrogenic solution intended for use as an additive to solutions for Total Parenteral Nutrition (TPN). Each mL contains Zinc Sulfate (Anhydrous) 2.46 mg, Water for Injection q.s. pH adjusted with Sulfuric Acid. It contains no preservatives. Discard any unused portion.
## Pharmacodynamics
- There is limited information regarding Pharmacodynamics of Zinc sulfate in the drug label.
## Pharmacokinetics
- There is limited information regarding Pharmacokinetics of Zinc sulfate in the drug label.
## Nonclinical Toxicology
- There is limited information regarding Nonclinical Toxicology of Zinc sulfate in the drug label.
# Clinical Studies
- There is limited information regarding Clinical Studies of Zinc sulfate in the drug label.
# How Supplied
- Zinc Sulfate Injection, USP 1 mg/mL
- NDC 0517-6110-25- 10 mL SDV- packed in a box of 25
## Storage
- Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) (See USP Controlled Room Temperature).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- There is limited information regarding Patient Counseling Information of Zinc sulfate in the drug label.
# Precautions with Alcohol
- Alcohol-Zinc sulfate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
M2 Zinc 50,
Zn Plus Protein.
# Look-Alike Drug Names
- A® — B®[1]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/White_vitriol | |
0dabbcd5f6267bc3a5ebae80c2caa42cd71ec64f | wikidoc | Who named it | Who named it
Who Named It? is an English-language dictionary of medical eponyms and the people associated with their identification.
Though this is a dictionary, many eponyms and persons are presented in extensive articles with comprehensive bibliographies.
It is hosted in Norway and maintained by medical historian Ole Daniel Enersen. | Who named it
Who Named It? is an English-language dictionary of medical eponyms and the people associated with their identification.
Though this is a dictionary, many eponyms and persons are presented in extensive articles with comprehensive bibliographies.
It is hosted in Norway and maintained by medical historian Ole Daniel Enersen.
# External links
- Home page
Template:WS | https://www.wikidoc.org/index.php/Who_Named_It | |
dc3d237741610a5d79f8ef3ca7d633bd053b6906 | wikidoc | Widow's peak | Widow's peak
A widow's peak (widow's brow) is a descending V-shaped point in the middle of the hairline (above the forehead). The trait is inherited genetically and is dominant. The term comes from English folklore, where it was believed that this hair formation was a sign of a woman who would outlive her husband.
The peak refers to the beak or bill of a headdress, particularly a widow's hood, making people think a woman was being given a mourning hood for her husband's soon-to-be passing.
Vampires such as Dracula are often depicted in popular culture with a widow's peak. Hannibal Lecter is described as possessing a widow's peak.
Men with male-pattern baldness develop what appears to be a large widow's peak. | Widow's peak
Template:This
A widow's peak (widow's brow) is a descending V-shaped point in the middle of the hairline (above the forehead). The trait is inherited genetically and is dominant.[1] The term comes from English folklore, where it was believed that this hair formation was a sign of a woman who would outlive her husband.[1]
The peak refers to the beak or bill of a headdress, particularly a widow's hood, making people think a woman was being given a mourning hood for her husband's soon-to-be passing.[2]
Vampires such as Dracula are often depicted in popular culture with a widow's peak. Hannibal Lecter is described as possessing a widow's peak.
Men with male-pattern baldness develop what appears to be a large widow's peak. | https://www.wikidoc.org/index.php/Widow%27s_peak | |
1b1f116674cd18aeca641b5ac1c4f5c273d2b7dc | wikidoc | World Vision | World Vision
World Vision, founded in the United States in 1950, is an international Christian relief and development organization whose stated goal is "working for the well being of all people, especially children." Working on six continents, World Vision is one of the largest Christian relief and development organisations in the world with a $2.6 billion budget (2007).
# History
World Vision was founded in 1950 by Dr. Bob Pierce, a young pastor and missionary, who had first been sent to China and South Korea in 1947 by the Youth for Christ missionary organization. Pierce remained at the head of World Vision for nearly two decades, but resigned from the organization in 1967.
Pierce also founded the evangelical organization
Samaritan's Purse.
World Vision began caring for orphans and other children in need first in South Korea, then expanding throughout Asia and, eventually, in more than 90 countries, embracing larger issues of community development and advocacy for the poor as part of its basic mission to help children and their families build a sustainable future.
# Organizational structure
World Vision International operates as a federation of interdependent national offices, each overseen by their own boards or advisory councils. A common mission statement and shared core values bind the partnership offices and members together. Each national partner abides by common policies and standards and holds each other accountable through an ongoing system of peer review.
The partnership offices – located in Geneva, Bangkok, Nairobi, Cyprus, Los Angeles, and San José, Costa Rica – coordinate strategic operations of the organization and represent World Vision in the international arena. Each national office, whether in the developed or developing world, enjoys an equal voice in the organization's governance of world vision.
An international board of directors oversees the World Vision partnership. The full board meets twice a year to appoint senior officers, approve strategic plans and budgets, and determine international policy. The current chairperson of the international board is Denis St. Armour of Canada. The international president is Dr. Dean R Hirsch
# Funding
According to World Vision's 2006 Consolidated Financial Statements, around 40% of their revenue comes from private sources, including individuals, World Vision clubs in schools, corporations and foundations. 27% comes from governments and multilateral aid agencies such as USAID. 30% comes from other World Vision programs and nonprofit organizaion as Gift in Kind. Aside from cash contributions, World Vision accepts gifts in kind, typically food commodities, medicine, and clothing donated through corporations and government agencies.
Approximately half of World Vision's programs are funded through child sponsorship. Individuals, families, churches, schools, and other groups sponsor specific children or specific community projects in their own country or abroad. Sponsors send funds each month to provide support for the sponsored children or projects.
World Vision Famine events like the 30 Hour Famine and 40 Hour Famine also help to raise money for impoverished countries. Typically, a group signs up to organize such an event, and then spends the next 30 or 40 hours abstaining from food, technology or other things that are taken for granted and increasing awareness about world hunger. Many schools and individuals are annually successful with this fundraising activity.
According to World Vision's annual report, in 2005, 87% of its funding was spent on programs, 8% on fundraising and 5% on management and general overhead. World Vision has announced a goal of reducing the fundraising and overhead costs from the current 13% to 10%.
# Activities
World Vision aims to contribute to people’s needs in five major areas; emergency relief, education, health care, economic development, and promotion of justice. World Vision activities include transformational development, emergency relief, strategic initiatives, public awareness campaigns and promoting Christianity.
Transformational development occurs through focusing on improvement of children's lives. This process first helps people and their communities recognize the resources that lie within themselves to make change possible. With support from World Vision, communities transform themselves by carrying out their own development projects in health care, agriculture production, water projects, education, micro-enterprise development, advocacy and other community programs.
World Vision provides emergency relief to people whose lives are endangered by disasters or conflict and who need immediate, skilled assistance. World Vision attempts to respond to all major emergencies around the world themselves or in cooperation with their partner agencies. For example, World Vision has responded to famine in Ethiopia and North Korea, hurricanes in Central America, the tsunami in the Indian Ocean nations, earthquakes in El Salvador, India, Taiwan and Turkey, and war refugees in Kosovo, Chechnya, Sierra Leone, Angola, and East Timor.
World Vision also addresses the complex, systematic factors that perpetuate poverty by promoting justice. World Vision supports community awareness of the collective ability to address unjust practices and begin working for change. World Vision speaks out on issues such as child labor, debt relief for poor nations, and the use of children as combatants in armed conflict. World Vision International has endorsed the Universal Declaration of Human Rights and the United Nations Convention on the Rights of the Child as fundamental expressions of the freedoms and responsibilities that should exist in every country. World Vision fosters opportunities to help reduce conflict levels and to contribute to the peaceful resolution of hostilities and reconciliation of disputes.
As a Christian organization, World Vision participates in strategic initiatives with Christian leaders and lay people of all denominations through conferences, consultations, training programmes and various educational opportunities. World Vision is an ecumenical organization willing to partner with all Christian churches. Yet, World Vision is respectful of other faiths.
World Vision encourages public awareness about the needs of others, the causes of poverty, and the nature of compassionate response. These efforts include collaboration with media and community participation in fundraising. In all its communications, World Vision upholds the dignity of suffering children and families in presenting explanations of the causes and consequences of poverty, war, neglect, and abuse.
World Vision believes witnessing from Christ is a fundamental part of their relief work. The organization believes that God, in the person of Jesus, offers hope of renewal, restoration, and reconciliation. World Vision seeks to express this message through "life, deed, word, and sign". World Vision's programs and services are provided without regard to race, ethnic origin, gender, or religion.
World Vision offices often hire non-Christian staff, and in some countries the majority of staff may be people of other faiths who are sympathetic to World Vision's ethos and objectives. However, in the US all staff are required to sign a statement affirming their belief in Jesus Christ and background checks are often made with a candidate's pastor or priest. | World Vision
Template:Multiplemergefrom
Template:POV-check
Template:Two other uses
Template:Infobox Non-profit
World Vision, founded in the United States in 1950, is an international Christian relief and development organization whose stated goal is "working for the well being of all people, especially children." Working on six continents, World Vision is one of the largest Christian relief and development organisations in the world with a $2.6 billion budget (2007).
# History
World Vision was founded in 1950 by Dr. Bob Pierce, a young pastor and missionary, who had first been sent to China and South Korea in 1947 by the Youth for Christ missionary organization. Pierce remained at the head of World Vision for nearly two decades, but resigned from the organization in 1967.
Pierce also founded the evangelical organization
Samaritan's Purse.
World Vision began caring for orphans and other children in need first in South Korea, then expanding throughout Asia and, eventually, in more than 90 countries, embracing larger issues of community development and advocacy for the poor as part of its basic mission to help children and their families build a sustainable future.
# Organizational structure
World Vision International operates as a federation of interdependent national offices, each overseen by their own boards or advisory councils. A common mission statement and shared core values bind the partnership offices and members together. Each national partner abides by common policies and standards and holds each other accountable through an ongoing system of peer review.
The partnership offices – located in Geneva, Bangkok, Nairobi, Cyprus, Los Angeles, and San José, Costa Rica – coordinate strategic operations of the organization and represent World Vision in the international arena. Each national office, whether in the developed or developing world, enjoys an equal voice in the organization's governance of world vision.
An international board of directors oversees the World Vision partnership. The full board meets twice a year to appoint senior officers, approve strategic plans and budgets, and determine international policy. The current chairperson of the international board is Denis St. Armour of Canada. The international president is Dr. Dean R Hirsch
# Funding
According to World Vision's 2006 Consolidated Financial Statements, around 40% of their revenue comes from private sources, including individuals, World Vision clubs in schools, corporations and foundations. 27% comes from governments and multilateral aid agencies such as USAID. 30% comes from other World Vision programs and nonprofit organizaion as Gift in Kind. Aside from cash contributions, World Vision accepts gifts in kind, typically food commodities, medicine, and clothing donated through corporations and government agencies.
Approximately half of World Vision's programs are funded through child sponsorship. Individuals, families, churches, schools, and other groups sponsor specific children or specific community projects in their own country or abroad. Sponsors send funds each month to provide support for the sponsored children or projects.
World Vision Famine events like the 30 Hour Famine and 40 Hour Famine also help to raise money for impoverished countries. Typically, a group signs up to organize such an event, and then spends the next 30 or 40 hours abstaining from food, technology or other things that are taken for granted and increasing awareness about world hunger. Many schools and individuals are annually successful with this fundraising activity.
According to World Vision's annual report, in 2005, 87% of its funding was spent on programs, 8% on fundraising and 5% on management and general overhead. World Vision has announced a goal of reducing the fundraising and overhead costs from the current 13% to 10%.
# Activities
World Vision aims to contribute to people’s needs in five major areas; emergency relief, education, health care, economic development, and promotion of justice. World Vision activities include transformational development, emergency relief, strategic initiatives, public awareness campaigns and promoting Christianity.
Transformational development occurs through focusing on improvement of children's lives. This process first helps people and their communities recognize the resources that lie within themselves to make change possible. With support from World Vision, communities transform themselves by carrying out their own development projects in health care, agriculture production, water projects, education, micro-enterprise development, advocacy and other community programs.
World Vision provides emergency relief to people whose lives are endangered by disasters or conflict and who need immediate, skilled assistance. World Vision attempts to respond to all major emergencies around the world themselves or in cooperation with their partner agencies. For example, World Vision has responded to famine in Ethiopia and North Korea, hurricanes in Central America, the tsunami in the Indian Ocean nations, earthquakes in El Salvador, India, Taiwan and Turkey, and war refugees in Kosovo, Chechnya, Sierra Leone, Angola, and East Timor.
World Vision also addresses the complex, systematic factors that perpetuate poverty by promoting justice. World Vision supports community awareness of the collective ability to address unjust practices and begin working for change. World Vision speaks out on issues such as child labor, debt relief for poor nations, and the use of children as combatants in armed conflict. World Vision International has endorsed the Universal Declaration of Human Rights and the United Nations Convention on the Rights of the Child as fundamental expressions of the freedoms and responsibilities that should exist in every country. World Vision fosters opportunities to help reduce conflict levels and to contribute to the peaceful resolution of hostilities and reconciliation of disputes.
As a Christian organization, World Vision participates in strategic initiatives with Christian leaders and lay people of all denominations through conferences, consultations, training programmes and various educational opportunities. World Vision is an ecumenical organization willing to partner with all Christian churches. Yet, World Vision is respectful of other faiths.
World Vision encourages public awareness about the needs of others, the causes of poverty, and the nature of compassionate response. These efforts include collaboration with media and community participation in fundraising. In all its communications, World Vision upholds the dignity of suffering children and families in presenting explanations of the causes and consequences of poverty, war, neglect, and abuse.
World Vision believes witnessing from Christ is a fundamental part of their relief work. The organization believes that God, in the person of Jesus, offers hope of renewal, restoration, and reconciliation. World Vision seeks to express this message through "life, deed, word, and sign". World Vision's programs and services are provided without regard to race, ethnic origin, gender, or religion.
World Vision offices often hire non-Christian staff, and in some countries the majority of staff may be people of other faiths who are sympathetic to World Vision's ethos and objectives. However, in the US all staff are required to sign a statement affirming their belief in Jesus Christ and background checks are often made with a candidate's pastor or priest. | https://www.wikidoc.org/index.php/World_Vision | |
7017d6614261e93fdf3d5dd3388660c7e4dd0b8b | wikidoc | Wrong Planet | Wrong Planet
Wrong Planet (sometimes referred to by its URL, WrongPlanet.net) is an online forum for individuals with Asperger syndrome. The site was started in 2004 by Dan Grover and Alex Plank and includes a chatroom, a large forum, a dating section, and articles describing how to deal with daily issues.
After a post to Slashdot describing an interview with Bram Cohen, Wrong Planet grew; the success of the Cohen interview spurred the site to produce a series of interviews with other figures in the Autism community such as author Temple Grandin and movie producer Joey Travolta. The site conducted an interview with America's Next Top Model contestant Heather Kuzmich who frequently talked about her Asperger's during Cycle 9 of the show.
Wrong Planet has been referenced by the mainstream U.S. media and has gained more than 10,000 registered members since its creation.
In 2005, a 19-year-old member of the site, William Freund, gave Wrong Planet national mainstream publicity in the United States after being mentioned on Fox News and programs such as Good Morning America after he donned a cape and paintball mask and went on a shooting rampage in Aliso Viejo, California. He shot and killed two people before going home and killing himself with a shot to the torso. | Wrong Planet
Wrong Planet (sometimes referred to by its URL, WrongPlanet.net) is an online forum for individuals with Asperger syndrome. The site was started in 2004 by Dan Grover and Alex Plank[1] and includes a chatroom, a large forum, a dating section, and articles describing how to deal with daily issues.
After a post to Slashdot describing an interview with Bram Cohen,[2] Wrong Planet grew; the success of the Cohen interview spurred the site to produce a series of interviews with other figures in the Autism community such as author Temple Grandin and movie producer Joey Travolta. The site conducted an interview with America's Next Top Model contestant Heather Kuzmich who frequently talked about her Asperger's during Cycle 9 of the show. [3]
Wrong Planet has been referenced by the mainstream U.S. media[4] and has gained more than 10,000 registered members since its creation.
In 2005, a 19-year-old member of the site, William Freund,[5] gave Wrong Planet national mainstream publicity in the United States after being mentioned on Fox News[6] and programs such as Good Morning America after he donned a cape and paintball mask and went on a shooting rampage in Aliso Viejo, California. He shot and killed two people before going home and killing himself with a shot to the torso. | https://www.wikidoc.org/index.php/Wrong_Planet | |
453d367fb2efbb1abda705731a317a812ec2e0d3 | wikidoc | XK (protein) | XK (protein)
XK (also known as Kell blood group precursor) is a protein found on human red blood cells and other tissues which is responsible for the Kx antigen which helps determine a person's blood type.
# Clinical significance
The Kx antigen plays a role in matching blood for blood transfusions.
Mutation of XK protein may lead to McLeod syndrome, a multi-system disorder characterized by hemolytic anemia, myopathy, acanthocytosis, and chorea.
XK is located on the X chromosome (cytogenetic band Xp21.1) and absence of the XK protein is an X-linked disease.
# Function
XK is a membrane transport protein of unknown action. | XK (protein)
XK (also known as Kell blood group precursor) is a protein found on human red blood cells and other tissues which is responsible for the Kx antigen which helps determine a person's blood type.
# Clinical significance
The Kx antigen plays a role in matching blood for blood transfusions.
Mutation of XK protein may lead to McLeod syndrome,[1] a multi-system disorder characterized by hemolytic anemia, myopathy, acanthocytosis, and chorea.[2]
XK is located on the X chromosome (cytogenetic band Xp21.1) and absence of the XK protein is an X-linked disease.[3]
# Function
XK is a membrane transport protein of unknown action.[4] | https://www.wikidoc.org/index.php/XK_(protein) | |
6bc745a16ec47652eb112a8b1b59b08d54cb1bb7 | wikidoc | Xenoestrogen | Xenoestrogen
Xenoestrogens are synthetic substances that differ from those produced by living organisms and imitate or enhance the effect of estrogens. The estrogenic stimulation is an unintended side-effect of these agents or their metabolites.
Xenoestrogens are part of a heterogeneous group of chemicals that are hormone or endocrine disruptors. They differ from phytoestrogens (estrogenic substances from plants), mycoestrogens (estrogenic substances from fungi), and pharmacological estrogens (estrogenic action is intended). External estrogens from a variety of sources may have a cumulative effect upon living organisms, and xenoestrogens may be part of a larger picture of a process of estrogenization of the environment. Xenoestrogens have only been recently (less than 70 years) introduced into the environment, as produced by industrial, agricultural, and chemical companies.
# Effects
Xenoestrogens have been implicated in a variety of medical problems. Foremost is the concern that xenoestrogens as false messengers disrupt the process of reproduction. Studies have implicated observations of disturbances in wildlife with estrogenic exposure. Reproductive issues which are of concerns in humans are fetal exposure (perhaps leading to hypospadias) and decreased reproductive ability in men (i.e. decrease in sperm numbers). Another issue is the potential effect of xenoestrogens on oncogenes, specifically in relation to breast cancer.
# Presence
The ubiquitous presence of such estrogenic substances is a significant health concern, both individually and for a population. Life relies on the transmission of biochemical information to the next generation, and the presence of xenoestrogens may interfere with this transgenerational information process through "chemical confusion" (Vidaeff, Sever). Environmental protection laws and regulations are supposed to protect the environment from hormonal disruption. Agencies such as the United States Environmental Protection Agency and the World Health Organization International Program on Chemical Safety are charged to address these issues.
# Research
The study of the problem is difficult and complex. Transgenerational effects are difficult to prove, effects may be multifactorial, and the large variety of substances in question with the absence of unexposed controls do not lend themselves to easy interpretation. Believers that environmental estrogen disruption is a major health hazard are opposed by detractors who argue that observed effects are spurious and inconsistent, or that the quantities of the agents are too low to have any effect.
A 2005 study by Belcher and coworkers demonstrated that even very low levels of a xenoestrogen, in this case Bisphenol A, could affect fetal neural development more than higher levels (PMID 16123166), indicating that classical models where dose equals response may not be applicable in susceptible tissue.
# Synthetic chemicals shown to have unintended estrogenic effects
- 4-Methylbenzylidene camphor (4-MBC) (sunscreen lotions)
- butylated hydroxyanisole / BHA (food preservative)
- atrazine (weedkiller)
- bisphenol A (monomer for polycarbonate plastic and epoxy resin; antioxidant in plasticizers)
- dieldrin (insecticide)
- DDT (insecticide)
- endosulfan (insecticide)
- erythrosine / FD&C Red No. 3
- heptachlor (insecticide)
- lindane / hexachlorocyclohexane (insecticide)
- methoxychlor (insecticide)
- nonylphenol and derivatives (industrial surfactants; emulsifiers for emulsion polymerization; laboratory detergents; pesticides)
- polychlorinated biphenyls / PCBs (in electrical oils, lubricants, adhesives, paints)
- parabens (lotions)
- phenosulfothiazine (a red dye)
- phthalates (plasticizers)
DEHP (plasticizer for PVC)
- DEHP (plasticizer for PVC) | Xenoestrogen
Xenoestrogens are synthetic substances that differ from those produced by living organisms and imitate or enhance the effect of estrogens. The estrogenic stimulation is an unintended side-effect of these agents or their metabolites.
Xenoestrogens are part of a heterogeneous group of chemicals that are hormone or endocrine disruptors. They differ from phytoestrogens (estrogenic substances from plants), mycoestrogens (estrogenic substances from fungi), and pharmacological estrogens (estrogenic action is intended). External estrogens from a variety of sources may have a cumulative effect upon living organisms, and xenoestrogens may be part of a larger picture of a process of estrogenization of the environment. Xenoestrogens have only been recently (less than 70 years) introduced into the environment, as produced by industrial, agricultural, and chemical companies.
# Effects
Xenoestrogens have been implicated in a variety of medical problems. Foremost is the concern that xenoestrogens as false messengers disrupt the process of reproduction. Studies have implicated observations of disturbances in wildlife with estrogenic exposure. Reproductive issues which are of concerns in humans are fetal exposure (perhaps leading to hypospadias) and decreased reproductive ability in men (i.e. decrease in sperm numbers). Another issue is the potential effect of xenoestrogens on oncogenes, specifically in relation to breast cancer.
# Presence
The ubiquitous presence of such estrogenic substances is a significant health concern, both individually and for a population. Life relies on the transmission of biochemical information to the next generation, and the presence of xenoestrogens may interfere with this transgenerational information process through "chemical confusion" (Vidaeff, Sever). Environmental protection laws and regulations are supposed to protect the environment from hormonal disruption. Agencies such as the United States Environmental Protection Agency and the World Health Organization International Program on Chemical Safety are charged to address these issues.
# Research
The study of the problem is difficult and complex. Transgenerational effects are difficult to prove, effects may be multifactorial, and the large variety of substances in question with the absence of unexposed controls do not lend themselves to easy interpretation. Believers that environmental estrogen disruption is a major health hazard are opposed by detractors who argue that observed effects are spurious and inconsistent, or that the quantities of the agents are too low to have any effect.
A 2005 study by Belcher and coworkers demonstrated that even very low levels of a xenoestrogen, in this case Bisphenol A, could affect fetal neural development more than higher levels (PMID 16123166), indicating that classical models where dose equals response may not be applicable in susceptible tissue.
# Synthetic chemicals shown to have unintended estrogenic effects
- 4-Methylbenzylidene camphor (4-MBC) (sunscreen lotions)
- butylated hydroxyanisole / BHA (food preservative)
- atrazine (weedkiller)
- bisphenol A (monomer for polycarbonate plastic and epoxy resin; antioxidant in plasticizers)
- dieldrin (insecticide)
- DDT (insecticide)
- endosulfan (insecticide)
- erythrosine / FD&C Red No. 3
- heptachlor (insecticide)
- lindane / hexachlorocyclohexane (insecticide)
- methoxychlor (insecticide)
- nonylphenol and derivatives (industrial surfactants; emulsifiers for emulsion polymerization; laboratory detergents; pesticides)
- polychlorinated biphenyls / PCBs (in electrical oils, lubricants, adhesives, paints)
- parabens (lotions)
- phenosulfothiazine (a red dye)
- phthalates (plasticizers)
DEHP (plasticizer for PVC)
- DEHP (plasticizer for PVC) | https://www.wikidoc.org/index.php/Xenoestrogen | |
7aabebe5858b980187779c1869e0a9641a6b90f8 | wikidoc | Yanova esrog | Yanova esrog
The citron of Diamante as it is known in the botanical world, is mainly grown in the region of Calabria, province of Cosenza, at the south-western coast of Italy. That's why some people are calling it Calabria Esrog, which is the Hebrew name for the citron. However, by most religious Jews the variety is called Yanova Esrog, most probably because it used to be shipped to the Jewish centers in Europe via Genoa, a city and seaport in north Italy.
The Diamante variety goes back to the times of the Balei Tosfot, and is considered to be of oldest Ashkenazic tradition, for the Jewish ritual during the Feast of Tabernacles.
The citron in Calabria was celebrated by poets like Byron and D'Annunzio, but was only saved from extinction, thanks to the Jewish tradition.
While Calabria is at the southern point of Italy it is of hottest climate, it is the most suitable for the citron. However, during the winter it is still to cold for the citron, and this is why the farmers need to protect them with blue plastic covers. Most of the citron trees in the area are grafted onto foreign rootstock, to save them from freeze and all different illness. While this practice renders them to non-kosher, no citron is to be picked off for the ritual use, unless the tree is carefully inspected by a rabbi.
A Jewish delegation comes from Israel to Santa Maria del Cedro every year between July and August to choose the best fruit to be used in the most important holiday for the Jewish community. The selection of the best fruit is a virtual ritual. The rabbis, each followed by a peasant carrying a box and a pair of scissors, go to the citron farms at five in the morning. The rabbi proceeds slowly looking left and right. Then he stops and looks at the base of the tree, right where the trunk comes up from the ground. A smooth trunk means the tree has not been grafted and the fruit can be picked. The rabbi lies down on the ground to examine better the lower branches between the leaves. Once the good fruit is found, the rabbi shows it to the peasant who cuts it off leaving a piece of the stalk. Then the rabbi analyses the picked citron one more time and if he decides it is worthy he wraps it in oakum and puts it in the box. The farmer receives the agreed sum for each picked fruit. Then the boxes are sealed and sent to the Lamezia Terme airport with a final destination Tel Aviv.
Seeds of inspected trees were planted in the Israeli village of Kefar Khabad, with certification by major kashrus organizations. | Yanova esrog
The citron of Diamante as it is known in the botanical world, is mainly grown in the region of Calabria, province of Cosenza, at the south-western coast of Italy. That's why some people are calling it Calabria Esrog, which is the Hebrew name for the citron. However, by most religious Jews the variety is called Yanova Esrog, most probably because it used to be shipped to the Jewish centers in Europe via Genoa, a city and seaport in north Italy.
The Diamante variety goes back to the times of the Balei Tosfot, and is considered to be of oldest Ashkenazic tradition, for the Jewish ritual during the Feast of Tabernacles.
The citron in Calabria was celebrated by poets like Byron and D'Annunzio, but was only saved from extinction, thanks to the Jewish tradition.[1]
While Calabria is at the southern point of Italy it is of hottest climate, it is the most suitable for the citron. However, during the winter it is still to cold for the citron, and this is why the farmers need to protect them with blue plastic covers. Most of the citron trees in the area are grafted onto foreign rootstock, to save them from freeze and all different illness. While this practice renders them to non-kosher, no citron is to be picked off for the ritual use, unless the tree is carefully inspected by a rabbi.
A Jewish delegation comes from Israel to Santa Maria del Cedro every year between July and August to choose the best fruit to be used in the most important holiday for the Jewish community. The selection of the best fruit is a virtual ritual. The rabbis, each followed by a peasant carrying a box and a pair of scissors, go to the citron farms at five in the morning. The rabbi proceeds slowly looking left and right. Then he stops and looks at the base of the tree, right where the trunk comes up from the ground. A smooth trunk means the tree has not been grafted and the fruit can be picked. The rabbi lies down on the ground to examine better the lower branches between the leaves. Once the good fruit is found, the rabbi shows it to the peasant who cuts it off leaving a piece of the stalk. Then the rabbi analyses the picked citron one more time and if he decides it is worthy he wraps it in oakum and puts it in the box. The farmer receives the agreed sum for each picked fruit. Then the boxes are sealed and sent to the Lamezia Terme airport with a final destination Tel Aviv. [2]
Seeds of inspected trees were planted in the Israeli village of Kefar Khabad, with certification by major kashrus organizations. | https://www.wikidoc.org/index.php/Yanova_esrog | |
26f510b5efa1ef02a2e8f675db594036f0eb3695 | wikidoc | Yaupon Holly | Yaupon Holly
Yaupon Holly (Ilex vomitoria), also called Yaupon or Cassina (the latter shared with the Dahoon Holly), is an evergreen holly found in the southeast United States. It is a shrub or small tree reaching 5-8 m tall. The leaves are alternate, ovate to elliptical with an acute apex and crenate or finely serrated margin, 2-4.5 cm long and 1-2 cm broad, glossy dark green above, slightly paler below.
Yaupon flowers are white, with a four-lobed corolla. The fruit is a small round or red (occasionally yellow) berry 5-6 mm diameter containing four seeds.
## Cultivation and uses
Native Americans used the leaves and stems to brew a tea called Asi or Black drink for male-only purification and unity rituals. The ceremony included vomiting, and Europeans incorrectly believed that it was the drink itself that caused it (hence the Latin name). The active ingredient is actually caffeine, and the vomiting was either learned or as a result of the great quantities in which they drank the beverage (Hudson, The Southeastern Indians, ISBN 0-87049-248-9).
# Further reading
- Gilman, Edward F. and Watson, Dennis G. Ilex vomitoria: Yaupon Holly Fact Sheet ST-311 (November 1993), Institute of Food and Agricultural Sciences, University of Florida accessed at June 19, 2006 End | Yaupon Holly
Yaupon Holly (Ilex vomitoria), also called Yaupon or Cassina (the latter shared with the Dahoon Holly), is an evergreen holly found in the southeast United States. It is a shrub or small tree reaching 5-8 m tall. The leaves are alternate, ovate to elliptical with an acute apex and crenate or finely serrated margin, 2-4.5 cm long and 1-2 cm broad, glossy dark green above, slightly paler below.
Yaupon flowers are white, with a four-lobed corolla. The fruit is a small round or red (occasionally yellow) berry 5-6 mm diameter containing four seeds.
## Cultivation and uses
Native Americans used the leaves and stems to brew a tea called Asi or Black drink for male-only purification and unity rituals. The ceremony included vomiting, and Europeans incorrectly believed that it was the drink itself that caused it (hence the Latin name). The active ingredient is actually caffeine, and the vomiting was either learned or as a result of the great quantities in which they drank the beverage (Hudson, The Southeastern Indians, ISBN 0-87049-248-9).
# Further reading
- Gilman, Edward F. and Watson, Dennis G. Ilex vomitoria: Yaupon Holly Fact Sheet ST-311 (November 1993), Institute of Food and Agricultural Sciences, University of Florida accessed at [1] June 19, 2006 End
# External links
- Ilex vomitoria images at bioimages.vanderbilt.edu
- Gardening Calendar - Yearly tasks for a healthy Yaupon Holly
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Yaupon_Holly | |
e22ed03f3ea599c6100685fe80806e88d4163ed6 | wikidoc | Zanthi Fever | Zanthi Fever
In the fictional Star Trek universe, Zanthi fever is a condition which targets the empathic abilities of mature Betazoids (in effect, those Betazoids of advancing years). It causes the Betazoid to project their own emotions onto others - but only in those individuals where a latent propensity for that emotion was present (for example, a Betazoid who was fearful of someone would project that emotional state, causing others in the vicinity to act upon their latent fears).
# Remedies for Zanthi Fever
The nature of Zanthi Fever is not known; also, there is no information on if there is a treatment to prevent the disease. However, inoculations of simple wide-spectrum anti-viral agents to the infected Betazoid is enough to cure the condition. Individuals who are influenced by the Betazoid's projections usially return to normal within a three- to four-day period.
# Recorded instances of Zanthi Fever
In 2371, during a visit to Deep Space 9 during the Bajoran Gratitude Festival, Lwaxana Troi projected her feelings for Odo onto several members of the station's population. As a result, Jake Sisko developed feelings for Major Kira Nerys, Vedek Bareil lusted for Lieutenant Jadzia Dax, Dax became attracted to Commander Benjamin Sisko, Doctor Julian Bashir coupled up with Major Kira, and Quark went for Keiko O'Brien. Chief Miles O'Brien and Constable Odo seemed immune to the effects.
These events transpired in the DS9 episode "Fascination". | Zanthi Fever
In the fictional Star Trek universe, Zanthi fever is a condition which targets the empathic abilities of mature Betazoids (in effect, those Betazoids of advancing years). It causes the Betazoid to project their own emotions onto others - but only in those individuals where a latent propensity for that emotion was present (for example, a Betazoid who was fearful of someone would project that emotional state, causing others in the vicinity to act upon their latent fears).
# Remedies for Zanthi Fever
The nature of Zanthi Fever is not known; also, there is no information on if there is a treatment to prevent the disease. However, inoculations of simple wide-spectrum anti-viral agents to the infected Betazoid is enough to cure the condition. Individuals who are influenced by the Betazoid's projections usially return to normal within a three- to four-day period.
# Recorded instances of Zanthi Fever
In 2371, during a visit to Deep Space 9 during the Bajoran Gratitude Festival, Lwaxana Troi projected her feelings for Odo onto several members of the station's population. As a result, Jake Sisko developed feelings for Major Kira Nerys, Vedek Bareil lusted for Lieutenant Jadzia Dax, Dax became attracted to Commander Benjamin Sisko, Doctor Julian Bashir coupled up with Major Kira, and Quark went for Keiko O'Brien. Chief Miles O'Brien and Constable Odo seemed immune to the effects.
These events transpired in the DS9 episode "Fascination".
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Zanthi_Fever | |
4807c7a2490c99b42675fc876bdb2d970513c7b2 | wikidoc | Zinc acetate | Zinc acetate
# 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
Zinc acetate is a mineral supplement that is FDA approved for the treatment of of patients with Wilson’s disease who have been initially treated with a chelating agent. Common adverse reactions include gastric irritation; elevations of serum alkaline phosphatase, amylase and lipase lasting from weeks to months suggesting pancreatitis..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Zinc acetate therapy is indicated for maintenance treatment of patients with Wilson’s disease who have been initially treated with a chelating agent
- The recommended adult dose is 50 mg as zinc three times daily
- Since 25 mg t.i.d. is also an effective dose in children 10 years of age or older or in women who are pregnant, it may be advisable to use a dose of zinc to 25 mg three times a day, as long as the patient is compliant with therapy. The dose can be raised to 50 mg t.i.d. if monitoring indicates a lessening of control
- Patients should take zinc acetate on an empty stomach, at least one hour before or two to three hours after meals.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Zinc acetate in adult patients.
### Non–Guideline-Supported Use
- zinc gluconate lozenges (13.3 mg), or zinc acetate lozenges (5 mg or 11.5 mg), administered every 2 to 3 waking hours (total of 6 lozenges per day) for up to 14 days.
- Patients with rheumatoid arthritis (RA), whether of low or high activity, appear to have impaired zinc absorption.
- A 50 mg dose of zinc is given.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Zinc acetate therapy is indicated for maintenance treatment of patients with Wilson’s disease who have been initially treated with a chelating agent
- The recommended adult dose is 50 mg as zinc three times daily
- Since 25 mg t.i.d. is also an effective dose in children 10 years of age or older or in women who are pregnant, it may be advisable to use a dose of zinc to 25 mg three times a day, as long as the patient is compliant with therapy. The dose can be raised to 50 mg t.i.d. if monitoring indicates a lessening of control
- Patients should take zinc acetate on an empty stomach, at least one hour before or two to three hours after meals.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Zinc acetate in pediatric patients.
### Non–Guideline-Supported Use
- Zinc gluconate glycine lozenges each providing 10 mg zinc 5 or 6 times per day (5 times for children in grades 1 through 6, and 6 times for students in grades 7 through 12), beginning within 24 hours of the first manifestations of a cold.
- Infants were given zinc sulfate, 3 mg/kg there was complete remission by 4 weeks
# Contraindications
- Zinc Acetate Capsules are contraindicated in patients with known hypersensitivity to any of the components of the formulation.
# Warnings
### Precautions
- Zinc acetate is not recommended for the initial therapy of symptomatic patients because of the delay required for zinc-induced increase in enterocytic metallothionein and blockade of copper uptake. Symptomatic patients should be treated initially, using chelating agents. During initial therapy, neurological deterioration may occur as stores of copper are mobilized. Once initial therapy has been completed, and the patient is clinically stable, maintenance treatment with zinc acetate can be considered, but patients may be continued on initial therapy as clinically indicated.
# Adverse Reactions
## Clinical Trials Experience
- Clinical experience with zinc acetate has been limited. The following adverse reactions have been reported in patients with Wilson’s disease on zinc therapy: a death following overdosage with zinc sulfate and a death in a patient with advanced liver disease and hemolytic crisis where zinc sulfate was used as initial treatment; gastric irritation; elevations of serum alkaline phosphatase, amylase and lipase lasting from weeks to months suggesting pancreatitis. The levels usually return to high normal within the first one or two years of zinc therapy.
- Zinc acetate has no potential for abuse, and it is not related pharmacologically or structurally to any other drug known to have abuse potential.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Zinc acetate in the drug label.
# Drug Interactions
- Pharmacodynamic studies in Wilson’s disease patients failed to demonstrate drug interactions between zinc acetate (50 mg t.i.d.) and ascorbic acid (1 g daily), penicillamine (1 g daily), and trientine (1 g daily). Therefore, precautions for zinc acetate effects do not seem necessary when Wilson’s disease patients are taking vitamin C or approved chelating agents. However, no data are available to demonstrate that zinc acetate should be added to other drugs used for the treatment of Wilson’s disease patients or is safe.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): A
- Teratogenic Effects
- Studies in pregnant women have not shown that zinc acetate or zinc sulfate increases the risk of fetal abnormalities if administered during all trimesters of pregnancy. If this drug is used during pregnancy, the possibility of fetal harm appears remote. Because studies cannot rule out the possibility of harm, however, zinc acetate should be used during pregnancy only if clearly needed. While zinc acetate should be used during pregnancy only if clearly needed, copper toxicosis can develop during pregnancy if anti-copper therapy is stopped.
- Oral teratology studies have been performed with zinc sulfate in pregnant rats at doses up to 42.5 mg/Kg/day (2 times the recommended human dose based on body surface area), mice at doses up to 30 mg/Kg/day (1 time the recommended human dose based on body surface area), rabbits at doses up to 60 mg/Kg/day (6 times the recommended human dose based on body surface area) and hamsters at doses up to 88 mg/Kg/day (5 times the recommended human dose based on body surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to zinc sulfate.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Zinc acetate in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Zinc acetate during labor and delivery.
### Nursing Mothers
- Zinc does appear in breast milk and zinc-induced copper deficiency in the nursing baby may occur. Therefore, it is recommended that women on zinc therapy not nurse their babies.
### Pediatric Use
- Results of observations in a small number of patients in the two clinical trials suggest that pediatric patients aged 10 years and above can be adequately maintained at doses between 75 to 150 mg elemental zinc daily in divided doses. No patients below the age of 10 years have been studied.
### Geriatic Use
There is no FDA guidance on the use of Zinc acetate with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Zinc acetate with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Zinc acetate with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Zinc acetate in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Zinc acetate in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Zinc acetate in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Zinc acetate in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- Patients should be monitored primarily by assessment of existing signs and symptoms of Wilson’s disease and 24-hour urine copper. Neuropsychiatric evaluations including speech as well as liver function tests including bilirubin and aminotransferases, should be done as appropriate.
- The urinary excretion of copper is an accurate reflection of the body status of copper when patients are not on chelation therapy. The clinician should be aware that urinary copper levels are usually increased with chelation therapy such as penicillamine or trientine. Adequate zinc therapy will eventually decrease urinary copper excretion to 125 μg per 24 hours or less. A significant trend upward indicates impending loss of copper control. The non-ceruloplasmin plasma copper (also known as free copper) is obtained by subtracting the ceruloplasmin-bound copper from the total plasma copper. Each mg of ceruloplasmin contains 3 μg of copper. In the United States study, non-ceruloplasmin plasma copper concentration was kept below 20 μg/dL. Urine and plasma for copper determinations should be collected in copper-free containers and assayed with equipment capable of accurately measuring copper at levels as low as 0.01 μg/mL.
- An additional monitoring tool, if available, is the amount of radioactivity measured in the plasma 1 or 2 hours after orally administered 64copper. In adequately controlled patients, the amount is less than 1.2% of the administered dose. The level of hepatic copper should not be used to manage therapy since it does not differentiate between potentially toxic free copper and safely bound copper.
- In all treated patients, 24-hour urinary zinc levels may be a useful measure of compliance with the zinc acetate regimen.
# IV Compatibility
There is limited information regarding IV Compatibility of Zinc acetate in the drug label.
# Overdosage
- Acute oral overdosage with inorganic salts of zinc in humans is reported rarely. In the event of overdosage, the unabsorbed zinc salt should be removed from the stomach by lavage as quickly as possible. The plasma level of zinc should be measured, and heavy metal chelation therapy should be considered if the plasma level of zinc is elevated markedly (>1000 μg/dL). In addition, any signs or symptoms of toxicity should be treated as medically indicated.
- One fatality associated with overdosage of zinc sulfate has been reported. The death of this adult woman followed the accidental ingestion of approximately 28 g of zinc sulfate. Death occurred on the fifth day after ingestion and was attributed to renal failure. Hemorrhagic pancreatitis and hyperglycemic coma resulted from the overdose. The amount ingested was 500 mg/Kg of zinc sulfate, a value that is in the same order of magnitude as that found to be lethal in animals.
# Pharmacology
## Mechanism of Action
- Wilson's disease (hepatolenticular degeneration) is an autosomal recessive metabolic defect in hepatic excretion of copper in the bile, resulting in accumulation of excess copper in the liver, and subsequently in other organs, including the brain, kidneys, eyes, bone, and muscles. In this disease, hepatocytes store excess copper, but when their capacity is exceeded copper is released into the blood and is taken up in extrahepatic sites, such as the brain, resulting in motor disorders (ataxia, tremors, speech difficulties) and psychiatric manifestations (irritability, depression, deterioration of work performance). Redistribution of excess copper in hepatocytes leads to hepatocellular injury, inflammation, necrosis, and eventual cirrhosis. Patients may present clinically with predominantly hepatic, neurologic, or psychiatric symptoms.
- The disease has been treated by restricting copper in the diet, and the use of chelating agents to bind free copper to reduce its toxicity and facilitate its excretion. The purpose of initial treatment of symptomatic patients with a chelating agent is to detoxify copper. Once the patient's symptoms have stabilized clinically, maintenance treatment begins. Clinical measures are used to determine whether the patient remains stable.
- The active moiety in zinc acetate is zinc cation. Regardless of the ligand, zinc blocks the intestinal absorption of copper from the diet and the reabsorption of endogenously secreted copper such as that from the saliva, gastric juice and bile. Zinc induces the production of metallothionein in the enterocyte, a protein that binds copper thereby preventing its serosal transfer into the blood. The bound copper is then lost in the stool following desquamation of the intestinal cells.
## Structure
- Zinc acetate as the dihydrate is a salt of zinc used to inhibit the absorption of copper in patients with Wilson's disease. Its structural formula is:
- Zinc acetate occurs as white crystals or granules, freely soluble in water and in boiling alcohol, and slightly soluble in alcohol.
- Zinc Acetate Capsules contain the equivalent of 25 or 50 mg of zinc, in addition to corn starch and magnesium stearate in gelatin capsules. The 25 mg capsule shells contain titanium dioxide and the 50 mg capsule shells contain titanium dioxide, methylparaben and propylparaben. The 25 mg capsule shells contain FD&C Blue #1; the 50 mg capsule shells contain FD&C Red #40, D&C Red #28, and D&C Yellow #10.
## Pharmacodynamics
- In pharmacodynamic studies, the methods used included net copper balance and radiolabeled copper uptake in Wilson’s disease patients. These studies showed that a regimen of 50 mg t.i.d. of zinc acetate was effective in inducing a negative mean copper balance (-0.44 mg/day) and an adequate mean 64Cu uptake (0.82% of the administered dose). A regimen of 25 mg t.i.d. of zinc acetate was also pharmacodynamically active but fewer patients have been treated with this regimen than 50 mg t.i.d.
## Pharmacokinetics
- Because the proposed site of action of zinc is an effect on copper uptake at the level of the intestinal cell, pharmacokinetic evaluations based on blood levels of zinc do not provide useful information on zinc bioavailability at the site of action. *Determinations of zinc content in the liver and the plasma zinc concentration after the oral administration of zinc acetate have yielded inconsistent results. However, foods and beverages have been shown to decrease the uptake of zinc thereby decreasing the levels of zinc in the plasma of healthy volunteers. For this reason, the oral dose of zinc should be separated from food and beverages, other than water, by at least one hour.
## Nonclinical Toxicology
- Zinc acetate has not been tested for its carcinogenic potential in long-term animal studies, for its mutagenic potential or for its effect on fertility in animals.
- However, testing with other salts of zinc (zinc oxide, zinc stearate, zinc sulfate) did not reveal a mutagenicity potential in in vitro Ames assays, and human embryonic lung cell chromosomal aberration assay, and in in vivo rat dominant lethal assay, and rat bone marrow cell chromosomal aberration assay.
- Other salts of zinc (zinc oxide, zinc chloride, zinc citrate, zinc maleate, zinc carbonate, zinc sulfate) and pure zinc dust at oral doses up to 326 mg/Kg/day (18 times the recommended human dose based on body surface area) were found to have no effect on fertility and reproductive performance of male and female rats.
# Clinical Studies
- In the single center United States trial, 60 patients with Wilson’s disease (31 male, 29 female) who had adequate detoxification of copper after initial chelation therapy were entered into a copper balance study of various dose regimens of zinc acetate. Patients were hospitalized to carefully control food and liquid intake. Food, urine and feces were analyzed for copper content, and copper balance was defined as the difference between copper intake and copper elimination/excretion over a 10-day period. A patient was considered in adequate copper balance if the result was less than +0.25 mg copper/day. Results for the groups in each dose regimen tested and for adequacy of individual results are provided in the following table
- While all zinc acetate regimens appeared better than no therapy, there was little experience with doses other than 50 mg t.i.d. Once daily dosing did not appear to give satisfactory control in many cases, and would be inadequate in patients with poor compliance. Based on the limited data available 25 mg t.i.d. was also thought to be an adequate dose regimen, and not shown to be inferior to 50 mg t.i.d. Dose related toxicity was not found in this study.
- Symptomatic Patients Initially Treated With a Chelating Drug
Clinical parameters such as neuropsychiatric status including evaluation of speech, and liver function tests were followed as the patients continued therapy on an adequate zinc acetate dose regimen. One hundred and thirty-three patients were followed for up to 14 years. There was no deterioration of neuropsychiatric function including speech and biochemical liver function tests, including bilirubin, transaminases, alkaline phosphatase and lactic dehydrogenase. The liver function tests remained either within normal range or slightly above the upper limit of normal for up to 9 years of treatment.
- Pre-symptomatic Patients
- In this study 30 pre-symptomatic patients were followed for up to 10 years. Diagnosis of the pre-symptomatic Wilson’s disease was made on the basis of a liver copper value greater than 200 μg of copper per gram dry weight of tissue.
- Non-ceruloplasmin copper levels, 64Cu balance studies, and clinical parameters were assessed. No patient developed symptoms of Wilson’s disease in this cohort. Since the cloning and sequencing of the abnormal genes in Wilson’s disease patients, many mutations have been identified that may affect the rate of disease progression. No matched historical control has been compared to this experience, nor has another center replicated this experience.
- In a study in the Netherlands, using zinc sulfate, 27 patients were followed up to 29 years by mainly clinical parameters such as tremors, dysarthria, dystonia, ataxia and Kayser-Fleischer rings. No deterioration of the clinical status was observed. In some cases, Kayser-Fleischer rings disappeared and clinical signs and symptoms improved.
- Pregnant Patients
- Included in a continuing single center United States trial are 19 symptomatic and presymptomatic women who became pregnant and continued Galzin therapy. These women delivered 26 live birth babies. At the time of delivery, the duration of zinc acetate therapy had ranged from 0.7 to 13.7 years. At the time of delivery all patients were using zinc acetate. The zinc acetate dosage at the start of pregnancy ranged from 25 to 50 mg two to three times a day. Two patients were being treated with penicillamine at the start of pregnancy and were switched to zinc acetate during the second month of pregnancy.
- Urinary copper excretion was measured to monitor the copper status. Twenty-four hour urine excretion of copper indicated adequate control of copper levels in most patients before and during pregnancies. The results also indicated that during pregnancy, the mothers’ health was protected by zinc acetate therapy, and no adverse effects on liver or neurological functions were reported. Limited pregnancy outcome data indicates an incidence of miscarriages consistent with those in the general population. From this limited experience, the rate of birth defects is 7.7%, while that in the general population is (4%).
# How Supplied
- GALZIN®, Zinc Acetate Capsules (25 mg zinc content) are #1 capsules with aqua blue opaque cap and body, imprinted "93-215." Packaged in bottles of 250 (NDC 57844-215-52).
- GALZIN®, Zinc Acetate Capsules (50 mg zinc content) are #1 capsules with orange opaque cap and body, imprinted "93-208." Packaged in bottles of 250 (NDC 57844-208-52).
## Storage
- Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). *See USP Controlled Room Temperature. Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients should take GALZIN® on an empty stomach, at least one hour before or two to three hours after meals. Capsules should be swallowed whole, not opened or chewed. In the rare event of gastric intolerance of zinc, generally occurring with the morning dose, this dose may be taken between breakfast and lunch. Patients must be clinically monitored to determine the adequacy of zinc acetate therapy. Since strict adherence to the zinc regimen is essential for optimal control of copper distribution and metabolism, the physician must reinforce the need for compliance at each contact with the patient.
# Precautions with Alcohol
- Alcohol-Zinc Acetate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Derma Gran
- Dermafix
- Galzin
- Peleverus
- Peleverus Gold ®
# Look-Alike Drug Names
- A® — B®
# Drug Shortage Status
# Price | Zinc acetate
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
Zinc acetate is a mineral supplement that is FDA approved for the treatment of of patients with Wilson’s disease who have been initially treated with a chelating agent. Common adverse reactions include gastric irritation; elevations of serum alkaline phosphatase, amylase and lipase lasting from weeks to months suggesting pancreatitis..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Zinc acetate therapy is indicated for maintenance treatment of patients with Wilson’s disease who have been initially treated with a chelating agent
- The recommended adult dose is 50 mg as zinc three times daily
- Since 25 mg t.i.d. is also an effective dose in children 10 years of age or older or in women who are pregnant, it may be advisable to use a dose of zinc to 25 mg three times a day, as long as the patient is compliant with therapy. The dose can be raised to 50 mg t.i.d. if monitoring indicates a lessening of control
- Patients should take zinc acetate on an empty stomach, at least one hour before or two to three hours after meals.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Zinc acetate in adult patients.
### Non–Guideline-Supported Use
- zinc gluconate lozenges (13.3 mg), or zinc acetate lozenges (5 mg or 11.5 mg), administered every 2 to 3 waking hours (total of 6 lozenges per day) for up to 14 days.[1]
- Patients with rheumatoid arthritis (RA), whether of low or high activity, appear to have impaired zinc absorption.
- A 50 mg dose of zinc is given. [2]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Zinc acetate therapy is indicated for maintenance treatment of patients with Wilson’s disease who have been initially treated with a chelating agent
- The recommended adult dose is 50 mg as zinc three times daily
- Since 25 mg t.i.d. is also an effective dose in children 10 years of age or older or in women who are pregnant, it may be advisable to use a dose of zinc to 25 mg three times a day, as long as the patient is compliant with therapy. The dose can be raised to 50 mg t.i.d. if monitoring indicates a lessening of control
- Patients should take zinc acetate on an empty stomach, at least one hour before or two to three hours after meals.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Zinc acetate in pediatric patients.
### Non–Guideline-Supported Use
- Zinc gluconate glycine lozenges each providing 10 mg zinc 5 or 6 times per day (5 times for children in grades 1 through 6, and 6 times for students in grades 7 through 12), beginning within 24 hours of the first manifestations of a cold. [3]
- Infants were given zinc sulfate, 3 mg/kg there was complete remission by 4 weeks [4]
# Contraindications
- Zinc Acetate Capsules are contraindicated in patients with known hypersensitivity to any of the components of the formulation.
# Warnings
### Precautions
- Zinc acetate is not recommended for the initial therapy of symptomatic patients because of the delay required for zinc-induced increase in enterocytic metallothionein and blockade of copper uptake. Symptomatic patients should be treated initially, using chelating agents. During initial therapy, neurological deterioration may occur as stores of copper are mobilized. Once initial therapy has been completed, and the patient is clinically stable, maintenance treatment with zinc acetate can be considered, but patients may be continued on initial therapy as clinically indicated.
# Adverse Reactions
## Clinical Trials Experience
- Clinical experience with zinc acetate has been limited. The following adverse reactions have been reported in patients with Wilson’s disease on zinc therapy: a death following overdosage with zinc sulfate and a death in a patient with advanced liver disease and hemolytic crisis where zinc sulfate was used as initial treatment; gastric irritation; elevations of serum alkaline phosphatase, amylase and lipase lasting from weeks to months suggesting pancreatitis. The levels usually return to high normal within the first one or two years of zinc therapy.
- Zinc acetate has no potential for abuse, and it is not related pharmacologically or structurally to any other drug known to have abuse potential.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Zinc acetate in the drug label.
# Drug Interactions
- Pharmacodynamic studies in Wilson’s disease patients failed to demonstrate drug interactions between zinc acetate (50 mg t.i.d.) and ascorbic acid (1 g daily), penicillamine (1 g daily), and trientine (1 g daily). Therefore, precautions for zinc acetate effects do not seem necessary when Wilson’s disease patients are taking vitamin C or approved chelating agents. However, no data are available to demonstrate that zinc acetate should be added to other drugs used for the treatment of Wilson’s disease patients or is safe.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): A
- Teratogenic Effects
- Studies in pregnant women have not shown that zinc acetate or zinc sulfate increases the risk of fetal abnormalities if administered during all trimesters of pregnancy. If this drug is used during pregnancy, the possibility of fetal harm appears remote. Because studies cannot rule out the possibility of harm, however, zinc acetate should be used during pregnancy only if clearly needed. While zinc acetate should be used during pregnancy only if clearly needed, copper toxicosis can develop during pregnancy if anti-copper therapy is stopped.
- Oral teratology studies have been performed with zinc sulfate in pregnant rats at doses up to 42.5 mg/Kg/day (2 times the recommended human dose based on body surface area), mice at doses up to 30 mg/Kg/day (1 time the recommended human dose based on body surface area), rabbits at doses up to 60 mg/Kg/day (6 times the recommended human dose based on body surface area) and hamsters at doses up to 88 mg/Kg/day (5 times the recommended human dose based on body surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to zinc sulfate.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Zinc acetate in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Zinc acetate during labor and delivery.
### Nursing Mothers
- Zinc does appear in breast milk and zinc-induced copper deficiency in the nursing baby may occur. Therefore, it is recommended that women on zinc therapy not nurse their babies.
### Pediatric Use
- Results of observations in a small number of patients in the two clinical trials suggest that pediatric patients aged 10 years and above can be adequately maintained at doses between 75 to 150 mg elemental zinc daily in divided doses. No patients below the age of 10 years have been studied.
### Geriatic Use
There is no FDA guidance on the use of Zinc acetate with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Zinc acetate with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Zinc acetate with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Zinc acetate in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Zinc acetate in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Zinc acetate in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Zinc acetate in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- Patients should be monitored primarily by assessment of existing signs and symptoms of Wilson’s disease and 24-hour urine copper. Neuropsychiatric evaluations including speech as well as liver function tests including bilirubin and aminotransferases, should be done as appropriate.
- The urinary excretion of copper is an accurate reflection of the body status of copper when patients are not on chelation therapy. The clinician should be aware that urinary copper levels are usually increased with chelation therapy such as penicillamine or trientine. Adequate zinc therapy will eventually decrease urinary copper excretion to 125 μg per 24 hours or less. A significant trend upward indicates impending loss of copper control. The non-ceruloplasmin plasma copper (also known as free copper) is obtained by subtracting the ceruloplasmin-bound copper from the total plasma copper. Each mg of ceruloplasmin contains 3 μg of copper. In the United States study, non-ceruloplasmin plasma copper concentration was kept below 20 μg/dL. Urine and plasma for copper determinations should be collected in copper-free containers and assayed with equipment capable of accurately measuring copper at levels as low as 0.01 μg/mL.
- An additional monitoring tool, if available, is the amount of radioactivity measured in the plasma 1 or 2 hours after orally administered 64copper. In adequately controlled patients, the amount is less than 1.2% of the administered dose. The level of hepatic copper should not be used to manage therapy since it does not differentiate between potentially toxic free copper and safely bound copper.
- In all treated patients, 24-hour urinary zinc levels may be a useful measure of compliance with the zinc acetate regimen.
# IV Compatibility
There is limited information regarding IV Compatibility of Zinc acetate in the drug label.
# Overdosage
- Acute oral overdosage with inorganic salts of zinc in humans is reported rarely. In the event of overdosage, the unabsorbed zinc salt should be removed from the stomach by lavage as quickly as possible. The plasma level of zinc should be measured, and heavy metal chelation therapy should be considered if the plasma level of zinc is elevated markedly (>1000 μg/dL). In addition, any signs or symptoms of toxicity should be treated as medically indicated.
- One fatality associated with overdosage of zinc sulfate has been reported. The death of this adult woman followed the accidental ingestion of approximately 28 g of zinc sulfate. Death occurred on the fifth day after ingestion and was attributed to renal failure. Hemorrhagic pancreatitis and hyperglycemic coma resulted from the overdose. The amount ingested was 500 mg/Kg of zinc sulfate, a value that is in the same order of magnitude as that found to be lethal in animals.
# Pharmacology
## Mechanism of Action
- Wilson's disease (hepatolenticular degeneration) is an autosomal recessive metabolic defect in hepatic excretion of copper in the bile, resulting in accumulation of excess copper in the liver, and subsequently in other organs, including the brain, kidneys, eyes, bone, and muscles. In this disease, hepatocytes store excess copper, but when their capacity is exceeded copper is released into the blood and is taken up in extrahepatic sites, such as the brain, resulting in motor disorders (ataxia, tremors, speech difficulties) and psychiatric manifestations (irritability, depression, deterioration of work performance). Redistribution of excess copper in hepatocytes leads to hepatocellular injury, inflammation, necrosis, and eventual cirrhosis. Patients may present clinically with predominantly hepatic, neurologic, or psychiatric symptoms.
- The disease has been treated by restricting copper in the diet, and the use of chelating agents to bind free copper to reduce its toxicity and facilitate its excretion. The purpose of initial treatment of symptomatic patients with a chelating agent is to detoxify copper. Once the patient's symptoms have stabilized clinically, maintenance treatment begins. Clinical measures are used to determine whether the patient remains stable.
- The active moiety in zinc acetate is zinc cation. Regardless of the ligand, zinc blocks the intestinal absorption of copper from the diet and the reabsorption of endogenously secreted copper such as that from the saliva, gastric juice and bile. Zinc induces the production of metallothionein in the enterocyte, a protein that binds copper thereby preventing its serosal transfer into the blood. The bound copper is then lost in the stool following desquamation of the intestinal cells.
## Structure
- Zinc acetate as the dihydrate is a salt of zinc used to inhibit the absorption of copper in patients with Wilson's disease. Its structural formula is:
- Zinc acetate occurs as white crystals or granules, freely soluble in water and in boiling alcohol, and slightly soluble in alcohol.
- Zinc Acetate Capsules contain the equivalent of 25 or 50 mg of zinc, in addition to corn starch and magnesium stearate in gelatin capsules. The 25 mg capsule shells contain titanium dioxide and the 50 mg capsule shells contain titanium dioxide, methylparaben and propylparaben. The 25 mg capsule shells contain FD&C Blue #1; the 50 mg capsule shells contain FD&C Red #40, D&C Red #28, and D&C Yellow #10.
## Pharmacodynamics
- In pharmacodynamic studies, the methods used included net copper balance and radiolabeled copper uptake in Wilson’s disease patients. These studies showed that a regimen of 50 mg t.i.d. of zinc acetate was effective in inducing a negative mean copper balance (-0.44 mg/day) and an adequate mean 64Cu uptake (0.82% of the administered dose). A regimen of 25 mg t.i.d. of zinc acetate was also pharmacodynamically active but fewer patients have been treated with this regimen than 50 mg t.i.d.
## Pharmacokinetics
- Because the proposed site of action of zinc is an effect on copper uptake at the level of the intestinal cell, pharmacokinetic evaluations based on blood levels of zinc do not provide useful information on zinc bioavailability at the site of action. *Determinations of zinc content in the liver and the plasma zinc concentration after the oral administration of zinc acetate have yielded inconsistent results. However, foods and beverages have been shown to decrease the uptake of zinc thereby decreasing the levels of zinc in the plasma of healthy volunteers. For this reason, the oral dose of zinc should be separated from food and beverages, other than water, by at least one hour.
## Nonclinical Toxicology
- Zinc acetate has not been tested for its carcinogenic potential in long-term animal studies, for its mutagenic potential or for its effect on fertility in animals.
- However, testing with other salts of zinc (zinc oxide, zinc stearate, zinc sulfate) did not reveal a mutagenicity potential in in vitro Ames assays, and human embryonic lung cell chromosomal aberration assay, and in in vivo rat dominant lethal assay, and rat bone marrow cell chromosomal aberration assay.
- Other salts of zinc (zinc oxide, zinc chloride, zinc citrate, zinc maleate, zinc carbonate, zinc sulfate) and pure zinc dust at oral doses up to 326 mg/Kg/day (18 times the recommended human dose based on body surface area) were found to have no effect on fertility and reproductive performance of male and female rats.
# Clinical Studies
- In the single center United States trial, 60 patients with Wilson’s disease (31 male, 29 female) who had adequate detoxification of copper after initial chelation therapy were entered into a copper balance study of various dose regimens of zinc acetate. Patients were hospitalized to carefully control food and liquid intake. Food, urine and feces were analyzed for copper content, and copper balance was defined as the difference between copper intake and copper elimination/excretion over a 10-day period. A patient was considered in adequate copper balance if the result was less than +0.25 mg copper/day. Results for the groups in each dose regimen tested and for adequacy of individual results are provided in the following table
- While all zinc acetate regimens appeared better than no therapy, there was little experience with doses other than 50 mg t.i.d. Once daily dosing did not appear to give satisfactory control in many cases, and would be inadequate in patients with poor compliance. Based on the limited data available 25 mg t.i.d. was also thought to be an adequate dose regimen, and not shown to be inferior to 50 mg t.i.d. Dose related toxicity was not found in this study.
- Symptomatic Patients Initially Treated With a Chelating Drug
Clinical parameters such as neuropsychiatric status including evaluation of speech, and liver function tests were followed as the patients continued therapy on an adequate zinc acetate dose regimen. One hundred and thirty-three patients were followed for up to 14 years. There was no deterioration of neuropsychiatric function including speech and biochemical liver function tests, including bilirubin, transaminases, alkaline phosphatase and lactic dehydrogenase. The liver function tests remained either within normal range or slightly above the upper limit of normal for up to 9 years of treatment.
- Pre-symptomatic Patients
- In this study 30 pre-symptomatic patients were followed for up to 10 years. Diagnosis of the pre-symptomatic Wilson’s disease was made on the basis of a liver copper value greater than 200 μg of copper per gram dry weight of tissue.
- Non-ceruloplasmin copper levels, 64Cu balance studies, and clinical parameters were assessed. No patient developed symptoms of Wilson’s disease in this cohort. Since the cloning and sequencing of the abnormal genes in Wilson’s disease patients, many mutations have been identified that may affect the rate of disease progression. No matched historical control has been compared to this experience, nor has another center replicated this experience.
- In a study in the Netherlands, using zinc sulfate, 27 patients were followed up to 29 years by mainly clinical parameters such as tremors, dysarthria, dystonia, ataxia and Kayser-Fleischer rings. No deterioration of the clinical status was observed. In some cases, Kayser-Fleischer rings disappeared and clinical signs and symptoms improved.
- Pregnant Patients
- Included in a continuing single center United States trial are 19 symptomatic and presymptomatic women who became pregnant and continued Galzin therapy. These women delivered 26 live birth babies. At the time of delivery, the duration of zinc acetate therapy had ranged from 0.7 to 13.7 years. At the time of delivery all patients were using zinc acetate. The zinc acetate dosage at the start of pregnancy ranged from 25 to 50 mg two to three times a day. Two patients were being treated with penicillamine at the start of pregnancy and were switched to zinc acetate during the second month of pregnancy.
- Urinary copper excretion was measured to monitor the copper status. Twenty-four hour urine excretion of copper indicated adequate control of copper levels in most patients before and during pregnancies. The results also indicated that during pregnancy, the mothers’ health was protected by zinc acetate therapy, and no adverse effects on liver or neurological functions were reported. Limited pregnancy outcome data indicates an incidence of miscarriages consistent with those in the general population. From this limited experience, the rate of birth defects is 7.7%, while that in the general population is (4%).
# How Supplied
- GALZIN®, Zinc Acetate Capsules (25 mg zinc content) are #1 capsules with aqua blue opaque cap and body, imprinted "93-215." Packaged in bottles of 250 (NDC 57844-215-52).
- GALZIN®, Zinc Acetate Capsules (50 mg zinc content) are #1 capsules with orange opaque cap and body, imprinted "93-208." Packaged in bottles of 250 (NDC 57844-208-52).
## Storage
- Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). *See USP Controlled Room Temperature. Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients should take GALZIN® on an empty stomach, at least one hour before or two to three hours after meals. Capsules should be swallowed whole, not opened or chewed. In the rare event of gastric intolerance of zinc, generally occurring with the morning dose, this dose may be taken between breakfast and lunch. Patients must be clinically monitored to determine the adequacy of zinc acetate therapy. Since strict adherence to the zinc regimen is essential for optimal control of copper distribution and metabolism, the physician must reinforce the need for compliance at each contact with the patient.
# Precautions with Alcohol
- Alcohol-Zinc Acetate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Derma Gran
- Dermafix
- Galzin
- Peleverus
- Peleverus Gold ®
# Look-Alike Drug Names
- A® — B®
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Zinc_acetate | |
63609cc8da2c735f3aa53b3ccd288606151bc50d | wikidoc | Zinc sulfide | Zinc sulfide
# Overview
Zinc sulfide (or zinc sulphide) is a chemical compound with the formula ZnS. Zinc sulfide is a white- to yellow-colored powder or crystal. It is typically encountered in the more stable cubic form, known also as the mineral sphalerite. The hexagonal form is also known both as a synthetic material and as the mineral wurtzite. Both sphalerite and wurtzite are intrinsic, wide-bandgap semiconductors. The cubic form has a band gap of 3.54 eV at 300 K whereas the hexagonal form has a band gap of 3.91 eV.
A transition from the sphalerite form to the wurtzite form occurs at around 1293.15 K. Sphalerite melts at 1991 K. It has a standard enthalpy of formation of −204.6 kJ mol−1 at 298 K.
# Applications
ZnS was used by Ernest Rutherford and others in the early years of nuclear physics as a scintillation detector, because it emits light on excitation by x-rays or electron beam, making it useful for x-ray screens and cathode ray tubes. It also exhibits phosphorescence due to impurities on illumination with blue or ultraviolet light.
Zinc sulfide, with addition of few ppm of suitable activator, is used as phosphor in many applications, from cathode ray tubes through x-ray screens to glow in the dark products. When silver is used as activator, the resulting color is bright blue, with maximum at 450 nm. Manganese yields an orange-red color at around 590 nm. Copper provides long glow time and the familiar glow-in-the-dark greenish color. Copper doped zinc sulfide (ZnS+Cu) is used also in electroluminescent panels.
Zinc sulfide is also used as an infrared optical material, transmitting from visible wavelengths to over 12 micrometres. It can be used planar as an optical window or shaped into a lens. It is made as microcrystalline sheets by the synthesis from H2S gas and zinc vapour and sold as FLIR (Forward Looking IR) grade ZnS a pale milky yellow visibly opaque form. This material when hot isostatically pressed (HIPed) can be converted to a water-clear form known as Cleartran (trademark). Early commercial forms were marketed as Irtran-2 but this designation is now obsolete.
It can be doped as both n-type semiconductor and p-type semiconductor, which is unusual for the II-VI semiconductors. ZnS is a covalently bonded solid.
# Production in lab
It is easily produced by mixing an amount of zinc and sulfur and then igniting it and as it extingushes zinc sulfide is obtained. This can be a very dangerous process. | Zinc sulfide
Template:Chembox new
# Overview
Zinc sulfide (or zinc sulphide) is a chemical compound with the formula ZnS. Zinc sulfide is a white- to yellow-colored powder or crystal. It is typically encountered in the more stable cubic form, known also as the mineral sphalerite. The hexagonal form is also known both as a synthetic material and as the mineral wurtzite. Both sphalerite and wurtzite are intrinsic, wide-bandgap semiconductors. The cubic form has a band gap of 3.54 eV at 300 K whereas the hexagonal form has a band gap of 3.91 eV.
A transition from the sphalerite form to the wurtzite form occurs at around 1293.15 K. Sphalerite melts at 1991 K. It has a standard enthalpy of formation of −204.6 kJ mol−1 at 298 K.
# Applications
ZnS was used by Ernest Rutherford and others in the early years of nuclear physics as a scintillation detector, because it emits light on excitation by x-rays or electron beam, making it useful for x-ray screens and cathode ray tubes. It also exhibits phosphorescence due to impurities on illumination with blue or ultraviolet light.
Zinc sulfide, with addition of few ppm of suitable activator, is used as phosphor in many applications, from cathode ray tubes through x-ray screens to glow in the dark products. When silver is used as activator, the resulting color is bright blue, with maximum at 450 nm. Manganese yields an orange-red color at around 590 nm. Copper provides long glow time and the familiar glow-in-the-dark greenish color. Copper doped zinc sulfide (ZnS+Cu) is used also in electroluminescent panels.
Zinc sulfide is also used as an infrared optical material, transmitting from visible wavelengths to over 12 micrometres. It can be used planar as an optical window or shaped into a lens. It is made as microcrystalline sheets by the synthesis from H2S gas and zinc vapour and sold as FLIR (Forward Looking IR) grade ZnS a pale milky yellow visibly opaque form. This material when hot isostatically pressed (HIPed) can be converted to a water-clear form known as Cleartran (trademark). Early commercial forms were marketed as Irtran-2 but this designation is now obsolete.
It can be doped as both n-type semiconductor and p-type semiconductor, which is unusual for the II-VI semiconductors. ZnS is a covalently bonded solid.
# Production in lab
It is easily produced by mixing an amount of zinc and sulfur and then igniting it and as it extingushes zinc sulfide is obtained. This can be a very dangerous process. | https://www.wikidoc.org/index.php/Zinc_sulfide | |
ff2d2926c0b840f3e3f80c00a1d309c86e8b1c0d | wikidoc | Zooxanthella | Zooxanthella
Zooxanthellae (Template:IPAEng) are golden-brown intracellular endosymbionts of various marine animals and protozoa, especially anthozoans. They are members of the phylum Dinoflagellata and are typically dinoflagellate algae, although algae such as diatoms can also be zooxanthellae. They may be acquired by direct ingestion, and subsequently reproduce by splitting apart; a process known as budding. In other cases, zooxanthellae may be transmitted by the coral eggs and planulae. Most are autotrophs and provide the host with energy in the form of translocated reduced carbon compounds derived from photosynthesis. Zooxanthellae can provide up to 90% of a coral’s energy requirements. In return, the coral provides the zooxanthellae with protection, shelter, and a constant supply of the carbon dioxide required for photosynthesis. Their population in the host tissue is limited by available nutrients and incident light, and by expulsion of excess cells. However, zooxanthellae do not appear to be digested by their hosts.
Hermatypic (reef-building) corals have zooxanthellae and are largely dependent on them, limiting their growth to the photic zone. The symbiotic relationship is probably responsible for the phenomenal success of corals as reef-building organisms in tropical waters. However, when corals are subjected to high environmental stress, they can lose their zooxanthellae by either expulsion or digestion and die. The process known as coral bleaching occurs when the zooxanthellae densities within the coral tissue become low or the concentration of photosynthetic pigments within each zooxanthella decline. Color loss is also attributed to the loss or lowering of concentrations of Green Fluorescent Proteins (GFP) from the cellular pigments of the cnidarian itself. The result is a ghostly white calcareous skeleton, absent of zooxanthellae, with the inevitable death of the coral unless conditions improve, allowing for the zooxanthellae to return.
Coral are under constant disturbance, which is ultimately felt by the zooxanthellae living within their tissues. Exposure to air during extremely low tides or damage from intensifying solar radiation in shallow water environments are some of the ecological stressors zooxanthellae face. Temperature changes have provided the most stress to the zooxanthellae-coral relationship. A rise in temperature of 1-2 degrees Celsius for 5-10 weeks or a decline in temperature of 3-5 degrees Celsius for 5-10 days has resulted in a coral bleaching event. Strong temperature changes shock the zooxanthellae and cause them to suffer cell adhesion dysfunction which sees the detachment of the cnidarian endodermal cells from the zooxanthellae.
Other organisms which may have zooxanthellae include jellyfish, clams, sea slugs, and radiolaria. There are several different species of zooxanthellae, typically grouped together as the genus Symbiodinium, which appears to be monophyletic.
The genus, Symbiodinium, was created by Hugo Freudenthal in 1959, after his identification of the life cycle of zooxanthella from Cassiopea. At that time he proved that they had a motile stage which resembled a "gymnodinioid" dinoflagellate. Being both symbiotic and a dinoflagellate, he named the Genus Symbiodinium, and the species "microadriaticium," after its resemblance to a similar free-living species. There is considerable disagreement as to whether there are a single or many species of Symbiodinium. DNA testing shows differences between the symbionts from different corals, but the issue is whether or not these are significant enough to represent different species. Dr. Freudenthal demonstrated that the zooxanthellae go through a vegetative stage, a cyst stage, and a motile stage as part of their life cycle. | Zooxanthella
Zooxanthellae (Template:IPAEng) are golden-brown intracellular endosymbionts of various marine animals and protozoa, especially anthozoans. They are members of the phylum Dinoflagellata and are typically dinoflagellate algae, although algae such as diatoms can also be zooxanthellae. They may be acquired by direct ingestion, and subsequently reproduce by splitting apart; a process known as budding. In other cases, zooxanthellae may be transmitted by the coral eggs and planulae. Most are autotrophs and provide the host with energy in the form of translocated reduced carbon compounds derived from photosynthesis. Zooxanthellae can provide up to 90% of a coral’s energy requirements.[1] In return, the coral provides the zooxanthellae with protection, shelter, and a constant supply of the carbon dioxide required for photosynthesis. Their population in the host tissue is limited by available nutrients and incident light, and by expulsion of excess cells. However, zooxanthellae do not appear to be digested by their hosts.
Hermatypic (reef-building) corals have zooxanthellae and are largely dependent on them, limiting their growth to the photic zone. The symbiotic relationship is probably responsible for the phenomenal success of corals as reef-building organisms in tropical waters. However, when corals are subjected to high environmental stress, they can lose their zooxanthellae by either expulsion or digestion and die. The process known as coral bleaching occurs when the zooxanthellae densities within the coral tissue become low or the concentration of photosynthetic pigments within each zooxanthella decline. Color loss is also attributed to the loss or lowering of concentrations of Green Fluorescent Proteins (GFP) from the cellular pigments of the cnidarian itself. The result is a ghostly white calcareous skeleton, absent of zooxanthellae, with the inevitable death of the coral unless conditions improve, allowing for the zooxanthellae to return.
Coral are under constant disturbance, which is ultimately felt by the zooxanthellae living within their tissues. Exposure to air during extremely low tides or damage from intensifying solar radiation in shallow water environments are some of the ecological stressors zooxanthellae face. Temperature changes have provided the most stress to the zooxanthellae-coral relationship. A rise in temperature of 1-2 degrees Celsius for 5-10 weeks or a decline in temperature of 3-5 degrees Celsius for 5-10 days has resulted in a coral bleaching event. Strong temperature changes shock the zooxanthellae and cause them to suffer cell adhesion dysfunction which sees the detachment of the cnidarian endodermal cells from the zooxanthellae.
Other organisms which may have zooxanthellae include jellyfish, clams, sea slugs, and radiolaria. There are several different species of zooxanthellae, typically grouped together as the genus Symbiodinium, which appears to be monophyletic.
The genus, Symbiodinium, was created by Hugo Freudenthal in 1959, after his identification of the life cycle of zooxanthella from Cassiopea. At that time he proved that they had a motile stage which resembled a "gymnodinioid" dinoflagellate. Being both symbiotic and a dinoflagellate, he named the Genus Symbiodinium, and the species "microadriaticium," after its resemblance to a similar free-living species. There is considerable disagreement as to whether there are a single or many species of Symbiodinium. DNA testing shows differences between the symbionts from different corals, but the issue is whether or not these are significant enough to represent different species. Dr. Freudenthal demonstrated that the zooxanthellae go through a vegetative stage, a cyst stage, and a motile stage as part of their life cycle. | https://www.wikidoc.org/index.php/Zooxanthella | |
cfaa188f0806849803376c9caae434ce9ab0d3c5 | wikidoc | Vagus nerve | Vagus nerve
# Overview
The vagus nerve (also called pneumogastric nerve or cranial nerve X) is the tenth of twelve paired cranial nerves, and is the only nerve that starts in the brainstem (within the medulla oblongata) and extends, through the jugular foramen, down below the head, to the neck, chest and abdomen.
The medieval Latin word vagus means literally "Wandering" (the words vagrant, vagabond, and vague come from the same root). It is also called the pneumogastric nerve since it innervates both the lungs and the stomach.
# Branches
- Auricular
- Pharyngeal
- Superior laryngeal
- Superior cervical cardiac branches of vagus nerve
- Inferior cervical cardiac branch
- Recurrent laryngeal
- Thoracic cardiac branches
- Branches to the pulmonary plexus
- Branches to the esophageal plexus
- Anterior vagal trunk
- Posterior vagal trunk
# Innervation
The vagus descends from the spinal cord in the carotid sheath, lateral to the carotid artery. It carries on past the aortic arch to dip inferiorly behind the left bronchus. Here it forms the pulmonary plexus, after giving rise to the recurrent laryngeal nerve.
The vagus nerve supplies motor parasympathetic fibers to all the organs except the suprarenal (adrenal) glands, from the neck down to the second segment of the transverse colon. The vagus also controls a few skeletal muscles, namely:
- Cricothyroid muscle
- Levator veli palatini muscle
- Salpingopharyngeus muscle
- Palatoglossus muscle
- Palatopharyngeus muscle
- Superior, middle and inferior pharyngeal constrictors
- Muscles of the larynx (speech).
This means that the vagus nerve is responsible for such varied tasks as heart rate, gastrointestinal peristalsis, sweating, and quite a few muscle movements in the mouth, including speech (via the recurrent laryngeal nerve) and keeping the larynx open for breathing. It also receives some sensation from the outer ear, via the Auricular branch (also known as Alderman's nerve) and part of the meninges.
# The vagus nerve and the heart
Parasympathetic innervation of the heart is mediated by the vagus nerve. The right vagus innervates the sinoatrial node. Parasympathetic hyperstimulation predisposes those affected to bradyarrhythmias. The left vagus when hyperstimulated predisposes the heart to atrioventricular (AV) blocks.
At this location Otto Loewi first proved that nerves secrete substances called neurotransmitters which have effects on receptors in target tissues. Loewi described the substance released by the vagus nerve as vagusstoff, which was later found to be acetylcholine.
The vagus nerve has three associated nuclei, the dorsal motor nucleus, the nucleus ambiguus and the solitary nucleus.
Drugs that inhibit the muscarinic cholinergic receptor (anticholinergics) such as atropine and scopolamine are called vagolytic because they inhibit the action of the vagus nerve on the heart, gastrointestinal tract and other organs. Anticholinergic drugs increase heart rate and are used to treat bradycardia (slow heart rate) and asystole, which is when the heart has no electrical activity. Anticholinergic drugs relax the detrusor muscle and cause constipation which again involves the vagus nerve.
Bulimics and anorexics have high vagal activity which is associated with the arrhythmias seen in these patients.
# Medical treatment involving the vagus nerve
Vagus nerve stimulation (VNS) therapy using a pacemaker-like device implanted in the chest is a treatment used since 1997 to control seizures in epilepsy patients and has recently been approved for treating drug-resistant cases of clinical depression. A convenient, non-invasive VNS device that stimulates an afferent branch of the vagus nerve is also being developed and will soon undergo trials.
A degree of intermittent VNS can be achieved by daily breathing exercises (for example, Pranayama) over a period of several weeks. In some patients, such proactive relaxation exercises have been found to correlate with lower blood pressure and lower heart rate and more stable moods. The Valsalva maneuver may activate the vagus nerve and is a "natural" way to achieve the same effect in some patients. Patients with atrial fibrillation, supraventricular tachycardia and other illnesses may be trained to perform the valsalva maneuver (or find it for themselves).
Vagotomy (cutting of the vagus nerve) is a now-obsolete therapy that was performed for peptic ulcer disease. Vagotomy is currently being researched as a less invasive alternative weight loss procedure to gastric bypass surgery. The procedure curbs the feeling of hunger and is sometimes performed in conjunction with putting bands on patients's stomachs, resulting in average weight loss of 43% at six months with diet and exercise. Five pencil-sized scars are the result of the procedure.
See also:
- Porphyria This rare disorder can cause seizures and damage to the vagal nerve. Diagnosis, in some cases, may require DNA testing.
# Physical and emotional effects
Activation of the vagus nerve typically leads to a reduction in heart rate, blood pressure, or both. This occurs commonly in the setting of gastrointestinal illness such as viral gastroenteritis or acute cholecystitis, or in response to other stimuli, including carotid sinus massage, Valsalva maneuver, or pain from any cause, particularly having blood drawn. When the circulatory changes are great enough, vasovagal syncope results. Relative dehydration tends to amplify these responses.
Excessive activation of the vagal nerve during emotional stress, which is a parasympathetic overcompensation of a strong sympathetic nervous system response associated with stress, can also cause vasovagal syncope because of a sudden drop in blood pressure and heart rate. Vasovagal syncope affects young children and women more often. It can also lead to temporary loss of bladder control under moments of extreme fear.
Research has shown that women who have complete transection of the spinal cord can experience orgasms through the vagus nerve, which can go from the uterus, cervix and probably the vagina to the brain.
# Effects of vagus nerve lesions
The patient complains of hoarse voice, difficulty in swallowing (dysphagia), pain during swallowing(odynophagia) and choking when drinking fluid. There is also loss of gag reflex. Uvula deviates away from the side of lesion and there is failure of palate elevation.
# Additional images
- Section of the neck at about the level of the sixth cervical vertebra.
- Transverse section of thorax, showing relations of pulmonary artery.
- The arch of the aorta, and its branches.
- Dura mater and its processes exposed by removing part of the right half of the skull, and the brain.
- The tracheobronchial lymph glands.
- Section of the medulla oblongata at about the middle of the olive.
- Hind- and mid-brains; postero-lateral view.
- Upper part of medulla spinalis and hind- and mid-brains; posterior aspect, exposed in situ.
- The right sympathetic chain and its connections with the thoracic, abdominal, and pelvic plexuses.
- The celiac ganglia with the sympathetic plexuses of the abdominal viscera radiating from the ganglia.
- The position and relation of the esophagus in the cervical region and in the posterior mediastinum. Seen from behind.
- The thyroid gland and its relations.
- The thymus of a full-term fetus, exposed in situ. | Vagus nerve
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Template:Infobox Nerve
# Overview
The vagus nerve (also called pneumogastric nerve or cranial nerve X) is the tenth of twelve paired cranial nerves, and is the only nerve that starts in the brainstem (within the medulla oblongata) and extends, through the jugular foramen, down below the head, to the neck, chest and abdomen.
The medieval Latin word vagus means literally "Wandering" (the words vagrant, vagabond, and vague come from the same root). It is also called the pneumogastric nerve since it innervates both the lungs and the stomach.
# Branches
- Auricular
- Pharyngeal
- Superior laryngeal
- Superior cervical cardiac branches of vagus nerve
- Inferior cervical cardiac branch
- Recurrent laryngeal
- Thoracic cardiac branches
- Branches to the pulmonary plexus
- Branches to the esophageal plexus
- Anterior vagal trunk
- Posterior vagal trunk
# Innervation
The vagus descends from the spinal cord in the carotid sheath, lateral to the carotid artery. It carries on past the aortic arch to dip inferiorly behind the left bronchus. Here it forms the pulmonary plexus, after giving rise to the recurrent laryngeal nerve.
The vagus nerve supplies motor parasympathetic fibers to all the organs except the suprarenal (adrenal) glands, from the neck down to the second segment of the transverse colon. The vagus also controls a few skeletal muscles, namely:
- Cricothyroid muscle
- Levator veli palatini muscle
- Salpingopharyngeus muscle
- Palatoglossus muscle
- Palatopharyngeus muscle
- Superior, middle and inferior pharyngeal constrictors
- Muscles of the larynx (speech).
This means that the vagus nerve is responsible for such varied tasks as heart rate, gastrointestinal peristalsis, sweating, and quite a few muscle movements in the mouth, including speech (via the recurrent laryngeal nerve) and keeping the larynx open for breathing. It also receives some sensation from the outer ear, via the Auricular branch (also known as Alderman's nerve) and part of the meninges.
# The vagus nerve and the heart
Parasympathetic innervation of the heart is mediated by the vagus nerve. The right vagus innervates the sinoatrial node. Parasympathetic hyperstimulation predisposes those affected to bradyarrhythmias. The left vagus when hyperstimulated predisposes the heart to atrioventricular (AV) blocks.
At this location Otto Loewi first proved that nerves secrete substances called neurotransmitters which have effects on receptors in target tissues. Loewi described the substance released by the vagus nerve as vagusstoff, which was later found to be acetylcholine.
The vagus nerve has three associated nuclei, the dorsal motor nucleus, the nucleus ambiguus and the solitary nucleus.
Drugs that inhibit the muscarinic cholinergic receptor (anticholinergics) such as atropine and scopolamine are called vagolytic because they inhibit the action of the vagus nerve on the heart, gastrointestinal tract and other organs. Anticholinergic drugs increase heart rate and are used to treat bradycardia (slow heart rate) and asystole, which is when the heart has no electrical activity. Anticholinergic drugs relax the detrusor muscle and cause constipation which again involves the vagus nerve.
Bulimics and anorexics have high vagal activity which is associated with the arrhythmias seen in these patients.[citation needed]
# Medical treatment involving the vagus nerve
Vagus nerve stimulation (VNS) therapy using a pacemaker-like device implanted in the chest is a treatment used since 1997 to control seizures in epilepsy patients and has recently been approved for treating drug-resistant cases of clinical depression.[1] A convenient, non-invasive VNS device that stimulates an afferent branch of the vagus nerve is also being developed and will soon undergo trials.
A degree of intermittent VNS can be achieved by daily breathing exercises (for example, Pranayama) over a period of several weeks. In some patients, such proactive relaxation exercises have been found to correlate with lower blood pressure and lower heart rate and more stable moods.[citation needed] The Valsalva maneuver may activate the vagus nerve and is a "natural" way to achieve the same effect in some patients. Patients with atrial fibrillation, supraventricular tachycardia and other illnesses may be trained to perform the valsalva maneuver (or find it for themselves).
Vagotomy (cutting of the vagus nerve) is a now-obsolete therapy that was performed for peptic ulcer disease. Vagotomy is currently being researched as a less invasive alternative weight loss procedure to gastric bypass surgery[2]. The procedure curbs the feeling of hunger and is sometimes performed in conjunction with putting bands on patients's stomachs, resulting in average weight loss of 43% at six months with diet and exercise[3]. Five pencil-sized scars are the result of the procedure.
See also:
- Porphyria This rare disorder can cause seizures and damage to the vagal nerve. Diagnosis, in some cases, may require DNA testing.
# Physical and emotional effects
Activation of the vagus nerve typically leads to a reduction in heart rate, blood pressure, or both. This occurs commonly in the setting of gastrointestinal illness such as viral gastroenteritis or acute cholecystitis, or in response to other stimuli, including carotid sinus massage, Valsalva maneuver, or pain from any cause, particularly having blood drawn. When the circulatory changes are great enough, vasovagal syncope results. Relative dehydration tends to amplify these responses.
Excessive activation of the vagal nerve during emotional stress, which is a parasympathetic overcompensation of a strong sympathetic nervous system response associated with stress, can also cause vasovagal syncope because of a sudden drop in blood pressure and heart rate. Vasovagal syncope affects young children and women more often. It can also lead to temporary loss of bladder control under moments of extreme fear.
Research has shown that women who have complete transection of the spinal cord can experience orgasms through the vagus nerve, which can go from the uterus, cervix and probably the vagina to the brain.[2][4]
# Effects of vagus nerve lesions
The patient complains of hoarse voice, difficulty in swallowing (dysphagia), pain during swallowing(odynophagia) and choking when drinking fluid. There is also loss of gag reflex. Uvula deviates away from the side of lesion and there is failure of palate elevation.
# Additional images
- Section of the neck at about the level of the sixth cervical vertebra.
- Transverse section of thorax, showing relations of pulmonary artery.
- The arch of the aorta, and its branches.
- Dura mater and its processes exposed by removing part of the right half of the skull, and the brain.
- The tracheobronchial lymph glands.
- Section of the medulla oblongata at about the middle of the olive.
- Hind- and mid-brains; postero-lateral view.
- Upper part of medulla spinalis and hind- and mid-brains; posterior aspect, exposed in situ.
- The right sympathetic chain and its connections with the thoracic, abdominal, and pelvic plexuses.
- The celiac ganglia with the sympathetic plexuses of the abdominal viscera radiating from the ganglia.
- The position and relation of the esophagus in the cervical region and in the posterior mediastinum. Seen from behind.
- The thyroid gland and its relations.
- The thymus of a full-term fetus, exposed in situ. | https://www.wikidoc.org/index.php/10th_cranial_nerve_disorder | |
543e996663d3d980c62b6c4a4360ff048de5fdda | wikidoc | Pralidoxime | Pralidoxime
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# Overview
Pralidoxime is a cholinesterase reactivator that is FDA approved for the treatment of of poisoning by nerve agents having anticholinesterase activity. Common adverse reactions include Increased creatine kinase level.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Mild cases: headache, blurred vision, mild muscarinic signs
- Moderately Severe Cases: excessive sweating, lacrimation, salivation, diarrhea, tightness in the chest
- Very severe cases: Cyanosis, Respiratory Embarrassment, Coma
- For optimal reactivation of organophosphate-inhibited cholinesterase, atropine and pralidoxime should be administered as soon as possible after exposure. Depending on the severity of symptoms, immediately administer one atropine-containing auto-injector, followed by one pralidoxime-containing auto-injector. Atropine must be given first until its effects become apparent and only then should pralidoxime be administered. If nerve agent symptoms are still present after 15 minutes, repeat injections. If symptoms still exist after an additional 15 minutes, repeat injections for a third time. If after the third set of injections, symptoms remain, do not give any more antidotes but seek medical help.
Directions for Use
When, as described above, auto-injector use is indicated, proceed as follows:
- 1.- Remove gray safety cap.
- 2.- Place black end against outer thigh and push hard until the injector functions.
- 3.- Hold firmly in place for ten seconds, then remove. Massage the area of injection.
- 4.- Dispose of properly. Push ejected needle through a pocket flap (or other thick and conspicuous part of outer clothing). Bend needle into a hook.
- Initial measures should include removal of secretions, maintenance of a patent airway and, if necessary, artificial ventilation. Atropine should not be used until cyanosis has been overcome since atropine produces ventricular fibrillations in the presence of hypoxia. Morphine, theophylline, aminophylline, or succincylcholine are contraindicated. Tranquilizers of the reserpine or phenothiazine type are to be avoided.
Pralidoxime is most effective if administered immediately after poisoning. Generally, little is accomplished if the drug is given more than 36 hours after termination of exposure. When the poison has been ingested, however, exposure may continue for some time due to slow absorption from the lower bowel, and fatal relapses have been reported after initial improvement. Continued administration for several days may be useful in such patients. Close supervision of the patient is indicated for at least 48 to 72 hours. If dermal exposure has occurred, clothing should be removed and the hair and skin washed thoroughly with sodium bicarbonate or alcohol as soon as possible. Diazepam may be given cautiously if convulsions are not controlled by atropine.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pralidoxime in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Pralidoxime in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Pralidoxime 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 Pralidoxime in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Pralidoxime in pediatric patients.
# Contraindications
The pralidoxime chloride auto-injector is contraindicated in patients who are hypersensitive to any component of the product.
# Warnings
- Pralidoxime is not effective in the treatment of poisoning due to phosphorus, inorganic phosphates or organophosphates not having anticholinesterase activity.
# Adverse Reactions
## Clinical Trials Experience
- Forty to 60 minutes after intramuscular injection, mild to moderate pain may be experienced at the site of injection. Pralidoxime may cause blurred vision, diplopia and impaired accommodation, dizziness, headache, drowsiness, nausea, tachycardia, increased systolic and diastolic blood pressure, hyperventilation, and muscular weakness when given parenterally to normal volunteers who have not been exposed to anticholinesterase poisons. In patients it is very difficult to differentiate the toxic effects produced by atropine or the organophosphate compounds from those of the drug.
- Elevations in SGOT and/or SGPT enzyme levels were observed in 1 of 6 normal volunteers given 1200 mg of pralidoxime chloride intramuscularly, and in 4 of 6 volunteers given 1800 mg intramuscularly. Levels returned to normal in about 2 weeks. Transient elevations in creatine phosphokinase were observed in all normal volunteers given the drug. A single intramuscular injection of 330 mg in 1 mL in rabbits caused myonecrosis, inflammation and hemorrhage.
- When atropine and pralidoxime are used together, the signs of atropinization may occur earlier than might be expected when atropine is used alone. This is especially true if the total dose of atropine has been large and the administration of pralidoxime has been delayed.2, 3, 4 Excitement and manic behavior immediately following recovery of consciousness have been reported in several cases. However, similar behavior has occurred in cases of organophosphate poisoning that were not treated with pralidoxime
## Postmarketing Experience
There is limited information regarding Pralidoxime Postmarketing Experience in the drug label.
# Drug Interactions
- When atropine and pralidoxime are used together, the signs of atropinization (flushing, mydriasis, tachycardia, dryness of the mouth and nose) may occur earlier than might be expected when atropine is used alone. This is especially true if the total dose of atropine has been large and the administration of pralidoxime has been delayed.
- The following precautions should be kept in mind in the treatment of anticholesterinase poisoning, although they do not bear directly on the use of pralidoxime; since barbiturates are potentiated by the anticholinesterases, they should be used cautiously in the treatment of convulsions; morphine, theophylline, aminophylline, succinylcholine, reser-pine, and phenothiazine-type tranquilizers should be avoided in patients with organophosphate poisoning.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Animal reproduction studies have not been conducted with pralidoxime. It is also not known whether pralidoxime can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Pralidoxime should be given to a pregnant woman only if clearly needed.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Pralidoxime in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Pralidoxime during labor and delivery.
### Nursing Mothers
- 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 pralidoxime is administered to a nursing woman.
### Pediatric Use
- Safety and effectiveness in children have not been established.
### Geriatic Use
There is no FDA guidance on the use of Pralidoxime in geriatric settings.
### Gender
There is no FDA guidance on the use of Pralidoxime with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Pralidoxime with respect to specific racial populations.
### Renal Impairment
- Because pralidoxime is excreted in the urine, a decrease in renal function will result in increased blood levels of the drug. Thus, the dosage of pralidoxime should be reduced in the presence of renal insufficiency.
### Hepatic Impairment
There is no FDA guidance on the use of Pralidoxime in patients with hepatic impairment.
### Females of Reproductive Potential and Males
- Since the pralidoxime chloride auto-injector is indicated for short-term emergency use only, no investigations of its potential for carcinogenesis, mutagenesis, or impairment of fertility have been conducted by the manufacturer, or reported in the literature.
### Immunocompromised Patients
There is no FDA guidance one the use of Pralidoxime in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Pralidoxime Administration in the drug label.
### Monitoring
There is limited information regarding Pralidoxime Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Pralidoxime and IV administrations.
# Overdosage
- Observed in normal subjects only: dizziness, blurred vision, diplopia, headache, impaired accommodation, nausea, slight tachycardia. In therapy it has been difficult to differentiate side effects due to the drug from those due to the effects of the poison.
- Artificial respiration and other supportive therapy should be administered as needed.
- i.v.—man TDLo: 14 mg/kg (toxic effects: CNS)
- i.v.— rat LD50: 96 mg/kg
- i.m.—rat LD50: 150 mg/kg
- oral—mouse LD50: 4100 mg/kg
- i.p.—mouse LD50: 155 mg/kg
- i.v.—mouse LD50: 90 mg/kg
- i.m.—mouse LD50: 180 mg/kg
- i.v.—rabbit LD50: 95 mg/kg
- i.m.—guinea pig LD50: 168 mg/kg
# Pharmacology
## Mechanism of Action
- The principal action of pralidoxime is to reactivate cholinesterase (mainly outside of the central nervous system) which has been inactivated by phosphorylation due to an organophosphate pesticide or related compound. The destruction of accumulated acetylcholine can then proceed and neuromuscular junctions will again function normally. Pralidoxime also slows the process of "aging" of phosphorylated cholinesterase to a non-reactivatable form, and detoxifies certain organophosphates by direct chemical reaction. The drug has its most critical effect in relieving paralysis of the muscles of respiration.
## Structure
- Chemical Name: 2-formyl-1 methylpyridinium chloride oxime (pyridine-2-aldoxime methochloride). Also referred to as 2-PAM Chloride.
- Structural Formula:
## Pharmacodynamics
- Because pralidoxime is less effective in relieving depression of the respiratory center, atropine is always required concomitantly to block the effect of accumulated acetylcholine at this site. Pralidoxime relieves muscarinic signs and symptoms, salivation, bronchospasm, etc., but this action is relatively unimportant since atropine is adequate for this purpose.
## Pharmacokinetics
- Pralidoxime is distributed throughout the extracellular water, it is not bound to plasma protein. The drug is rapidly excreted in the urine partly unchanged, and partly as a metabolite produced by the liver. Consequently, pralidoxime is relatively short acting and repeated doses may be needed, especially where there is any evidence of continuing absorption of the poison.
The minimum therapeutic concentration of pralidoxime in plasma is 4 μg/mL, this level is reached in about 16 minutes after a single injection of 600 mg pralidoxime chloride. The apparent half-life of pralidoxime chloride is 74-77 minutes.
It has been reported that the supplemental use of oxime cholinesterase reactivators (such as pralidoxime) reduces the incidence and severity of developmental defects in chick embryos exposed to such known teratogens as parathion, bidrin, carbachol and neostigmine. This protective effect of the oximes was shown to be dose related.
## Nonclinical Toxicology
There is limited information regarding Pralidoxime Nonclinical Toxicology in the drug label.
# Clinical Studies
There is limited information regarding Pralidoxime Clinical Studies in the drug label.
# How Supplied
- Pralidoxime chloride is supplied in aqueous solution prefilled in the auto-injector (600 mg, 2 mL) for military use and for use by qualified civilian emergency responders. Auto-injectors are supplied through the Directorate of Medical Materiel, Defense Supply Center Philadelphia or other analogous local, state or federal agency.
- When activated, each auto-injector dispenses 600 mg of pralidoxime chloride in 2 mL of a sterile solution containing 20 mg/mL benzyl alcohol, 11.26 mg/mL glycine in Water for Injection, USP. The pH is adjusted with hydrochloric acid. *The pH is 2.0-3.0
- The product is pyrogen free.
## Storage
- Store at 25°C (77°F); Excursions permitted to 15-30°C (59-86°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Pralidoxime Patient Counseling Information in the drug label.
# Precautions with Alcohol
- Alcohol-Pralidoxime interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Protopam Chloride
# Look-Alike Drug Names
There is limited information regarding Pralidoxime Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Pralidoxime
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alberto Plate [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
Pralidoxime is a cholinesterase reactivator that is FDA approved for the treatment of of poisoning by nerve agents having anticholinesterase activity. Common adverse reactions include Increased creatine kinase level.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Mild cases: headache, blurred vision, mild muscarinic signs
- Moderately Severe Cases: excessive sweating, lacrimation, salivation, diarrhea, tightness in the chest
- Very severe cases: Cyanosis, Respiratory Embarrassment, Coma
- For optimal reactivation of organophosphate-inhibited cholinesterase, atropine and pralidoxime should be administered as soon as possible after exposure. Depending on the severity of symptoms, immediately administer one atropine-containing auto-injector, followed by one pralidoxime-containing auto-injector. Atropine must be given first until its effects become apparent and only then should pralidoxime be administered. If nerve agent symptoms are still present after 15 minutes, repeat injections. If symptoms still exist after an additional 15 minutes, repeat injections for a third time. If after the third set of injections, symptoms remain, do not give any more antidotes but seek medical help.
Directions for Use
When, as described above, auto-injector use is indicated, proceed as follows:
- 1.- Remove gray safety cap.
- 2.- Place black end against outer thigh and push hard until the injector functions.
- 3.- Hold firmly in place for ten seconds, then remove. Massage the area of injection.
- 4.- Dispose of properly. Push ejected needle through a pocket flap (or other thick and conspicuous part of outer clothing). Bend needle into a hook.
- Initial measures should include removal of secretions, maintenance of a patent airway and, if necessary, artificial ventilation. Atropine should not be used until cyanosis has been overcome since atropine produces ventricular fibrillations in the presence of hypoxia. Morphine, theophylline, aminophylline, or succincylcholine are contraindicated. Tranquilizers of the reserpine or phenothiazine type are to be avoided.
Pralidoxime is most effective if administered immediately after poisoning. Generally, little is accomplished if the drug is given more than 36 hours after termination of exposure. When the poison has been ingested, however, exposure may continue for some time due to slow absorption from the lower bowel, and fatal relapses have been reported after initial improvement. Continued administration for several days may be useful in such patients. Close supervision of the patient is indicated for at least 48 to 72 hours. If dermal exposure has occurred, clothing should be removed and the hair and skin washed thoroughly with sodium bicarbonate or alcohol as soon as possible. Diazepam may be given cautiously if convulsions are not controlled by atropine.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pralidoxime in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Pralidoxime in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Pralidoxime 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 Pralidoxime in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Pralidoxime in pediatric patients.
# Contraindications
The pralidoxime chloride auto-injector is contraindicated in patients who are hypersensitive to any component of the product.
# Warnings
- Pralidoxime is not effective in the treatment of poisoning due to phosphorus, inorganic phosphates or organophosphates not having anticholinesterase activity.
# Adverse Reactions
## Clinical Trials Experience
- Forty to 60 minutes after intramuscular injection, mild to moderate pain may be experienced at the site of injection. Pralidoxime may cause blurred vision, diplopia and impaired accommodation, dizziness, headache, drowsiness, nausea, tachycardia, increased systolic and diastolic blood pressure, hyperventilation, and muscular weakness when given parenterally to normal volunteers who have not been exposed to anticholinesterase poisons. In patients it is very difficult to differentiate the toxic effects produced by atropine or the organophosphate compounds from those of the drug.
- Elevations in SGOT and/or SGPT enzyme levels were observed in 1 of 6 normal volunteers given 1200 mg of pralidoxime chloride intramuscularly, and in 4 of 6 volunteers given 1800 mg intramuscularly. Levels returned to normal in about 2 weeks. Transient elevations in creatine phosphokinase were observed in all normal volunteers given the drug. A single intramuscular injection of 330 mg in 1 mL in rabbits caused myonecrosis, inflammation and hemorrhage.
- When atropine and pralidoxime are used together, the signs of atropinization may occur earlier than might be expected when atropine is used alone. This is especially true if the total dose of atropine has been large and the administration of pralidoxime has been delayed.2, 3, 4 Excitement and manic behavior immediately following recovery of consciousness have been reported in several cases. However, similar behavior has occurred in cases of organophosphate poisoning that were not treated with pralidoxime
## Postmarketing Experience
There is limited information regarding Pralidoxime Postmarketing Experience in the drug label.
# Drug Interactions
- When atropine and pralidoxime are used together, the signs of atropinization (flushing, mydriasis, tachycardia, dryness of the mouth and nose) may occur earlier than might be expected when atropine is used alone. This is especially true if the total dose of atropine has been large and the administration of pralidoxime has been delayed.
- The following precautions should be kept in mind in the treatment of anticholesterinase poisoning, although they do not bear directly on the use of pralidoxime; since barbiturates are potentiated by the anticholinesterases, they should be used cautiously in the treatment of convulsions; morphine, theophylline, aminophylline, succinylcholine, reser-pine, and phenothiazine-type tranquilizers should be avoided in patients with organophosphate poisoning.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Animal reproduction studies have not been conducted with pralidoxime. It is also not known whether pralidoxime can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Pralidoxime should be given to a pregnant woman only if clearly needed.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Pralidoxime in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Pralidoxime during labor and delivery.
### Nursing Mothers
- 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 pralidoxime is administered to a nursing woman.
### Pediatric Use
- Safety and effectiveness in children have not been established.
### Geriatic Use
There is no FDA guidance on the use of Pralidoxime in geriatric settings.
### Gender
There is no FDA guidance on the use of Pralidoxime with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Pralidoxime with respect to specific racial populations.
### Renal Impairment
- Because pralidoxime is excreted in the urine, a decrease in renal function will result in increased blood levels of the drug. Thus, the dosage of pralidoxime should be reduced in the presence of renal insufficiency.
### Hepatic Impairment
There is no FDA guidance on the use of Pralidoxime in patients with hepatic impairment.
### Females of Reproductive Potential and Males
- Since the pralidoxime chloride auto-injector is indicated for short-term emergency use only, no investigations of its potential for carcinogenesis, mutagenesis, or impairment of fertility have been conducted by the manufacturer, or reported in the literature.
### Immunocompromised Patients
There is no FDA guidance one the use of Pralidoxime in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Pralidoxime Administration in the drug label.
### Monitoring
There is limited information regarding Pralidoxime Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Pralidoxime and IV administrations.
# Overdosage
- Observed in normal subjects only: dizziness, blurred vision, diplopia, headache, impaired accommodation, nausea, slight tachycardia. In therapy it has been difficult to differentiate side effects due to the drug from those due to the effects of the poison.
- Artificial respiration and other supportive therapy should be administered as needed.
- i.v.—man TDLo: 14 mg/kg (toxic effects: CNS)
- i.v.— rat LD50: 96 mg/kg
- i.m.—rat LD50: 150 mg/kg
- oral—mouse LD50: 4100 mg/kg
- i.p.—mouse LD50: 155 mg/kg
- i.v.—mouse LD50: 90 mg/kg
- i.m.—mouse LD50: 180 mg/kg
- i.v.—rabbit LD50: 95 mg/kg
- i.m.—guinea pig LD50: 168 mg/kg
# Pharmacology
## Mechanism of Action
- The principal action of pralidoxime is to reactivate cholinesterase (mainly outside of the central nervous system) which has been inactivated by phosphorylation due to an organophosphate pesticide or related compound. The destruction of accumulated acetylcholine can then proceed and neuromuscular junctions will again function normally. Pralidoxime also slows the process of "aging" of phosphorylated cholinesterase to a non-reactivatable form, and detoxifies certain organophosphates by direct chemical reaction. The drug has its most critical effect in relieving paralysis of the muscles of respiration.
## Structure
- Chemical Name: 2-formyl-1 methylpyridinium chloride oxime (pyridine-2-aldoxime methochloride). Also referred to as 2-PAM Chloride.
- Structural Formula:
## Pharmacodynamics
- Because pralidoxime is less effective in relieving depression of the respiratory center, atropine is always required concomitantly to block the effect of accumulated acetylcholine at this site. Pralidoxime relieves muscarinic signs and symptoms, salivation, bronchospasm, etc., but this action is relatively unimportant since atropine is adequate for this purpose.
## Pharmacokinetics
- Pralidoxime is distributed throughout the extracellular water, it is not bound to plasma protein. The drug is rapidly excreted in the urine partly unchanged, and partly as a metabolite produced by the liver. Consequently, pralidoxime is relatively short acting and repeated doses may be needed, especially where there is any evidence of continuing absorption of the poison.
The minimum therapeutic concentration of pralidoxime in plasma is 4 μg/mL, this level is reached in about 16 minutes after a single injection of 600 mg pralidoxime chloride. The apparent half-life of pralidoxime chloride is 74-77 minutes.
It has been reported that the supplemental use of oxime cholinesterase reactivators (such as pralidoxime) reduces the incidence and severity of developmental defects in chick embryos exposed to such known teratogens as parathion, bidrin, carbachol and neostigmine. This protective effect of the oximes was shown to be dose related.
## Nonclinical Toxicology
There is limited information regarding Pralidoxime Nonclinical Toxicology in the drug label.
# Clinical Studies
There is limited information regarding Pralidoxime Clinical Studies in the drug label.
# How Supplied
- Pralidoxime chloride is supplied in aqueous solution prefilled in the auto-injector (600 mg, 2 mL) for military use and for use by qualified civilian emergency responders. Auto-injectors are supplied through the Directorate of Medical Materiel, Defense Supply Center Philadelphia or other analogous local, state or federal agency.
- When activated, each auto-injector dispenses 600 mg of pralidoxime chloride in 2 mL of a sterile solution containing 20 mg/mL benzyl alcohol, 11.26 mg/mL glycine in Water for Injection, USP. The pH is adjusted with hydrochloric acid. *The pH is 2.0-3.0
- The product is pyrogen free.
## Storage
- Store at 25°C (77°F); Excursions permitted to 15-30°C (59-86°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Pralidoxime Patient Counseling Information in the drug label.
# Precautions with Alcohol
- Alcohol-Pralidoxime interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Protopam Chloride
# Look-Alike Drug Names
There is limited information regarding Pralidoxime Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/2-PAM | |
d949d04cd9c2bb5c34a40607efb7835fb1601a75 | wikidoc | Azacytidine | Azacytidine
# 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
Azacytidine is an antineoplastic agent that is FDA approved for the treatment of patients with the following French-American-British (FAB) myelodysplastic syndrome subtypes such as refractory anemia (RA) or refractory anemia with ringed sideroblasts (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts (RAEB), refractory anemia with excess blasts in transformation (RAEB-T), and chronic myelomonocytic leukemia. Common adverse reactions include anemia, neutropenia, thrombocytopenia, hepatic coma and elevated serum creatinine, renal failure, and renal tubular acidosis.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Azacitidine® is indicated for treatment of patients with the following French-American-British (FAB) myelodysplastic syndrome subtypes: refractory anemia (RA) or refractory anemia with ringed sideroblasts (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts (RAEB),refractory anemia with excess blasts in transformation (RAEB-T), and chronic myelomonocytic leukemia
- The recommended starting dose for the first treatment cycle, for all patients regardless of baseline hematology laboratory values, is 75 mg/m2 subcutaneously or intravenously, daily for 7 days. Patients should be premedicated for nausea and vomiting.
- Complete blood counts, liver chemistries and serum creatinine should be obtained prior to first dose.
- Cycles should be repeated every 4 weeks. The dose may be increased to 100 mg/m2 if no beneficial effect is seen after 2 treatment cycles and if no toxicity other than nausea and vomiting has occurred. It is recommended that patients be treated for a minimum of 4 to 6 cycles. However, complete or partial response may require additional treatment cycles. *Treatment may be continued as long as the patient continues to benefit.
- Patients should be monitored for hematologic response and renal toxicities, and dosage delay or reduction as described below may be necessary.
- For patients with baseline (start of treatment) WBC ≥3.0 x109/L, ANC ≥1.5 x109/L, and platelets ≥75.0 x109/L, adjust the dose as follows, based on nadir counts for any given cycle:
- For patients whose baseline counts are WBC <3.0 x109/L, ANC<1.5 x109/L, or platelets <75.0 x109/L, dose adjustments should be based on nadir counts and bone marrow biopsy cellularity at the time of the nadir as noted below, unless there is clear improvement in differentiation (percentage of mature granulocytes is higher and ANC is higher than at onset of that course) at the time of the next cycle, in which case the dose of the current treatment should be continued.
- If a nadir as defined in the table above has occurred, the next course of treatment should be given 28 days after the start of the preceding course, provided that both the WBC and the platelet counts are >25% above the nadir and rising. If a >25% increase above the nadir is not seen by day 28, counts should be reassessed every 7 days. If a 25% increase is not seen by day 42, then the patient should be treated with 50% of the scheduled dose.
- If unexplained reductions in serum bicarbonate levels to <20 mEq/L occur, the dosage should be reduced by 50% on the next course. Similarly, if unexplained elevations of BUN or serum creatinine occur, the next cycle should be delayed until values return to normal or baseline and the dose should be reduced by 50% on the next treatment course.
- Azacitidine and its metabolites are known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
- Azacitidine is a cytotoxic drug and, as with other potentially toxic compounds, caution should be exercised when handling and preparing Azacitidine suspensions.
- If reconstituted Azacitidine comes into contact with the skin, immediately and thoroughly wash with soap and water. If it comes into contact with mucous membranes, flush thoroughly with water.
- The Azacitidine vial is single-use and does not contain any preservatives. Unused portions of each vial should be discarded properly . Do not save any unused portions for later administration.
- Azacitidine should be reconstituted aseptically with 4 mL sterile water for injection. The diluent should be injected slowly into the vial. Vigorously shake or roll the vial until a uniform suspension is achieved. The suspension will be cloudy. The resulting suspension will contain azacitidine 25 mg/mL. Do not filter the suspension after reconstitution. Doing so could remove the active substance.
- Preparation for Immediate Subcutaneous Administration: Doses greater than 4 mL should be divided equally into 2 syringes. The product may be held at room temperature for up to 1 hour, but must be administered within 1 hour after reconstitution.
- Preparation for Delayed Subcutaneous Administration: The reconstituted product may be kept in the vial or drawn into a syringe. Doses greater than 4 mL should be divided equally into 2 syringes. The product must be refrigerated immediately. When Azacitidine is reconstituted using water for injection that has not been refrigerated, the reconstituted product may be held under refrigerated conditions (2ºC - 8ºC, 36ºF - 46ºF) for up to 8 hours. When Azacitidine is reconstituted using refrigerated (2ºC - 8ºC, 36ºF - 46ºF) water for injection, the reconstituted product may be stored under refrigerated conditions (2ºC - 8ºC, 36ºF - 46ºF) for up to 22 hours. After removal from refrigerated conditions, the suspension may be allowed to equilibrate to room temperature for up to 30 minutes prior to administration.
- To provide a homogeneous suspension, the contents of the dosing syringe must be re-suspended immediately prior to administration. To re-suspend, vigorously roll the syringe between the palms until a uniform, cloudy suspension is achieved.
- Azacitidine suspension is administered subcutaneously. Doses greater than 4 mL should be divided equally into 2 syringes and injected into 2 separate sites. Rotate sites for each injection (thigh, abdomen, or upper arm). New injections should be given at least one inch from an old site and never into areas where the site is tender, bruised, red, or hard.
- Suspension Stability: Azacitidine reconstituted with non-refrigerated water for injection for subcutaneous administration may be stored for up to 1 hour at 25°C (77°F) or for up to 8 hours between 2°C and 8°C (36°F and 46°F); when reconstituted with refrigerated (2ºC - 8ºC, 36ºF - 46ºF) water for injection, it may be stored for 22 hours between 2°C and 8°C (36°F and 46°F).
- Reconstitute the appropriate number of Azacitidine vials to achieve the desired dose. Reconstitute each vial with 10 mL sterile water for injection. Vigorously shake or roll the vial until all solids are dissolved. The resulting solution will contain azacitidine 10 mg/mL. The solution should be clear. Parenteral drug product should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
- Withdraw the required amount of Azacitidine solution to deliver the desired dose and inject into a 50 -100 mL infusion bag of either 0.9% Sodium Chloride Injection or Lactated Ringer's Injection.
- Azacitidine is incompatible with 5% Dextrose solutions, Hespan, or solutions that contain bicarbonate. These solutions have the potential to increase the rate of degradation of Azacitidine and should therefore be avoided.
- Azacitidine solution is administered intravenously. Administer the total dose over a period of 10 - 40 minutes. The administration must be completed within 1 hour of reconstitution of the Azacitidine vial.
- Solution Stability: Azacitidine reconstituted for intravenous administration may be stored at 25°C (77°F), but administration must be completed within 1 hour of reconstitution.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of 5-Azacytidine in adult patients.
### Non–Guideline-Supported Use
- Ara-C 100 mg/m(2)/day IV continuously for 7 days and daunorubicin 45 mg/m(2) IV on days 1 to 3.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Safety and effectiveness in pediatric patients have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
Safety and effectiveness in pediatric patients have not been established.
### Non–Guideline-Supported Use
Safety and effectiveness in pediatric patients have not been established.
# Contraindications
- Azacitidine is contraindicated in patients with advanced malignant hepatic tumors.
- Azacitidine is contraindicated in patients with a known hypersensitivity to azacitidine or mannitol.
# Warnings
- Azacitidine causes anemia, neutropenia and thrombocytopenia. Monitor complete blood counts frequently for response and/or toxicity, at a minimum, prior to each dosing cycle. After administration of the recommended dosage for the first cycle, adjust dosage for subsequent cycles based on nadir counts and hematologic response .
# Adverse Reactions
## Clinical Trials Experience
The following adverse reactions are described in other labeling sections:
- Anemia, neutropenia and thrombocytopenia
- Hepatic coma
- Elevated serum creatinine, renal failure, and renal tubular acidosis
- Nausea, anemia, thrombocytopenia, vomiting, pyrexia, leukopenia, diarrhea, injection site erythema, constipation, neutropenia, ecchymosis. The most common adverse reactions by IV route also included petechiae, rigors, weakness and hypokalemia.
- Discontinuation: leukopenia, thrombocytopenia, neutropenia.
- Dose Held: leukopenia, neutropenia, thrombocytopenia, pyrexia, pneumonia, febrile neutropenia.
- Dose Reduced: leukopenia, neutropenia, thrombocytopenia.
- 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.
- The data described below reflect exposure to Azacitidine in 443 MDS patients from 4 clinical studies. Study 1 was a supportive-care controlled trial (SC administration), Studies 2 and 3 were single arm studies (one with SC administration and one with IV administration), and Study 4 was an international randomized trial (SC administration) .
- In Studies 1, 2 and 3, a total of 268 patients were exposed to Azacitidine, including 116 exposed for 6 cycles (approximately 6 months) or more and 60 exposed for greater than 12 cycles (approximately one year). Azacitidine was studied primarily in supportive-care controlled and uncontrolled trials (n=150 and n=118, respectively). The population in the subcutaneous studies (n=220) was 23 to 92 years old (mean 66.4 years), 68% male, and 94% white, and had MDS or AML. The population in the IV study (n=48) was 35 to 81 years old (mean 63.1 years), 65% male, and 100% white. Most patients received average daily doses between 50 and 100 mg/m2.
- In Study 4, a total of 175 patients with higher-risk MDS (primarily RAEB and RAEB-T subtypes) were exposed to Azacitidine. Of these patients, 119 were exposed for 6 or more cycles, and 63 for at least 12 cycles. The mean age of this population was 68.1 years (ranging from 42 to 83 years), 74% were male, and 99% were white. Most patients received daily Azacitidine doses of 75 mg/m2.
- TABLE 1 presents adverse reactions occurring in at least 5% of patients treated with Azacitidine (SC) in Studies 1 and 2. It is important to note that duration of exposure was longer for the Azacitidine-treated group than for the observation group: patients received Azacitidine for a mean of 11.4 months while mean time in the observation arm was 6.1 months.
- In Studies 1, 2 and 4 with SC administration of Azacitidine, adverse reactions of neutropenia, thrombocytopenia, anemia, nausea, vomiting, diarrhea, constipation, and ]injection site erythema/reaction tended to increase in incidence with higher doses of Azacitidine. Adverse reactions that tended to be more pronounced during the first 1 to 2 cycles of SC treatment compared with later cycles included thrombocytopenia, neutropenia, anemia, nausea, vomiting, injection site erythema/pain/bruising/reaction, constipation, petechiae, dizziness, anxiety, hypokalemia, and insomnia. There did not appear to be any adverse reactions that increased in frequency over the course of treatment.
- Overall, adverse reactions were qualitatively similar between the IV and SC studies. Adverse reactions that appeared to be specifically associated with the IV route of administration included infusion site reactions (e.g. erythema or pain) and catheter site reactions (e.g. infection, erythema, or hemorrhage).
- In clinical studies of either SC or IV Azacitidine, the following serious adverse reactions occurring at a rate of < 5% (and not described in TABLES 1 or 2) were reported:
- Agranulocytosis, bone marrow failure, pancytopenia splenomegaly.
- Atrial fibrillation, cardiac failure, cardiac failure congestive, cardio-respiratory arrest, congestive cardiomyopathy.
- Eye hemorrhage
- Diverticulitis, gastrointestinal hemorrhage, melena, perirectal abscess.
- Catheter site hemorrhage, general physical health deterioration, systemic inflammatory response syndrome.
- Cholecystitis.
- Anaphylactic shock, hypersensitivity.
- Abscess limb, bacterial infection, cellulitis, blastomycosis, injection site infection, Klebsiella sepsis, neutropenic sepsis, pharyngitis streptococcal, pneumonia Klebsiella, sepsis, septic shock, Staphylococcal bacteremia, Staphylococcal infection, toxoplasmosis.
- Dehydration.
- Bone pain aggravated, muscle weakness, neck pain.
- Leukemia cutis.
- Cerebral hemorrhage, convulsions, intracranial hemorrhage.
- Loin pain, renal failure.
- Hemoptysis, lung infiltration, pneumonitis, respiratory distress.
- Pyoderma gangrenosum, rash pruritic, skin induration.
- Cholecystectomy.
- Orthostatic hypotension.
## Postmarketing Experience
- The following adverse reactions have been identified during postmarketing use of Azacitidine. 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.
- Interstitial lung disease
- Tumor lysis syndrome
- Injection site necrosis
- Sweet’s syndrome (acute febrile neutrophilic dermatosis)
# Drug Interactions
- No formal clinical assessments of drug-drug interactions between Azacitidine and other agents have been conducted
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
- Azacitidine may cause fetal harm when administered to a pregnant woman. Azacitidine was teratogenic in animals. There are no adequate and well controlled studies with Azacitidine in pregnant women. Women of childbearing potential should be advised to avoid pregnancy during treatment with Azacitidine. If this drug is used during pregnancy or if a patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
- Female partners of male patients receiving Azacitidine should not become pregnant.
- Early embryotoxicity studies in mice revealed a 44% frequency of intrauterine embryonal death (increased resorption) after a single IP (intraperitoneal) injection of 6 mg/m2 (approximately 8% of the recommended human daily dose on a mg/m2 basis) azacitidine on gestation day 10. Developmental abnormalities in the brain have been detected in mice given azacitidine on or before gestation day 15 at doses of ~3-12 mg/m2 (approximately 4%-16% the recommended human daily dose on a mg/m2 basis).
- In rats, azacitidine was clearly embryotoxic when given IP on gestation days 4-8 (postimplantation) at a dose of 6 mg/m2 (approximately 8% of the recommended human daily dose on a mg/m2 basis), although treatment in the preimplantation period (on gestation days 1-3) had no adverse effect on the embryos. Azacitidine caused multiple fetal abnormalities in rats after a single IP dose of 3 to 12 mg/m2 (approximately 8% the recommended human daily dose on a mg/m2 basis) given on gestation day 9, 10, 11 or 12. In this study azacitidine caused fetal death when administered at 3-12 mg/m2 on gestation days 9 and 10; average live animals per litter was reduced to 9% of control at the highest dose on gestation day 9. Fetal anomalies included: CNS anomalies (exencephaly/encephalocele), limb anomalies (micromelia, club foot, syndactyly, oligodactyly), and others (micrognathia, gastroschisis, edema, and rib abnormalities).
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Azacitidine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Azacitidine during labor and delivery.
### Nursing Mothers
- It is not known whether azacitidine or its metabolites are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for tumorigenicity shown for azacitidine in animal studies and the potential for serious adverse reactions in nursing infants from Azacitidine, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into consideration 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 patients in Studies 1, 2 and 3, 62% were 65 years and older and 21% were 75 years and older. No overall differences in effectiveness were observed between these patients and younger patients. In addition there were no relevant differences in the frequency of adverse reactions observed in patients 65 years and older compared to younger patients.
- Of the 179 patients randomized to azacitidine in Study 4, 68% were 65 years and older and 21% were 75 years and older. Survival data for patients 65 years and older were consistent with overall survival results. The majority of adverse reactions occurred at similar frequencies in patients < 65 years of age and patients 65 years of age and older.
- Elderly patients are more likely to have decreased renal function. Monitor renal function in these patients
### Gender
CLcr
- Men should be advised to not father a child while receiving treatment with Azacitidine. In animal studies, pre-conception treatment of male mice and rats resulted in increased embryofetal loss in mated females.
### Race
- Greater than 90% of all patients in all trials were Caucasian. Therefore, no comparisons between Caucasians and non-Caucasians were possible.
### Renal Impairment
- Renal toxicity ranging from elevated serum creatinine to renal failure and death have been reported in patients treated with intravenous azacitidine in combination with other chemotherapeutic agents for nonMDS conditions. In addition, renal tubular acidosis, defined as a fall in serum bicarbonate to <20 mEq/L in association with an alkaline urine and hypokalemia (serum potassium <3 mEq/L) developed in 5 patients with CML treated with azacitidine and etoposide. If unexplained reductions in serum bicarbonate <20 mEq/L or elevations of BUN or serum creatinine occur, the dosage should be reduced or held.
- Patients with renal impairment may be at increased risk for renal toxicity. Also, azacitidine and its metabolites are primarily excreted by the kidney. Therefore, these patients should be closely monitored for toxicity . Patients with MDS and renal impairment were excluded from the clinical studies.
- Severe renal impairment ( < 30 mL/min) has no major effect on the exposure of azacitidine after multiple SC administrations. Therefore, azacitidine can be administered to patients with renal impairment without Cycle 1 dose adjustment
### Hepatic Impairment
- Because azacitidine is potentially hepatotoxic in patients with severe pre-existing hepatic impairment, caution is needed in patients with liver disease. Patients with extensive tumor burden due to metastatic disease have been reported to experience progressive hepatic coma and death during azacitidine treatment, especially in such patients with baseline albumin <30 g/L. Azacitidine is contraindicated in patients with advanced malignant hepatic tumors.
- Safety and effectiveness of Azacitidine in patients with MDS and hepatic impairment have not been studied as these patients were excluded from the clinical trials
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Azacitidine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Azacitidine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Subcutaneous
- Intravenous
### Monitoring
- Monitor complete blood counts frequently (CBC)There is limited information regarding Monitoring of Azacitidine in the drug label.
- Monitor patients with renal impairment for toxicity since azacitidine and its metabolites are primarily excreted by the kidneys
- Monitor liver chemistries and serum creatinine prior to initiation of therapy and with each cycle
# IV Compatibility
There is limited information regarding IV Compatibility of Azacitidine in the drug label.
# Overdosage
- One case of overdose with Azacitidine was reported during clinical trials. A patient experienced diarrhea, nausea, and vomiting after receiving a single IV dose of approximately 290 mg/m2, almost 4 times the recommended starting dose. The events resolved without sequelae, and the correct dose was resumed the following day. In the event of overdosage, the patient should be monitored with appropriate blood counts and should receive supportive treatment, as necessary. There is no known specific antidote for Azacitidine overdosage.
# Pharmacology
## Mechanism of Action
- Azacitidine is a pyrimidine nucleoside analog of cytidine. Azacitidine is believed to exert its antineoplastic effects by causing hypomethylation of DNA and direct cytotoxicity on abnormal hematopoietic cells in the bone marrow. The concentration of azacitidine required for maximum inhibition of DNA methylation in vitro does not cause major suppression of DNA synthesis. Hypomethylation may restore normal function to genes that are critical for differentiation and proliferation. The cytotoxic effects of azacitidine cause the death of rapidly dividing cells, including cancer cells that are no longer responsive to normal growth control mechanisms. Non-proliferating cells are relatively insensitive to azacitidine.
## Structure
- Azacitidine (azacitidine for injection) contains azacitidine, which is a pyrimidine nucleoside analog of cytidine. Azacitidine is 4-amino-1-β-D-ribofuranosyl-s-triazin-2(1H)-one. The structural formula is as follows:
The empirical formula is C8H12N4O5. The molecular weight is 244. Azacitidine is a white to off-white solid. Azacitidine was found to be insoluble in acetone, ethanol, and methyl ethyl ketone; slightly soluble in ethanol/water (50/50), propylene glycol, and polyethylene glycol; sparingly soluble in water, water saturated octanol, 5% dextrose in water, N-methyl-2-pyrrolidone, normal saline and 5% Tween 80 in water; and soluble in dimethylsulfoxide (DMSO).
The finished product is supplied in a sterile form for reconstitution as a suspension for subcutaneous injection or reconstitution as a solution with further dilution for intravenous infusion. Vials of Azacitidine contain 100 mg of azacitidine and 100 mg mannitol as a sterile lyophilized powder.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Azacitidine in the drug label.
## Pharmacokinetics
- The pharmacokinetics of azacitidine were studied in 6 MDS patients following a single 75 mg/m2 subcutaneous (SC) dose and a single 75 mg/m2 intravenous (IV) dose. Azacitidine is rapidly absorbed after SC administration; the peak plasma azacitidine concentration of 750 ± 403 ng/ml occurred in 0.5 hour. The bioavailability of SC azacitidine relative to IV azacitidine is approximately 89%, based on area under the curve. Mean volume of distribution following IV dosing is 76 ± 26 L. Mean apparent SC clearance is 167 ± 49 L/hour and mean half-life after SC administration is 41 ± 8 minutes. The AUC and Cmax of SC administration of azacitidine in 21 patients with cancer were approximately dose proportional within the 25 to 100 mg/m2 dose range. Multiple dosing at the recommended dose-regimen does not result in drug accumulation.
- Published studies indicate that urinary excretion is the primary route of elimination of azacitidine and its metabolites. Following IV administration of radioactive azacitidine to 5 cancer patients, the cumulative urinary excretion was 85% of the radioactive dose. Fecal excretion accounted for <1% of administered radioactivity over 3 days. Mean excretion of radioactivity in urine following SC administration of 14C-azacitidine was 50%. The mean elimination half-lives of total radioactivity (azacitidine and its metabolites) were similar after IV and SC administrations, about 4 hours.
- In patients with cancer the pharmacokinetics of azacitidine in 6 patients with normal renal function (CLcr > 80 mL/min) and 6 patients with severe renal impairment (CLcr < 30 mL/min) were compared following daily SC dosing (Days 1 through 5) at 75 mg/m2/day. Severe renal impairment increased azacitidine exposure by approximately 70% after single and 41% after multiple subcutaneous administrations. This increase in exposure was not correlated with an increase in adverse events. The exposure was similar to exposure in patients with normal renal function receiving 100 mg/m2. Therefore, a Cycle 1 dose modification is not recommended.
- The effects of hepatic impairment, gender, age, or race on the pharmacokinetics of azacitidine have not been studied.
- No formal clinical drug interaction studies with azacitidine have been conducted.
- An in vitro study of azacitidine incubation in human liver fractions indicated that azacitidine may be metabolized by the liver. Whether azacitidine metabolism may be affected by known microsomal enzyme inhibitors or inducers has not been studied.
- An in vitro study with cultured human hepatocytes indicated that azacitidine at concentrations up to 100 µM (IV Cmax = 10.6 µM) does not cause any inhibition of CYP2B6 and CYP2C8.
- The potential of azacitidine to inhibit other cytochrome P450 (CYP) enzymes is not known.
- In vitro studies with human cultured hepatocytes indicate that azacitidine at concentrations of 1.0 μM to 100 μM does not induce CYP 1A2, 2C19, or 3A4/5.
## Nonclinical Toxicology
- The potential carcinogenicity of azacitidine was evaluated in mice and rats. Azacitidine induced tumors of the hematopoietic system in female mice at 2.2 mg/kg (6.6 mg/m2, approximately 8% the recommended human daily dose on a mg/m2 basis) administered IP three times per week for 52 weeks. An increased incidence of tumors in the lymphoreticular system, lung, mammary gland, and skin was seen in mice treated with azacitidine IP at 2.0 mg/kg (6.0 mg/m2, approximately 8% the recommended human daily dose on a mg/m2 basis) once a week for 50 weeks. A tumorigenicity study in rats dosed twice weekly at 15 or 60 mg/m2 (approximately 20-80% the recommended human daily dose on a mg/m2 basis) revealed an increased incidence of testicular tumors compared with controls.
- The mutagenic and clastogenic potential of azacitidine was tested in in vitro bacterial systems Salmonella typhimurium strains TA100 and several strains of trpE8, Escherichia coli strains WP14 Pro, WP3103P, WP3104P, and CC103; in in vitro forward gene mutation assay in mouse lymphoma cells and human lymphoblast cells; and in an in vitro micronucleus assay in mouse L5178Y lymphoma cells and Syrian hamster embryo cells. Azacitidine was mutagenic in bacterial and mammalian cell systems. The clastogenic effect of azacitidine was shown by the induction of micronuclei in L5178Y mouse cells and Syrian hamster embryo cells.
- Administration of azacitidine to male mice at 9.9 mg/m2 (approximately 9% the recommended human daily dose on a mg/m2 basis) daily for 3 days prior to mating with untreated female mice resulted in decreased fertility and loss of offspring during subsequent embryonic and postnatal development. Treatment of male rats 3 times per week for 11 or 16 weeks at doses of 15-30 mg/m2 (approximately 20-40%, the recommended human daily dose on a mg/m2 basis) resulted in decreased weight of the testes and epididymides, and decreased sperm counts accompanied by decreased pregnancy rates and increased loss of embryos in mated females. In a related study, male rats treated for 16 weeks at 24 mg/m2 resulted in an increase in abnormal embryos in mated females when examined on day 2 of gestation.
# Clinical Studies
- Study 1 was a randomized, open-label, controlled trial carried out in 53 U.S. sites compared the safety and efficacy of subcutaneous Azacitidine plus supportive care with supportive care alone (“observation”) in patients with any of the five FAB subtypes of myelodysplastic syndromes (MDS): refractory anemia (RA), RA with ringed sideroblasts (RARS), RA with excess blasts (RAEB), RAEB in transformation (RAEB-T), and chronic myelomonocytic leukemia (CMMoL). RA and RARS patients were included if they met one or more of the following criteria: required packed RBC transfusions; had platelet counts ≤50.0 x 109/L; required platelet transfusions; or were neutropenic (ANC <1.0 x 109/L) with infections requiring treatment with antibiotics. Patients with acute myelogenous leukemia (AML) were not intended to be included. Supportive care allowed in this study included blood transfusion products, antibiotics, antiemetics, analgesics and antipyretics. The use of hematopoeitic growth factors was prohibited. Baseline patient and disease characteristics are summarized in TABLE 3; the 2 groups were similar.
- Azacitidine was administered at a subcutaneous dose of 75 mg/m2 daily for 7 days every 4 weeks. The dose was increased to 100 mg/m2 if no beneficial effect was seen after 2 treatment cycles. The dose was decreased and/or delayed based on hematologic response or evidence of renal toxicity. Patients in the observation arm were allowed by protocol to cross over to Azacitidine if they had increases in bone marrow blasts, decreases in hemoglobin, increases in red cell transfusion requirements, or decreases in platelets, or if they required a platelet transfusion or developed a clinical infection requiring treatment with antibiotics. For purposes of assessing efficacy, the primary endpoint was response rate (as defined in TABLE 4).
- Of the 191 patients included in the study, independent review (adjudicated diagnosis) found that 19 had the diagnosis of AML at baseline. These patients were excluded from the primary analysis of response rate, although they were included in an intent-to-treat (ITT) analysis of all patients randomized. Approximately 55% of the patients randomized to observation crossed over to receive Azacitidine treatment.
- The overall response rate (CR + PR) of 15.7% in Azacitidine-treated patients without AML (16.2% for all Azacitidine randomized patients including AML) was statistically significantly higher than the response rate of 0% in the observation group (p<0.0001) (TABLE 5). The majority of patients who achieved either CR or PR had either 2 or 3 cell line abnormalities at baseline (79%; 11/14) and had elevated bone marrow blasts or were transfusion dependent at baseline. Patients responding to Azacitidine had a decrease in bone marrow blasts percentage, or an increase in platelets, hemoglobin or WBC. Greater than 90% of the responders initially demonstrated these changes by the 5th treatment cycle. All patients who had been transfusion dependent became transfusion independent during PR or CR. The mean and median duration of clinical response of PR or better was estimated as 512 and 330 days, respectively; 75% of the responding patients were still in PR or better at completion of treatment. Response occurred in all MDS subtypes as well as in patients with adjudicated baseline diagnosis of AML.
- Patients in the observation group who crossed over to receive Azacitidine treatment (47 patients) had a response rate of 12.8%.
- Study 2, a multi-center, open-label, single-arm study of 72 patients with RAEB, RAEB-T, CMMoL, or AML was also carried out. Treatment with subcutaneous Azacitidine resulted in a response rate (CR + PR) of 13.9%, using criteria similar to those described above. The mean and median duration of clinical response of PR or better was estimated as 810 and 430 days, respectively; 80% of the responding patients were still in PR or better at the time of completion of study involvement. In Study 3, another open-label, single-arm study of 48 patients with RAEB, RAEB-T, or AML, treatment with intravenous Azacitidine resulted in a response rate of 18.8%, again using criteria similar to those described above. The mean and median duration of clinical response of PR or better was estimated as 389 and 281 days, respectively; 67% of the responding patients were still in PR or better at the time of completion of treatment. Response occurred in all MDS subtypes as well as in patients with adjudicated baseline diagnosis of AML in both of these studies. Azacitidine dosage regimens in these 2 studies were similar to the regimen used in the controlled study.
- Benefit was seen in patients who did not meet the criteria for PR or better, but were considered “improved.” About 24% of Azacitidine-treated patients were considered improved, and about 2/3 of those lost transfusion dependence. In the observation group, only 5/83 patients met criteria for improvement; none lost transfusion dependence. In all 3 studies, about 19% of patients met criteria for improvement with a median duration of 195 days.
- Study 4 was an international, multicenter, open-label, randomized trial in MDS patients with RAEB, RAEB-T or modified CMMoL according to FAB classification and Intermediate-2 and High risk according to IPSS classification. Of the 358 patients enrolled in the study, 179 were randomized to receive azacitidine plus best supportive care (BSC) and 179 were randomized to receive conventional care regimens (CCR) plus BSC (105 to BSC alone, 49 to low dose cytarabine and 25 to chemotherapy with cytarabine and anthracycline). The primary efficacy endpoint was overall survival.
- The azacitidine and CCR groups were comparable for baseline parameters. The median age of patients was 69 years (range was 38-88 years), 98% were Caucasian, and 70% were male. At baseline, 95% of the patients were higher risk by FAB classification: RAEB (58%), RAEB-T (34%), and CMMoL (3%). By IPSS classification, 87% were higher risk: Int-2 (41%), High (47%). At baseline, 32% of patients met WHO criteria for AML.
- Azacitidine was administered subcutaneously at a dose of 75 mg/m2 daily for 7 consecutive days every 28 days (which constituted one cycle of therapy). Patients continued treatment until disease progression, relapse after response, or unacceptable toxicity. Azacitidine patients were treated for a median of 9 cycles (range 1 to 39), BSC only patients for a median of 7 cycles (range 1 to 26), low dose cytarabine patients for a median of 4.5 cycles (range 1 to 15), and chemotherapy with cytarabine and anthracycline patients for a median of 1 cycle (range 1 to 3, i.e. induction plus 1 or 2 consolidation cycles).
- In the Intent-to-Treat analysis, patients treated with azacitidine demonstrated a statistically significant difference in overall survival as compared to patients treated with CCR (median survival of 24.5 months vs. 15.0 months; stratified log-rank p=0.0001). The hazard ratio describing this treatment effect was 0.58 (95% CI: 0.43, 0.77).
- Azacitidine treatment led to a reduced need for red blood cell transfusions (see TABLE 6). In patients treated with azacitidine who were RBC transfusion dependent at baseline and became transfusion independent, the median duration of RBC transfusion independence was 13.0 months.
# How Supplied
- Azacitidine (azacitidine for injection) is supplied as a lyophilized powder in 100 mg single-use vials packaged in cartons of 1 vial (NDC 59572-102-01).
## Storage
- Store unreconstituted vials at 25º C (77º F); excursions permitted to 15º-30º C (59º-86º F) .
- Procedures for proper handling and disposal of anticancer drugs should be applied. Several guidelines on this subject have been published.1-4 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Instruct patients to inform their physician about any underlying liver or renal disease.
- Advise women of childbearing potential to avoid becoming pregnant while receiving treatment with Azacitidine. For nursing mothers, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into consideration the importance of the drug to the mother.
- Advise men not to father a child while receiving treatment with Azacitidine.
# Precautions with Alcohol
- Alcohol-Azacitidine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Vidaza ®
# Look-Alike Drug Names
- A® — B®
# Drug Shortage Status
# Price | Azacytidine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aparna Vuppala, M.B.B.S. [2]
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# Overview
Azacytidine is an antineoplastic agent that is FDA approved for the treatment of patients with the following French-American-British (FAB) myelodysplastic syndrome subtypes such as refractory anemia (RA) or refractory anemia with ringed sideroblasts (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts (RAEB), refractory anemia with excess blasts in transformation (RAEB-T), and chronic myelomonocytic leukemia. Common adverse reactions include anemia, neutropenia, thrombocytopenia, hepatic coma and elevated serum creatinine, renal failure, and renal tubular acidosis.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Azacitidine® is indicated for treatment of patients with the following French-American-British (FAB) myelodysplastic syndrome subtypes: refractory anemia (RA) or refractory anemia with ringed sideroblasts (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts (RAEB),refractory anemia with excess blasts in transformation (RAEB-T), and chronic myelomonocytic leukemia
- The recommended starting dose for the first treatment cycle, for all patients regardless of baseline hematology laboratory values, is 75 mg/m2 subcutaneously or intravenously, daily for 7 days. Patients should be premedicated for nausea and vomiting.
- Complete blood counts, liver chemistries and serum creatinine should be obtained prior to first dose.
- Cycles should be repeated every 4 weeks. The dose may be increased to 100 mg/m2 if no beneficial effect is seen after 2 treatment cycles and if no toxicity other than nausea and vomiting has occurred. It is recommended that patients be treated for a minimum of 4 to 6 cycles. However, complete or partial response may require additional treatment cycles. *Treatment may be continued as long as the patient continues to benefit.
- Patients should be monitored for hematologic response and renal toxicities, and dosage delay or reduction as described below may be necessary.
- For patients with baseline (start of treatment) WBC ≥3.0 x109/L, ANC ≥1.5 x109/L, and platelets ≥75.0 x109/L, adjust the dose as follows, based on nadir counts for any given cycle:
- For patients whose baseline counts are WBC <3.0 x109/L, ANC<1.5 x109/L, or platelets <75.0 x109/L, dose adjustments should be based on nadir counts and bone marrow biopsy cellularity at the time of the nadir as noted below, unless there is clear improvement in differentiation (percentage of mature granulocytes is higher and ANC is higher than at onset of that course) at the time of the next cycle, in which case the dose of the current treatment should be continued.
- If a nadir as defined in the table above has occurred, the next course of treatment should be given 28 days after the start of the preceding course, provided that both the WBC and the platelet counts are >25% above the nadir and rising. If a >25% increase above the nadir is not seen by day 28, counts should be reassessed every 7 days. If a 25% increase is not seen by day 42, then the patient should be treated with 50% of the scheduled dose.
- If unexplained reductions in serum bicarbonate levels to <20 mEq/L occur, the dosage should be reduced by 50% on the next course. Similarly, if unexplained elevations of BUN or serum creatinine occur, the next cycle should be delayed until values return to normal or baseline and the dose should be reduced by 50% on the next treatment course.
- Azacitidine and its metabolites are known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
- Azacitidine is a cytotoxic drug and, as with other potentially toxic compounds, caution should be exercised when handling and preparing Azacitidine suspensions.
- If reconstituted Azacitidine comes into contact with the skin, immediately and thoroughly wash with soap and water. If it comes into contact with mucous membranes, flush thoroughly with water.
- The Azacitidine vial is single-use and does not contain any preservatives. Unused portions of each vial should be discarded properly . Do not save any unused portions for later administration.
- Azacitidine should be reconstituted aseptically with 4 mL sterile water for injection. The diluent should be injected slowly into the vial. Vigorously shake or roll the vial until a uniform suspension is achieved. The suspension will be cloudy. The resulting suspension will contain azacitidine 25 mg/mL. Do not filter the suspension after reconstitution. Doing so could remove the active substance.
- Preparation for Immediate Subcutaneous Administration: Doses greater than 4 mL should be divided equally into 2 syringes. The product may be held at room temperature for up to 1 hour, but must be administered within 1 hour after reconstitution.
- Preparation for Delayed Subcutaneous Administration: The reconstituted product may be kept in the vial or drawn into a syringe. Doses greater than 4 mL should be divided equally into 2 syringes. The product must be refrigerated immediately. When Azacitidine is reconstituted using water for injection that has not been refrigerated, the reconstituted product may be held under refrigerated conditions (2ºC - 8ºC, 36ºF - 46ºF) for up to 8 hours. When Azacitidine is reconstituted using refrigerated (2ºC - 8ºC, 36ºF - 46ºF) water for injection, the reconstituted product may be stored under refrigerated conditions (2ºC - 8ºC, 36ºF - 46ºF) for up to 22 hours. After removal from refrigerated conditions, the suspension may be allowed to equilibrate to room temperature for up to 30 minutes prior to administration.
- To provide a homogeneous suspension, the contents of the dosing syringe must be re-suspended immediately prior to administration. To re-suspend, vigorously roll the syringe between the palms until a uniform, cloudy suspension is achieved.
- Azacitidine suspension is administered subcutaneously. Doses greater than 4 mL should be divided equally into 2 syringes and injected into 2 separate sites. Rotate sites for each injection (thigh, abdomen, or upper arm). New injections should be given at least one inch from an old site and never into areas where the site is tender, bruised, red, or hard.
- Suspension Stability: Azacitidine reconstituted with non-refrigerated water for injection for subcutaneous administration may be stored for up to 1 hour at 25°C (77°F) or for up to 8 hours between 2°C and 8°C (36°F and 46°F); when reconstituted with refrigerated (2ºC - 8ºC, 36ºF - 46ºF) water for injection, it may be stored for 22 hours between 2°C and 8°C (36°F and 46°F).
- Reconstitute the appropriate number of Azacitidine vials to achieve the desired dose. Reconstitute each vial with 10 mL sterile water for injection. Vigorously shake or roll the vial until all solids are dissolved. The resulting solution will contain azacitidine 10 mg/mL. The solution should be clear. Parenteral drug product should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
- Withdraw the required amount of Azacitidine solution to deliver the desired dose and inject into a 50 -100 mL infusion bag of either 0.9% Sodium Chloride Injection or Lactated Ringer's Injection.
- Azacitidine is incompatible with 5% Dextrose solutions, Hespan, or solutions that contain bicarbonate. These solutions have the potential to increase the rate of degradation of Azacitidine and should therefore be avoided.
- Azacitidine solution is administered intravenously. Administer the total dose over a period of 10 - 40 minutes. The administration must be completed within 1 hour of reconstitution of the Azacitidine vial.
- Solution Stability: Azacitidine reconstituted for intravenous administration may be stored at 25°C (77°F), but administration must be completed within 1 hour of reconstitution.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of 5-Azacytidine in adult patients.
### Non–Guideline-Supported Use
- Ara-C 100 mg/m(2)/day IV continuously for 7 days and daunorubicin 45 mg/m(2) IV on days 1 to 3.[1]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Safety and effectiveness in pediatric patients have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
Safety and effectiveness in pediatric patients have not been established.
### Non–Guideline-Supported Use
Safety and effectiveness in pediatric patients have not been established.
# Contraindications
- Azacitidine is contraindicated in patients with advanced malignant hepatic tumors.
- Azacitidine is contraindicated in patients with a known hypersensitivity to azacitidine or mannitol.
# Warnings
- Azacitidine causes anemia, neutropenia and thrombocytopenia. Monitor complete blood counts frequently for response and/or toxicity, at a minimum, prior to each dosing cycle. After administration of the recommended dosage for the first cycle, adjust dosage for subsequent cycles based on nadir counts and hematologic response .
.
# Adverse Reactions
## Clinical Trials Experience
The following adverse reactions are described in other labeling sections:
- Anemia, neutropenia and thrombocytopenia
- Hepatic coma
- Elevated serum creatinine, renal failure, and renal tubular acidosis
- Nausea, anemia, thrombocytopenia, vomiting, pyrexia, leukopenia, diarrhea, injection site erythema, constipation, neutropenia, ecchymosis. The most common adverse reactions by IV route also included petechiae, rigors, weakness and hypokalemia.
- Discontinuation: leukopenia, thrombocytopenia, neutropenia.
- Dose Held: leukopenia, neutropenia, thrombocytopenia, pyrexia, pneumonia, febrile neutropenia.
- Dose Reduced: leukopenia, neutropenia, thrombocytopenia.
- 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.
- The data described below reflect exposure to Azacitidine in 443 MDS patients from 4 clinical studies. Study 1 was a supportive-care controlled trial (SC administration), Studies 2 and 3 were single arm studies (one with SC administration and one with IV administration), and Study 4 was an international randomized trial (SC administration) .
- In Studies 1, 2 and 3, a total of 268 patients were exposed to Azacitidine, including 116 exposed for 6 cycles (approximately 6 months) or more and 60 exposed for greater than 12 cycles (approximately one year). Azacitidine was studied primarily in supportive-care controlled and uncontrolled trials (n=150 and n=118, respectively). The population in the subcutaneous studies (n=220) was 23 to 92 years old (mean 66.4 years), 68% male, and 94% white, and had MDS or AML. The population in the IV study (n=48) was 35 to 81 years old (mean 63.1 years), 65% male, and 100% white. Most patients received average daily doses between 50 and 100 mg/m2.
- In Study 4, a total of 175 patients with higher-risk MDS (primarily RAEB and RAEB-T subtypes) were exposed to Azacitidine. Of these patients, 119 were exposed for 6 or more cycles, and 63 for at least 12 cycles. The mean age of this population was 68.1 years (ranging from 42 to 83 years), 74% were male, and 99% were white. Most patients received daily Azacitidine doses of 75 mg/m2.
- TABLE 1 presents adverse reactions occurring in at least 5% of patients treated with Azacitidine (SC) in Studies 1 and 2. It is important to note that duration of exposure was longer for the Azacitidine-treated group than for the observation group: patients received Azacitidine for a mean of 11.4 months while mean time in the observation arm was 6.1 months.
- In Studies 1, 2 and 4 with SC administration of Azacitidine, adverse reactions of neutropenia, thrombocytopenia, anemia, nausea, vomiting, diarrhea, constipation, and ]injection site erythema/reaction tended to increase in incidence with higher doses of Azacitidine. Adverse reactions that tended to be more pronounced during the first 1 to 2 cycles of SC treatment compared with later cycles included thrombocytopenia, neutropenia, anemia, nausea, vomiting, injection site erythema/pain/bruising/reaction, constipation, petechiae, dizziness, anxiety, hypokalemia, and insomnia. There did not appear to be any adverse reactions that increased in frequency over the course of treatment.
- Overall, adverse reactions were qualitatively similar between the IV and SC studies. Adverse reactions that appeared to be specifically associated with the IV route of administration included infusion site reactions (e.g. erythema or pain) and catheter site reactions (e.g. infection, erythema, or hemorrhage).
- In clinical studies of either SC or IV Azacitidine, the following serious adverse reactions occurring at a rate of < 5% (and not described in TABLES 1 or 2) were reported:
- Agranulocytosis, bone marrow failure, pancytopenia splenomegaly.
- Atrial fibrillation, cardiac failure, cardiac failure congestive, cardio-respiratory arrest, congestive cardiomyopathy.
- Eye hemorrhage
- Diverticulitis, gastrointestinal hemorrhage, melena, perirectal abscess.
- Catheter site hemorrhage, general physical health deterioration, systemic inflammatory response syndrome.
- Cholecystitis.
- Anaphylactic shock, hypersensitivity.
- Abscess limb, bacterial infection, cellulitis, blastomycosis, injection site infection, Klebsiella sepsis, neutropenic sepsis, pharyngitis streptococcal, pneumonia Klebsiella, sepsis, septic shock, Staphylococcal bacteremia, Staphylococcal infection, toxoplasmosis.
- Dehydration.
- Bone pain aggravated, muscle weakness, neck pain.
- Leukemia cutis.
- Cerebral hemorrhage, convulsions, intracranial hemorrhage.
- Loin pain, renal failure.
- Hemoptysis, lung infiltration, pneumonitis, respiratory distress.
- Pyoderma gangrenosum, rash pruritic, skin induration.
- Cholecystectomy.
- Orthostatic hypotension.
## Postmarketing Experience
- The following adverse reactions have been identified during postmarketing use of Azacitidine. 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.
- Interstitial lung disease
- Tumor lysis syndrome
- Injection site necrosis
- Sweet’s syndrome (acute febrile neutrophilic dermatosis)
# Drug Interactions
- No formal clinical assessments of drug-drug interactions between Azacitidine and other agents have been conducted
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
- Azacitidine may cause fetal harm when administered to a pregnant woman. Azacitidine was teratogenic in animals. There are no adequate and well controlled studies with Azacitidine in pregnant women. Women of childbearing potential should be advised to avoid pregnancy during treatment with Azacitidine. If this drug is used during pregnancy or if a patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
- Female partners of male patients receiving Azacitidine should not become pregnant.
- Early embryotoxicity studies in mice revealed a 44% frequency of intrauterine embryonal death (increased resorption) after a single IP (intraperitoneal) injection of 6 mg/m2 (approximately 8% of the recommended human daily dose on a mg/m2 basis) azacitidine on gestation day 10. Developmental abnormalities in the brain have been detected in mice given azacitidine on or before gestation day 15 at doses of ~3-12 mg/m2 (approximately 4%-16% the recommended human daily dose on a mg/m2 basis).
- In rats, azacitidine was clearly embryotoxic when given IP on gestation days 4-8 (postimplantation) at a dose of 6 mg/m2 (approximately 8% of the recommended human daily dose on a mg/m2 basis), although treatment in the preimplantation period (on gestation days 1-3) had no adverse effect on the embryos. Azacitidine caused multiple fetal abnormalities in rats after a single IP dose of 3 to 12 mg/m2 (approximately 8% the recommended human daily dose on a mg/m2 basis) given on gestation day 9, 10, 11 or 12. In this study azacitidine caused fetal death when administered at 3-12 mg/m2 on gestation days 9 and 10; average live animals per litter was reduced to 9% of control at the highest dose on gestation day 9. Fetal anomalies included: CNS anomalies (exencephaly/encephalocele), limb anomalies (micromelia, club foot, syndactyly, oligodactyly), and others (micrognathia, gastroschisis, edema, and rib abnormalities).
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Azacitidine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Azacitidine during labor and delivery.
### Nursing Mothers
- It is not known whether azacitidine or its metabolites are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for tumorigenicity shown for azacitidine in animal studies and the potential for serious adverse reactions in nursing infants from Azacitidine, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into consideration 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 patients in Studies 1, 2 and 3, 62% were 65 years and older and 21% were 75 years and older. No overall differences in effectiveness were observed between these patients and younger patients. In addition there were no relevant differences in the frequency of adverse reactions observed in patients 65 years and older compared to younger patients.
- Of the 179 patients randomized to azacitidine in Study 4, 68% were 65 years and older and 21% were 75 years and older. Survival data for patients 65 years and older were consistent with overall survival results. The majority of adverse reactions occurred at similar frequencies in patients < 65 years of age and patients 65 years of age and older.
- Elderly patients are more likely to have decreased renal function. Monitor renal function in these patients
### Gender
CLcr
- Men should be advised to not father a child while receiving treatment with Azacitidine. In animal studies, pre-conception treatment of male mice and rats resulted in increased embryofetal loss in mated females.
### Race
- Greater than 90% of all patients in all trials were Caucasian. Therefore, no comparisons between Caucasians and non-Caucasians were possible.
### Renal Impairment
- Renal toxicity ranging from elevated serum creatinine to renal failure and death have been reported in patients treated with intravenous azacitidine in combination with other chemotherapeutic agents for nonMDS conditions. In addition, renal tubular acidosis, defined as a fall in serum bicarbonate to <20 mEq/L in association with an alkaline urine and hypokalemia (serum potassium <3 mEq/L) developed in 5 patients with CML treated with azacitidine and etoposide. If unexplained reductions in serum bicarbonate <20 mEq/L or elevations of BUN or serum creatinine occur, the dosage should be reduced or held.
- Patients with renal impairment may be at increased risk for renal toxicity. Also, azacitidine and its metabolites are primarily excreted by the kidney. Therefore, these patients should be closely monitored for toxicity . Patients with MDS and renal impairment were excluded from the clinical studies.
- Severe renal impairment ( < 30 mL/min) has no major effect on the exposure of azacitidine after multiple SC administrations. Therefore, azacitidine can be administered to patients with renal impairment without Cycle 1 dose adjustment
### Hepatic Impairment
- Because azacitidine is potentially hepatotoxic in patients with severe pre-existing hepatic impairment, caution is needed in patients with liver disease. Patients with extensive tumor burden due to metastatic disease have been reported to experience progressive hepatic coma and death during azacitidine treatment, especially in such patients with baseline albumin <30 g/L. Azacitidine is contraindicated in patients with advanced malignant hepatic tumors.
- Safety and effectiveness of Azacitidine in patients with MDS and hepatic impairment have not been studied as these patients were excluded from the clinical trials
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Azacitidine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Azacitidine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Subcutaneous
- Intravenous
### Monitoring
- Monitor complete blood counts frequently (CBC)There is limited information regarding Monitoring of Azacitidine in the drug label.
- Monitor patients with renal impairment for toxicity since azacitidine and its metabolites are primarily excreted by the kidneys
- Monitor liver chemistries and serum creatinine prior to initiation of therapy and with each cycle
# IV Compatibility
There is limited information regarding IV Compatibility of Azacitidine in the drug label.
# Overdosage
- One case of overdose with Azacitidine was reported during clinical trials. A patient experienced diarrhea, nausea, and vomiting after receiving a single IV dose of approximately 290 mg/m2, almost 4 times the recommended starting dose. The events resolved without sequelae, and the correct dose was resumed the following day. In the event of overdosage, the patient should be monitored with appropriate blood counts and should receive supportive treatment, as necessary. There is no known specific antidote for Azacitidine overdosage.
# Pharmacology
## Mechanism of Action
- Azacitidine is a pyrimidine nucleoside analog of cytidine. Azacitidine is believed to exert its antineoplastic effects by causing hypomethylation of DNA and direct cytotoxicity on abnormal hematopoietic cells in the bone marrow. The concentration of azacitidine required for maximum inhibition of DNA methylation in vitro does not cause major suppression of DNA synthesis. Hypomethylation may restore normal function to genes that are critical for differentiation and proliferation. The cytotoxic effects of azacitidine cause the death of rapidly dividing cells, including cancer cells that are no longer responsive to normal growth control mechanisms. Non-proliferating cells are relatively insensitive to azacitidine.
## Structure
- Azacitidine (azacitidine for injection) contains azacitidine, which is a pyrimidine nucleoside analog of cytidine. Azacitidine is 4-amino-1-β-D-ribofuranosyl-s-triazin-2(1H)-one. The structural formula is as follows:
The empirical formula is C8H12N4O5. The molecular weight is 244. Azacitidine is a white to off-white solid. Azacitidine was found to be insoluble in acetone, ethanol, and methyl ethyl ketone; slightly soluble in ethanol/water (50/50), propylene glycol, and polyethylene glycol; sparingly soluble in water, water saturated octanol, 5% dextrose in water, N-methyl-2-pyrrolidone, normal saline and 5% Tween 80 in water; and soluble in dimethylsulfoxide (DMSO).
The finished product is supplied in a sterile form for reconstitution as a suspension for subcutaneous injection or reconstitution as a solution with further dilution for intravenous infusion. Vials of Azacitidine contain 100 mg of azacitidine and 100 mg mannitol as a sterile lyophilized powder.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Azacitidine in the drug label.
## Pharmacokinetics
- The pharmacokinetics of azacitidine were studied in 6 MDS patients following a single 75 mg/m2 subcutaneous (SC) dose and a single 75 mg/m2 intravenous (IV) dose. Azacitidine is rapidly absorbed after SC administration; the peak plasma azacitidine concentration of 750 ± 403 ng/ml occurred in 0.5 hour. The bioavailability of SC azacitidine relative to IV azacitidine is approximately 89%, based on area under the curve. Mean volume of distribution following IV dosing is 76 ± 26 L. Mean apparent SC clearance is 167 ± 49 L/hour and mean half-life after SC administration is 41 ± 8 minutes. The AUC and Cmax of SC administration of azacitidine in 21 patients with cancer were approximately dose proportional within the 25 to 100 mg/m2 dose range. Multiple dosing at the recommended dose-regimen does not result in drug accumulation.
- Published studies indicate that urinary excretion is the primary route of elimination of azacitidine and its metabolites. Following IV administration of radioactive azacitidine to 5 cancer patients, the cumulative urinary excretion was 85% of the radioactive dose. Fecal excretion accounted for <1% of administered radioactivity over 3 days. Mean excretion of radioactivity in urine following SC administration of 14C-azacitidine was 50%. The mean elimination half-lives of total radioactivity (azacitidine and its metabolites) were similar after IV and SC administrations, about 4 hours.
- In patients with cancer the pharmacokinetics of azacitidine in 6 patients with normal renal function (CLcr > 80 mL/min) and 6 patients with severe renal impairment (CLcr < 30 mL/min) were compared following daily SC dosing (Days 1 through 5) at 75 mg/m2/day. Severe renal impairment increased azacitidine exposure by approximately 70% after single and 41% after multiple subcutaneous administrations. This increase in exposure was not correlated with an increase in adverse events. The exposure was similar to exposure in patients with normal renal function receiving 100 mg/m2. Therefore, a Cycle 1 dose modification is not recommended.
- The effects of hepatic impairment, gender, age, or race on the pharmacokinetics of azacitidine have not been studied.
- No formal clinical drug interaction studies with azacitidine have been conducted.
- An in vitro study of azacitidine incubation in human liver fractions indicated that azacitidine may be metabolized by the liver. Whether azacitidine metabolism may be affected by known microsomal enzyme inhibitors or inducers has not been studied.
- An in vitro study with cultured human hepatocytes indicated that azacitidine at concentrations up to 100 µM (IV Cmax = 10.6 µM) does not cause any inhibition of CYP2B6 and CYP2C8.
- The potential of azacitidine to inhibit other cytochrome P450 (CYP) enzymes is not known.
- In vitro studies with human cultured hepatocytes indicate that azacitidine at concentrations of 1.0 μM to 100 μM does not induce CYP 1A2, 2C19, or 3A4/5.
## Nonclinical Toxicology
- The potential carcinogenicity of azacitidine was evaluated in mice and rats. Azacitidine induced tumors of the hematopoietic system in female mice at 2.2 mg/kg (6.6 mg/m2, approximately 8% the recommended human daily dose on a mg/m2 basis) administered IP three times per week for 52 weeks. An increased incidence of tumors in the lymphoreticular system, lung, mammary gland, and skin was seen in mice treated with azacitidine IP at 2.0 mg/kg (6.0 mg/m2, approximately 8% the recommended human daily dose on a mg/m2 basis) once a week for 50 weeks. A tumorigenicity study in rats dosed twice weekly at 15 or 60 mg/m2 (approximately 20-80% the recommended human daily dose on a mg/m2 basis) revealed an increased incidence of testicular tumors compared with controls.
- The mutagenic and clastogenic potential of azacitidine was tested in in vitro bacterial systems Salmonella typhimurium strains TA100 and several strains of trpE8, Escherichia coli strains WP14 Pro, WP3103P, WP3104P, and CC103; in in vitro forward gene mutation assay in mouse lymphoma cells and human lymphoblast cells; and in an in vitro micronucleus assay in mouse L5178Y lymphoma cells and Syrian hamster embryo cells. Azacitidine was mutagenic in bacterial and mammalian cell systems. The clastogenic effect of azacitidine was shown by the induction of micronuclei in L5178Y mouse cells and Syrian hamster embryo cells.
- Administration of azacitidine to male mice at 9.9 mg/m2 (approximately 9% the recommended human daily dose on a mg/m2 basis) daily for 3 days prior to mating with untreated female mice resulted in decreased fertility and loss of offspring during subsequent embryonic and postnatal development. Treatment of male rats 3 times per week for 11 or 16 weeks at doses of 15-30 mg/m2 (approximately 20-40%, the recommended human daily dose on a mg/m2 basis) resulted in decreased weight of the testes and epididymides, and decreased sperm counts accompanied by decreased pregnancy rates and increased loss of embryos in mated females. In a related study, male rats treated for 16 weeks at 24 mg/m2 resulted in an increase in abnormal embryos in mated females when examined on day 2 of gestation.
# Clinical Studies
- Study 1 was a randomized, open-label, controlled trial carried out in 53 U.S. sites compared the safety and efficacy of subcutaneous Azacitidine plus supportive care with supportive care alone (“observation”) in patients with any of the five FAB subtypes of myelodysplastic syndromes (MDS): refractory anemia (RA), RA with ringed sideroblasts (RARS), RA with excess blasts (RAEB), RAEB in transformation (RAEB-T), and chronic myelomonocytic leukemia (CMMoL). RA and RARS patients were included if they met one or more of the following criteria: required packed RBC transfusions; had platelet counts ≤50.0 x 109/L; required platelet transfusions; or were neutropenic (ANC <1.0 x 109/L) with infections requiring treatment with antibiotics. Patients with acute myelogenous leukemia (AML) were not intended to be included. Supportive care allowed in this study included blood transfusion products, antibiotics, antiemetics, analgesics and antipyretics. The use of hematopoeitic growth factors was prohibited. Baseline patient and disease characteristics are summarized in TABLE 3; the 2 groups were similar.
- Azacitidine was administered at a subcutaneous dose of 75 mg/m2 daily for 7 days every 4 weeks. The dose was increased to 100 mg/m2 if no beneficial effect was seen after 2 treatment cycles. The dose was decreased and/or delayed based on hematologic response or evidence of renal toxicity. Patients in the observation arm were allowed by protocol to cross over to Azacitidine if they had increases in bone marrow blasts, decreases in hemoglobin, increases in red cell transfusion requirements, or decreases in platelets, or if they required a platelet transfusion or developed a clinical infection requiring treatment with antibiotics. For purposes of assessing efficacy, the primary endpoint was response rate (as defined in TABLE 4).
- Of the 191 patients included in the study, independent review (adjudicated diagnosis) found that 19 had the diagnosis of AML at baseline. These patients were excluded from the primary analysis of response rate, although they were included in an intent-to-treat (ITT) analysis of all patients randomized. Approximately 55% of the patients randomized to observation crossed over to receive Azacitidine treatment.
- The overall response rate (CR + PR) of 15.7% in Azacitidine-treated patients without AML (16.2% for all Azacitidine randomized patients including AML) was statistically significantly higher than the response rate of 0% in the observation group (p<0.0001) (TABLE 5). The majority of patients who achieved either CR or PR had either 2 or 3 cell line abnormalities at baseline (79%; 11/14) and had elevated bone marrow blasts or were transfusion dependent at baseline. Patients responding to Azacitidine had a decrease in bone marrow blasts percentage, or an increase in platelets, hemoglobin or WBC. Greater than 90% of the responders initially demonstrated these changes by the 5th treatment cycle. All patients who had been transfusion dependent became transfusion independent during PR or CR. The mean and median duration of clinical response of PR or better was estimated as 512 and 330 days, respectively; 75% of the responding patients were still in PR or better at completion of treatment. Response occurred in all MDS subtypes as well as in patients with adjudicated baseline diagnosis of AML.
- Patients in the observation group who crossed over to receive Azacitidine treatment (47 patients) had a response rate of 12.8%.
- Study 2, a multi-center, open-label, single-arm study of 72 patients with RAEB, RAEB-T, CMMoL, or AML was also carried out. Treatment with subcutaneous Azacitidine resulted in a response rate (CR + PR) of 13.9%, using criteria similar to those described above. The mean and median duration of clinical response of PR or better was estimated as 810 and 430 days, respectively; 80% of the responding patients were still in PR or better at the time of completion of study involvement. In Study 3, another open-label, single-arm study of 48 patients with RAEB, RAEB-T, or AML, treatment with intravenous Azacitidine resulted in a response rate of 18.8%, again using criteria similar to those described above. The mean and median duration of clinical response of PR or better was estimated as 389 and 281 days, respectively; 67% of the responding patients were still in PR or better at the time of completion of treatment. Response occurred in all MDS subtypes as well as in patients with adjudicated baseline diagnosis of AML in both of these studies. Azacitidine dosage regimens in these 2 studies were similar to the regimen used in the controlled study.
- Benefit was seen in patients who did not meet the criteria for PR or better, but were considered “improved.” About 24% of Azacitidine-treated patients were considered improved, and about 2/3 of those lost transfusion dependence. In the observation group, only 5/83 patients met criteria for improvement; none lost transfusion dependence. In all 3 studies, about 19% of patients met criteria for improvement with a median duration of 195 days.
- Study 4 was an international, multicenter, open-label, randomized trial in MDS patients with RAEB, RAEB-T or modified CMMoL according to FAB classification and Intermediate-2 and High risk according to IPSS classification. Of the 358 patients enrolled in the study, 179 were randomized to receive azacitidine plus best supportive care (BSC) and 179 were randomized to receive conventional care regimens (CCR) plus BSC (105 to BSC alone, 49 to low dose cytarabine and 25 to chemotherapy with cytarabine and anthracycline). The primary efficacy endpoint was overall survival.
- The azacitidine and CCR groups were comparable for baseline parameters. The median age of patients was 69 years (range was 38-88 years), 98% were Caucasian, and 70% were male. At baseline, 95% of the patients were higher risk by FAB classification: RAEB (58%), RAEB-T (34%), and CMMoL (3%). By IPSS classification, 87% were higher risk: Int-2 (41%), High (47%). At baseline, 32% of patients met WHO criteria for AML.
- Azacitidine was administered subcutaneously at a dose of 75 mg/m2 daily for 7 consecutive days every 28 days (which constituted one cycle of therapy). Patients continued treatment until disease progression, relapse after response, or unacceptable toxicity. Azacitidine patients were treated for a median of 9 cycles (range 1 to 39), BSC only patients for a median of 7 cycles (range 1 to 26), low dose cytarabine patients for a median of 4.5 cycles (range 1 to 15), and chemotherapy with cytarabine and anthracycline patients for a median of 1 cycle (range 1 to 3, i.e. induction plus 1 or 2 consolidation cycles).
- In the Intent-to-Treat analysis, patients treated with azacitidine demonstrated a statistically significant difference in overall survival as compared to patients treated with CCR (median survival of 24.5 months vs. 15.0 months; stratified log-rank p=0.0001). The hazard ratio describing this treatment effect was 0.58 (95% CI: 0.43, 0.77).
- Azacitidine treatment led to a reduced need for red blood cell transfusions (see TABLE 6). In patients treated with azacitidine who were RBC transfusion dependent at baseline and became transfusion independent, the median duration of RBC transfusion independence was 13.0 months.
# How Supplied
- Azacitidine (azacitidine for injection) is supplied as a lyophilized powder in 100 mg single-use vials packaged in cartons of 1 vial (NDC 59572-102-01).
## Storage
- Store unreconstituted vials at 25º C (77º F); excursions permitted to 15º-30º C (59º-86º F) .
- Procedures for proper handling and disposal of anticancer drugs should be applied. Several guidelines on this subject have been published.1-4 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Instruct patients to inform their physician about any underlying liver or renal disease.
- Advise women of childbearing potential to avoid becoming pregnant while receiving treatment with Azacitidine. For nursing mothers, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into consideration the importance of the drug to the mother.
- Advise men not to father a child while receiving treatment with Azacitidine.
# Precautions with Alcohol
- Alcohol-Azacitidine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Vidaza ®
# Look-Alike Drug Names
- A® — B®
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/5-Azacytidine | |
f785384f017f0faf68e31748a145b32d5c4afc6a | wikidoc | Flucytosine | Flucytosine
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# Black Box Warning
# Overview
Flucytosine is a antifungal , anti-Infective agent that is FDA approved for the treatment of candidiasis and cryptococcosis. There is a Black Box Warning for this drug as shown here. Common adverse reactions include abdominal pain, diarrhea, nausea, vomiting, confusion, headache and hallucinations.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Ancobon is indicated only in the treatment of serious infections caused by susceptible strains of Candida and/or Cryptococcus.
- Candida: Septicemia, endocarditis and urinary system infections have been effectively treated with flucytosine. Limited trials in pulmonary infections justify the use of flucytosine.
- Cryptococcus: Meningitis and pulmonary infections have been treated effectively. Studies in septicemias and urinary tract infections are limited, but good responses have been reported.
- Ancobon should be used in combination with amphotericin B for the treatment of systemic candidiasis and cryptococcosis because of the emergence of resistance to Ancobon.
### Dosing Information
- The usual dosage of Ancobon is 50 to 150 mg/kg/day administered in divided doses at 6-hour intervals. Nausea or vomiting may be reduced or avoided if the capsules are given a few at a time over a 15-minute period. If the BUN or the serum creatinine is elevated, or if there are other signs of renal impairment, the initial dose should be at the lower level.
- Ancobon should be used in combination with amphotericin B for the treatment of systemic candidiasis and cryptococcosis because of the emergence of resistance to Ancobon.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Flucytosine in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Flucytosine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Flucytosine in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Flucytosine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Flucytosine in pediatric patients.
# Contraindications
- Ancobon should not be used in patients with a known hypersensitivity to the drug.
# Warnings
- Ancobon must be given with extreme caution to patients with impaired renal function. Since Ancobon is excreted primarily by the kidneys, renal impairment may lead to accumulation of the drug. Ancobon serum concentrations should be monitored to determine the adequacy of renal excretion in such patients. Dosage adjustments should be made in patients with renal insufficiency to prevent progressive accumulation of active drug.
- Ancobon must be given with extreme caution to patients with bone marrow depression. Patients may be more prone to depression of bone marrow function if they: 1) have a hematologic disease, 2) are being treated with radiation or drugs which depress bone marrow, or 3) have a history of treatment with such drugs or radiation. Bone marrow toxicity can be irreversible and may lead to death in immunosuppressed patients. Frequent monitoring of hepatic function and of the hematopoietic system is indicated during therapy.
### PRECAUTIONS
- Before therapy with Ancobon is instituted, electrolytes (because of hypokalemia) and the hematologic and renal status of the patient should be determined. Close monitoring of the patient during therapy is essential.
# Adverse Reactions
## Clinical Trials Experience
- The adverse reactions which have occurred during treatment with Ancobon are grouped according to organ system affected.
- Cardiac arrest, myocardial toxicity, ventricular dysfunction.
- Respiratory arrest, chest pain, dyspnea.
- Rash, pruritus, urticaria, photosensitivity.
- Nausea, emesis, abdominal pain, diarrhea, anorexia, dry mouth, duodenal ulcer, gastrointestinal hemorrhage, acute hepatic injury including hepatic necrosis with possible fatal outcome in debilitated patients, hepatic dysfunction, jaundice, ulcerative colitis, enterocolitis, bilirubin elevation, increased hepatic enzymes.
- Azotemia, creatinine and BUN elevation, crystalluria, renal failure.
- Anemia, agranulocytosis, aplastic anemia, eosinophilia, leukopenia, pancytopenia, thrombocytopenia, and fatal cases of bone marrow aplasia.
- Ataxia, hearing loss, headache, paresthesia, parkinsonism, peripheral neuropathy, pyrexia, vertigo, sedation, convulsions.
- Confusion, hallucinations, psychosis.
- Fatigue, hypoglycemia, hypokalemia, weakness, allergic reactions, Lyell’s syndrome.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Flucytosine in the drug label.
# Drug Interactions
- Cytosine arabinoside, a cytostatic agent, has been reported to inactivate the antifungal activity of Ancobon by competitive inhibition. Drugs which impair glomerular filtration may prolong the biological half-life of flucytosine.
- Since renal impairment can cause progressive accumulation of the drug, blood concentrations and kidney function should be monitored during therapy. Hematologic status (leucocyte and thrombocyte count) and liver function (alkaline phosphatase, SGOT and SGPT) should be determined at frequent intervals during treatment as indicated.
- Measurement of serum creatinine levels should be determined by the Jaffé reaction, since Ancobon does not interfere with the determination of creatinine values by this method. Most automated equipment for measurement of creatinine makes use of the Jaffé reaction.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Flucytosine was shown to be teratogenic (vertebral fusions) in the rat at doses of 40 mg/kg/day (298 mg/M2/day or 0.051 times the human dose) administered on days 7 to 13 of gestation. At higher doses (700 mg/kg/day; 5208 mg/M2/day or 0.89 times the human dose administered on days 9 to 12 of gestation), cleft lip and palate and micrognathia were reported. Flucytosine was not teratogenic in rabbits up to a dose of 100 mg/kg/day (1423 mg/M2/day or 0.243 times the human dose) administered on days 6 to 18 of gestation. In mice, 400 mg/kg/day of flucytosine (1380 mg/M2/day or 0.236 times the human dose) administered on days 7 to 13 of gestation was associated with a low incidence of cleft palate that was not statistically significant. Studies in pregnant rats have shown that flucytosine injected intraperitoneally crosses the placental barrier. There are no adequate and well-controlled studies in pregnant women. Ancobon should be used during pregnancy only if the potential benefit justifies the potential 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 Flucytosine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Flucytosine during labor and delivery.
### Nursing Mothers
- It is not known whether this drug is 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 Ancobon, 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
- The efficacy and safety of Ancobon have not been systematically studied in pediatric patients. A small number of neonates have been treated with 25 to 200 mg/kg/day of flucytosine, with and without the addition of amphotericin B, for systemic candidiasis. No unexpected adverse reactions were reported in these patients. It should be noted, however, that hypokalemia and acidemia were reported in one patient who received flucytosine in combination with amphotericin B, and anemia was observed in a second patient who received flucytosine alone. Transient thrombocytopenia was noted in two additional patients, one of whom also received amphotericin B.
### Geriatic Use
There is no FDA guidance on the use of Flucytosine with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Flucytosine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Flucytosine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Flucytosine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Flucytosine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Flucytosine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Flucytosine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- Ancobon must be given with extreme caution to patients with impaired renal function. Since Ancobon is excreted primarily by the kidneys, renal impairment may lead to accumulation of the drug. Ancobon serum concentrations should be monitored to determine the adequacy of renal excretion in such patients. Dosage adjustments should be made in patients with renal insufficiency to prevent progressive accumulation of active drug.
- Ancobon must be given with extreme caution to patients with bone marrow depression. Patients may be more prone to depression of bone marrow function if they: 1) have a hematologic disease, 2) are being treated with radiation or drugs which depress bone marrow, or 3) have a history of treatment with such drugs or radiation. Bone marrow toxicity can be irreversible and may lead to death in immunosuppressed patients. Frequent monitoring of hepatic function and of the hematopoietic system is indicated during therapy.
- Before therapy with Ancobon is instituted, electrolytes (because of hypokalemia) and the hematologic and renal status of the patient should be determined. Close monitoring of the patient during therapy is essential.
- Since renal impairment can cause progressive accumulation of the drug, blood concentrations and kidney function should be monitored during therapy. Hematologic status (leucocyte and thrombocyte count) and liver function (alkaline phosphatase, SGOT and SGPT) should be determined at frequent intervals during treatment as indicated.
# IV Compatibility
There is limited information regarding IV Compatibility of Flucytosine in the drug label.
# Overdosage
- There is no experience with intentional overdosage. It is reasonable to expect that overdosage may produce pronounced manifestations of the known clinical adverse reactions. Prolonged serum concentrations in excess of 100 µg/mL may be associated with an increased incidence of toxicity, especially gastrointestinal (diarrhea, nausea, vomiting), hematologic (leukopenia, thrombocytopenia) and hepatic (hepatitis).
- In the management of overdosage, prompt gastric lavage or the use of an emetic is recommended. Adequate fluid intake should be maintained, by the intravenous route if necessary, since Ancobon is excreted unchanged via the renal tract. The hematologic parameters should be monitored frequently; liver and kidney function should be carefully monitored. Should any abnormalities appear in any of these parameters, appropriate therapeutic measures should be instituted.
- Since hemodialysis has been shown to rapidly reduce serum concentrations in anuric patients, this method may be considered in the management of overdosage.
# Pharmacology
There is limited information regarding Flucytosine Pharmacology in the drug label.
## Mechanism of Action
- Flucytosine is taken up by fungal organisms via the enzyme cytosine permease. Inside the fungal cell, flucytosine is rapidly converted to fluorouracil by the enzyme cytosine deaminase. Fluorouracil exerts its antifungal activity through the subsequent conversion into several active metabolites, which inhibit protein synthesis by being falsely incorporated into fungal RNA or interfere with the biosynthesis of fungal DNA through the inhibition of the enzyme thymidylate synthetase.
## Structure
- Ancobon (flucytosine), an antifungal agent, is available as 250 mg and 500 mg capsules for oral administration. Each capsule also contains corn starch, lactose and talc. Gelatin capsule shells contain parabens (butyl, methyl, propyl) and sodium propionate, with the following dye systems: 250 mg capsules — black iron oxide, FD&C Blue No. 1, FD&C Yellow No. 6, D&C Yellow No. 10 and titanium dioxide; 500 mg capsules — black iron oxide and titanium dioxide. Chemically, flucytosine is 5-fluorocytosine, a fluorinated pyrimidine which is related to fluorouracil and floxuridine. It is a white to off-white crystalline powder with a molecular weight of 129.09 and the following structural formula:
## Pharmacodynamics
### Microbiology
- Flucytosine has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections.
- The following in vitro data are available, but their clinical significance is unknown.
- Flucytosine exhibits in vitro minimum inhibitory concentrations (MIC values) of 4 μg/mL, or less against most (≥90%) strains of the following microorganisms, however, the safety and effectiveness of flucytosine in treating clinical infections due to these microorganisms have not been established in adequate and well control trials.
- Candida dubliniensisCandida glabrataCandida guilliermondiiCandida lusitaniaeCandida parapsilosisCandida tropicalis
- Candida krusei should be considered to be resistant to flucytosine.
- In vitro activity of flucytosine is affected by the test conditions. It is essential to follow the approved standard method guidelines.1
### Susceptibility Testing Methods
- No interpretive criteria have been established for Cryptococcus neoformans.
- Broth Dilution Techniques:
- Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of Candida spp. to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method (broth)1 with standardized inoculum concentrations and standardized concentrations of flucytosine powder. The MIC values should be interpreted according to the criteria in Table 1.
- A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentration usually achievable. A report of "Intermediate" indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where a high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentration usually achievable; other therapy should be selected. Because of other significant host factors, in vitro susceptibility may not correlate with clinical outcomes.
- Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard flucytosine powder should provide the range of MIC values noted in Table 2. NOTE: Quality control microorganisms are specific strains of organisms with intrinsic biological properties relating to resistance mechanisms and their genetic expression within fungi; the specific strains used for microbiological control are not clinically significant.
- Flucytosine resistance may arise from a mutation of an enzyme necessary for the cellular uptake or metabolism of flucytosine or from an increased synthesis of pyrimidines, which compete with the active metabolites of flucytosine (fluorinated antimetabolites). Resistance to flucytosine has been shown to develop during monotherapy after prolonged exposure to the drug.
- Candida krusei should be considered to be resistant to flucytosine.
- Antifungal synergism between flucytosine and polyene antibiotics, particularly amphotericin B has been reported in vitro. Ancobon is usually administered in combination with amphotericin B due to lack of cross-resistance and reported synergistic activity of both drugs.
## Pharmacokinetics
- Flucytosine is rapidly and virtually completely absorbed following oral administration. Ancobon is not metabolized significantly when given orally to man. Bioavailability estimated by comparing the area under the curve of serum concentrations after oral and intravenous administration showed 78% to 89% absorption of the oral dose. Peak serum concentrations of 30 to 40 µg/mL were reached within 2 hours of administration of a 2 g oral dose to normal subjects. Other studies revealed mean serum concentrations of approximately 70 to 80 μg/mL 1 to 2 hours after a dose in patients with normal renal function receiving a 6-week regimen of flucytosine (150 mg/kg/day given in divided doses every 6 hours) in combination with amphotericin B. The half-life in the majority of healthy subjects ranged between 2.4 and 4.8 hours. Flucytosine is excreted via the kidneys by means of glomerular filtration without significant tubular reabsorption. More than 90% of the total radioactivity after oral administration was recovered in the urine as intact drug. Flucytosine is deaminated (probably by gut bacteria) to 5-fluorouracil. The area under the curve (AUC) ratio of 5-fluorouracil to flucytosine is 4%. Approximately 1% of the dose is present in the urine as the α-fluoro-β-ureido-propionic acid metabolite. A small portion of the dose is excreted in the feces.
- The half-life of flucytosine is prolonged in patients with renal insufficiency; the average half-life in nephrectomized or anuric patients was 85 hours (range: 29.9 to 250 hours). A linear correlation was found between the elimination rate constant of flucytosine and creatinine clearance.
- In vitro studies have shown that 2.9% to 4% of flucytosine is protein-bound over the range of therapeutic concentrations found in the blood. Flucytosine readily penetrates the blood-brain barrier, achieving clinically significant concentrations in cerebrospinal fluid.
- Limited data are available regarding the pharmacokinetics of Ancobon administered to neonatal patients being treated for systemic candidiasis. After five days of continuous therapy, median peak levels in infants were 19.6 µg/mL, 27.7 µg/mL, and 83.9 µg/mL at doses of 25 mg/kg (N=3), 50 mg/kg (N=4), and 100 mg/kg (N=3), respectively. Mean time to peak serum levels was of 2.5 ± 1.3 hours, similar to that observed in adult patients. A good deal of interindividual variability was noted, which did not correlate with gestational age. Some patients had serum levels > 100 µg/mL, suggesting a need for drug level monitoring during therapy. In another study, serum concentrations were determined during flucytosine therapy in two patients (total assays performed =10). Median serum flucytosine concentrations at steady state were calculated to be 57 ± 10 µg/mL (doses of 50 to 125 mg/kg/day, normalized to 25 mg/kg per dose for comparison). In three infants receiving flucytosine 25 mg/kg/day (four divided doses), a median flucytosine half-life of 7.4 hours was observed, approximately double that seen in adult patients. The concentration of flucytosine in the cerebrospinal fluid of one infant was 43 µg/mL 3 hours after a 25 mg oral dose, and ranged from 20 to 67 mg/L in another neonate receiving oral doses of 120 to 150 mg/kg/day.
## Nonclinical Toxicology
- Flucytosine has not undergone adequate animal testing to evaluate carcinogenic potential. The mutagenic potential of flucytosine was evaluated in Ames-type studies with five different mutants of S. typhimurium and no mutagenicity was detected in the presence or absence of activating enzymes. Flucytosine was nonmutagenic in three different repair assay systems (i.e., rec, uvr and pol).
- There have been no adequate trials in animals on the effects of flucytosine on fertility or reproductive performance. The fertility and reproductive performance of the offspring (F1 generation) of mice treated with 100 mg/kg/day (345 mg/M2/day or 0.059 times the human dose), 200 mg/kg/day (690 mg/M2/day or 0.118 times the human dose) or 400 mg/kg/day (1380 mg/M2/day or 0.236 times the human dose) of flucytosine on days 7 to 13 of gestation was studied; the in utero treatment had no adverse effect on the fertility or reproductive performance of the offspring.
# Clinical Studies
There is limited information regarding Clinical Studies of Flucytosine in the drug label.
# How Supplied
Capsules, 250 mg (gray and green), imprinted ANCOBON® 250 ICN, bottles of 100 (NDC 0187-3554-10).
Capsules, 500 mg (gray and white), imprinted ANCOBON® 500 ICN, bottles of 100 (NDC 0187-3555-10).
## Storage
Store at 25°C (77°F); excursions permitted to 15°C - 30°C (59°F - 86°F).
# Images
## Drug Images
## Package and Label Display Panel
NDC 0187-3554-10
Rx Only
Ancobon®
(flucytosine)
250 mg
Each capsule
contains 250
mg flucytosine
100 Capsules
VALEANT
Pharmaceuticals North America LLC
NDC 0187-3555-10
Rx Only
Ancobon®
(flucytosine)
500 mg
Each capsule
contains 500
mg flucytosine
100 Capsules
VALEANT
Pharmaceuticals North America LLC
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Flucytosine in the drug label.
# Precautions with Alcohol
- Alcohol-Flucytosine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Ancobon®
# Look-Alike Drug Names
There is limited information regarding Flucytosine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Flucytosine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Adeel Jamil, M.D. [2]
# Disclaimer
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# Black Box Warning
# Overview
Flucytosine is a antifungal , anti-Infective agent that is FDA approved for the treatment of candidiasis and cryptococcosis. There is a Black Box Warning for this drug as shown here. Common adverse reactions include abdominal pain, diarrhea, nausea, vomiting, confusion, headache and hallucinations.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Ancobon is indicated only in the treatment of serious infections caused by susceptible strains of Candida and/or Cryptococcus.
- Candida: Septicemia, endocarditis and urinary system infections have been effectively treated with flucytosine. Limited trials in pulmonary infections justify the use of flucytosine.
- Cryptococcus: Meningitis and pulmonary infections have been treated effectively. Studies in septicemias and urinary tract infections are limited, but good responses have been reported.
- Ancobon should be used in combination with amphotericin B for the treatment of systemic candidiasis and cryptococcosis because of the emergence of resistance to Ancobon.
### Dosing Information
- The usual dosage of Ancobon is 50 to 150 mg/kg/day administered in divided doses at 6-hour intervals. Nausea or vomiting may be reduced or avoided if the capsules are given a few at a time over a 15-minute period. If the BUN or the serum creatinine is elevated, or if there are other signs of renal impairment, the initial dose should be at the lower level.
- Ancobon should be used in combination with amphotericin B for the treatment of systemic candidiasis and cryptococcosis because of the emergence of resistance to Ancobon.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Flucytosine in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Flucytosine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Flucytosine in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Flucytosine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Flucytosine in pediatric patients.
# Contraindications
- Ancobon should not be used in patients with a known hypersensitivity to the drug.
# Warnings
- Ancobon must be given with extreme caution to patients with impaired renal function. Since Ancobon is excreted primarily by the kidneys, renal impairment may lead to accumulation of the drug. Ancobon serum concentrations should be monitored to determine the adequacy of renal excretion in such patients. Dosage adjustments should be made in patients with renal insufficiency to prevent progressive accumulation of active drug.
- Ancobon must be given with extreme caution to patients with bone marrow depression. Patients may be more prone to depression of bone marrow function if they: 1) have a hematologic disease, 2) are being treated with radiation or drugs which depress bone marrow, or 3) have a history of treatment with such drugs or radiation. Bone marrow toxicity can be irreversible and may lead to death in immunosuppressed patients. Frequent monitoring of hepatic function and of the hematopoietic system is indicated during therapy.
### PRECAUTIONS
- Before therapy with Ancobon is instituted, electrolytes (because of hypokalemia) and the hematologic and renal status of the patient should be determined. Close monitoring of the patient during therapy is essential.
# Adverse Reactions
## Clinical Trials Experience
- The adverse reactions which have occurred during treatment with Ancobon are grouped according to organ system affected.
- Cardiac arrest, myocardial toxicity, ventricular dysfunction.
- Respiratory arrest, chest pain, dyspnea.
- Rash, pruritus, urticaria, photosensitivity.
- Nausea, emesis, abdominal pain, diarrhea, anorexia, dry mouth, duodenal ulcer, gastrointestinal hemorrhage, acute hepatic injury including hepatic necrosis with possible fatal outcome in debilitated patients, hepatic dysfunction, jaundice, ulcerative colitis, enterocolitis, bilirubin elevation, increased hepatic enzymes.
- Azotemia, creatinine and BUN elevation, crystalluria, renal failure.
- Anemia, agranulocytosis, aplastic anemia, eosinophilia, leukopenia, pancytopenia, thrombocytopenia, and fatal cases of bone marrow aplasia.
- Ataxia, hearing loss, headache, paresthesia, parkinsonism, peripheral neuropathy, pyrexia, vertigo, sedation, convulsions.
- Confusion, hallucinations, psychosis.
- Fatigue, hypoglycemia, hypokalemia, weakness, allergic reactions, Lyell’s syndrome.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Flucytosine in the drug label.
# Drug Interactions
- Cytosine arabinoside, a cytostatic agent, has been reported to inactivate the antifungal activity of Ancobon by competitive inhibition. Drugs which impair glomerular filtration may prolong the biological half-life of flucytosine.
- Since renal impairment can cause progressive accumulation of the drug, blood concentrations and kidney function should be monitored during therapy. Hematologic status (leucocyte and thrombocyte count) and liver function (alkaline phosphatase, SGOT and SGPT) should be determined at frequent intervals during treatment as indicated.
- Measurement of serum creatinine levels should be determined by the Jaffé reaction, since Ancobon does not interfere with the determination of creatinine values by this method. Most automated equipment for measurement of creatinine makes use of the Jaffé reaction.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Flucytosine was shown to be teratogenic (vertebral fusions) in the rat at doses of 40 mg/kg/day (298 mg/M2/day or 0.051 times the human dose) administered on days 7 to 13 of gestation. At higher doses (700 mg/kg/day; 5208 mg/M2/day or 0.89 times the human dose administered on days 9 to 12 of gestation), cleft lip and palate and micrognathia were reported. Flucytosine was not teratogenic in rabbits up to a dose of 100 mg/kg/day (1423 mg/M2/day or 0.243 times the human dose) administered on days 6 to 18 of gestation. In mice, 400 mg/kg/day of flucytosine (1380 mg/M2/day or 0.236 times the human dose) administered on days 7 to 13 of gestation was associated with a low incidence of cleft palate that was not statistically significant. Studies in pregnant rats have shown that flucytosine injected intraperitoneally crosses the placental barrier. There are no adequate and well-controlled studies in pregnant women. Ancobon should be used during pregnancy only if the potential benefit justifies the potential 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 Flucytosine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Flucytosine during labor and delivery.
### Nursing Mothers
- It is not known whether this drug is 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 Ancobon, 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
- The efficacy and safety of Ancobon have not been systematically studied in pediatric patients. A small number of neonates have been treated with 25 to 200 mg/kg/day of flucytosine, with and without the addition of amphotericin B, for systemic candidiasis. No unexpected adverse reactions were reported in these patients. It should be noted, however, that hypokalemia and acidemia were reported in one patient who received flucytosine in combination with amphotericin B, and anemia was observed in a second patient who received flucytosine alone. Transient thrombocytopenia was noted in two additional patients, one of whom also received amphotericin B.
### Geriatic Use
There is no FDA guidance on the use of Flucytosine with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Flucytosine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Flucytosine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Flucytosine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Flucytosine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Flucytosine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Flucytosine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- Ancobon must be given with extreme caution to patients with impaired renal function. Since Ancobon is excreted primarily by the kidneys, renal impairment may lead to accumulation of the drug. Ancobon serum concentrations should be monitored to determine the adequacy of renal excretion in such patients. Dosage adjustments should be made in patients with renal insufficiency to prevent progressive accumulation of active drug.
- Ancobon must be given with extreme caution to patients with bone marrow depression. Patients may be more prone to depression of bone marrow function if they: 1) have a hematologic disease, 2) are being treated with radiation or drugs which depress bone marrow, or 3) have a history of treatment with such drugs or radiation. Bone marrow toxicity can be irreversible and may lead to death in immunosuppressed patients. Frequent monitoring of hepatic function and of the hematopoietic system is indicated during therapy.
- Before therapy with Ancobon is instituted, electrolytes (because of hypokalemia) and the hematologic and renal status of the patient should be determined. Close monitoring of the patient during therapy is essential.
- Since renal impairment can cause progressive accumulation of the drug, blood concentrations and kidney function should be monitored during therapy. Hematologic status (leucocyte and thrombocyte count) and liver function (alkaline phosphatase, SGOT and SGPT) should be determined at frequent intervals during treatment as indicated.
# IV Compatibility
There is limited information regarding IV Compatibility of Flucytosine in the drug label.
# Overdosage
- There is no experience with intentional overdosage. It is reasonable to expect that overdosage may produce pronounced manifestations of the known clinical adverse reactions. Prolonged serum concentrations in excess of 100 µg/mL may be associated with an increased incidence of toxicity, especially gastrointestinal (diarrhea, nausea, vomiting), hematologic (leukopenia, thrombocytopenia) and hepatic (hepatitis).
- In the management of overdosage, prompt gastric lavage or the use of an emetic is recommended. Adequate fluid intake should be maintained, by the intravenous route if necessary, since Ancobon is excreted unchanged via the renal tract. The hematologic parameters should be monitored frequently; liver and kidney function should be carefully monitored. Should any abnormalities appear in any of these parameters, appropriate therapeutic measures should be instituted.
- Since hemodialysis has been shown to rapidly reduce serum concentrations in anuric patients, this method may be considered in the management of overdosage.
# Pharmacology
There is limited information regarding Flucytosine Pharmacology in the drug label.
## Mechanism of Action
- Flucytosine is taken up by fungal organisms via the enzyme cytosine permease. Inside the fungal cell, flucytosine is rapidly converted to fluorouracil by the enzyme cytosine deaminase. Fluorouracil exerts its antifungal activity through the subsequent conversion into several active metabolites, which inhibit protein synthesis by being falsely incorporated into fungal RNA or interfere with the biosynthesis of fungal DNA through the inhibition of the enzyme thymidylate synthetase.
## Structure
- Ancobon (flucytosine), an antifungal agent, is available as 250 mg and 500 mg capsules for oral administration. Each capsule also contains corn starch, lactose and talc. Gelatin capsule shells contain parabens (butyl, methyl, propyl) and sodium propionate, with the following dye systems: 250 mg capsules — black iron oxide, FD&C Blue No. 1, FD&C Yellow No. 6, D&C Yellow No. 10 and titanium dioxide; 500 mg capsules — black iron oxide and titanium dioxide. Chemically, flucytosine is 5-fluorocytosine, a fluorinated pyrimidine which is related to fluorouracil and floxuridine. It is a white to off-white crystalline powder with a molecular weight of 129.09 and the following structural formula:
## Pharmacodynamics
### Microbiology
- Flucytosine has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections.
- The following in vitro data are available, but their clinical significance is unknown.
- Flucytosine exhibits in vitro minimum inhibitory concentrations (MIC values) of 4 μg/mL, or less against most (≥90%) strains of the following microorganisms, however, the safety and effectiveness of flucytosine in treating clinical infections due to these microorganisms have not been established in adequate and well control trials.
- Candida dubliniensisCandida glabrataCandida guilliermondiiCandida lusitaniaeCandida parapsilosisCandida tropicalis
- Candida krusei should be considered to be resistant to flucytosine.
- In vitro activity of flucytosine is affected by the test conditions. It is essential to follow the approved standard method guidelines.1
### Susceptibility Testing Methods
- No interpretive criteria have been established for Cryptococcus neoformans.
- Broth Dilution Techniques:
- Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of Candida spp. to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method (broth)1 with standardized inoculum concentrations and standardized concentrations of flucytosine powder. The MIC values should be interpreted according to the criteria in Table 1.
- A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentration usually achievable. A report of "Intermediate" indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where a high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentration usually achievable; other therapy should be selected. Because of other significant host factors, in vitro susceptibility may not correlate with clinical outcomes.
- Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard flucytosine powder should provide the range of MIC values noted in Table 2. NOTE: Quality control microorganisms are specific strains of organisms with intrinsic biological properties relating to resistance mechanisms and their genetic expression within fungi; the specific strains used for microbiological control are not clinically significant.
- Flucytosine resistance may arise from a mutation of an enzyme necessary for the cellular uptake or metabolism of flucytosine or from an increased synthesis of pyrimidines, which compete with the active metabolites of flucytosine (fluorinated antimetabolites). Resistance to flucytosine has been shown to develop during monotherapy after prolonged exposure to the drug.
- Candida krusei should be considered to be resistant to flucytosine.
- Antifungal synergism between flucytosine and polyene antibiotics, particularly amphotericin B has been reported in vitro. Ancobon is usually administered in combination with amphotericin B due to lack of cross-resistance and reported synergistic activity of both drugs.
## Pharmacokinetics
- Flucytosine is rapidly and virtually completely absorbed following oral administration. Ancobon is not metabolized significantly when given orally to man. Bioavailability estimated by comparing the area under the curve of serum concentrations after oral and intravenous administration showed 78% to 89% absorption of the oral dose. Peak serum concentrations of 30 to 40 µg/mL were reached within 2 hours of administration of a 2 g oral dose to normal subjects. Other studies revealed mean serum concentrations of approximately 70 to 80 μg/mL 1 to 2 hours after a dose in patients with normal renal function receiving a 6-week regimen of flucytosine (150 mg/kg/day given in divided doses every 6 hours) in combination with amphotericin B. The half-life in the majority of healthy subjects ranged between 2.4 and 4.8 hours. Flucytosine is excreted via the kidneys by means of glomerular filtration without significant tubular reabsorption. More than 90% of the total radioactivity after oral administration was recovered in the urine as intact drug. Flucytosine is deaminated (probably by gut bacteria) to 5-fluorouracil. The area under the curve (AUC) ratio of 5-fluorouracil to flucytosine is 4%. Approximately 1% of the dose is present in the urine as the α-fluoro-β-ureido-propionic acid metabolite. A small portion of the dose is excreted in the feces.
- The half-life of flucytosine is prolonged in patients with renal insufficiency; the average half-life in nephrectomized or anuric patients was 85 hours (range: 29.9 to 250 hours). A linear correlation was found between the elimination rate constant of flucytosine and creatinine clearance.
- In vitro studies have shown that 2.9% to 4% of flucytosine is protein-bound over the range of therapeutic concentrations found in the blood. Flucytosine readily penetrates the blood-brain barrier, achieving clinically significant concentrations in cerebrospinal fluid.
- Limited data are available regarding the pharmacokinetics of Ancobon administered to neonatal patients being treated for systemic candidiasis. After five days of continuous therapy, median peak levels in infants were 19.6 µg/mL, 27.7 µg/mL, and 83.9 µg/mL at doses of 25 mg/kg (N=3), 50 mg/kg (N=4), and 100 mg/kg (N=3), respectively. Mean time to peak serum levels was of 2.5 ± 1.3 hours, similar to that observed in adult patients. A good deal of interindividual variability was noted, which did not correlate with gestational age. Some patients had serum levels > 100 µg/mL, suggesting a need for drug level monitoring during therapy. In another study, serum concentrations were determined during flucytosine therapy in two patients (total assays performed =10). Median serum flucytosine concentrations at steady state were calculated to be 57 ± 10 µg/mL (doses of 50 to 125 mg/kg/day, normalized to 25 mg/kg per dose for comparison). In three infants receiving flucytosine 25 mg/kg/day (four divided doses), a median flucytosine half-life of 7.4 hours was observed, approximately double that seen in adult patients. The concentration of flucytosine in the cerebrospinal fluid of one infant was 43 µg/mL 3 hours after a 25 mg oral dose, and ranged from 20 to 67 mg/L in another neonate receiving oral doses of 120 to 150 mg/kg/day.
## Nonclinical Toxicology
- Flucytosine has not undergone adequate animal testing to evaluate carcinogenic potential. The mutagenic potential of flucytosine was evaluated in Ames-type studies with five different mutants of S. typhimurium and no mutagenicity was detected in the presence or absence of activating enzymes. Flucytosine was nonmutagenic in three different repair assay systems (i.e., rec, uvr and pol).
- There have been no adequate trials in animals on the effects of flucytosine on fertility or reproductive performance. The fertility and reproductive performance of the offspring (F1 generation) of mice treated with 100 mg/kg/day (345 mg/M2/day or 0.059 times the human dose), 200 mg/kg/day (690 mg/M2/day or 0.118 times the human dose) or 400 mg/kg/day (1380 mg/M2/day or 0.236 times the human dose) of flucytosine on days 7 to 13 of gestation was studied; the in utero treatment had no adverse effect on the fertility or reproductive performance of the offspring.
# Clinical Studies
There is limited information regarding Clinical Studies of Flucytosine in the drug label.
# How Supplied
Capsules, 250 mg (gray and green), imprinted ANCOBON® 250 ICN, bottles of 100 (NDC 0187-3554-10).
Capsules, 500 mg (gray and white), imprinted ANCOBON® 500 ICN, bottles of 100 (NDC 0187-3555-10).
## Storage
Store at 25°C (77°F); excursions permitted to 15°C - 30°C (59°F - 86°F).
# Images
## Drug Images
## Package and Label Display Panel
NDC 0187-3554-10
Rx Only
Ancobon®
(flucytosine)
250 mg
Each capsule
contains 250
mg flucytosine
100 Capsules
VALEANT
Pharmaceuticals North America LLC
NDC 0187-3555-10
Rx Only
Ancobon®
(flucytosine)
500 mg
Each capsule
contains 500
mg flucytosine
100 Capsules
VALEANT
Pharmaceuticals North America LLC
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Flucytosine in the drug label.
# Precautions with Alcohol
- Alcohol-Flucytosine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Ancobon®
# Look-Alike Drug Names
There is limited information regarding Flucytosine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/5-Fluorocytosine |
Subsets and Splits