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f8eee61fd4cacea01e50f345431ca9c7edc25d13 | wikidoc | Fenoldopam | Fenoldopam
# 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
Fenoldopam is a dopaminergic agonist that is FDA approved for the treatment of severe hypertension when rapid, but quickly reversible, emergency reduction of blood pressure is clinically indicated. Common adverse reactions include hypotension, tachycardia, flushing, nausea, headache.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- The optimal magnitude and rate of blood pressure reduction in acutely hypertensive patients have not been rigorously determined, but, in general, both delay and too rapid decreases appear undesirable in sick adult patients. An initial fenoldopam dose may be chosen from Tables 2 and 3 below in the Clinical studies section that produces the desired magnitude and rate of blood pressure reduction in a given clinical situation. Doses below 0.1 mcg/kg/min have very modest effects and appear only marginally useful in this population. In general, as the initial dose increases, there is a greater and more rapid blood pressure reduction. However, lower initial doses (0.03 to 0.1 mcg/kg/min) titrated slowly have been associated with less reflex tachycardia than have higher initial doses (≥ 0.3 mcg/kg/min). In clinical trials, doses from 0.01 to 1.6 mcg/kg/min have been studied. Most of the effect of a given infusion rate is attained in 15 minutes.
- Fenoldopam should be administered by continuous intravenous infusion. A bolus dose should not be used. Hypotension and rapid decreases of blood pressure should be avoided. The initial dose should be titrated upward or downward, no more frequently than every 15 minutes (and less frequently as goal pressure is approached) to achieve the desired therapeutic effect. The recommended increments for titration are 0.05 to 0.1 mcg/kg/min.
- Use of a calibrated, mechanical infusion pump is recommended for proper control of infusion rate during fenoldopam infusion. In clinical trials, fenoldopam treatment was safely performed without the need for intra-arterial blood pressure monitoring; blood pressure and heart rate were monitored at frequent intervals, typically every 15 minutes. Frequent blood pressure monitoring is recommended.
- Fenoldopam infusion can be abruptly discontinued or gradually tapered prior to discontinuation. Oral antihypertensive agents can be added during fenoldopam infusion or following its discontinuation. Patients in controlled clinical trials have received intravenous fenoldopam for as long as 48 hours.
Warning: contents of ampules must be diluted before infusion. Each ampule is for single use only.
Dilution:
- The fenoldopam injection ampule concentrate must be diluted in 0.9% Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP, using the following dilution schedule:
- The drug dose rate must be individualized according to body weight and according to the desired rapidity and extent of pharmacodynamic effect. Table 5 provides the calculated infusion volume in mL/hour for a range of drug doses and body weights. The infusion should be administered using a calibrated mechanical infusion pump that can accurately and reliably deliver the desired infusion rate.
Infusion rates:
- The diluted solution is stable under normal ambient light and temperature conditions for at least 24 hours. Diluted solution that is not used within 24 hours of preparation should be discarded. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If particulate matter or cloudiness is observed, the drug should be discarded.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Fenoldopam in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- Infusion of 0.1 mcg/kg/min.
- Dosing information
- 0.03 mcg/kg/min infusion administered via central catheter during anesthesia induction. The infusion should be maintained thought all the surgical time and continued until patient stabilization during the postoperative period.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Fenoldopam should be administered intravenously to pediatric patients by a continuous infusion pump appropriate for the delivery of low infusion rates.
- Monitoring of blood pressure should be continuous, usually by way of an intra-arterial line. Heart rate should also be continuously monitored. In the clinical trial, the usual starting dose was 0.2 mcg/kg/min with an effect on MAP evident within 5 minutes. At a constant infusion rate the effect was maximal after 20 to 25 minutes. Increased dosages of up to 0.3 to 0.5 mcg/kg/min every 20 to 30 minutes were generally well tolerated. Tachycardia without further decrease in MAP occurred at dosages greater than 0.8 mcg/kg/min. Upon discontinuation of the fenoldopam infusion after an average of 4 hours of therapy, blood pressure and heart rate returned to near baseline within 30 minutes.
Warning: contents of ampules must be diluted before infusion. Each ampule is for single use only.
Dilution:
- Table below provides the calculated infusion volume in mL/hour for a range of drug doses and body weights. The infusion should be administered using a calibrated mechanical infusion pump that can accurately and reliably deliver the desired infusion rate. As low flow rates (e.g., <0.5 mL/hr) may not be practical, and due to volume overload, it may be necessary to increase the concentration of fenoldopam in the infused solutions.
- The diluted solution is stable under normal ambient light and temperature conditions for at least 24 hours. Diluted solution that is not used within 24 hours of preparation should be discarded. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If particulate matter or cloudiness is observed, the drug should be discarded.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Fenoldopam in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Fenoldopam in pediatric patients.
# Contraindications
There is limited information provided by the label regarding the contraindications of fenoldopam.
# Warnings
- Contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people.
- Intraocular Pressure: In a clinical study of 12 patients with open-angle glaucoma or intraocular hypertension (mean baseline intraocular pressure was 29.2 mm Hg with a range of 22 to 33 mm Hg), infusion of fenoldopam at escalating doses ranging from 0.05 to 0.5 mcg/kg/min over a 3.5 hour period caused a dose-dependent increase in intraocular pressure (IOP). At the peak effect, the intraocular pressure was raised by a mean of 6.5 mm Hg (range -2 to +8.5 mm Hg, corrected for placebo effect). Upon discontinuation of the fenoldopam infusion, the IOP returned to baseline values within 2 hours. Fenoldopam administration to patients with glaucoma or intraocular hypertension should be undertaken with caution.
- Tachycardia: Fenoldopam causes a dose-related tachycardia (Table 2 and Table 3), particularly with infusion rates above 0.1 mcg/kg/min. Tachycardia in adults diminishes over time but remains substantial at higher doses. Tachycardia in pediatric patients at doses > 0.8 mcg/kg/min persists at least for 4 hours.
- Hypotension: Fenoldopam may occasionally produce symptomatic hypotension and close monitoring of blood pressure during administration is essential. It is particularly important to avoid systemic hypotension when administering the drug to patients who have sustained an acute cerebral infarction or acute cerebral hemorrhage. In pediatric patients, fenoldopam was only administered to patients with an indwelling intraarterial line.
- Hypokalemia: Decreases in serum potassium occasionally to values below 3 mEq/L were observed after less than 6 hours of fenoldopam infusion. It is not clear if the hypokalemia reflects a pressure natriuresis with enhanced potassium-sodium exchange or a direct drug effect. During clinical trials, electrolytes were monitored at intervals of 6 hours. Hypokalemia was treated with either oral or intravenous potassium supplementation. Patient management should include appropriate attention to serum electrolytes.
- Intracranial Pressure: The effect of fenoldopam in the presence of increased intracranial pressure has not been studied.
# Adverse Reactions
## Clinical Trials Experience
### Adult Patients
- Fenoldopam causes a dose-related fall in blood pressure and increase in heart rate. In controlled clinical studies of severe hypertension in patients with end-organ damage, 3% (4/137) of patients withdrew because of excessive falls in blood pressure. Increased heart rate could, in theory, lead to ischemic cardiac events or worsened heart failure, although these events have not been observed.
- The most common events reported as associated with fenoldopam use are headache, cutaneous dilation (flushing), nausea, and hypotension, each reported in more than 5% of patients.
- Adverse events occurring more than once in any dosing group (once if potentially important or plausibly drug-related) in the fixed-dose constant-infusion studies are presented in the following Table by infusion-rate group. There was no clear dose relationship, except possibly for headache, nausea, flushing.
- The adverse event incidences listed below are based on observations of over 1,000 fenoldopam treated adult patients and not listed in the table above.
Events reported with a frequency between 0.5 to 5% in patients treated with IV fenoldopam:
Cardiovascular: Extrasystoles, palpitations, bradycardia, heart failure, ischemic heart disease, myocardial infarction, angina pectoris.
Metabolic: Elevated BUN, elevated serum glucose, elevated transaminase, elevated LDH.
General Body: Non-specific chest pain, pyrexia.
Hematologic/Lymphatic: Leukocytosis, bleeding.
Respiratory: Dyspnea, upper respiratory disorder.
Genitourinary: Oliguria.
Musculoskeletal: Limb cramp.
### Pediatric Patients
- In pediatric patients, the most common adverse events reported during short-term administration in controlled trials (30 minutes) were hypotension and tachycardia. However, because of the short exposure, there is limited experience with defining adverse events in children. The long-term effects of fenoldopam on growth and development have not been studied.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Fenoldopam in the drug label.
# Drug Interactions
- Beta-Blockers: Concomitant use of fenoldopam with beta blockers should be avoided. If the drugs are used together, caution should be exercised because unexpected hypotension could result from beta blocker inhibition of the sympathetic reflex response to fenoldopam.
- There is limited experience with concomitant antihypertensive agents such as alpha blockers, calcium channel blockers, ACE inhibitors, and diuretics (both thiazide-like and loop).
- Intravenous fenoldopam has been administered safely with drugs such as digitalis and sublingual nitroglycerin.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
- Oral reproduction studies have been performed in rats and rabbits at doses of 12.5 to 200 mg/kg/day and 6.25 to 25 mg/kg/day, respectively. Studies have revealed maternal toxicity at the highest doses tested but no evidence of impaired fertility or harm to the fetus due to fenoldopam. However, there are no adequate and well-controlled studies in pregnant women. Since animal reproduction studies are not always predictive of human response, fenoldopam should be used in pregnancy only if clearly needed.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Fenoldopam in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Fenoldopam during labor and delivery.
### Nursing Mothers
Fenoldopam is excreted in milk in rats. 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 fenoldopam is administered to a nursing woman.
### Pediatric Use
- Anti-hypertensive effects of fenoldopam have been studied in pediatric patients age < 1 month (at least 2 kg or full term) to 12 years old requiring blood pressure reduction.
- Clinical studies of fenoldopam did not include subjects ages 12 to 16 years of age to determine if they respond differently from younger subjects or adults. The pharmacokinetics of fenoldopam are independent of age when corrected for body weight. - Dose selection for patients 12 to 16 years of age should consider the patient's clinical condition and concomitant drug therapy.
### Geriatic Use
- Clinical studies of fenoldopam 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 responses 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.
### Gender
There is no FDA guidance on the use of Fenoldopam with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Fenoldopam with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Fenoldopam in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Fenoldopam in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Fenoldopam in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Fenoldopam in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
### Monitoring
Frequent blood pressure monitoring is recommended.
# IV Compatibility
Fenoldopam is compatible with:
- 0.9% Sodium Chloride.
- 5% Dextrose.
# Overdosage
- Intentional fenoldopam overdosage has not been reported. The most likely reaction would be excessive hypotension which should be treated with drug discontinuation and appropriate supportive measures.
# Pharmacology
## Mechanism of Action
- Fenoldopam is a rapid-acting vasodilator. It is an agonist for D1-like dopamine receptors and binds with moderate affinity to α2-adrenoceptors. It has no significant affinity for D2-like receptors, α1 and β adrenoceptors, 5HT1 and 5HT2 receptors, or muscarinic receptors. Fenoldopam is a racemic mixture with the R-isomer responsible for the biological activity. The R-isomer has approximately 250-fold higher affinity for D1-like receptors than does the S-isomer. In non-clinical studies, fenoldopam had no agonist effect on presynaptic D2-like dopamine receptors, or α- or β-adrenoceptors, nor did it affect angiotensin-converting enzyme activity. Fenoldopam may increase norepinephrine plasma concentration.
## Structure
- Corlopam (Fenoldopam Mesylate Injection, USP) is a dopamine D1-like receptor agonist. The product is formulated as a solution to be diluted for intravenous infusion. Chemically it is 6-chloro-2,3,4,5-tetrahydro-1-(4-hydroxyphenyl)--3-benzazepine-7,8-diol methanesulfonate with the following structure:
- Fenoldopam mesylate is a white to off-white powder with a molecular weight of 401.87 and a molecular formula of C16H16ClNO3CH3SO3H. It is sparingly soluble in water, ethanol and methanol, and is soluble in propylene glycol.
- Ampules: Each 1 mL contains, in sterile aqueous solution, citric acid 3.44 mg; fenoldopam mesylate equivalent to fenoldopam 10 mg; propylene glycol 518 mg; sodium citrate dihydrate 0.61 mg; sodium metabisulfite 1 mg.
## Pharmacodynamics
- In a randomized double-blind, placebo-controlled, 5-group study in 32 patients with mild to moderate essential hypertension (diastolic blood pressure between 95 and 119 mm Hg), and a mean baseline pressure of about 154/98 mm Hg, and heart rate of about 75 bpm, fixed-rate IV infusions of fenoldopam produced dose-related reductions in systolic blood pressures and diastolic blood pressures.
- In animals, fenoldopam has vasodilating effects in coronary, renal, mesenteric and peripheral arteries. All vascular beds, however, do not respond uniformly to fenoldopam. Vasodilating effects have been demonstrated in renal efferent and afferent arterioles.
## Pharmacokinetics
- Adult Patients: Fenoldopam, administered as a constant infusion at dosages of 0.01 to 1.6 mcg/kg/min, produced steady-state plasma concentrations that were proportional to infusion rates. The elimination half-life was about 5 minutes in mild to moderate hypertensives, with little difference between the R (active) and S isomers. Steady state concentrations are attained in about 20 minutes (4 half-lives). - The steady state plasma concentrations of fenoldopam, at comparable infusion rates, were similar in normotensive patients and in patients with mild to moderate hypertension or hypertensive emergencies.
- The pharmacokinetics of fenoldopam were not influenced by age, gender, or race in adult patients with a hypertensive emergency. There have been no formal drug-drug interaction studies using intravenous fenoldopam. Clearance of parent (active) fenoldopam is not altered in adult patients with end-stage renal disease on continuous ambulatory peritoneal dialysis (CAPD) and is not altered in adult patients with severe hepatic failure. The effects of hemodialysis on the pharmacokinetics of fenoldopam have not been evaluated.
- Pediatric Patients: In children, aged 1 month to 12 years old, steady-state fenoldopam plasma concentrations were proportional to dose (0.05 mcg/kg/min to 3.2 mcg/kg/min). The elimination half-life and clearance were 3 to 5 minutes and 3 L/h/kg, respectively.
- In radiolabeled studies in rats, no more than 0.005% of fenoldopam crossed the blood-brain barrier.
- Radiolabeled studies show that about 90% of infused fenoldopam is eliminated in urine, 10% in feces. Elimination is largely by conjugation, without participation of cytochrome P-450 enzymes. The principal routes of conjugation are methylation, glucuronidation, and sulfation. Only 4% of the administered dose is excreted unchanged. Animal data indicate that the metabolites are inactive.
## Nonclinical Toxicology
- In a 24-month study, mice treated orally with fenoldopam at 12.5, 25, or 50 mg/kg/day, reduced to 25 mg/kg/day on day 209 of study, showed no increase above controls in the incidence of neoplasms. Female mice in the highest dose group had an increased incidence and degree of severity of a fibro-osseous lesion of the sternum compared with control or low-dose animals. Compared to controls, female mice in the middle- and upper-dose groups had a higher incidence and degree of severity of chronic nephritis. These pathologic lesions were not seen in male mice treated with fenoldopam.
- In a 24-month study, rats treated orally with fenoldopam at 5, 10 or 20 mg/kg/day, with the mid- and high-dose groups increased to 15 or 25 mg/kg/day, respectively, on day 372 of the study, showed no increase above controls in the incidence or type of neoplasms. Compared with the controls, rats in the mid- and high-dose groups had a higher incidence of hyperplasia of collecting duct epithelium at the tip of the renal papilla.
- Fenoldopam did not induce bacterial gene mutation in the Ames test or mammalian gene mutation in the Chinese hamster ovary (CHO) cell assay. In the in vitro chromosomal aberration assay with CHO cells, fenoldopam was associated with statistically significant and dose-dependent increases in chromosomal aberrations, and in the proportion of aberrant metaphases. However, no chromosomal damage was seen in the in vivo mice micronucleus or bone marrow assays.
- Oral fertility and general reproduction performance studies in male and female rats at 12.5, 37.5 or 75 mg/kg/day revealed no impairment of fertility or reproduction performance due to fenoldopam.
- Unusual toxicologic findings (arterial lesions in the rat) with fenoldopam are summarized below. These findings have not been observed in mice or dogs. No evidence of a similar lesion in humans has been observed.
- Arterial lesions characterized by medial necrosis and hemorrhage have been seen in renal and splanchnic arteries of rats given fenoldopam mesylate by continuous intravenous infusion at doses of 1 to 100 mcg/kg/min for 24 hours. The incidence of these lesions is dose related. Arterial lesions morphologically identical to those observed with fenoldopam have been reported in rats infused with dopamine. Data suggest that the mechanism for this injury involves activation of D1-like dopaminergic receptors. Such lesions have not been seen in dogs given doses up to 100 mcg/kg/min by continuous intravenous infusion for 24 hours, nor were they seen in dogs infused at the same dose for 6 hours daily for 24 days. The clinical significance of this finding is not known.
- Oral administration of fenoldopam doses of 10 to 15 mg/kg/day or 20 to 25 mg/kg/day to rats for 24 months induced a higher incidence of polyarteritis nodosa compared to controls. Such lesions were not seen in rats given 5 mg/kg/day of fenoldopam or in mice given the drug at doses up to 50 mg/kg/day for 24 months.
# Clinical Studies
- In a randomized double-blind, placebo-controlled, 5-group study in 32 patients with mild to moderate essential hypertension (diastolic blood pressure between 95 and 119 mm Hg), and a mean baseline pressure of about 154/98 mm Hg, and heart rate of about 75 bpm, fixed-rate IV infusions of fenoldopam produced dose-related reductions in systolic and diastolic blood pressures. Infusions were maintained at a fixed rate for 48 hours. The table below shows the results of the study. The onset of response was rapid at all infusion rates, with the 15-minute response representing 50 to 100% of the 1 hour response in all groups. There was some suggestion of partial tolerance at 48 hours in the 2 higher dose infusions, but a substantial effect persisted through 48 hours. When infusions were stopped, blood pressure gradually returned to pretreatment values with no evidence of rebound.
- This study suggests that there is no greater response to 0.8 mcg/kg/min than to 0.4 mcg/kg/min.
- In a multicenter, randomized, double-blind comparison of four infusion rates, fenoldopam was administered as constant rate infusions of 0.01, 0.03, 0.1 and 0.3 mcg/kg/min for up to 24 hours to 94 adult patients experiencing hypertensive emergencies (defined as diastolic blood pressure ≥ 120 mm Hg with evidence of compromise of end-organ function involving the cardiovascular, renal, cerebral or retinal systems). Infusion rates could be doubled after one hour if clinically indicated. There were dose-related, rapid-onset, decreases in systolic and diastolic blood pressures and increases in heart rate.
- Two hundred thirty-six (236) severely hypertensive adult patients (DBP ≥ 120 mm Hg), with or without end-organ compromise, were randomized to receive in 2 open-label studies either fenoldopam or nitroprusside. The response rate was 79% (92/117) in the fenoldopam group and 77% (90/119) in the nitroprusside group. Response required a decline in supine diastolic blood pressure to less than 110 mm Hg if the baseline were between 120 and 150 mm Hg, inclusive, or by ≥ 40 mm Hg if the baseline were ≥ 150 mm Hg. Patients were titrated to the desired effect. For fenoldopam, the dose ranged from 0.1 to 1.5 mcg/kg/min; for nitroprusside, the dose ranged from 1 to 8 mcg/kg/min. As in the study in mild to moderate hypertensives, most of the effect seen at 1 hour is present at 15 minutes. The additional effect seen after 1 hour occurs in all groups and may not be drug-related (there was no placebo group for evaluation).
- In a randomized, multi-center, double-blind, placebo-controlled, dose-ranging study, pediatric patients were randomized in equal proportions to 1 of 5 treatment groups: 0.05, 0.2, 0.8, or 3.2 mcg/kg/min fenoldopam or placebo. Fenoldopam or placebo was administered as a blinded continuous IV infusion for 30 minutes. Following this, open-label titration of fenoldopam was given to induce hypotension or normotension (defined as mean arterial pressure, MAP, between 50 and 80 mmHg for patients > 1 month of age and MAP between 40 and 70 mmHg for patients ≤ 1 month). Seventy-seven pediatric patients (up to 12 years of age – Tanner Stages 1 and 2) were treated for at least two hours. Of these, 2 were < 1 month of age, 25 were between 1 month of age and 1 year of age, 7 were between 1 and 2 years of age, and 43 were between 2 and 12 years of age. Of the 77 patients enrolled in the trial, 58 were enrolled in association with surgery, and 19 were treated in an ICU setting.
- The lowest dosage at which decreases in MAP were seen during blinded administration was 0.2 mcg/kg/min. The dose at which the maximum effect was seen was 0.8 mcg/kg/min. - Doses higher than 0.8 mcg/kg/min generally produced no further decreases in MAP but did worsen tachycardia (Table 3). Changes in blood pressure and heart rate occurred as early as 5 minutes after starting infusion. Doses as high as 4 mcg/kg/min were administered during the open-label period. The effects increased with time for 15 to 25 minutes, and an effect could still be detected after an average of 4 hours of infusion. When the infusion was discontinued, blood pressure and heart rates approached baseline values during the following 30 minutes.
# How Supplied
- Single-dose ampule: 10 mg/mL, 1 mL (one per carton).
- Single-dose ampule: 10 mg/mL, 2 mL (one per carton).
## Storage
- Store at 2 to 30°C (35.6 to 86°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Fenoldopam in the drug label.
# Precautions with Alcohol
- Alcohol-Fenoldopam interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- CORLOPAM®
# Look-Alike Drug Names
There is limited information regarding Fenoldopam Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Fenoldopam
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alonso Alvarado, M.D. [2]; Sheng Shi, M.D. [3]; Ammu Susheela, M.D. [4]
# 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
Fenoldopam is a dopaminergic agonist that is FDA approved for the treatment of severe hypertension when rapid, but quickly reversible, emergency reduction of blood pressure is clinically indicated. Common adverse reactions include hypotension, tachycardia, flushing, nausea, headache.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- The optimal magnitude and rate of blood pressure reduction in acutely hypertensive patients have not been rigorously determined, but, in general, both delay and too rapid decreases appear undesirable in sick adult patients. An initial fenoldopam dose may be chosen from Tables 2 and 3 below in the Clinical studies section that produces the desired magnitude and rate of blood pressure reduction in a given clinical situation. Doses below 0.1 mcg/kg/min have very modest effects and appear only marginally useful in this population. In general, as the initial dose increases, there is a greater and more rapid blood pressure reduction. However, lower initial doses (0.03 to 0.1 mcg/kg/min) titrated slowly have been associated with less reflex tachycardia than have higher initial doses (≥ 0.3 mcg/kg/min). In clinical trials, doses from 0.01 to 1.6 mcg/kg/min have been studied. Most of the effect of a given infusion rate is attained in 15 minutes.
- Fenoldopam should be administered by continuous intravenous infusion. A bolus dose should not be used. Hypotension and rapid decreases of blood pressure should be avoided. The initial dose should be titrated upward or downward, no more frequently than every 15 minutes (and less frequently as goal pressure is approached) to achieve the desired therapeutic effect. The recommended increments for titration are 0.05 to 0.1 mcg/kg/min.
- Use of a calibrated, mechanical infusion pump is recommended for proper control of infusion rate during fenoldopam infusion. In clinical trials, fenoldopam treatment was safely performed without the need for intra-arterial blood pressure monitoring; blood pressure and heart rate were monitored at frequent intervals, typically every 15 minutes. Frequent blood pressure monitoring is recommended.
- Fenoldopam infusion can be abruptly discontinued or gradually tapered prior to discontinuation. Oral antihypertensive agents can be added during fenoldopam infusion or following its discontinuation. Patients in controlled clinical trials have received intravenous fenoldopam for as long as 48 hours.
Warning: contents of ampules must be diluted before infusion. Each ampule is for single use only.
Dilution:
- The fenoldopam injection ampule concentrate must be diluted in 0.9% Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP, using the following dilution schedule:
- The drug dose rate must be individualized according to body weight and according to the desired rapidity and extent of pharmacodynamic effect. Table 5 provides the calculated infusion volume in mL/hour for a range of drug doses and body weights. The infusion should be administered using a calibrated mechanical infusion pump that can accurately and reliably deliver the desired infusion rate.
Infusion rates:
- The diluted solution is stable under normal ambient light and temperature conditions for at least 24 hours. Diluted solution that is not used within 24 hours of preparation should be discarded. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If particulate matter or cloudiness is observed, the drug should be discarded.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Fenoldopam in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- Infusion of 0.1 mcg/kg/min.[1]
- Dosing information
- 0.03 mcg/kg/min infusion administered via central catheter during anesthesia induction. The infusion should be maintained thought all the surgical time and continued until patient stabilization during the postoperative period.[2]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Fenoldopam should be administered intravenously to pediatric patients by a continuous infusion pump appropriate for the delivery of low infusion rates.
- Monitoring of blood pressure should be continuous, usually by way of an intra-arterial line. Heart rate should also be continuously monitored. In the clinical trial, the usual starting dose was 0.2 mcg/kg/min with an effect on MAP evident within 5 minutes. At a constant infusion rate the effect was maximal after 20 to 25 minutes. Increased dosages of up to 0.3 to 0.5 mcg/kg/min every 20 to 30 minutes were generally well tolerated. Tachycardia without further decrease in MAP occurred at dosages greater than 0.8 mcg/kg/min. Upon discontinuation of the fenoldopam infusion after an average of 4 hours of therapy, blood pressure and heart rate returned to near baseline within 30 minutes.
Warning: contents of ampules must be diluted before infusion. Each ampule is for single use only.
Dilution:
- Table below provides the calculated infusion volume in mL/hour for a range of drug doses and body weights. The infusion should be administered using a calibrated mechanical infusion pump that can accurately and reliably deliver the desired infusion rate. As low flow rates (e.g., <0.5 mL/hr) may not be practical, and due to volume overload, it may be necessary to increase the concentration of fenoldopam in the infused solutions.
- The diluted solution is stable under normal ambient light and temperature conditions for at least 24 hours. Diluted solution that is not used within 24 hours of preparation should be discarded. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If particulate matter or cloudiness is observed, the drug should be discarded.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Fenoldopam in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Fenoldopam in pediatric patients.
# Contraindications
There is limited information provided by the label regarding the contraindications of fenoldopam.
# Warnings
- Contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people.
- Intraocular Pressure: In a clinical study of 12 patients with open-angle glaucoma or intraocular hypertension (mean baseline intraocular pressure was 29.2 mm Hg with a range of 22 to 33 mm Hg), infusion of fenoldopam at escalating doses ranging from 0.05 to 0.5 mcg/kg/min over a 3.5 hour period caused a dose-dependent increase in intraocular pressure (IOP). At the peak effect, the intraocular pressure was raised by a mean of 6.5 mm Hg (range -2 to +8.5 mm Hg, corrected for placebo effect). Upon discontinuation of the fenoldopam infusion, the IOP returned to baseline values within 2 hours. Fenoldopam administration to patients with glaucoma or intraocular hypertension should be undertaken with caution.
- Tachycardia: Fenoldopam causes a dose-related tachycardia (Table 2 and Table 3), particularly with infusion rates above 0.1 mcg/kg/min. Tachycardia in adults diminishes over time but remains substantial at higher doses. Tachycardia in pediatric patients at doses > 0.8 mcg/kg/min persists at least for 4 hours.
- Hypotension: Fenoldopam may occasionally produce symptomatic hypotension and close monitoring of blood pressure during administration is essential. It is particularly important to avoid systemic hypotension when administering the drug to patients who have sustained an acute cerebral infarction or acute cerebral hemorrhage. In pediatric patients, fenoldopam was only administered to patients with an indwelling intraarterial line.
- Hypokalemia: Decreases in serum potassium occasionally to values below 3 mEq/L were observed after less than 6 hours of fenoldopam infusion. It is not clear if the hypokalemia reflects a pressure natriuresis with enhanced potassium-sodium exchange or a direct drug effect. During clinical trials, electrolytes were monitored at intervals of 6 hours. Hypokalemia was treated with either oral or intravenous potassium supplementation. Patient management should include appropriate attention to serum electrolytes.
- Intracranial Pressure: The effect of fenoldopam in the presence of increased intracranial pressure has not been studied.
# Adverse Reactions
## Clinical Trials Experience
### Adult Patients
- Fenoldopam causes a dose-related fall in blood pressure and increase in heart rate. In controlled clinical studies of severe hypertension in patients with end-organ damage, 3% (4/137) of patients withdrew because of excessive falls in blood pressure. Increased heart rate could, in theory, lead to ischemic cardiac events or worsened heart failure, although these events have not been observed.
- The most common events reported as associated with fenoldopam use are headache, cutaneous dilation (flushing), nausea, and hypotension, each reported in more than 5% of patients.
- Adverse events occurring more than once in any dosing group (once if potentially important or plausibly drug-related) in the fixed-dose constant-infusion studies are presented in the following Table by infusion-rate group. There was no clear dose relationship, except possibly for headache, nausea, flushing.
- The adverse event incidences listed below are based on observations of over 1,000 fenoldopam treated adult patients and not listed in the table above.
Events reported with a frequency between 0.5 to 5% in patients treated with IV fenoldopam:
Cardiovascular: Extrasystoles, palpitations, bradycardia, heart failure, ischemic heart disease, myocardial infarction, angina pectoris.
Metabolic: Elevated BUN, elevated serum glucose, elevated transaminase, elevated LDH.
General Body: Non-specific chest pain, pyrexia.
Hematologic/Lymphatic: Leukocytosis, bleeding.
Respiratory: Dyspnea, upper respiratory disorder.
Genitourinary: Oliguria.
Musculoskeletal: Limb cramp.
### Pediatric Patients
- In pediatric patients, the most common adverse events reported during short-term administration in controlled trials (30 minutes) were hypotension and tachycardia. However, because of the short exposure, there is limited experience with defining adverse events in children. The long-term effects of fenoldopam on growth and development have not been studied.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Fenoldopam in the drug label.
# Drug Interactions
- Beta-Blockers: Concomitant use of fenoldopam with beta blockers should be avoided. If the drugs are used together, caution should be exercised because unexpected hypotension could result from beta blocker inhibition of the sympathetic reflex response to fenoldopam.
- There is limited experience with concomitant antihypertensive agents such as alpha blockers, calcium channel blockers, ACE inhibitors, and diuretics (both thiazide-like and loop).
- Intravenous fenoldopam has been administered safely with drugs such as digitalis and sublingual nitroglycerin.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
- Oral reproduction studies have been performed in rats and rabbits at doses of 12.5 to 200 mg/kg/day and 6.25 to 25 mg/kg/day, respectively. Studies have revealed maternal toxicity at the highest doses tested but no evidence of impaired fertility or harm to the fetus due to fenoldopam. However, there are no adequate and well-controlled studies in pregnant women. Since animal reproduction studies are not always predictive of human response, fenoldopam should be used in pregnancy only if clearly needed.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Fenoldopam in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Fenoldopam during labor and delivery.
### Nursing Mothers
Fenoldopam is excreted in milk in rats. 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 fenoldopam is administered to a nursing woman.
### Pediatric Use
- Anti-hypertensive effects of fenoldopam have been studied in pediatric patients age < 1 month (at least 2 kg or full term) to 12 years old requiring blood pressure reduction.
- Clinical studies of fenoldopam did not include subjects ages 12 to 16 years of age to determine if they respond differently from younger subjects or adults. The pharmacokinetics of fenoldopam are independent of age when corrected for body weight. * Dose selection for patients 12 to 16 years of age should consider the patient's clinical condition and concomitant drug therapy.
### Geriatic Use
- Clinical studies of fenoldopam 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 responses 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.
### Gender
There is no FDA guidance on the use of Fenoldopam with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Fenoldopam with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Fenoldopam in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Fenoldopam in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Fenoldopam in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Fenoldopam in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
### Monitoring
Frequent blood pressure monitoring is recommended.
# IV Compatibility
Fenoldopam is compatible with:
- 0.9% Sodium Chloride.
- 5% Dextrose.
# Overdosage
- Intentional fenoldopam overdosage has not been reported. The most likely reaction would be excessive hypotension which should be treated with drug discontinuation and appropriate supportive measures.
# Pharmacology
## Mechanism of Action
- Fenoldopam is a rapid-acting vasodilator. It is an agonist for D1-like dopamine receptors and binds with moderate affinity to α2-adrenoceptors. It has no significant affinity for D2-like receptors, α1 and β adrenoceptors, 5HT1 and 5HT2 receptors, or muscarinic receptors. Fenoldopam is a racemic mixture with the R-isomer responsible for the biological activity. The R-isomer has approximately 250-fold higher affinity for D1-like receptors than does the S-isomer. In non-clinical studies, fenoldopam had no agonist effect on presynaptic D2-like dopamine receptors, or α- or β-adrenoceptors, nor did it affect angiotensin-converting enzyme activity. Fenoldopam may increase norepinephrine plasma concentration.
## Structure
- Corlopam (Fenoldopam Mesylate Injection, USP) is a dopamine D1-like receptor agonist. The product is formulated as a solution to be diluted for intravenous infusion. Chemically it is 6-chloro-2,3,4,5-tetrahydro-1-(4-hydroxyphenyl)-[1H]-3-benzazepine-7,8-diol methanesulfonate with the following structure:
- Fenoldopam mesylate is a white to off-white powder with a molecular weight of 401.87 and a molecular formula of C16H16ClNO3•CH3SO3H. It is sparingly soluble in water, ethanol and methanol, and is soluble in propylene glycol.
- Ampules: Each 1 mL contains, in sterile aqueous solution, citric acid 3.44 mg; fenoldopam mesylate equivalent to fenoldopam 10 mg; propylene glycol 518 mg; sodium citrate dihydrate 0.61 mg; sodium metabisulfite 1 mg.
## Pharmacodynamics
- In a randomized double-blind, placebo-controlled, 5-group study in 32 patients with mild to moderate essential hypertension (diastolic blood pressure between 95 and 119 mm Hg), and a mean baseline pressure of about 154/98 mm Hg, and heart rate of about 75 bpm, fixed-rate IV infusions of fenoldopam produced dose-related reductions in systolic blood pressures and diastolic blood pressures.
- In animals, fenoldopam has vasodilating effects in coronary, renal, mesenteric and peripheral arteries. All vascular beds, however, do not respond uniformly to fenoldopam. Vasodilating effects have been demonstrated in renal efferent and afferent arterioles.
## Pharmacokinetics
- Adult Patients: Fenoldopam, administered as a constant infusion at dosages of 0.01 to 1.6 mcg/kg/min, produced steady-state plasma concentrations that were proportional to infusion rates. The elimination half-life was about 5 minutes in mild to moderate hypertensives, with little difference between the R (active) and S isomers. Steady state concentrations are attained in about 20 minutes (4 half-lives). * The steady state plasma concentrations of fenoldopam, at comparable infusion rates, were similar in normotensive patients and in patients with mild to moderate hypertension or hypertensive emergencies.
- The pharmacokinetics of fenoldopam were not influenced by age, gender, or race in adult patients with a hypertensive emergency. There have been no formal drug-drug interaction studies using intravenous fenoldopam. Clearance of parent (active) fenoldopam is not altered in adult patients with end-stage renal disease on continuous ambulatory peritoneal dialysis (CAPD) and is not altered in adult patients with severe hepatic failure. The effects of hemodialysis on the pharmacokinetics of fenoldopam have not been evaluated.
- Pediatric Patients: In children, aged 1 month to 12 years old, steady-state fenoldopam plasma concentrations were proportional to dose (0.05 mcg/kg/min to 3.2 mcg/kg/min). The elimination half-life and clearance were 3 to 5 minutes and 3 L/h/kg, respectively.
- In radiolabeled studies in rats, no more than 0.005% of fenoldopam crossed the blood-brain barrier.
- Radiolabeled studies show that about 90% of infused fenoldopam is eliminated in urine, 10% in feces. Elimination is largely by conjugation, without participation of cytochrome P-450 enzymes. The principal routes of conjugation are methylation, glucuronidation, and sulfation. Only 4% of the administered dose is excreted unchanged. Animal data indicate that the metabolites are inactive.
## Nonclinical Toxicology
- In a 24-month study, mice treated orally with fenoldopam at 12.5, 25, or 50 mg/kg/day, reduced to 25 mg/kg/day on day 209 of study, showed no increase above controls in the incidence of neoplasms. Female mice in the highest dose group had an increased incidence and degree of severity of a fibro-osseous lesion of the sternum compared with control or low-dose animals. Compared to controls, female mice in the middle- and upper-dose groups had a higher incidence and degree of severity of chronic nephritis. These pathologic lesions were not seen in male mice treated with fenoldopam.
- In a 24-month study, rats treated orally with fenoldopam at 5, 10 or 20 mg/kg/day, with the mid- and high-dose groups increased to 15 or 25 mg/kg/day, respectively, on day 372 of the study, showed no increase above controls in the incidence or type of neoplasms. Compared with the controls, rats in the mid- and high-dose groups had a higher incidence of hyperplasia of collecting duct epithelium at the tip of the renal papilla.
- Fenoldopam did not induce bacterial gene mutation in the Ames test or mammalian gene mutation in the Chinese hamster ovary (CHO) cell assay. In the in vitro chromosomal aberration assay with CHO cells, fenoldopam was associated with statistically significant and dose-dependent increases in chromosomal aberrations, and in the proportion of aberrant metaphases. However, no chromosomal damage was seen in the in vivo mice micronucleus or bone marrow assays.
- Oral fertility and general reproduction performance studies in male and female rats at 12.5, 37.5 or 75 mg/kg/day revealed no impairment of fertility or reproduction performance due to fenoldopam.
- Unusual toxicologic findings (arterial lesions in the rat) with fenoldopam are summarized below. These findings have not been observed in mice or dogs. No evidence of a similar lesion in humans has been observed.
- Arterial lesions characterized by medial necrosis and hemorrhage have been seen in renal and splanchnic arteries of rats given fenoldopam mesylate by continuous intravenous infusion at doses of 1 to 100 mcg/kg/min for 24 hours. The incidence of these lesions is dose related. Arterial lesions morphologically identical to those observed with fenoldopam have been reported in rats infused with dopamine. Data suggest that the mechanism for this injury involves activation of D1-like dopaminergic receptors. Such lesions have not been seen in dogs given doses up to 100 mcg/kg/min by continuous intravenous infusion for 24 hours, nor were they seen in dogs infused at the same dose for 6 hours daily for 24 days. The clinical significance of this finding is not known.
- Oral administration of fenoldopam doses of 10 to 15 mg/kg/day or 20 to 25 mg/kg/day to rats for 24 months induced a higher incidence of polyarteritis nodosa compared to controls. Such lesions were not seen in rats given 5 mg/kg/day of fenoldopam or in mice given the drug at doses up to 50 mg/kg/day for 24 months.
# Clinical Studies
- In a randomized double-blind, placebo-controlled, 5-group study in 32 patients with mild to moderate essential hypertension (diastolic blood pressure between 95 and 119 mm Hg), and a mean baseline pressure of about 154/98 mm Hg, and heart rate of about 75 bpm, fixed-rate IV infusions of fenoldopam produced dose-related reductions in systolic and diastolic blood pressures. Infusions were maintained at a fixed rate for 48 hours. The table below shows the results of the study. The onset of response was rapid at all infusion rates, with the 15-minute response representing 50 to 100% of the 1 hour response in all groups. There was some suggestion of partial tolerance at 48 hours in the 2 higher dose infusions, but a substantial effect persisted through 48 hours. When infusions were stopped, blood pressure gradually returned to pretreatment values with no evidence of rebound.
- This study suggests that there is no greater response to 0.8 mcg/kg/min than to 0.4 mcg/kg/min.
- In a multicenter, randomized, double-blind comparison of four infusion rates, fenoldopam was administered as constant rate infusions of 0.01, 0.03, 0.1 and 0.3 mcg/kg/min for up to 24 hours to 94 adult patients experiencing hypertensive emergencies (defined as diastolic blood pressure ≥ 120 mm Hg with evidence of compromise of end-organ function involving the cardiovascular, renal, cerebral or retinal systems). Infusion rates could be doubled after one hour if clinically indicated. There were dose-related, rapid-onset, decreases in systolic and diastolic blood pressures and increases in heart rate.
- Two hundred thirty-six (236) severely hypertensive adult patients (DBP ≥ 120 mm Hg), with or without end-organ compromise, were randomized to receive in 2 open-label studies either fenoldopam or nitroprusside. The response rate was 79% (92/117) in the fenoldopam group and 77% (90/119) in the nitroprusside group. Response required a decline in supine diastolic blood pressure to less than 110 mm Hg if the baseline were between 120 and 150 mm Hg, inclusive, or by ≥ 40 mm Hg if the baseline were ≥ 150 mm Hg. Patients were titrated to the desired effect. For fenoldopam, the dose ranged from 0.1 to 1.5 mcg/kg/min; for nitroprusside, the dose ranged from 1 to 8 mcg/kg/min. As in the study in mild to moderate hypertensives, most of the effect seen at 1 hour is present at 15 minutes. The additional effect seen after 1 hour occurs in all groups and may not be drug-related (there was no placebo group for evaluation).
- In a randomized, multi-center, double-blind, placebo-controlled, dose-ranging study, pediatric patients were randomized in equal proportions to 1 of 5 treatment groups: 0.05, 0.2, 0.8, or 3.2 mcg/kg/min fenoldopam or placebo. Fenoldopam or placebo was administered as a blinded continuous IV infusion for 30 minutes. Following this, open-label titration of fenoldopam was given to induce hypotension or normotension (defined as mean arterial pressure, MAP, between 50 and 80 mmHg for patients > 1 month of age and MAP between 40 and 70 mmHg for patients ≤ 1 month). Seventy-seven pediatric patients (up to 12 years of age – Tanner Stages 1 and 2) were treated for at least two hours. Of these, 2 were < 1 month of age, 25 were between 1 month of age and 1 year of age, 7 were between 1 and 2 years of age, and 43 were between 2 and 12 years of age. Of the 77 patients enrolled in the trial, 58 were enrolled in association with surgery, and 19 were treated in an ICU setting.
- The lowest dosage at which decreases in MAP were seen during blinded administration was 0.2 mcg/kg/min. The dose at which the maximum effect was seen was 0.8 mcg/kg/min. * Doses higher than 0.8 mcg/kg/min generally produced no further decreases in MAP but did worsen tachycardia (Table 3). Changes in blood pressure and heart rate occurred as early as 5 minutes after starting infusion. Doses as high as 4 mcg/kg/min were administered during the open-label period. The effects increased with time for 15 to 25 minutes, and an effect could still be detected after an average of 4 hours of infusion. When the infusion was discontinued, blood pressure and heart rates approached baseline values during the following 30 minutes.
# How Supplied
- Single-dose ampule: 10 mg/mL, 1 mL (one per carton).
- Single-dose ampule: 10 mg/mL, 2 mL (one per carton).
## Storage
- Store at 2 to 30°C (35.6 to 86°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Fenoldopam in the drug label.
# Precautions with Alcohol
- Alcohol-Fenoldopam interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- CORLOPAM®[3]
# Look-Alike Drug Names
There is limited information regarding Fenoldopam Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Corlopam | |
0330b451ecf98d3fbe16e66883038b8c225eb3ed | wikidoc | Corn poppy | Corn poppy
The Corn Poppy, Field Poppy, Flanders Poppy, or Red Poppy is the wild poppy of agricultural cultivation—Papaver rhoeas. It is a variable annual plant. The four petals are vivid red, most commonly with a black spot at their base. In the northern hemisphere it generally flowers in late spring, but if the weather is warm enough other flowers frequently appear at the beginning of autumn. It has a variety of common names.
It is known to have been associated with agriculture in the Old World since early times. It has most of the characteristics of a successful weed of agriculture. These include an annual lifecycle that fits into that of most cereals, a tolerance of simple weed control methods, the ability to flower and seed itself before the crop is harvested. Like many such weeds, it also shows the tendency to become a crop in its own right; its seed is a moderately useful commodity, and its flower is edible.
Its origin is not known for certain. As with many such plants, the area of origin is often ascribed by Americans to Europe, and by northern Europeans to southern Europe. The European Garden Flora suggests that it is ‘Eurasia and North Africa’; in other words, the lands where agriculture has been practised since the earliest times.
The leaves are mildly poisonous to grazing animals. The seed is harmless and is used sometimes as a condiment. The commonly grown decorative Shirley Poppy is derived from forms of this plant.
The commonly used parts of the corn poppy are the seeds (in baking), the fresh green parts as vegetable, and the red petals by making syrups and alcoholic/non-alcoholic drinks. Red poppy syrup is a traditional beverage of Mediterranean regions like Bozcaada.
It has had an old symbolism and association with agricultural fertility.
It has become associated with wartime remembrance in the 20th century, especially during Remembrance Day in Commonwealth countries. As poppies bloomed in much of the western front in World War I, poppies are a symbol of military veterans, especially of that war.
Since the poppy symbol is largely associated with Remembrance Day in Canada, the Canadian Mint has released a series of quarters into circulation that have the poppy imprinted on them in the center of the coin. | Corn poppy
The Corn Poppy, Field Poppy, Flanders Poppy, or Red Poppy is the wild poppy of agricultural cultivation—Papaver rhoeas. It is a variable annual plant. The four petals are vivid red, most commonly with a black spot at their base. In the northern hemisphere it generally flowers in late spring, but if the weather is warm enough other flowers frequently appear at the beginning of autumn. It has a variety of common names.
It is known to have been associated with agriculture in the Old World since early times. It has most of the characteristics of a successful weed of agriculture. These include an annual lifecycle that fits into that of most cereals, a tolerance of simple weed control methods, the ability to flower and seed itself before the crop is harvested. Like many such weeds, it also shows the tendency to become a crop in its own right; its seed is a moderately useful commodity, and its flower is edible[citation needed].
Its origin is not known for certain. As with many such plants, the area of origin is often ascribed by Americans to Europe, and by northern Europeans to southern Europe. The European Garden Flora suggests that it is ‘Eurasia and North Africa’; in other words, the lands where agriculture has been practised since the earliest times.
The leaves are mildly poisonous to grazing animals. The seed is harmless and is used sometimes as a condiment. The commonly grown decorative Shirley Poppy is derived from forms of this plant.
The commonly used parts of the corn poppy are the seeds (in baking), the fresh green parts as vegetable, and the red petals by making syrups and alcoholic/non-alcoholic drinks. Red poppy syrup is a traditional beverage of Mediterranean regions like Bozcaada.
It has had an old symbolism and association with agricultural fertility.
It has become associated with wartime remembrance in the 20th century, especially during Remembrance Day in Commonwealth countries. As poppies bloomed in much of the western front in World War I, poppies are a symbol of military veterans, especially of that war.
Since the poppy symbol is largely associated with Remembrance Day in Canada, the Canadian Mint has released a series of quarters into circulation that have the poppy imprinted on them in the center of the coin. | https://www.wikidoc.org/index.php/Corn_poppy | |
ccd7a31f4513fd4e0ac977511529aab0253b045a | wikidoc | Corncockle | Corncockle
Corncockle (Agrostemma githago - also Corn cockle and Corn-cockle) is a slender pink flower of European corn fields. In the 19th century, it was reported as a very common weed of wheat fields and its seeds were inadvertently included in harvested wheat seed and then re-sown the following season. It is very likely that until the 20th century, most wheat contained some corncockle seed. It is now present in many parts of the temperate world as an alien species, probably introduced with imported European wheat. It is known to occur throughout much of the USA and parts of Canada, parts of Australia and New Zealand. In parts of Europe such as the UK, intensive mechanised farming has put the plant at risk and it is now uncommon or local. This is partly due to increased use of herbicides but probably much more to do with changing patterns of agriculture with most wheat now sown in the autumn as winter wheat and then harvested before any corncockle would have flowered or set seed.
It is a stiffly erect plant up to 1 metre tall and covered with fine hairs. Its few branches are each tipped with a single deep pink to purple flower. The flowers are scentless, are 25 mm to 50 mm across and are produced in the summer months - May to September in the northern hemisphere, November to March in the southern hemisphere. Each petal bears 2 or 3 discontinous black lines. The five narrow pointed sepals exceed the petals and are joined at the base to form a rigid tube with 10 ribs. Leaves are pale green, opposite, narrowly lanceolate, held nearly erect against stem and are 45 mm to 145 mm long. Seeds are produced in a many-seeded capsule. All parts of the plant are reported to be poisonous.
It can be found in fields, roadsides, railway lines, waste places, and other disturbed areas. | Corncockle
Corncockle (Agrostemma githago - also Corn cockle and Corn-cockle) is a slender pink flower of European corn fields. In the 19th century, it was reported as a very common weed of wheat fields and its seeds were inadvertently included in harvested wheat seed and then re-sown the following season. It is very likely that until the 20th century, most wheat contained some corncockle seed. It is now present in many parts of the temperate world as an alien species, probably introduced with imported European wheat. It is known to occur throughout much of the USA and parts of Canada, parts of Australia and New Zealand. In parts of Europe such as the UK, intensive mechanised farming has put the plant at risk and it is now uncommon or local. This is partly due to increased use of herbicides but probably much more to do with changing patterns of agriculture with most wheat now sown in the autumn as winter wheat and then harvested before any corncockle would have flowered or set seed.
It is a stiffly erect plant up to 1 metre tall and covered with fine hairs. Its few branches are each tipped with a single deep pink to purple flower. The flowers are scentless, are 25 mm to 50 mm across and are produced in the summer months - May to September in the northern hemisphere, November to March in the southern hemisphere. Each petal bears 2 or 3 discontinous black lines. The five narrow pointed sepals exceed the petals and are joined at the base to form a rigid tube with 10 ribs. Leaves are pale green, opposite, narrowly lanceolate, held nearly erect against stem and are 45 mm to 145 mm long. Seeds are produced in a many-seeded capsule. All parts of the plant are reported to be poisonous.
It can be found in fields, roadsides, railway lines, waste places, and other disturbed areas.
# External links
- How to Grow Corncockle
Template:Caryophyllales-stub
cs:Koukol polní
de:Kornrade
lt:Dirvinė raugė
nl:Bolderik
sv:Klätt
uk:Кукіль звичайний
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Corncockle | |
f40249ed20ecf7f207f36782b9a1bc5f896cfe07 | wikidoc | Cornstarch | Cornstarch
# Overview
Cornstarch, or cornflour, is the starch of the corn (maize) grain. It is also grown from the endosperm of the corn kernel. It has a distinctive appearance and feel when mixed raw with water or milk, giving easily to gentle pressure but resisting sudden pressure (see Non-Newtonian fluid). It is usually included as an anti-caking agent in powdered sugar (10X or confectioner's sugar). For this reason, recipes calling for powdered sugar often call for at least light cooking to remove the raw cornstarch taste. Cornstarch or cornflour is also used as a thickening agent in soups and liquids. As the starch is heated by the liquid, the molecule chains unravel, allowing them to collide with other starch chains to form a mesh - thus slowing the movement of water molecules. This results in thickening of the liquid, be it soup, stock or other culinary liquids.
# Manufacture
The corn is steeped for 30 to 48 hours, which ferments it a little. The germ is separated from the endosperm and those two components are ground separately (still soaked). Next the starch is removed from each by washing. It is separated from the gluten and other substances, mostly in hydrocyclones and centrifuges, and dried. (The residue from every stage is used in animal feed and other products.) Finally the starch may be modified for specific purposes.
# Other
Amylophagia is a condition involving the compulsive consumption of excessive amounts of purified starch, often cornstarch.
# Other names and varieties
- Called cornflour in Commonwealth countries. | Cornstarch
# Overview
Cornstarch, or cornflour, is the starch of the corn (maize) grain. It is also grown from the endosperm of the corn kernel. It has a distinctive appearance and feel when mixed raw with water or milk, giving easily to gentle pressure but resisting sudden pressure (see Non-Newtonian fluid). It is usually included as an anti-caking agent in powdered sugar (10X or confectioner's sugar). For this reason, recipes calling for powdered sugar often call for at least light cooking to remove the raw cornstarch taste. Cornstarch or cornflour is also used as a thickening agent in soups and liquids. As the starch is heated by the liquid, the molecule chains unravel, allowing them to collide with other starch chains to form a mesh - thus slowing the movement of water molecules. This results in thickening of the liquid, be it soup, stock or other culinary liquids.
# Manufacture
The corn is steeped for 30 to 48 hours, which ferments it a little. The germ is separated from the endosperm and those two components are ground separately (still soaked). Next the starch is removed from each by washing. It is separated from the gluten and other substances, mostly in hydrocyclones and centrifuges, and dried. (The residue from every stage is used in animal feed and other products.) Finally the starch may be modified for specific purposes.[1]
# Other
Amylophagia is a condition involving the compulsive consumption of excessive amounts of purified starch, often cornstarch.[2]
# Other names and varieties
- Called cornflour in Commonwealth countries. | https://www.wikidoc.org/index.php/Cornstarch | |
1fbc2fdf8206d98c2243a89d653a3f5ca7631448 | wikidoc | Restenosis | Restenosis
# Overview
Restenosis literally means the reoccurrence of stenosis. This is usually restenosis of an artery, or other blood vessel, but possibly any hollow organ that has been "unblocked". This term is common in vascular surgery, cardiac surgery, interventional radiology, or interventional cardiology following angioplasty, all branches of medicine that frequently treat stenotic lesions. In simple words, coronary restenosis can be considered as the reduction in the lumen diameter after a percutaneous coronary intervention (PCI), which induces iatrogenic arterial injury and results in neointimal tissue proliferation. It can be defined based on angiography or as clinical restenosis. By angiography, the term 'Binary Angiographic Re-stenosis' is defined as > 50% luminal narrowing at follow-up angiography. However, the most widely accepted and relevant definition would be a 'Clinical Re-stenosis', which is defined as need for a repeat target lesion revascularization (TLR) due to symptomatic coronary ischemia from the previously intervened vessel (proposed by the Academic Research Consortium). Therefore, this definition needs angiographic narrowing as well as clinical correlation. If the lesion does not meet angiographic criteria, but meets the criteria for a physiologically significant lesion by fractional flow reserve (FFR) or anatomically by intravascular ultrasound (IVUS) with the appropriate clinical context, it is still considered 'Clinical Re-stenosis'. PCI has evolved significantly from plain balloon angioplasty to the development of biodegradable stents in the last few decades. Currently, almost all coronary interventions use a bare metal stent (BMS) or more so a drug eluting stent (DES). Hence, the discussion in the following paragraphs will focus on in-stent re-stenosis of drug eluting and bare metal stents.
# Coronary Restenosis
There are probably several mechanisms that lead to restenosis. An important one is the inflammatory response, which induces tissue proliferation around an angioplasty site.
Cardiologists have tried a number of approaches to decrease the risk of restenosis. Stenting is becoming more commonplace; replacing balloon angioplasty. During the stenting procedure, a metal mesh (stent) is deployed against the wall of the artery revascularizing the artery. Other approaches include local radiotherapy and the use of immunosuppressive drugs, coated onto the stenting mesh. Analogues of rapamycin, such as tacrolimus (FK-506), sirolimus and more so everolimus, normally used as immunosuppressants but recently discovered to also inhibit the proliferation of vascular smooth muscle cells, have appeared to be quite effective in preventing restenosis in clinical trials. Antisense knockdown of c-myc, a protein critical for progression of cell replication, is another approach to inhibit cell proliferation in the artery wall and has been through preliminary clinical trials using Morpholino oligos.
# Histopathology and Molecular Mechanisms
Restenosis can considered a local vascular manifestation of the general biological response to arterial wall injury. Following vessel wall injury with endothelium damage, the exposure of tunica media to the flowing blood results in platelet adhesion to the media's collagen via the Von Williebrand factor. This results in platelet activation, which is followed by aggregation and soon evolving into a vicious cycle, which feeds and nurtures itself till a clot is formed from the coagulation cascade (which is activated from the tissue thromboplastin released from the media following vessel wall injury) and fibrin. Basically, this phenomenon can be considered synonymous to hemostasis. Activated platelets express adhesion molecules, to which circulating leukocytes attach and begin the process of leukocyte migration. Also during this process, several chemotactic factors are released and multiple adhesion molecules are expressed by various activated inflammatory cells in the vicinity of the inflammation, which cause chemotaxis of leukocytes to the core of the inflammation. Growth factors, cytokines and adhesion molecules released and expressed by platelets, leukocytes and other inflammatory cells, result in the migration of vascular smooth muscle cells from the media and proliferation with resultant neo-intima formation . Hence, neo-intima consists of vascular smooth muscle cells, macrophages and extracellular matrix, which has formed over several weeks.
When reading through the above process, we realize that plaque rupture and stent thrombosis uses the same tools of inflammation mentioned above. The phenomenon of stent thrombosis and acute coronary syndrome can be thought of as an acute phenomenon, evolving in minutes to a couple of hours. Thus, depending on several factors (which favor acute thrombosis) the above mentioned process can evolve very quickly resulting in thrombosis of the coronary vessel. This process can then follow any of the pathways:
- the patient seeks immediate help and the percutaneous coronary intervention can open up the vessel and prevent progression of the acute coronary syndrome
- the patient fails to seek help and can die from a massive myocardial infarction
- sometimes, without seeking help, the patient lives through this coronary thrombosis and the clot becomes organised and recanalised.
In more simple words, coronary restenosis can be thought of as a sub-acute to chronic vascular inflammatory response to iatrogenic controlled injury; while stent thrombosis is an acute vascular response resulting in acute thrombosis and a high propensity to cause sudden death or significant morbidity.
In balloon angioplasty, the lumen size is increased from its baseline diseased state through the dilatation of the balloon at the site of the diseased region. However, the elastic recoil (of the artery), negative remodeling, contraction and finally neo-intima formation, results in restenosis. Also, to be noted is the fact that there is a 30% risk of abrupt closure of the vessel from acute thrombosis from plain balloon angioplasty as it is a form of vascular injury too (iatrogenic controlled injury). Based on individual clinical and angiographic characteristics, some patients develop this fatal complication, while others do not.
In stent implantation, the lumen size is increased from its baseline diseased state and has a better patency than plain balloon angioplasty, as the stent scaffold holds the vessel open; therefore the component of elastic recoil and negative remodeling is reduced significantly. Thus the restenosis rates are lower in BMS when compared to plain balloon angioplasty, as the elastic recoil and negative remodeling is virtually eliminated. Hence, the final lumen size is greater and neo-intima formation does not materialize into clinical restenosis as seen to occur more commonly with balloon angioplasty. Similarly, it is well known that DES has a lower re-stenosis rate than BMS as the DES have the added advantage of releasing anti-stenotic drug which can retard the neo-intima formation. Rapamycin, an immunosuppresant agent approved by the FDA, inhibits both rat and human vascular smooth muscle proliferation and migration in vitro. A study investigated (1) whether rapamycin administration could reduce neointimal thickening in a porcine model of restenosis post-PTCA and (2) the mechanism by which rapamycin inhibits VSMCs in vivo. It was found that rapamycin administration significantly reduced the arterial proliferative response after PTCA in the pig by increasing the level of the CDKI p27(kip1) and inhibition of the pRb phosphorylation within the vessel wall. Therefore, pharmacological interventions that elevate CDKI in the vessel wall and target cyclin-dependent kinase activity may have a therapeutic role in the treatment of restenosis after angioplasty in humans. These common pathways finally act on the cell cycle and result in vascular smooth muscle cell proliferation. Given that the anti-stenotic drug of DES act at the level of the cell cycle, they are thus the most effective strategy available to prevent coronary restenosis after a percutaneous coronary intervention.
Once again, there are several other factors involved in re-stenosis of BMS and DES (as discussed below).
Coronary re-stenosis can be considered in two different settings of a percutaneous coronary intervention:
- In pure balloon angioplasty (in the absence of stenting)- Following balloon angioplasty, there is injury to the vessel wall, which triggers the expected inflammatory response from the vessel wall. Hence, there is elastic recoil, negative remodelling (reduction in lumen size due to the healing process) or contraction, thrombus at the site of injury (i.e., release of prothrombotic thromboplastin like material from the vessel wall, exposure of the collagen of the media), smooth muscle proliferation and migration and excessive extracellular matrix production.
- With stenting- Stenting prevents elastic recoil and negative remodelling. However, neointimal formation progresses and causes re-stenosis, which is reduced with antistenotic drugs. Restenosis in patients after stent implantation is caused predominantly by neointimal hyperplasia. However neointima formation in plain balloon angioplasty has a minor role. Through immunohistochemical identification, it has been shown that there is a steady accumulation of macrophages within stented segments (with clustering of macrophages around stent struts), where as there virtually no accumulation within balloon-injured segments of pure balloon angioplasty.
The porcine model of in-stent restenosis (ISR) has demonstrated the formation of a thick neointima in 28 days-which may be the reason as to why the earlier DES released their antistenotic drug by the end of 30 days. However, it is well known that the peak period of ISR development in humans is approximately 3 to 6 months-hence the newer DES are aiming to release the drug for an extended period. Interestingly, in these porcine models they found a positive correlation between the inflammatory infiltrate, degree of arterial injury and extent of stent strut penetration into the vessel wall with the neointimal thickness. Interestingly, in a rat model of carotid artery dilatation the gate-keeper step in initiating vascular smooth muscle cell proliferation from tunica media to intima is the rupture of internal elastic lamina.
The above mentioned responses and time periods were in porcine models with near normal coronaries and this may not be the case in humans who have had balloon angioplasty, BMS and DES for atherosclerotic lesions. The inflammatory response in DES is very different in terms of cell composition and timing, when compared to balloon angioplasty and BMS and also among the different DES. These differences could be explained by the presence of various forms of polymer among DES. For example, the inflammatory response (predominantly giant cell infiltrates) to Sirolimus DES has been shown to persist beyond 180 days and up to 2 years. In contrast, the inflammatory response to BMS and the second generation Everolimus DES (which has a more biocompatible polymer) has been limited to 90 days and 12 months, respectively. Evidence of such persistence of inflammatory response has been found in autopsy cases and from thrombus aspirates taken from patients during percutaneous coronary intervention for late stent thrombosis.
As mentioned earlier, the neointima consists of the hyperplastic vascular smooth muscle cells and the extracellular protein rich matrix. The current evidence points to the fact that these smooth muscle cells are of luminal origin, however, there is data that indicates that they can be of adventitial origin too. The later stages of restenosis is contributed predominantly by the deposition of extracellular matrix.
After reviewing the existing evidence, it seems that migration and proliferation of vascular smooth muscle cells form the major final common pathway for restenosis. In the presence of growth factors and cytokines, these vascular smooth cells undergo a phenotypic modulation from a contractile state to a synthetic phenotype. Hence, most of the molecular research in the past few years has been focused on understanding the common pathways that multiple receptors employ to transmit mitogenic signals from the cell membrane to the nucleus of the vascular smooth cells after arterial injury. The three common pathways which result in pathological mitosis of the vascular smooth cells are:
- Ras-raf mitogen activated protein kinase
- Cyclic adenosine monophosphate-protein kinase dependent signalling
- Cyclin dependent kinase complexes
Several rat models have shown that alteration of these pathways can worsen or prevent neo initmal formation.
# Pathophysiology
In this section we will discuss the etiological and various pathophysiological factors, which lead to restenosis.
DES predominantly consist of 3 elements:
- Scaffold or the stent platform, which forms the skeleton of the stent (this made of stainless steel or cobalt chromium).
- The antistenotic drug (such as paclitaxel, everolimus, etc).
- The polymer or the carrier on which the drug is mounted.
Unlike, the DES the BMS consist only the scaffold or the platform.
The pathophysiology seems to be the interplay of clinical characteristics, biological factors, mechanical factors, technical factors and finally de-novo lesions which arise within the stent itself.
The various pathophysiological factors are discussed as follows:
- Biological and Genetic Factors:
Drug Resistance: Recent studies have revealed a genetic basis for drug resistance. Depending on the penetrance and expressivity of these mutations, the sensitivity to these drugs vary. This resistance can be the result of inherited genetic mutations or acquired following the exposure of a cytotoxic drug.
Genetic Factors Affecting the Inflammatory Response: Polymorphism of glycoprotein IIIa and a mutant form of methylenetetrahydrofolate reductase appear to increase the risk of ISR. Interestingly, allele 2 of interleukin IL-1ra gene appears to be protective. However, these are just some of the genetic factors which have been identified in the causation of ISR. Hence, there remains the possibility of complex multigenic abnormalities (interplay of multiple variant forms of genes and environmental factors), which can play a significant role in ISR. These identified and yet to be identified genetic factors may explain as to why some patients develop ISR and some don’t despite identical clinical factors and stent characteristics.
Hypersensitivity: The implantation of these stents is recognized as foreign antigens and hence a hypersensitivity reaction can be triggered, which can lead to ISR. As mentioned earlier, the DES has 3 components and the BMS has only the scaffold, which can all contribute towards this hypersensitivity reaction.
- Drug Resistance: Recent studies have revealed a genetic basis for drug resistance. Depending on the penetrance and expressivity of these mutations, the sensitivity to these drugs vary. This resistance can be the result of inherited genetic mutations or acquired following the exposure of a cytotoxic drug.
- Genetic Factors Affecting the Inflammatory Response: Polymorphism of glycoprotein IIIa and a mutant form of methylenetetrahydrofolate reductase appear to increase the risk of ISR. Interestingly, allele 2 of interleukin IL-1ra gene appears to be protective. However, these are just some of the genetic factors which have been identified in the causation of ISR. Hence, there remains the possibility of complex multigenic abnormalities (interplay of multiple variant forms of genes and environmental factors), which can play a significant role in ISR. These identified and yet to be identified genetic factors may explain as to why some patients develop ISR and some don’t despite identical clinical factors and stent characteristics.
- Hypersensitivity: The implantation of these stents is recognized as foreign antigens and hence a hypersensitivity reaction can be triggered, which can lead to ISR. As mentioned earlier, the DES has 3 components and the BMS has only the scaffold, which can all contribute towards this hypersensitivity reaction.
- Stent Platform: The stent platforms of the BMS and first generation DES (paclitaxel and sirolimus) is made up of 316L stainless steel, which contains more nickel and molybdenum than the second generation DES, where the scaffold is made up of cobalt chromium. This nickel and molybdenum are known to trigger these hypersensitivity reactions. Interestingly, to date, no prospective studies have confirmed this association.
- Stent Platform: The stent platforms of the BMS and first generation DES (paclitaxel and sirolimus) is made up of 316L stainless steel, which contains more nickel and molybdenum than the second generation DES, where the scaffold is made up of cobalt chromium. This nickel and molybdenum are known to trigger these hypersensitivity reactions. Interestingly, to date, no prospective studies have confirmed this association.
- Stent Platform: The stent platforms of the BMS and first generation DES (paclitaxel and sirolimus) is made up of 316L stainless steel, which contains more nickel and molybdenum than the second generation DES, where the scaffold is made up of cobalt chromium. This nickel and molybdenum are known to trigger these hypersensitivity reactions. Interestingly, to date, no prospective studies have confirmed this association.
- Polymer: The durable polymer which remains covering the stent after releasing the anti-stenotic drug has known to cause hypersensitivity and is suspected as the culprit for stent thrombosis and progressive or late re-stenosis.
- Polymer: The durable polymer which remains covering the stent after releasing the anti-stenotic drug has known to cause hypersensitivity and is suspected as the culprit for stent thrombosis and progressive or late re-stenosis.
- Polymer: The durable polymer which remains covering the stent after releasing the anti-stenotic drug has known to cause hypersensitivity and is suspected as the culprit for stent thrombosis and progressive or late re-stenosis.
- Matrix Metalloproteinases: Circulating matrix metalloproteinase(MMP) have been associated with ISR as they play significant roles in migration of vascular smooth cells and matrix remodelling during healing post-stenting. Elevated levels of MMP-9 at baseline and MMP-2 and MMP-9 levels 24 hours post-percutaneous coronary intervention have proven to be strongly associated with the development of ISR following DES implantation. On the contrary, low and near normal levels of MMP-2 and MMP-9 were associated with a lack of a significant re-stenotic response.
- Matrix Metalloproteinases: Circulating matrix metalloproteinase(MMP) have been associated with ISR as they play significant roles in migration of vascular smooth cells and matrix remodelling during healing post-stenting. Elevated levels of MMP-9 at baseline and MMP-2 and MMP-9 levels 24 hours post-percutaneous coronary intervention have proven to be strongly associated with the development of ISR following DES implantation. On the contrary, low and near normal levels of MMP-2 and MMP-9 were associated with a lack of a significant re-stenotic response.
- Matrix Metalloproteinases: Circulating matrix metalloproteinase(MMP) have been associated with ISR as they play significant roles in migration of vascular smooth cells and matrix remodelling during healing post-stenting. Elevated levels of MMP-9 at baseline and MMP-2 and MMP-9 levels 24 hours post-percutaneous coronary intervention have proven to be strongly associated with the development of ISR following DES implantation. On the contrary, low and near normal levels of MMP-2 and MMP-9 were associated with a lack of a significant re-stenotic response.
- Genetic factors: As mentioned above can play a significant role in the inflammatory response, which can result in ISR.
- Genetic factors: As mentioned above can play a significant role in the inflammatory response, which can result in ISR.
- Genetic factors: As mentioned above can play a significant role in the inflammatory response, which can result in ISR.
- B) Arterial Factors:
Wall Shear Stress: The laminar flow of blood is a well known phenomenon, where the blood flows the fastest at the vessel center (or at the carina of a bifurcation) and slowest when it flows closest to the vessel wall (or at the ostium of a bifurcation). Hence, regions of low shear stress lead to accumulation of biological mediators, which promote atherosclerosis or neointimal formation. Adapting this principle would mean that a divider or the formation of a new carina should reduce the incidence of ISR. Kim at al demonstrated reduced occurrence of ISR by 'shotgun stenting' (i.e., simultaneous V-stenting with the formation of a new carina in the left main stem or other suitably sized vessels) but conversely, Stinus et al demonstrated increased target lesion revascularization rate with V-stenting when compared with the 'Crush' technique. This disparity can have a couple of explanations: 1) lesion location 2) post stent lumen size 3) reference lumen size 4) exposure of the new carina (formed by stent struts) for thrombus formation.
- Wall Shear Stress: The laminar flow of blood is a well known phenomenon, where the blood flows the fastest at the vessel center (or at the carina of a bifurcation) and slowest when it flows closest to the vessel wall (or at the ostium of a bifurcation). Hence, regions of low shear stress lead to accumulation of biological mediators, which promote atherosclerosis or neointimal formation. Adapting this principle would mean that a divider or the formation of a new carina should reduce the incidence of ISR. Kim at al demonstrated reduced occurrence of ISR by 'shotgun stenting' (i.e., simultaneous V-stenting with the formation of a new carina in the left main stem or other suitably sized vessels) but conversely, Stinus et al demonstrated increased target lesion revascularization rate with V-stenting when compared with the 'Crush' technique. This disparity can have a couple of explanations: 1) lesion location 2) post stent lumen size 3) reference lumen size 4) exposure of the new carina (formed by stent struts) for thrombus formation.
The presence of patchy areas of low shear stress within stented segments, secondary to local geometric factors (such as angulation or curvature) can predispose towards increased neointimal formation and hence ISR. This was demonstrated by Papafaklis et al on 6 month follow-up with BMS and Paclitaxel DES. However, this was not seen with Sirolimus DES. This difference can be explained by the differing pharmacological mode of action and shorter drug-release kinetics.
- Progression of Atherosclerosis within a Stented Segment: If the necrotic plaque within the stent progresses or if a lipid core plaque at the stent edge is not covered completely, then these lesions can progress to cause ISR or even thrombus formation.
- Progression of Atherosclerosis within a Stented Segment: If the necrotic plaque within the stent progresses or if a lipid core plaque at the stent edge is not covered completely, then these lesions can progress to cause ISR or even thrombus formation.
- "Thrombostenosis" Phenomenon: Oikawa et al was the first to describe the intriguing theory in which chronic thrombus formation may play an integral role in the development of ISR.
- "Thrombostenosis" Phenomenon: Oikawa et al was the first to describe the intriguing theory in which chronic thrombus formation may play an integral role in the development of ISR.
- Vessel Remodelling: The implantation of DES in vessels that have already undergone positive remodelling secondary to large plaque burden ("Glagov" phenomenon) have an increased risk for ISR.
- Vessel Remodelling: The implantation of DES in vessels that have already undergone positive remodelling secondary to large plaque burden ("Glagov" phenomenon) have an increased risk for ISR.
- Stent Factors:
Polymer Release Characteristics: In one the earlier trials involving Paclitaxel, they found that the duration of the drug release had a far greater impact on the inhibition of neointimal proliferation than the actual drug dose delivered. Several molecular biological studies have indicated that the genetic mechanisms responsible for the inflammatory proliferative response remain potentially active for a period of 21 days after vessel wall injury. These polymer release kinetics could explain some of the disparities in the ISR among different DES. It seems clear that when the antistenotic drug is delivered at a set threshold dose for a sustained prolonged period of time may be required to control the inflammatory proliferative response and hence reduce the occurrence of ISR.
- Polymer Release Characteristics: In one the earlier trials involving Paclitaxel, they found that the duration of the drug release had a far greater impact on the inhibition of neointimal proliferation than the actual drug dose delivered. Several molecular biological studies have indicated that the genetic mechanisms responsible for the inflammatory proliferative response remain potentially active for a period of 21 days after vessel wall injury. These polymer release kinetics could explain some of the disparities in the ISR among different DES. It seems clear that when the antistenotic drug is delivered at a set threshold dose for a sustained prolonged period of time may be required to control the inflammatory proliferative response and hence reduce the occurrence of ISR.
- Non-uniform Drug Distribution:
Ideally, the anti-stenotic drug should be delivered in a homogeneous fashion to the vessel wall (i.e., transmural and circumferential). However, due to local blood flow alterations (secondary to atherosclerotic plaque and calcified lesions), non-compliant vessels (i.e., calcified, tortuous), strut overlap, stent design, stent gap, vessel curvature, bifurcation lesions, ostial lesions, stent fracture and polymer damage can result in focal areas of the vessel receiving sub-optimal anti-stenotic drug.
- Non-uniform Drug Distribution:
Ideally, the anti-stenotic drug should be delivered in a homogeneous fashion to the vessel wall (i.e., transmural and circumferential). However, due to local blood flow alterations (secondary to atherosclerotic plaque and calcified lesions), non-compliant vessels (i.e., calcified, tortuous), strut overlap, stent design, stent gap, vessel curvature, bifurcation lesions, ostial lesions, stent fracture and polymer damage can result in focal areas of the vessel receiving sub-optimal anti-stenotic drug.
- Ideally, the anti-stenotic drug should be delivered in a homogeneous fashion to the vessel wall (i.e., transmural and circumferential). However, due to local blood flow alterations (secondary to atherosclerotic plaque and calcified lesions), non-compliant vessels (i.e., calcified, tortuous), strut overlap, stent design, stent gap, vessel curvature, bifurcation lesions, ostial lesions, stent fracture and polymer damage can result in focal areas of the vessel receiving sub-optimal anti-stenotic drug.
- Stent delivery in calcified lesions can result in stripping of the polymer base.
- Stent delivery in calcified lesions can result in stripping of the polymer base.
- Stent delivery in calcified lesions can result in stripping of the polymer base.
- Finally, individual variations in metal to artery ratio and variability in drug elution can all contribute to stent re-stenosis.
- Finally, individual variations in metal to artery ratio and variability in drug elution can all contribute to stent re-stenosis.
- Finally, individual variations in metal to artery ratio and variability in drug elution can all contribute to stent re-stenosis.
- Strut Thickness: Thicker stent struts have been associated with increased risk of ISR with BMS and smaller vessels. This could be explained by the fact that the thinner stent strut would have a lesser dose of foreign body exposure to the vessel wall, hence reducing the intensity of the inflammatory proliferative response.
- Strut Thickness: Thicker stent struts have been associated with increased risk of ISR with BMS and smaller vessels. This could be explained by the fact that the thinner stent strut would have a lesser dose of foreign body exposure to the vessel wall, hence reducing the intensity of the inflammatory proliferative response.
- On- and Off-Label Use: The STENT group is the largest, multicenter, prospective registry involving >15,000 patients, evaluating the late outcomes associated with DES implantation in the United States showed an almost 2 fold increase in target vessel revascularization (TVR) at 9 months for off-label use (ostial, left main stem, chronic total occlusions, saphenous venous graft, small or large vessels, multivessel, ST-elevation myocardial infarction, ISR lesions) when compared to on-label use (short de novo lesions measuring >2.5mm and <3.5mm for Sirolimus DES or <3.75mm for Paclitaxel DES). Also, when looking at the SYNTAX study, there were higher TVR rates in patients with highly complex 3-vessel or left main disease who underwent DES (which was an off-label use of DES). When analyzing the list of off-label uses, it seems that these patients have complex coronary lesions (with a higher SYNTAX score), more sicker and have more comorbidities which could easily influence TVR.
- On- and Off-Label Use: The STENT group is the largest, multicenter, prospective registry involving >15,000 patients, evaluating the late outcomes associated with DES implantation in the United States showed an almost 2 fold increase in target vessel revascularization (TVR) at 9 months for off-label use (ostial, left main stem, chronic total occlusions, saphenous venous graft, small or large vessels, multivessel, ST-elevation myocardial infarction, ISR lesions) when compared to on-label use (short de novo lesions measuring >2.5mm and <3.5mm for Sirolimus DES or <3.75mm for Paclitaxel DES). Also, when looking at the SYNTAX study, there were higher TVR rates in patients with highly complex 3-vessel or left main disease who underwent DES (which was an off-label use of DES). When analyzing the list of off-label uses, it seems that these patients have complex coronary lesions (with a higher SYNTAX score), more sicker and have more comorbidities which could easily influence TVR.
- Polymer Disruption, Peeling and Crackling: This can result in exposure of bare-metal areas, which has been demonstrated in bench studies involving both first and second generation DES using light or scanning electron microscopy. It is plausible that this bare metal exposure and stent regions in the absence of anti-stenotic drug can form a nidus for inflammatory and proliferative response. Seen more so in stent implantation in tortuous calcified lesions.
- Polymer Disruption, Peeling and Crackling: This can result in exposure of bare-metal areas, which has been demonstrated in bench studies involving both first and second generation DES using light or scanning electron microscopy. It is plausible that this bare metal exposure and stent regions in the absence of anti-stenotic drug can form a nidus for inflammatory and proliferative response. Seen more so in stent implantation in tortuous calcified lesions.
- Mechanical Factors:
Stent Underexpansion: When the stent is deployed and it is not well expanded, it results in a vessel lumen size whose stent cross-sectional area is significantly smaller that of the reference lumen size or other cross-sectional areas within the stent, despite good apposition of the stent struts against the vessel wall. If the minimum stent area is smaller than the reference lumen size to begin with, then the same amount of neointimal formation would be of greater significance than in a scenario where the minimum stent area was larger. An excellent expansion is considered if the minimal cross-sectional area in the stent is >90% of the average reference cross-sectional area.
- Stent Underexpansion: When the stent is deployed and it is not well expanded, it results in a vessel lumen size whose stent cross-sectional area is significantly smaller that of the reference lumen size or other cross-sectional areas within the stent, despite good apposition of the stent struts against the vessel wall. If the minimum stent area is smaller than the reference lumen size to begin with, then the same amount of neointimal formation would be of greater significance than in a scenario where the minimum stent area was larger. An excellent expansion is considered if the minimal cross-sectional area in the stent is >90% of the average reference cross-sectional area.
- Stent Malapposition: In malapposition, the stent struts are not apposed to the vessel wall (blood occupies the space between the stent struts and vessel wall). It is commonly seen with undersized stents, tortuous arteries and non-homogeneity in the reference arterial lumen diameter within the treated segment.
- Stent Malapposition: In malapposition, the stent struts are not apposed to the vessel wall (blood occupies the space between the stent struts and vessel wall). It is commonly seen with undersized stents, tortuous arteries and non-homogeneity in the reference arterial lumen diameter within the treated segment.
- Stent Fracture: It is defined as complete or partial separation of a stent, which was contiguous on initial implantation. This commonly happens with non-uniform stent expansion in region with both very compliant and resilient vessel walls. IVUS is an accurate imaging modality to recognize this abnormality. Partial stent fracture is defined as the absence of atleast one third or 120 degrees of stent struts for at least 1 frame. Complete stent fracture is defined as the complete absence of stent struts within the stented segment for at least 1 frame. There have been various classification systems to represent the severity of stent fracture. The incidence of DES fracture has been reported from 1% to 8%. In fact, in the only randomized controlled trial reporting the incidence and outcomes of stent fracture in DES (LONG-DES II study), where they had a follow-up angiography, a 14% incidence of restenosis was observed.
- Stent Fracture: It is defined as complete or partial separation of a stent, which was contiguous on initial implantation. This commonly happens with non-uniform stent expansion in region with both very compliant and resilient vessel walls. IVUS is an accurate imaging modality to recognize this abnormality. Partial stent fracture is defined as the absence of atleast one third or 120 degrees of stent struts for at least 1 frame. Complete stent fracture is defined as the complete absence of stent struts within the stented segment for at least 1 frame. There have been various classification systems to represent the severity of stent fracture. The incidence of DES fracture has been reported from 1% to 8%. In fact, in the only randomized controlled trial reporting the incidence and outcomes of stent fracture in DES (LONG-DES II study), where they had a follow-up angiography, a 14% incidence of restenosis was observed.
There are 2 important mechanisms for stent fracture. Firstly, with excessive movements during myocardial contraction, significant tension is exerted at hinge points where the myocardial contractility forces act in opposing direction and result in fracture. Secondly, when a stent has a closed cell design (as seen with Sirolimus DES), the stent cannot dissipate the myocardial contractility pressures and hence the stent itself succumbs to this force and results in a fracture. Hence, with these principle mechanisms in mind; long stents, right coronary artery lesions, excessive tortuosity, angulation and torsion of the vessel, overlapping stents, saphenous vein graft lesions, tight calcified lesions that have been vigorously post dilated and expanded, myocardial bridges' sites and closed cell design stents (such as Sirolimus DES) predispose towards stent fracture.
- Technical Factors:
Barotrauma/Geographical Miss (GM): When a stent is deployed and if its fails to cover the sites of balloon injury or the atherosclerotic in its entirety, then these missed sites can become a nidus for re-stenosis. GM can be classified as longitudinal or axial. Longitudinal GM was defined as injured or diseased stenotic segment, which was not fully covered by the DES. Whereas, axial GM was defined as inadequate or overzealous sizing of the balloon, which results in effects similar to stent underexpansion/malapposition and uncontrolled vessel wall injury (increasing the stimulus for inflammation and proliferative response, respectively. Hence, the presence of injured or diseased segment not covered by the stent or balloon-artery ratio 1.3 was noted to have an increased association with target vessel revascularization and myocardial infarction at 1 year.
- Technical Factors:
Barotrauma/Geographical Miss (GM): When a stent is deployed and if its fails to cover the sites of balloon injury or the atherosclerotic in its entirety, then these missed sites can become a nidus for re-stenosis. GM can be classified as longitudinal or axial. Longitudinal GM was defined as injured or diseased stenotic segment, which was not fully covered by the DES. Whereas, axial GM was defined as inadequate or overzealous sizing of the balloon, which results in effects similar to stent underexpansion/malapposition and uncontrolled vessel wall injury (increasing the stimulus for inflammation and proliferative response, respectively. Hence, the presence of injured or diseased segment not covered by the stent or balloon-artery ratio 1.3 was noted to have an increased association with target vessel revascularization and myocardial infarction at 1 year.
- Barotrauma/Geographical Miss (GM): When a stent is deployed and if its fails to cover the sites of balloon injury or the atherosclerotic in its entirety, then these missed sites can become a nidus for re-stenosis. GM can be classified as longitudinal or axial. Longitudinal GM was defined as injured or diseased stenotic segment, which was not fully covered by the DES. Whereas, axial GM was defined as inadequate or overzealous sizing of the balloon, which results in effects similar to stent underexpansion/malapposition and uncontrolled vessel wall injury (increasing the stimulus for inflammation and proliferative response, respectively. Hence, the presence of injured or diseased segment not covered by the stent or balloon-artery ratio 1.3 was noted to have an increased association with target vessel revascularization and myocardial infarction at 1 year.
- Stent Gap: It is simply defined as a discontinuous coverage between 2 stents. A gap between 2 stents exposes the site of balloon injury as well the lack of anti-stenotic drug distribution (if it is in between 2 DES) will clearly increase the risk for re-stenosis
- Stent Gap: It is simply defined as a discontinuous coverage between 2 stents. A gap between 2 stents exposes the site of balloon injury as well the lack of anti-stenotic drug distribution (if it is in between 2 DES) will clearly increase the risk for re-stenosis
- Stent Gap: It is simply defined as a discontinuous coverage between 2 stents. A gap between 2 stents exposes the site of balloon injury as well the lack of anti-stenotic drug distribution (if it is in between 2 DES) will clearly increase the risk for re-stenosis
- DES Deployment in a Clot-Laden Segment: Logically, it seems that there is significant reduction in penetrance of anti-stenotic drug in regions, where the DES is deployed in clot-laden arterial segment. However, with the widespread use of glycoprotein-IIb/IIIa inhibitors, potent P2Y12 receptor antagonists and aspiration thrombectomy, these concerns do not translate into clinical events. This is demonstrated in a recent meta-analysis of 13 trials (n=7244) has shown significant benefits of DES over BMS in reducing TVR and recurrent MI (at the end of one year) in STEMI patients.
- DES Deployment in a Clot-Laden Segment: Logically, it seems that there is significant reduction in penetrance of anti-stenotic drug in regions, where the DES is deployed in clot-laden arterial segment. However, with the widespread use of glycoprotein-IIb/IIIa inhibitors, potent P2Y12 receptor antagonists and aspiration thrombectomy, these concerns do not translate into clinical events. This is demonstrated in a recent meta-analysis of 13 trials (n=7244) has shown significant benefits of DES over BMS in reducing TVR and recurrent MI (at the end of one year) in STEMI patients.
- DES Deployment in a Clot-Laden Segment: Logically, it seems that there is significant reduction in penetrance of anti-stenotic drug in regions, where the DES is deployed in clot-laden arterial segment. However, with the widespread use of glycoprotein-IIb/IIIa inhibitors, potent P2Y12 receptor antagonists and aspiration thrombectomy, these concerns do not translate into clinical events. This is demonstrated in a recent meta-analysis of 13 trials (n=7244) has shown significant benefits of DES over BMS in reducing TVR and recurrent MI (at the end of one year) in STEMI patients.
# Clinical Presentation
In-stent restenosis (ISR) can be clinically silent, but majority of them present with recurrent symptoms of angina. The incidence of recurrent angina pectoris after a percutaneous coronary intervention (PCI) was reported in the past to be around 50% with a wide range. This number may have reduced as most the PCIs end up in a DES as opposed to a BMS. The positive predictive value of symptoms indicating a significant stenosis is as low as 60%. ISR is often thought to be a benign phenomenon since the process of neointimal formation and proliferation is of gradual onset and progressive in nature. Given the pathophysiology of coronary re-stenosis, it is thought that re-stenosis is a rare cause of acute myocardial infarction or death. However, there are several reports which have shown that ISR can present as an acute coronary syndrome. 26% to 53% and 3.5% to 20% of BMS ISR can present as unstable angina and myocardial infarction, respectively. Similarly, 16% to 66% and 1% to 20% of DES ISR can present as unstable angina and myocardial infarction, respectively. A highly stenotic ISR lesion can lead to an non-occlusive thrombus, which can result in an acute coronary syndrome. Also, patients with clinically silent re-stenosis can be identified on coronary cineangiograms when neighbouring plaques undergo rupture or intimal tear and present as an acute coronary syndrome. Sometimes, local plaque rupture or intimal tear can initiate an inflammatory process which can promote thrombosis of neighbouring stenotic lesions. Thus, it is important to thoroughly evaluate the patient as coronary re-stenosis can present as an acute coronary syndrome.
BMS ISR has been reported to occur usually after five and half months after stent implantation. The time frame for DES ISR presentation is not well-known with one study reporting a mean time duration of 12 months. Delayed restenosis is known to occur especially with DES. There have been reports, using intravascular ultrasound that have shown neointimal proliferation to occur even at 4 years after stent implantation. The exact reasons as to why this delayed neointimal proliferation occurs is not well known. Some of the suspected pathophysiological mechanisms are delayed healing response, persistent biological reaction caused by the drug present in the polymer, or a hypersensitivity reaction to the polymer and a possible a genetic predisposition. This eludes to the fact that the clinician should entertain the possibility of coronary re-stenosis in patients who present with recurrent angina about 2 years after the stent implantation.
Among the clinical predictors of coronary re-stenosis, diabetes mellitus continues to be a strong clinical predictor. In a study conducted by Singh et al., they found that patients with treated diabetes mellitus had a 45% higher risk of restenosis compared with nondiabetics. Interestingly, in their study they found that current smokers have less restenosis. This smoker's paradox has been described in the past. Some of the other predictors are increasing age, female sex and chronic renal disease and patients on hemodialysis. Angiographic and other predictors are listed under the other sections.
# ACCF/AHA/SCAI 2011 Guideline for Percutaneous Coronary Intervention: Restenosis (DO NOT EDIT)
# Related Chapters
- Drug-eluting stent | Restenosis
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1], Associate Editor(s)-In-Chief:: Bhaskar Purushottam, M.D. [2]
# Overview
Restenosis literally means the reoccurrence of stenosis. This is usually restenosis of an artery, or other blood vessel, but possibly any hollow organ that has been "unblocked". This term is common in vascular surgery, cardiac surgery, interventional radiology, or interventional cardiology following angioplasty, all branches of medicine that frequently treat stenotic lesions. In simple words, coronary restenosis can be considered as the reduction in the lumen diameter after a percutaneous coronary intervention (PCI), which induces iatrogenic arterial injury and results in neointimal tissue proliferation.[1] It can be defined based on angiography or as clinical restenosis. By angiography, the term 'Binary Angiographic Re-stenosis' is defined as > 50% luminal narrowing at follow-up angiography.[2] However, the most widely accepted and relevant definition would be a 'Clinical Re-stenosis', which is defined as need for a repeat target lesion revascularization (TLR) due to symptomatic coronary ischemia from the previously intervened vessel (proposed by the Academic Research Consortium). Therefore, this definition needs angiographic narrowing as well as clinical correlation. If the lesion does not meet angiographic criteria, but meets the criteria for a physiologically significant lesion by fractional flow reserve (FFR) or anatomically by intravascular ultrasound (IVUS) with the appropriate clinical context, it is still considered 'Clinical Re-stenosis'. PCI has evolved significantly from plain balloon angioplasty to the development of biodegradable stents in the last few decades. Currently, almost all coronary interventions use a bare metal stent (BMS) or more so a drug eluting stent (DES). Hence, the discussion in the following paragraphs will focus on in-stent re-stenosis of drug eluting and bare metal stents.
# Coronary Restenosis
There are probably several mechanisms that lead to restenosis. An important one is the inflammatory response, which induces tissue proliferation around an angioplasty site.
Cardiologists have tried a number of approaches to decrease the risk of restenosis. Stenting is becoming more commonplace; replacing balloon angioplasty. During the stenting procedure, a metal mesh (stent) is deployed against the wall of the artery revascularizing the artery. Other approaches include local radiotherapy and the use of immunosuppressive drugs, coated onto the stenting mesh. Analogues of rapamycin, such as tacrolimus (FK-506), sirolimus and more so everolimus, normally used as immunosuppressants but recently discovered to also inhibit the proliferation of vascular smooth muscle cells, have appeared to be quite effective in preventing restenosis in clinical trials. Antisense knockdown of c-myc, a protein critical for progression of cell replication, is another approach to inhibit cell proliferation in the artery wall and has been through preliminary clinical trials using Morpholino oligos.
# Histopathology and Molecular Mechanisms
Restenosis can considered a local vascular manifestation of the general biological response to arterial wall injury. Following vessel wall injury with endothelium damage, the exposure of tunica media to the flowing blood results in platelet adhesion to the media's collagen via the Von Williebrand factor. This results in platelet activation, which is followed by aggregation and soon evolving into a vicious cycle, which feeds and nurtures itself till a clot is formed from the coagulation cascade (which is activated from the tissue thromboplastin released from the media following vessel wall injury) and fibrin. Basically, this phenomenon can be considered synonymous to hemostasis. Activated platelets express adhesion molecules, to which circulating leukocytes attach and begin the process of leukocyte migration. Also during this process, several chemotactic factors are released and multiple adhesion molecules are expressed by various activated inflammatory cells in the vicinity of the inflammation, which cause chemotaxis of leukocytes to the core of the inflammation. Growth factors, cytokines and adhesion molecules released and expressed by platelets, leukocytes and other inflammatory cells, result in the migration of vascular smooth muscle cells from the media and proliferation with resultant neo-intima formation [3] [4] [5]. Hence, neo-intima consists of vascular smooth muscle cells, macrophages and extracellular matrix, which has formed over several weeks.
When reading through the above process, we realize that plaque rupture and stent thrombosis uses the same tools of inflammation mentioned above. The phenomenon of stent thrombosis and acute coronary syndrome can be thought of as an acute phenomenon, evolving in minutes to a couple of hours. Thus, depending on several factors (which favor acute thrombosis) the above mentioned process can evolve very quickly resulting in thrombosis of the coronary vessel. This process can then follow any of the pathways:
- the patient seeks immediate help and the percutaneous coronary intervention can open up the vessel and prevent progression of the acute coronary syndrome
- the patient fails to seek help and can die from a massive myocardial infarction
- sometimes, without seeking help, the patient lives through this coronary thrombosis and the clot becomes organised and recanalised.
In more simple words, coronary restenosis can be thought of as a sub-acute to chronic vascular inflammatory response to iatrogenic controlled injury; while stent thrombosis is an acute vascular response resulting in acute thrombosis and a high propensity to cause sudden death or significant morbidity.
In balloon angioplasty, the lumen size is increased from its baseline diseased state through the dilatation of the balloon at the site of the diseased region. However, the elastic recoil (of the artery), negative remodeling, contraction and finally neo-intima formation, results in restenosis. Also, to be noted is the fact that there is a 30% risk of abrupt closure of the vessel from acute thrombosis from plain balloon angioplasty as it is a form of vascular injury too (iatrogenic controlled injury). Based on individual clinical and angiographic characteristics, some patients develop this fatal complication, while others do not.
In stent implantation, the lumen size is increased from its baseline diseased state and has a better patency than plain balloon angioplasty, as the stent scaffold holds the vessel open; therefore the component of elastic recoil and negative remodeling is reduced significantly. Thus the restenosis rates are lower in BMS when compared to plain balloon angioplasty, as the elastic recoil and negative remodeling is virtually eliminated. Hence, the final lumen size is greater and neo-intima formation does not materialize into clinical restenosis as seen to occur more commonly with balloon angioplasty. Similarly, it is well known that DES has a lower re-stenosis rate than BMS as the DES have the added advantage of releasing anti-stenotic drug which can retard the neo-intima formation. Rapamycin, an immunosuppresant agent approved by the FDA, inhibits both rat and human vascular smooth muscle proliferation and migration in vitro. A study investigated (1) whether rapamycin administration could reduce neointimal thickening in a porcine model of restenosis post-PTCA and (2) the mechanism by which rapamycin inhibits VSMCs in vivo. It was found that rapamycin administration significantly reduced the arterial proliferative response after PTCA in the pig by increasing the level of the CDKI p27(kip1) and inhibition of the pRb phosphorylation within the vessel wall. Therefore, pharmacological interventions that elevate CDKI in the vessel wall and target cyclin-dependent kinase activity may have a therapeutic role in the treatment of restenosis after angioplasty in humans[6]. These common pathways finally act on the cell cycle and result in vascular smooth muscle cell proliferation. Given that the anti-stenotic drug of DES act at the level of the cell cycle, they are thus the most effective strategy available to prevent coronary restenosis after a percutaneous coronary intervention.
Once again, there are several other factors involved in re-stenosis of BMS and DES (as discussed below).
Coronary re-stenosis can be considered in two different settings of a percutaneous coronary intervention:
- In pure balloon angioplasty (in the absence of stenting)- Following balloon angioplasty, there is injury to the vessel wall, which triggers the expected inflammatory response from the vessel wall. Hence, there is elastic recoil, negative remodelling (reduction in lumen size due to the healing process) or contraction, thrombus at the site of injury (i.e., release of prothrombotic thromboplastin like material from the vessel wall, exposure of the collagen of the media), smooth muscle proliferation and migration and excessive extracellular matrix production.
- With stenting- Stenting prevents elastic recoil and negative remodelling. However, neointimal formation progresses and causes re-stenosis, which is reduced with antistenotic drugs. Restenosis in patients after stent implantation is caused predominantly by neointimal hyperplasia. However neointima formation in plain balloon angioplasty has a minor role.[7] [8] Through immunohistochemical identification, it has been shown that there is a steady accumulation of macrophages within stented segments (with clustering of macrophages around stent struts), where as there virtually no accumulation within balloon-injured segments of pure balloon angioplasty.[9] [10]
The porcine model of in-stent restenosis (ISR) has demonstrated the formation of a thick neointima in 28 days-which may be the reason as to why the earlier DES released their antistenotic drug by the end of 30 days. However, it is well known that the peak period of ISR development in humans is approximately 3 to 6 months-hence the newer DES are aiming to release the drug for an extended period. Interestingly, in these porcine models they found a positive correlation between the inflammatory infiltrate, degree of arterial injury and extent of stent strut penetration into the vessel wall with the neointimal thickness. Interestingly, in a rat model of carotid artery dilatation the gate-keeper step in initiating vascular smooth muscle cell proliferation from tunica media to intima is the rupture of internal elastic lamina.[11] [8]
The above mentioned responses and time periods were in porcine models with near normal coronaries and this may not be the case in humans who have had balloon angioplasty, BMS and DES for atherosclerotic lesions. The inflammatory response in DES is very different in terms of cell composition and timing, when compared to balloon angioplasty and BMS and also among the different DES. These differences could be explained by the presence of various forms of polymer among DES. For example, the inflammatory response (predominantly giant cell infiltrates) to Sirolimus DES has been shown to persist beyond 180 days and up to 2 years. In contrast, the inflammatory response to BMS and the second generation Everolimus DES (which has a more biocompatible polymer) has been limited to 90 days and 12 months, respectively. Evidence of such persistence of inflammatory response has been found in autopsy cases and from thrombus aspirates taken from patients during percutaneous coronary intervention for late stent thrombosis.
As mentioned earlier, the neointima consists of the hyperplastic vascular smooth muscle cells and the extracellular protein rich matrix. The current evidence points to the fact that these smooth muscle cells are of luminal origin, however, there is data that indicates that they can be of adventitial origin too.[12] [13] The later stages of restenosis is contributed predominantly by the deposition of extracellular matrix.[14] [15]
After reviewing the existing evidence, it seems that migration and proliferation of vascular smooth muscle cells form the major final common pathway for restenosis. In the presence of growth factors and cytokines, these vascular smooth cells undergo a phenotypic modulation from a contractile state to a synthetic phenotype. Hence, most of the molecular research in the past few years has been focused on understanding the common pathways that multiple receptors employ to transmit mitogenic signals from the cell membrane to the nucleus of the vascular smooth cells after arterial injury.[16] [17] The three common pathways which result in pathological mitosis of the vascular smooth cells are:
- Ras-raf mitogen activated protein kinase
- Cyclic adenosine monophosphate-protein kinase dependent signalling
- Cyclin dependent kinase complexes
Several rat models have shown that alteration of these pathways can worsen or prevent neo initmal formation.[18]
# Pathophysiology
In this section we will discuss the etiological and various pathophysiological factors, which lead to restenosis.
DES predominantly consist of 3 elements:
- Scaffold or the stent platform, which forms the skeleton of the stent (this made of stainless steel or cobalt chromium).
- The antistenotic drug (such as paclitaxel, everolimus, etc).
- The polymer or the carrier on which the drug is mounted.
Unlike, the DES the BMS consist only the scaffold or the platform.
The pathophysiology seems to be the interplay of clinical characteristics, biological factors, mechanical factors, technical factors and finally de-novo lesions which arise within the stent itself.
The various pathophysiological factors are discussed as follows:
- Biological and Genetic Factors:
Drug Resistance: Recent studies have revealed a genetic basis for drug resistance.[19] Depending on the penetrance and expressivity of these mutations, the sensitivity to these drugs vary. This resistance can be the result of inherited genetic mutations or acquired following the exposure of a cytotoxic drug.[20] [21]
Genetic Factors Affecting the Inflammatory Response: Polymorphism of glycoprotein IIIa and a mutant form of methylenetetrahydrofolate reductase appear to increase the risk of ISR.[22] Interestingly, allele 2 of interleukin IL-1ra gene appears to be protective. However, these are just some of the genetic factors which have been identified in the causation of ISR. Hence, there remains the possibility of complex multigenic abnormalities (interplay of multiple variant forms of genes and environmental factors), which can play a significant role in ISR. These identified and yet to be identified genetic factors may explain as to why some patients develop ISR and some don’t despite identical clinical factors and stent characteristics.
Hypersensitivity: The implantation of these stents is recognized as foreign antigens and hence a hypersensitivity reaction [23] can be triggered, which can lead to ISR. As mentioned earlier, the DES has 3 components and the BMS has only the scaffold, which can all contribute towards this hypersensitivity reaction.
- Drug Resistance: Recent studies have revealed a genetic basis for drug resistance.[19] Depending on the penetrance and expressivity of these mutations, the sensitivity to these drugs vary. This resistance can be the result of inherited genetic mutations or acquired following the exposure of a cytotoxic drug.[20] [21]
- Genetic Factors Affecting the Inflammatory Response: Polymorphism of glycoprotein IIIa and a mutant form of methylenetetrahydrofolate reductase appear to increase the risk of ISR.[22] Interestingly, allele 2 of interleukin IL-1ra gene appears to be protective. However, these are just some of the genetic factors which have been identified in the causation of ISR. Hence, there remains the possibility of complex multigenic abnormalities (interplay of multiple variant forms of genes and environmental factors), which can play a significant role in ISR. These identified and yet to be identified genetic factors may explain as to why some patients develop ISR and some don’t despite identical clinical factors and stent characteristics.
- Hypersensitivity: The implantation of these stents is recognized as foreign antigens and hence a hypersensitivity reaction [23] can be triggered, which can lead to ISR. As mentioned earlier, the DES has 3 components and the BMS has only the scaffold, which can all contribute towards this hypersensitivity reaction.
- Stent Platform: The stent platforms of the BMS and first generation DES (paclitaxel and sirolimus) is made up of 316L stainless steel, which contains more nickel and molybdenum than the second generation DES, where the scaffold is made up of cobalt chromium. This nickel and molybdenum are known to trigger these hypersensitivity reactions.[24] Interestingly, to date, no prospective studies have confirmed this association.
- Stent Platform: The stent platforms of the BMS and first generation DES (paclitaxel and sirolimus) is made up of 316L stainless steel, which contains more nickel and molybdenum than the second generation DES, where the scaffold is made up of cobalt chromium. This nickel and molybdenum are known to trigger these hypersensitivity reactions.[24] Interestingly, to date, no prospective studies have confirmed this association.
- Stent Platform: The stent platforms of the BMS and first generation DES (paclitaxel and sirolimus) is made up of 316L stainless steel, which contains more nickel and molybdenum than the second generation DES, where the scaffold is made up of cobalt chromium. This nickel and molybdenum are known to trigger these hypersensitivity reactions.[24] Interestingly, to date, no prospective studies have confirmed this association.
- Polymer: The durable polymer which remains covering the stent after releasing the anti-stenotic drug has known to cause hypersensitivity and is suspected as the culprit for stent thrombosis and progressive or late re-stenosis.
- Polymer: The durable polymer which remains covering the stent after releasing the anti-stenotic drug has known to cause hypersensitivity and is suspected as the culprit for stent thrombosis and progressive or late re-stenosis.
- Polymer: The durable polymer which remains covering the stent after releasing the anti-stenotic drug has known to cause hypersensitivity and is suspected as the culprit for stent thrombosis and progressive or late re-stenosis.
- Matrix Metalloproteinases: Circulating matrix metalloproteinase(MMP) have been associated with ISR as they play significant roles in migration of vascular smooth cells and matrix remodelling during healing post-stenting. Elevated levels of MMP-9 at baseline and MMP-2 and MMP-9 levels 24 hours post-percutaneous coronary intervention have proven to be strongly associated with the development of ISR following DES implantation. On the contrary, low and near normal levels of MMP-2 and MMP-9 were associated with a lack of a significant re-stenotic response.
- Matrix Metalloproteinases: Circulating matrix metalloproteinase(MMP) have been associated with ISR as they play significant roles in migration of vascular smooth cells and matrix remodelling during healing post-stenting. Elevated levels of MMP-9 at baseline and MMP-2 and MMP-9 levels 24 hours post-percutaneous coronary intervention have proven to be strongly associated with the development of ISR following DES implantation. On the contrary, low and near normal levels of MMP-2 and MMP-9 were associated with a lack of a significant re-stenotic response.
- Matrix Metalloproteinases: Circulating matrix metalloproteinase(MMP) have been associated with ISR as they play significant roles in migration of vascular smooth cells and matrix remodelling during healing post-stenting. Elevated levels of MMP-9 at baseline and MMP-2 and MMP-9 levels 24 hours post-percutaneous coronary intervention have proven to be strongly associated with the development of ISR following DES implantation. On the contrary, low and near normal levels of MMP-2 and MMP-9 were associated with a lack of a significant re-stenotic response.
- Genetic factors: As mentioned above can play a significant role in the inflammatory response, which can result in ISR.
- Genetic factors: As mentioned above can play a significant role in the inflammatory response, which can result in ISR.
- Genetic factors: As mentioned above can play a significant role in the inflammatory response, which can result in ISR.
- B) Arterial Factors:
Wall Shear Stress: The laminar flow of blood is a well known phenomenon, where the blood flows the fastest at the vessel center (or at the carina of a bifurcation) and slowest when it flows closest to the vessel wall (or at the ostium of a bifurcation). Hence, regions of low shear stress lead to accumulation of biological mediators, which promote atherosclerosis or neointimal formation. Adapting this principle would mean that a divider or the formation of a new carina should reduce the incidence of ISR. Kim at al demonstrated reduced occurrence of ISR by 'shotgun stenting' (i.e., simultaneous V-stenting with the formation of a new carina in the left main stem or other suitably sized vessels) but conversely, Stinus et al demonstrated increased target lesion revascularization rate with V-stenting when compared with the 'Crush' technique. This disparity can have a couple of explanations: 1) lesion location 2) post stent lumen size 3) reference lumen size 4) exposure of the new carina (formed by stent struts) for thrombus formation.
- Wall Shear Stress: The laminar flow of blood is a well known phenomenon, where the blood flows the fastest at the vessel center (or at the carina of a bifurcation) and slowest when it flows closest to the vessel wall (or at the ostium of a bifurcation). Hence, regions of low shear stress lead to accumulation of biological mediators, which promote atherosclerosis or neointimal formation. Adapting this principle would mean that a divider or the formation of a new carina should reduce the incidence of ISR. Kim at al demonstrated reduced occurrence of ISR by 'shotgun stenting' (i.e., simultaneous V-stenting with the formation of a new carina in the left main stem or other suitably sized vessels) but conversely, Stinus et al demonstrated increased target lesion revascularization rate with V-stenting when compared with the 'Crush' technique. This disparity can have a couple of explanations: 1) lesion location 2) post stent lumen size 3) reference lumen size 4) exposure of the new carina (formed by stent struts) for thrombus formation.
The presence of patchy areas of low shear stress within stented segments, secondary to local geometric factors (such as angulation or curvature) can predispose towards increased neointimal formation and hence ISR. This was demonstrated by Papafaklis et al on 6 month follow-up with BMS and Paclitaxel DES. However, this was not seen with Sirolimus DES. This difference can be explained by the differing pharmacological mode of action and shorter drug-release kinetics.
- Progression of Atherosclerosis within a Stented Segment: If the necrotic plaque within the stent progresses or if a lipid core plaque at the stent edge is not covered completely, then these lesions can progress to cause ISR or even thrombus formation.
- Progression of Atherosclerosis within a Stented Segment: If the necrotic plaque within the stent progresses or if a lipid core plaque at the stent edge is not covered completely, then these lesions can progress to cause ISR or even thrombus formation.
- "Thrombostenosis" Phenomenon: Oikawa et al was the first to describe the intriguing theory in which chronic thrombus formation may play an integral role in the development of ISR.
- "Thrombostenosis" Phenomenon: Oikawa et al was the first to describe the intriguing theory in which chronic thrombus formation may play an integral role in the development of ISR.
- Vessel Remodelling: The implantation of DES in vessels that have already undergone positive remodelling secondary to large plaque burden ("Glagov" phenomenon) have an increased risk for ISR.
- Vessel Remodelling: The implantation of DES in vessels that have already undergone positive remodelling secondary to large plaque burden ("Glagov" phenomenon) have an increased risk for ISR.
- Stent Factors:
Polymer Release Characteristics: In one the earlier trials involving Paclitaxel, they found that the duration of the drug release had a far greater impact on the inhibition of neointimal proliferation than the actual drug dose delivered. Several molecular biological studies have indicated that the genetic mechanisms responsible for the inflammatory proliferative response remain potentially active for a period of 21 days after vessel wall injury. These polymer release kinetics could explain some of the disparities in the ISR among different DES. It seems clear that when the antistenotic drug is delivered at a set threshold dose for a sustained prolonged period of time may be required to control the inflammatory proliferative response and hence reduce the occurrence of ISR.
- Polymer Release Characteristics: In one the earlier trials involving Paclitaxel, they found that the duration of the drug release had a far greater impact on the inhibition of neointimal proliferation than the actual drug dose delivered. Several molecular biological studies have indicated that the genetic mechanisms responsible for the inflammatory proliferative response remain potentially active for a period of 21 days after vessel wall injury. These polymer release kinetics could explain some of the disparities in the ISR among different DES. It seems clear that when the antistenotic drug is delivered at a set threshold dose for a sustained prolonged period of time may be required to control the inflammatory proliferative response and hence reduce the occurrence of ISR.
- Non-uniform Drug Distribution:
Ideally, the anti-stenotic drug should be delivered in a homogeneous fashion to the vessel wall (i.e., transmural and circumferential). However, due to local blood flow alterations (secondary to atherosclerotic plaque and calcified lesions), non-compliant vessels (i.e., calcified, tortuous), strut overlap, stent design, stent gap, vessel curvature, bifurcation lesions, ostial lesions, stent fracture and polymer damage can result in focal areas of the vessel receiving sub-optimal anti-stenotic drug.
- Non-uniform Drug Distribution:
Ideally, the anti-stenotic drug should be delivered in a homogeneous fashion to the vessel wall (i.e., transmural and circumferential). However, due to local blood flow alterations (secondary to atherosclerotic plaque and calcified lesions), non-compliant vessels (i.e., calcified, tortuous), strut overlap, stent design, stent gap, vessel curvature, bifurcation lesions, ostial lesions, stent fracture and polymer damage can result in focal areas of the vessel receiving sub-optimal anti-stenotic drug.
- Ideally, the anti-stenotic drug should be delivered in a homogeneous fashion to the vessel wall (i.e., transmural and circumferential). However, due to local blood flow alterations (secondary to atherosclerotic plaque and calcified lesions), non-compliant vessels (i.e., calcified, tortuous), strut overlap, stent design, stent gap, vessel curvature, bifurcation lesions, ostial lesions, stent fracture and polymer damage can result in focal areas of the vessel receiving sub-optimal anti-stenotic drug.
- Stent delivery in calcified lesions can result in stripping of the polymer base.
- Stent delivery in calcified lesions can result in stripping of the polymer base.
- Stent delivery in calcified lesions can result in stripping of the polymer base.
- Finally, individual variations in metal to artery ratio and variability in drug elution can all contribute to stent re-stenosis.
- Finally, individual variations in metal to artery ratio and variability in drug elution can all contribute to stent re-stenosis.
- Finally, individual variations in metal to artery ratio and variability in drug elution can all contribute to stent re-stenosis.
- Strut Thickness: Thicker stent struts have been associated with increased risk of ISR with BMS and smaller vessels. This could be explained by the fact that the thinner stent strut would have a lesser dose of foreign body exposure to the vessel wall, hence reducing the intensity of the inflammatory proliferative response.
- Strut Thickness: Thicker stent struts have been associated with increased risk of ISR with BMS and smaller vessels. This could be explained by the fact that the thinner stent strut would have a lesser dose of foreign body exposure to the vessel wall, hence reducing the intensity of the inflammatory proliferative response.
- On- and Off-Label Use: The STENT group is the largest, multicenter, prospective registry involving >15,000 patients, evaluating the late outcomes associated with DES implantation in the United States showed an almost 2 fold increase in target vessel revascularization (TVR) at 9 months for off-label use (ostial, left main stem, chronic total occlusions, saphenous venous graft, small or large vessels, multivessel, ST-elevation myocardial infarction, ISR lesions) when compared to on-label use (short de novo lesions measuring >2.5mm and <3.5mm for Sirolimus DES or <3.75mm for Paclitaxel DES). Also, when looking at the SYNTAX study, there were higher TVR rates in patients with highly complex 3-vessel or left main disease who underwent DES (which was an off-label use of DES). When analyzing the list of off-label uses, it seems that these patients have complex coronary lesions (with a higher SYNTAX score), more sicker and have more comorbidities which could easily influence TVR.
- On- and Off-Label Use: The STENT group is the largest, multicenter, prospective registry involving >15,000 patients, evaluating the late outcomes associated with DES implantation in the United States showed an almost 2 fold increase in target vessel revascularization (TVR) at 9 months for off-label use (ostial, left main stem, chronic total occlusions, saphenous venous graft, small or large vessels, multivessel, ST-elevation myocardial infarction, ISR lesions) when compared to on-label use (short de novo lesions measuring >2.5mm and <3.5mm for Sirolimus DES or <3.75mm for Paclitaxel DES). Also, when looking at the SYNTAX study, there were higher TVR rates in patients with highly complex 3-vessel or left main disease who underwent DES (which was an off-label use of DES). When analyzing the list of off-label uses, it seems that these patients have complex coronary lesions (with a higher SYNTAX score), more sicker and have more comorbidities which could easily influence TVR.
- Polymer Disruption, Peeling and Crackling: This can result in exposure of bare-metal areas, which has been demonstrated in bench studies involving both first and second generation DES using light or scanning electron microscopy. It is plausible that this bare metal exposure and stent regions in the absence of anti-stenotic drug can form a nidus for inflammatory and proliferative response. Seen more so in stent implantation in tortuous calcified lesions.
- Polymer Disruption, Peeling and Crackling: This can result in exposure of bare-metal areas, which has been demonstrated in bench studies involving both first and second generation DES using light or scanning electron microscopy. It is plausible that this bare metal exposure and stent regions in the absence of anti-stenotic drug can form a nidus for inflammatory and proliferative response. Seen more so in stent implantation in tortuous calcified lesions.
- Mechanical Factors:
Stent Underexpansion: When the stent is deployed and it is not well expanded, it results in a vessel lumen size whose stent cross-sectional area is significantly smaller that of the reference lumen size or other cross-sectional areas within the stent, despite good apposition of the stent struts against the vessel wall. If the minimum stent area is smaller than the reference lumen size to begin with, then the same amount of neointimal formation would be of greater significance than in a scenario where the minimum stent area was larger. An excellent expansion is considered if the minimal cross-sectional area in the stent is >90% of the average reference cross-sectional area.
- Stent Underexpansion: When the stent is deployed and it is not well expanded, it results in a vessel lumen size whose stent cross-sectional area is significantly smaller that of the reference lumen size or other cross-sectional areas within the stent, despite good apposition of the stent struts against the vessel wall. If the minimum stent area is smaller than the reference lumen size to begin with, then the same amount of neointimal formation would be of greater significance than in a scenario where the minimum stent area was larger. An excellent expansion is considered if the minimal cross-sectional area in the stent is >90% of the average reference cross-sectional area.
- Stent Malapposition: In malapposition, the stent struts are not apposed to the vessel wall (blood occupies the space between the stent struts and vessel wall). It is commonly seen with undersized stents, tortuous arteries and non-homogeneity in the reference arterial lumen diameter within the treated segment.
- Stent Malapposition: In malapposition, the stent struts are not apposed to the vessel wall (blood occupies the space between the stent struts and vessel wall). It is commonly seen with undersized stents, tortuous arteries and non-homogeneity in the reference arterial lumen diameter within the treated segment.
- Stent Fracture: It is defined as complete or partial separation of a stent, which was contiguous on initial implantation. This commonly happens with non-uniform stent expansion in region with both very compliant and resilient vessel walls. IVUS is an accurate imaging modality to recognize this abnormality. Partial stent fracture is defined as the absence of atleast one third or 120 degrees of stent struts for at least 1 frame. Complete stent fracture is defined as the complete absence of stent struts within the stented segment for at least 1 frame. There have been various classification systems to represent the severity of stent fracture. The incidence of DES fracture has been reported from 1% to 8%. In fact, in the only randomized controlled trial reporting the incidence and outcomes of stent fracture in DES (LONG-DES II study), where they had a follow-up angiography, a 14% incidence of restenosis was observed.
- Stent Fracture: It is defined as complete or partial separation of a stent, which was contiguous on initial implantation. This commonly happens with non-uniform stent expansion in region with both very compliant and resilient vessel walls. IVUS is an accurate imaging modality to recognize this abnormality. Partial stent fracture is defined as the absence of atleast one third or 120 degrees of stent struts for at least 1 frame. Complete stent fracture is defined as the complete absence of stent struts within the stented segment for at least 1 frame. There have been various classification systems to represent the severity of stent fracture. The incidence of DES fracture has been reported from 1% to 8%. In fact, in the only randomized controlled trial reporting the incidence and outcomes of stent fracture in DES (LONG-DES II study), where they had a follow-up angiography, a 14% incidence of restenosis was observed.
There are 2 important mechanisms for stent fracture. Firstly, with excessive movements during myocardial contraction, significant tension is exerted at hinge points where the myocardial contractility forces act in opposing direction and result in fracture. Secondly, when a stent has a closed cell design (as seen with Sirolimus DES), the stent cannot dissipate the myocardial contractility pressures and hence the stent itself succumbs to this force and results in a fracture. Hence, with these principle mechanisms in mind; long stents, right coronary artery lesions, excessive tortuosity, angulation and torsion of the vessel, overlapping stents, saphenous vein graft lesions, tight calcified lesions that have been vigorously post dilated and expanded, myocardial bridges' sites and closed cell design stents (such as Sirolimus DES) predispose towards stent fracture.
- Technical Factors:
Barotrauma/Geographical Miss (GM): When a stent is deployed and if its fails to cover the sites of balloon injury or the atherosclerotic in its entirety, then these missed sites can become a nidus for re-stenosis. GM can be classified as longitudinal or axial. Longitudinal GM was defined as injured or diseased stenotic segment, which was not fully covered by the DES. Whereas, axial GM was defined as inadequate or overzealous sizing of the balloon, which results in effects similar to stent underexpansion/malapposition and uncontrolled vessel wall injury (increasing the stimulus for inflammation and proliferative response, respectively. Hence, the presence of injured or diseased segment not covered by the stent or balloon-artery ratio <0.9 or >1.3 was noted to have an increased association with target vessel revascularization and myocardial infarction at 1 year.
- Technical Factors:
Barotrauma/Geographical Miss (GM): When a stent is deployed and if its fails to cover the sites of balloon injury or the atherosclerotic in its entirety, then these missed sites can become a nidus for re-stenosis. GM can be classified as longitudinal or axial. Longitudinal GM was defined as injured or diseased stenotic segment, which was not fully covered by the DES. Whereas, axial GM was defined as inadequate or overzealous sizing of the balloon, which results in effects similar to stent underexpansion/malapposition and uncontrolled vessel wall injury (increasing the stimulus for inflammation and proliferative response, respectively. Hence, the presence of injured or diseased segment not covered by the stent or balloon-artery ratio <0.9 or >1.3 was noted to have an increased association with target vessel revascularization and myocardial infarction at 1 year.
- Barotrauma/Geographical Miss (GM): When a stent is deployed and if its fails to cover the sites of balloon injury or the atherosclerotic in its entirety, then these missed sites can become a nidus for re-stenosis. GM can be classified as longitudinal or axial. Longitudinal GM was defined as injured or diseased stenotic segment, which was not fully covered by the DES. Whereas, axial GM was defined as inadequate or overzealous sizing of the balloon, which results in effects similar to stent underexpansion/malapposition and uncontrolled vessel wall injury (increasing the stimulus for inflammation and proliferative response, respectively. Hence, the presence of injured or diseased segment not covered by the stent or balloon-artery ratio <0.9 or >1.3 was noted to have an increased association with target vessel revascularization and myocardial infarction at 1 year.
- Stent Gap: It is simply defined as a discontinuous coverage between 2 stents. A gap between 2 stents exposes the site of balloon injury as well the lack of anti-stenotic drug distribution (if it is in between 2 DES) will clearly increase the risk for re-stenosis
- Stent Gap: It is simply defined as a discontinuous coverage between 2 stents. A gap between 2 stents exposes the site of balloon injury as well the lack of anti-stenotic drug distribution (if it is in between 2 DES) will clearly increase the risk for re-stenosis
- Stent Gap: It is simply defined as a discontinuous coverage between 2 stents. A gap between 2 stents exposes the site of balloon injury as well the lack of anti-stenotic drug distribution (if it is in between 2 DES) will clearly increase the risk for re-stenosis
- DES Deployment in a Clot-Laden Segment: Logically, it seems that there is significant reduction in penetrance of anti-stenotic drug in regions, where the DES is deployed in clot-laden arterial segment. However, with the widespread use of glycoprotein-IIb/IIIa inhibitors, potent P2Y12 receptor antagonists and aspiration thrombectomy, these concerns do not translate into clinical events. This is demonstrated in a recent meta-analysis of 13 trials (n=7244) has shown significant benefits of DES over BMS in reducing TVR and recurrent MI (at the end of one year) in STEMI patients.
- DES Deployment in a Clot-Laden Segment: Logically, it seems that there is significant reduction in penetrance of anti-stenotic drug in regions, where the DES is deployed in clot-laden arterial segment. However, with the widespread use of glycoprotein-IIb/IIIa inhibitors, potent P2Y12 receptor antagonists and aspiration thrombectomy, these concerns do not translate into clinical events. This is demonstrated in a recent meta-analysis of 13 trials (n=7244) has shown significant benefits of DES over BMS in reducing TVR and recurrent MI (at the end of one year) in STEMI patients.
- DES Deployment in a Clot-Laden Segment: Logically, it seems that there is significant reduction in penetrance of anti-stenotic drug in regions, where the DES is deployed in clot-laden arterial segment. However, with the widespread use of glycoprotein-IIb/IIIa inhibitors, potent P2Y12 receptor antagonists and aspiration thrombectomy, these concerns do not translate into clinical events. This is demonstrated in a recent meta-analysis of 13 trials (n=7244) has shown significant benefits of DES over BMS in reducing TVR and recurrent MI (at the end of one year) in STEMI patients.
# Clinical Presentation
In-stent restenosis (ISR) can be clinically silent, but majority of them present with recurrent symptoms of angina. The incidence of recurrent angina pectoris after a percutaneous coronary intervention (PCI) was reported in the past to be around 50% with a wide range. This number may have reduced as most the PCIs end up in a DES as opposed to a BMS. The positive predictive value of symptoms indicating a significant stenosis is as low as 60%. ISR is often thought to be a benign phenomenon since the process of neointimal formation and proliferation is of gradual onset and progressive in nature. Given the pathophysiology of coronary re-stenosis, it is thought that re-stenosis is a rare cause of acute myocardial infarction or death. However, there are several reports which have shown that ISR can present as an acute coronary syndrome. 26% to 53% and 3.5% to 20% of BMS ISR can present as unstable angina and myocardial infarction, respectively. Similarly, 16% to 66% and 1% to 20% of DES ISR can present as unstable angina and myocardial infarction, respectively. A highly stenotic ISR lesion can lead to an non-occlusive thrombus, which can result in an acute coronary syndrome. Also, patients with clinically silent re-stenosis can be identified on coronary cineangiograms when neighbouring plaques undergo rupture or intimal tear and present as an acute coronary syndrome. Sometimes, local plaque rupture or intimal tear can initiate an inflammatory process which can promote thrombosis of neighbouring stenotic lesions. Thus, it is important to thoroughly evaluate the patient as coronary re-stenosis can present as an acute coronary syndrome.
BMS ISR has been reported to occur usually after five and half months after stent implantation. The time frame for DES ISR presentation is not well-known with one study reporting a mean time duration of 12 months. Delayed restenosis is known to occur especially with DES. There have been reports, using intravascular ultrasound that have shown neointimal proliferation to occur even at 4 years after stent implantation. The exact reasons as to why this delayed neointimal proliferation occurs is not well known. Some of the suspected pathophysiological mechanisms are delayed healing response, persistent biological reaction caused by the drug present in the polymer, or a hypersensitivity reaction to the polymer and a possible a genetic predisposition. This eludes to the fact that the clinician should entertain the possibility of coronary re-stenosis in patients who present with recurrent angina about 2 years after the stent implantation.
Among the clinical predictors of coronary re-stenosis, diabetes mellitus continues to be a strong clinical predictor. In a study conducted by Singh et al., they found that patients with treated diabetes mellitus had a 45% higher risk of restenosis compared with nondiabetics. Interestingly, in their study they found that current smokers have less restenosis. This smoker's paradox has been described in the past. Some of the other predictors are increasing age, female sex and chronic renal disease and patients on hemodialysis. Angiographic and other predictors are listed under the other sections.
# ACCF/AHA/SCAI 2011 Guideline for Percutaneous Coronary Intervention: Restenosis[25] (DO NOT EDIT)
# Related Chapters
- Drug-eluting stent | https://www.wikidoc.org/index.php/Coronary_restenosis | |
99810ff7197cfd2e3524f1722edf82eabf411e52 | wikidoc | Corrective | Corrective
# Corrective
## Arterial switch
The Jatene procedure surgery is the preferred, and most frequently used, method of correcting d-TGA; ideally, it is performed on an infant between 8-14 days old.
The heart and vessels are accessed via median sternotomy, and a cardiopulmonary bypass machine is used; as this machine needs its "circulation" to be filled with blood, a child will require a blood transfusion for this surgery. The procedure involves transecting both the aorta and pulmonary artery; the coronary arteries are then detached from the aorta and reattached to the neo-aorta, before "swapping" the upper portion of the aorta and pulmonary artery to the opposite arterial root. Including the anaesthesia and immediate post operative recovery, this surgery takes an average of approximately six to eight hours to complete.
Some arterial switch recipients may present with post-operative pulmonary stenosis, which would then be repaired with angioplasty, pulmonary stenting via heart cath or median sternotomy, and/or xenograft.
## Atrial switch
In some cases, it is not possible to perform an arterial switch, either because of late diagnosis, sepsis, or a contraindicative coronary artery pattern. In the case of sepsis or late diagnosis, a delayed Arterial Switch can sometimes be made possible by PAB, which may also require a concomitant construction of an aortic-to-pulmonary artery shunt.
When an arterial switch is impossible, an atrial switch will be attempted using either the Senning or Mustard procedure. Both methods involve creating a baffle to redirect red and blue blood flow to the appropriate artery. Since the late 1970s the Mustard procedure has been preferred.
# Post-operative
Following corrective surgery but prior to cessation of anaesthesia, two small incisions are made immediately below the sternotomy incision which provide exit points for chest tubes used to drain fluid from the thoracic cavity, with one tube placed at the front and another at the rear of the heart.
The patient returns to the ICU post-operatively for recovery, maintenance, and close observation; recovery time may vary, but tends to average approximately two weeks, after which the patient may be transferred to a Transitional Care Unit (TCU), and eventually to a cardiac ward.
Post-operative care is very similar to the palliative care received, with the exception that the patient no longer requires PGE or the surgical palliation procedures. Additionally, the patient is kept on a cooling blanket for a period of time to prevent fever, which could cause brain damage. The sternum is not closed immediately which allows extra space in the thoracic cavity, preventing excess pressure on the heart, which swells considerably following the surgery; the sternum and incision are closed after a few days, when swelling is sufficiently reduced. | Corrective
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Associate Editors-In-Chief: Keri Shafer, M.D. [2]; Atif Mohammad, M.D., Priyamvada Singh, MBBS
## Corrective
### Arterial switch
The Jatene procedure surgery is the preferred, and most frequently used, method of correcting d-TGA; ideally, it is performed on an infant between 8-14 days old.
The heart and vessels are accessed via median sternotomy, and a cardiopulmonary bypass machine is used; as this machine needs its "circulation" to be filled with blood, a child will require a blood transfusion for this surgery. The procedure involves transecting both the aorta and pulmonary artery; the coronary arteries are then detached from the aorta and reattached to the neo-aorta, before "swapping" the upper portion of the aorta and pulmonary artery to the opposite arterial root. Including the anaesthesia and immediate post operative recovery, this surgery takes an average of approximately six to eight hours to complete.
Some arterial switch recipients may present with post-operative pulmonary stenosis, which would then be repaired with angioplasty, pulmonary stenting via heart cath or median sternotomy, and/or xenograft.
### Atrial switch
In some cases, it is not possible to perform an arterial switch, either because of late diagnosis, sepsis, or a contraindicative coronary artery pattern. In the case of sepsis or late diagnosis, a delayed Arterial Switch can sometimes be made possible by PAB, which may also require a concomitant construction of an aortic-to-pulmonary artery shunt.
When an arterial switch is impossible, an atrial switch will be attempted using either the Senning or Mustard procedure. Both methods involve creating a baffle to redirect red and blue blood flow to the appropriate artery. Since the late 1970s the Mustard procedure has been preferred.
## Post-operative
Following corrective surgery but prior to cessation of anaesthesia, two small incisions are made immediately below the sternotomy incision which provide exit points for chest tubes used to drain fluid from the thoracic cavity, with one tube placed at the front and another at the rear of the heart.
The patient returns to the ICU post-operatively for recovery, maintenance, and close observation; recovery time may vary, but tends to average approximately two weeks, after which the patient may be transferred to a Transitional Care Unit (TCU), and eventually to a cardiac ward.
Post-operative care is very similar to the palliative care received, with the exception that the patient no longer requires PGE or the surgical palliation procedures. Additionally, the patient is kept on a cooling blanket for a period of time to prevent fever, which could cause brain damage. The sternum is not closed immediately which allows extra space in the thoracic cavity, preventing excess pressure on the heart, which swells considerably following the surgery; the sternum and incision are closed after a few days, when swelling is sufficiently reduced. | https://www.wikidoc.org/index.php/Corrective | |
70f4c22311676c9d5f225569ceb800f6b7614f06 | wikidoc | Cosmic ray | Cosmic ray
Cosmic rays are energetic particles originating from space that impinge on Earth's atmosphere. Almost 90% of all the incoming cosmic ray particles are protons, about 9% are helium nuclei (alpha particles) and about 1% are electrons (beta minus particles). The term "ray" is a misnomer, as cosmic particles arrive individually, not in the form of a ray or beam of particles.
The variety of particle energies reflects the wide variety of sources. The origins of these particles range from energetic processes on the Sun all the way to as yet unknown events in the farthest reaches of the visible universe. Cosmic rays can have energies of over 1020 eV, far higher than the 1012 to 1013 eV that man-made particle accelerators can produce. (See Ultra-high-energy cosmic rays for a description of the detection of a single particle with an energy of about 50 J, the same as a well-hit tennis ball at 42 m/s .) There has been interest in investigating cosmic rays of even greater energies.
# Cosmic ray sources
Most cosmic rays originate from extrasolar sources within our own galaxy such as rotating neutron stars, supernovae, and black holes. However, the fact that some cosmic rays have extremely high energies provides evidence that at least some must be of extra-galactic origin (e.g. radio galaxies and quasars); the local galactic magnetic field would not be able to contain particles with such a high energy. The origin of cosmic rays with energies up to 1014 eV can be accounted for in terms of shock-wave acceleration in supernova shells. The origin of cosmic rays with energy greater than 1014 eV remained unknown until recently, when a large collaborative experiment at the Pierre Auger Observatory appears to have answered this question. In preliminary results announced in November 2007, they showed a strong correlation between their 27 most energetic events and active galactic nuclei . These results demonstrated that there is only a small chance (less than 1/100) that the highest energy protons originated from outside the AGN.
Observations have shown that cosmic rays with an energy above 10 GeV (10 x 109 eV) approach the Earth’s surface isotropically (equally from all directions); it has been hypothesized that this is not due to an even distribution of cosmic ray sources, but instead is due to galactic magnetic fields causing cosmic rays to travel in spiral paths. This limits cosmic ray’s usefulness in positional astronomy as they carry no information of their direction of origin. At energies below 10 GeV there is a directional dependence, due to the interaction of the charged component of the cosmic rays with the Earth's magnetic field.
## Solar cosmic rays
Solar cosmic rays or solar energetic particles (SEP) are cosmic rays that originate from the Sun. The average composition is similar to that of the Sun itself. There exists no clear and sharp boundary between the phase spaces of the solar wind and SEP plasma particle populations.
The name solar cosmic ray itself is a misnomer because the term cosmic implies that the rays are from the cosmos and not the solar system, but it has stuck. The misnomer arose because there is continuity in the energy spectra, i.e., the flux of particles as a function of their energy, because the low-energy solar cosmic rays fade more or less smoothly into the galactic ones as one looks at increasingly higher energies. Until the mid-1960s the energy distributions were generally averaged over long time intervals, which also obscured the difference. Later, it was found that the solar cosmic rays vary widely in their intensity and spectrum, increasing in strength after some solar events such as solar flares. Further, an increase in the intensity of solar cosmic rays is followed by a decrease in all other cosmic rays, called the Forbush decrease after their discoverer, the physicist Scott Forbush. These decreases are due to the solar wind with its entrained magnetic field sweeping some of the galactic cosmic rays outwards, away from the Sun and Earth. The overall or average rate of Forbush decreases tends to follow the 11-year sunspot cycle, but individual events are tied to events on the Sun, as explained above.
There are further differences between cosmic rays of solar and galactic origin, mainly in that the galactic cosmic rays show an enhancement of heavy elements such as calcium, iron and gallium, as well as of cosmically rare light elements such as lithium and beryllium. The latter result from the cosmic ray spallation (fragmentation) of heavy nuclei due to collisions in transit from the distant sources to the solar system.
## Galactic cosmic rays
See Galactic cosmic ray.
## Extragalactic cosmic rays
See Extragalactic cosmic ray.
## Ultra-high-energy cosmic rays
See Ultra-high-energy cosmic ray.
## Anomalous cosmic rays
Anomalous cosmic rays (ACRs) are cosmic rays with unexpectedly low energies. They are thought to be created near the edge of our solar system, in the heliosheath, the border region between the heliosphere and the interstellar medium. When electrically neutral atoms are able to enter the heliosheath (being unaffected by its magnetic fields) subsequently become ionized, they are thought to be accelerated into low-energy cosmic rays by the solar wind's termination shock which marks the inner edge of the heliosheath. It is also possible that high energy galactic cosmic rays which hit the shock front of the solar wind near the heliopause might be decelerated, resulting in their transformation into lower-energy anomalous cosmic rays.
The Voyager 1 space probe crossed the termination shock on December 16, 2004, according to papers published in the journal Science. Readings showed particle acceleration, but not of the kind that generates ACRs. It is unclear at this stage (September 2005) if this is typical of the termination shock (requiring a major rethink of the origin of ACRs), or a localised feature of that part of the termination shock that Voyager 1 passed through. Voyager 2 is expected to cross the termination shock during or after 2008, which will provide more data.
# Composition
Cosmic rays may broadly be divided into two categories, primary and secondary.
The cosmic rays that arise in extrasolar astrophysical sources are primary cosmic rays; these primary cosmic rays can interact with interstellar matter to create secondary cosmic rays. The sun also emits low energy cosmic rays associated with solar flares. The exact composition of primary cosmic rays, outside the Earth's atmosphere, is dependent on which part of the energy spectrum is observed. However, in general, almost 90% of all the incoming cosmic rays are protons, about 9% are helium nuclei (alpha particles) and about 1% are electrons. The remaining fraction is made up of the other heavier nuclei which are abundant end products of star’s nuclear synthesis. Secondary cosmic rays consist of the other nuclei which are not abundant nuclear synthesis end products, or products of the Big Bang, primarily lithium, beryllium and boron. These light nuclei appear in cosmic rays in much greater abundance (about 1:100 particles) than in solar atmospheres, where their abundance is about 10-7 that of helium.
This abundance difference is a result of the way secondary cosmic rays are formed. When the heavy nuclei components of primary cosmic rays, namely the carbon and oxygen nuclei, collide with interstellar matter, they break up into lighter nuclei (in a process termed cosmic ray spallation), into lithium, beryllium and boron. It is found that the energy spectra of Li, Be and B falls off somewhat steeper than that of carbon or oxygen, indicating that less cosmic ray spallation occurs for the higher energy nuclei presumably due to their escape from the galactic magnetic field. Spallation is also responsible for the abundances of Sc, Ti, V and Mn elements in cosmic rays, which are produced by collisions of Fe and Ni nuclei with interstellar matter; see Environmental radioactivity#Naturals.
In the past, it was believed that the cosmic ray flux has remained fairly constant over time. Recent research has, however, produced evidence for 1.5 to 2-fold millennium-timescale changes in the cosmic ray flux in the past forty thousand years.
# Modulation
The flux (flow rate) of cosmic rays incident on the Earth’s upper atmosphere is modulated (varied) by two processes; the sun’s solar wind and the Earth's magnetic field. Solar wind is expanding magnetized plasma generated by the sun, which has the effect of decelerating the incoming particles as well as partially excluding some of the particles with energies below about 1 GeV. The amount of solar wind is not constant due to changes in solar activity over its regular eleven-year cycle. Hence the level of modulation varies in autocorrelation with solar activity. Also the Earth's magnetic field deflects some of the cosmic rays, which is confirmed by the fact that the intensity of cosmic radiation is dependent on latitude, longitude and azimuth. The cosmic flux varies from eastern and western directions due to the polarity of the Earth’s geomagnetic field and the positive charge dominance in primary cosmic rays; this is termed the east-west effect. The cosmic ray intensity at the equator is lower than at the poles as the geomagnetic cutoff value is greatest at the equator. This can be understood by the fact that charged particle tend to move in the direction of field lines and not across them. This is the reason the Aurorae occur at the poles, since the field lines curve down towards the Earth’s surface there. Finally, the longitude dependence arises from the fact that the geomagnetic dipole axis is not parallel to the Earth’s rotation axis.
This modulation which describes the change in the interstellar intensities of cosmic rays as they propagate in the heliosphere is highly energy and spatial dependent, and it is described by the Parker's Transport Equation in the heliosphere. At large radial distances, far from the Sun ~ 94 AU, there exists the region where the solar wind undergoes a transition from supersonic to subsonic speeds called the solar wind termination shock. The region between the termination shock and the heliospause (the boundary marking the end of the heliosphere) is called the heliosheath. This region acts as a barrier to cosmic rays and it decreases their intensities at lower energies by about 90% indicating that it is not only the Earth's magnetic field that protect us from cosmic ray bombardment. For more on this topic and how the barrier effects occur the agile reader is referred to Mabedle Donald Ngobeni and Marius Potgieter (2007), and Mabedle Donald Ngobeni (2006).
From modelling point of view, there is a challenge in determining the Local Interstellar spectra (LIS) due to large adiabatic energy changes these particles experience owing to the diverging solar wind in the heliosphere. However, significant progress has been made in the field of cosmic ray studies with the development of an improved state-of-the-art 2D numerical model that includes the simulation of the solar wind termination shock, drifts and the heliosheath coupled with fresh descriptions of the diffusion tensor, see Langner et al. (2004). But challenges also exist because the structure of the solar wind and the turbulent magnetic field in the heliosheath is not well understood indicating the heliosheath as the region unknown beyond. With lack of knowledge of the diffusion coefficient perpendicular to the magnetic field our knowledge of the heliosphere and from the modelling point of view is far from complete. There exist promising theories like ab initio approaches, but the drawback is that such theories produce poor compatibility with observations (Minnie, 2006) indicating their failure in describing the mechanisms influencing the cosmic rays in the heliosphere.
# Detection
The nuclei that make up cosmic rays are able to travel from their distant sources to the Earth because of the low density of matter in space. Nuclei interact strongly with other matter, so when the cosmic rays approach Earth they begin to collide with the nuclei of atmospheric gases. These collisions, in a process known as a shower, result in the production of many pions and kaons, unstable mesons which quickly decay into muons. Because muons do not interact strongly with the atmosphere and because of the relativistic effect of time dilation many of these muons are able to reach the surface of the Earth. Muons are ionizing radiation, and may easily be detected by many types of particle detectors such as bubble chambers or scintillation detectors. If several muons are observed by separated detectors at the same instant it is clear that they must have been produced in the same shower event.
## Detection by particle track-etch technique
Cosmic rays can also be detected directly when they pass through particle detectors flown aboard satellites or in high altitude balloons. In a pioneering technique developed by P. Buford Price et al., sheets of clear plastic such as 1/4 mil Lexan polycarbonate can be stacked together and exposed directly to cosmic rays in space or high altitude. When returned to the laboratory, the plastic sheets are "etched" in warm caustic sodium hydroxide solution, which slowly removes the surface material at a slow, known rate. Wherever a bare cosmic ray nucleus passes through the detector, the nuclear charge causes chemical bond breaking in the plastic. The slower the particle, the more extensive is the bond-breaking along the path; and the higher the charge , the more extensive is the bond-breaking along the path. The caustic sodium hydroxide dissolves at a faster rate along the path of the damage, but thereafter dissolves at the slower base-rate along the surface of the minute hole that was drilled. The net result is a conical shaped pit in the plastic; typically with two pits per sheet . The etch pits can be measured under a high power microscope , and the etch rate plotted as a function of the depth in the stack of plastic. At the top of the stack, the ionization damage is less due to the higher speed. As the speed decreases due to deceleration in the stack, the ionization damage increases along the path. This generates a unique curve for each atomic nucleus of Z from 1 to 92, allowing identification of both the charge and energy of the particle that traverses the stack. This technique has been used with great success for detecting not only cosmic rays, but fission product nuclei for neutron detectors.
## Interaction with the Earth's atmosphere
When cosmic ray particles enter the Earth's atmosphere they collide with molecules, mainly oxygen and nitrogen, to produce a cascade of lighter particles, a so-called air shower. The general idea is shown in the figure which shows a cosmic ray shower produced by a high energy proton of cosmic ray origin striking an atmospheric molecule.
File:Atmospheric Collision.svg
This image is a simplified picture of an air shower: in reality, the number of particles created in an air shower event can reach in the billions, depending on the energy and chemical environment (i.e. atmospheric) of the primary particle. All of the produced particles stay within about one degree of the primary particle's path. Typical particles produced in such collisions are charged mesons (e.g. positive and negative pions and kaons); one common collision is:
p + \mathrm{O}^{16} \rightarrow n + \pi
Cosmic rays are also responsible for the continuous production of a number of unstable isotopes in the Earth’s atmosphere, such as carbon-14, via the reaction:
n + \mathrm{N}^{14} \rightarrow p + \mathrm{C}^{14}
Cosmic rays kept the level of carbon-14 in the atmosphere roughly constant (70 tons) for at least the past 100,000 years, until the beginning of aboveground nuclear weapons testing in the early 1950s. This is an important fact used in radiocarbon dating which is used in archaeology.
# Unusual cosmic rays
In 1975, a team of researchers headed by P. Buford Price at U.C. Berkeley announced the discovery of a cosmic ray track in a particle detector slung under a high-altitude balloon that was significantly different from all others ever measured. Using the particle track-etch method pioneered by Price, et al., they discovered the track of a particle that had passed through 32 sheets of 1/4 mil Lexan plastic without any measurable change in ionization. Yet, the Cerenkov detector admitted only of particles less than 2/3 c . The charge was measured as being 137, the same as predicted by Paul Dirac who first predicted the theoretical existence of magnetic monopoles. The particle track preliminarily identified as having been caused by a magnetic monopole had been spotted by technical assistant Walter L. Wagner.
A possible alternative explanation was offered by Alvarez. In his paper it was demonstrated that the path of the cosmic ray event that was claimed to be due to a magnetic monopole could be reproduced by a path followed by a platinum nucleus fragmenting to osmium and then to tantalum.
# Research and experiments
There are a number of cosmic ray research initiatives. These include, but are not limited to:
- CHICOS
- PAMELA
- Alpha Magnetic Spectrometer
- MARIACHI
- Pierre Auger Observatory
- Spaceship Earth
# History
After the discovery of radioactivity by Henri Becquerel in 1896, it was generally believed that atmospheric electricity (ionization of the air) was caused only by radiation from radioactive elements in the ground or the radioactive gases (isotopes of radon) they produce. Measurements of ionization rates at increasing heights above the ground during the decade from 1900 to 1910 showed a decrease that could be explained as due to absorption of the ionizing radiation by the intervening air. In 1912 Domenico Pacini observed simultaneous variations of the rate of ionization over a lake, and over the sea. Pacini concluded that a certain part of the ionization must be due to sources other than the radioactivity of the Earth or the air. Then, in 1912, Victor Hess carried three Wulf electrometers (a device to measure the rate of ion production inside a hermetically sealed container) to an altitude of 5300 meters in a free balloon flight. He found the ionization rate increased approximately fourfold over the rate at ground level. He concluded "The results of my observation are best explained by the assumption that a radiation of very great penetrating power enters our atmosphere from above." In 1913-14, Werner Kolhörster confirmed Victor Hess' results by measuring the increased ionization rate at an altitude of 9 km. Hess received the Nobel Prize in Physics in 1936 for his discovery of what came to be called "cosmic rays".
For many years it was generally believed that cosmic rays were high-energy photons (gamma rays) with some secondary electrons produced by Compton scattering of the gamma rays. Then, during the decade from 1927 to 1937 a wide variety of experimental investigations demonstrated that the primary cosmic rays are mostly positively charged particles, and the secondary radiation observed at ground level is composed primarily of a "soft component" of electrons and photons and a "hard component" of penetrating particles, muons. The muon was initially believed to be the unstable particle predicted by Hideki Yukawa in 1935 in his theory of the nuclear force. Experiments proved that the muon decays with a mean life of 2.2 microseconds into an electron and two neutrinos, but that it does not interact strongly with nuclei, so it could not be the Yukawa particle. The mystery was solved by the discovery in 1947 of the pion, which is produced directly in high-energy nuclear interactions. It decays into a muon and one neutrino with a mean life of 0.0026 microseconds. The pion→muon→electron decay sequence was observed directly in a microscopic examination of particle tracks in a special kind of photographic plate called a nuclear emulsion that had been exposed to cosmic rays at a high-altitude mountain station. In 1948, observations with nuclear emulsions carried by balloons to near the top of the atmosphere by Gottlieb and Van Allen showed that the primary cosmic particles are mostly protons with some helium nuclei (alpha particles) and a small fraction heavier nuclei.
In 1934 Bruno Rossi reported an observation of near-simultaneous discharges of two Geiger counters widely separated in a horizontal plane during a test of equipment he was using in a measurement of the so-called east-west effect. In his report on the experiment, Rossi wrote "...it seems that once in a while the recording equipment is struck by very extensive showers of particles, which causes coincidences between the counters, even placed at large distances from one another. Unfortunately, he did not have the time to study this phenomenon more closely." In 1937 Pierre Auger, unaware of Rossi's earlier report, detected the same phenomenon and investigated it in some detail. He concluded that extensive particle showers are generated by high-energy primary cosmic-ray particles that interact with air nuclei high in the atmosphere, initiating a cascade of secondary interactions that ultimately yield a shower of electrons, photons, and muons that reach ground level.
Homi J. Bhabha derived an expression for the probability of scattering positrons by electrons, a process now known as Bhabha scattering. His classic paper, jointly with Warren Heitler, published in 1937 described how primary cosmic rays from space interact with the upper atmosphere to produce particles observed at the ground level. Bhabha and Heitler explained the cosmic ray shower formation by the cascade production of gamma rays and positive and negative electron pairs. In 1938 Bhabha concluded that observations of the properties of such particles would lead to the straightforward experimental verification of Albert Einstein's theory of relativity.
Measurements of the energy and arrival directions of the ultra-high-energy primary cosmic rays by the techniques of "density sampling" and "fast timing" of extensive air showers were first carried out in 1954 by members of the Rossi Cosmic Ray Group at the Massachusetts Institute of Technology. The experiment employed eleven scintillation detectors arranged within a circle 460 meters in diameter on the grounds of the Agassiz Station of the Harvard College Observatory. From that work, and from many other experiments carried out all over the world, the energy spectrum of the primary cosmic rays is now known to extend beyond 1020 eV (past the GZK cutoff, beyond which very few cosmic rays should be observed). A huge air shower experiment called the Auger Project is currently operated at a site on the pampas of Argentina by an international consortium of physicists. Their aim is to explore the properties and arrival directions of the very highest energy primary cosmic rays. The results are expected to have important implications for particle physics and cosmology. In November, 2007 preliminary results were announced showing direction of origination of the 27 highest energy events were strongly correlated with the locations of active galactic nuclei , where bare protons are believed accelerated by strong magnetic fields associated with the large black holes at the AGN centers to energies of 1E20 eV and higher.
Three varieties of neutrino are produced when the unstable particles produced in cosmic ray showers decay. Since neutrinos interact only weakly with matter most of them simply pass through the Earth and exit the other side. They very occasionally interact, however, and these atmospheric neutrinos have been detected by several deep underground experiments. The Super-Kamiokande in Japan provided the first convincing evidence for neutrino oscillation in which one flavour of neutrino changes into another. The evidence was found in a difference in the ratio of electron neutrinos to muon neutrinos depending on the distance they have traveled through the air and earth.
# Effects
## Role in ambient radiation
Cosmic rays constitute a fraction of the annual radiation exposure of human beings on earth. For example, the average radiation exposure in Australia is 0.3 mSv due to cosmic rays, out of a total of 2.3 mSv.
## Effect on electronics
Cosmic rays have sufficient energy to alter the states of elements in electronic integrated circuits, causing transient errors to occur, such as corrupted data in memory, or incorrect behavior of a CPU. This has been a problem in high-altitude electronics, such as in satellites, but as transistors become smaller it is becoming an increasing concern in ground-level equipment as well.
To alleviate this problem, Intel has proposed a cosmic ray detector which could be integrated into future high-density microprocessors, allowing the processor to repeat the last command following a cosmic ray event.
## Significance to space travel
Galactic cosmic rays are one of the most important barriers standing in the way of plans for interplanetary travel by crewed spacecraft. See Health threat from cosmic rays.
## Role in lightning
Cosmic rays have been implicated in the triggering of electrical breakdown in lightning. It has been proposed that essentially all lightning is triggered through a relativistic process, "runaway breakdown", seeded by cosmic ray secondaries. Subsequent development of the lightning discharge then occurs through "conventional breakdown" mechanisms.
## Role in climate change
Whether cosmic rays have any role in climate change is disputed. Different groups have made different arguments regarding the role of cosmic ray forcing in climate change.
Shaviv et al. have argued that galactic cosmic ray (GCR) climate signals on geological time scales are attributable to changing positions of the galactic spiral arms of the Milky Way, and that cosmic ray flux variability is the dominant climate driver over these time periods. They also argue that GCR flux variability plays an important role in climate variability over shorter time scales, though the relative contribution of anthropogenic factors in relation to GCR flux presently is a matter of continued debate. Because of uncertainty about which GCR energies are the most important drivers of cloud cover variation (if any), and because of the paucity of historical data on cosmic ray flux at various ranges of energies, controversies remain.
Henrik Svensmark et al. have argued that solar variations modulate the cosmic ray signal seen at the earth and that this would affect cloud formation and hence climate. Cosmic rays have been experimentally determined to be able to produce ultra-small aerosol particles, orders of magnitude smaller than cloud condensation nuclei (CCN). Whether this mechanism is relevant to the real atmosphere is unknown; in particular, the steps from this to modulation of cloud formation and thence climate have not been established. The analogy is with the Wilson cloud chamber, however acting on a global scale, where earth's atmosphere acts as the cloud chamber and the cosmic rays catalyze the production of CCN. But unlike a cloud chamber, where the air is carefully purified, the real atmosphere always has many CCN naturally. Various proposals have been made for the mechanism by which cosmic rays might affect clouds, including ion mediated nucleation, and indirect effects on current flow density in the global electric circuit (see Tinsley 2000, and F. Yu 1999). Claims have been made of identification of GCR climate signals in atmospheric parameters such as high latitude precipitation (Todd & Kniveton), and Svensmark's annual cloud cover variations, which were said to be correlated to GCR variation.
That Svensmark's work can be extrapolated to suggest any meaningful connection with global warming is disputed:
More recently a Lancaster University study produced further compelling evidence showing that modern-day climate change is not caused by changes in the Sun's activity.
See-also Global warming#Solar variation.
# Cosmic rays and fiction
Because of the metaphysical connotations of the word "cosmic", the very name of these particles enables their misinterpretation by the public, giving them an aura of mysterious powers. Were they merely referred to as "high-speed protons and atomic nuclei" this might not be so.
In fiction, cosmic rays have been used as a catchall, mostly in comics (notably the Marvel Comics group the Fantastic Four), as a source for mutation and therefore the powers gained by being bombarded with them.
Also, in the book Atlas Shrugged by author Ayn Rand, Dr. Robert Stadler's research of cosmic rays is said to have contributed to Project X: a weapon of mass destruction. | Cosmic ray
Cosmic rays are energetic particles originating from space that impinge on Earth's atmosphere. Almost 90% of all the incoming cosmic ray particles are protons, about 9% are helium nuclei (alpha particles) and about 1% are electrons (beta minus particles). The term "ray" is a misnomer, as cosmic particles arrive individually, not in the form of a ray or beam of particles.
The variety of particle energies reflects the wide variety of sources. The origins of these particles range from energetic processes on the Sun all the way to as yet unknown events in the farthest reaches of the visible universe. Cosmic rays can have energies of over 1020 eV, far higher than the 1012 to 1013 eV that man-made particle accelerators can produce. (See Ultra-high-energy cosmic rays for a description of the detection of a single particle with an energy of about 50 J, the same as a well-hit tennis ball at 42 m/s [about 94 mph].) There has been interest in investigating cosmic rays of even greater energies.[1]
# Cosmic ray sources
Most cosmic rays originate from extrasolar sources within our own galaxy such as rotating neutron stars, supernovae, and black holes. However, the fact that some cosmic rays have extremely high energies provides evidence that at least some must be of extra-galactic origin (e.g. radio galaxies and quasars); the local galactic magnetic field would not be able to contain particles with such a high energy. The origin of cosmic rays with energies up to 1014 eV can be accounted for in terms of shock-wave acceleration in supernova shells. The origin of cosmic rays with energy greater than 1014 eV remained unknown until recently, when a large collaborative experiment at the Pierre Auger Observatory appears to have answered this question. In preliminary results announced in November 2007, they showed a strong correlation between their 27 most energetic events and active galactic nuclei [AGN]. These results demonstrated that there is only a small chance (less than 1/100) that the highest energy protons originated from outside the AGN.
Observations have shown that cosmic rays with an energy above 10 GeV (10 x 109 eV) approach the Earth’s surface isotropically (equally from all directions); it has been hypothesized that this is not due to an even distribution of cosmic ray sources, but instead is due to galactic magnetic fields causing cosmic rays to travel in spiral paths. This limits cosmic ray’s usefulness in positional astronomy as they carry no information of their direction of origin. At energies below 10 GeV there is a directional dependence, due to the interaction of the charged component of the cosmic rays with the Earth's magnetic field.
## Solar cosmic rays
Solar cosmic rays or solar energetic particles (SEP) are cosmic rays that originate from the Sun. The average composition is similar to that of the Sun itself. There exists no clear and sharp boundary between the phase spaces of the solar wind and SEP plasma particle populations.[2]
The name solar cosmic ray itself is a misnomer because the term cosmic implies that the rays are from the cosmos and not the solar system, but it has stuck. The misnomer arose because there is continuity in the energy spectra, i.e., the flux of particles as a function of their energy, because the low-energy solar cosmic rays fade more or less smoothly into the galactic ones as one looks at increasingly higher energies.[citation needed] Until the mid-1960s the energy distributions were generally averaged over long time intervals, which also obscured the difference. Later, it was found that the solar cosmic rays vary widely in their intensity and spectrum, increasing in strength after some solar events such as solar flares. Further, an increase in the intensity of solar cosmic rays is followed by a decrease in all other cosmic rays, called the Forbush decrease after their discoverer, the physicist Scott Forbush. These decreases are due to the solar wind with its entrained magnetic field sweeping some of the galactic cosmic rays outwards, away from the Sun and Earth. The overall or average rate of Forbush decreases tends to follow the 11-year sunspot cycle, but individual events are tied to events on the Sun, as explained above.
There are further differences between cosmic rays of solar and galactic origin, mainly in that the galactic cosmic rays show an enhancement of heavy elements such as calcium, iron and gallium, as well as of cosmically rare light elements such as lithium and beryllium. The latter result from the cosmic ray spallation (fragmentation) of heavy nuclei due to collisions in transit from the distant sources to the solar system.[citation needed]
## Galactic cosmic rays
See Galactic cosmic ray.
## Extragalactic cosmic rays
See Extragalactic cosmic ray.
## Ultra-high-energy cosmic rays
See Ultra-high-energy cosmic ray.
## Anomalous cosmic rays
Anomalous cosmic rays (ACRs) are cosmic rays with unexpectedly low energies. They are thought to be created near the edge of our solar system, in the heliosheath, the border region between the heliosphere and the interstellar medium. When electrically neutral atoms are able to enter the heliosheath (being unaffected by its magnetic fields) subsequently become ionized, they are thought to be accelerated into low-energy cosmic rays by the solar wind's termination shock which marks the inner edge of the heliosheath. It is also possible that high energy galactic cosmic rays which hit the shock front of the solar wind near the heliopause might be decelerated, resulting in their transformation into lower-energy anomalous cosmic rays.
The Voyager 1 space probe crossed the termination shock on December 16, 2004, according to papers published in the journal Science.[3] Readings showed particle acceleration, but not of the kind that generates ACRs. It is unclear at this stage (September 2005) if this is typical of the termination shock (requiring a major rethink of the origin of ACRs), or a localised feature of that part of the termination shock that Voyager 1 passed through. Voyager 2 is expected to cross the termination shock during or after 2008, which will provide more data.
# Composition
Cosmic rays may broadly be divided into two categories, primary and secondary.
The cosmic rays that arise in extrasolar astrophysical sources are primary cosmic rays; these primary cosmic rays can interact with interstellar matter to create secondary cosmic rays. The sun also emits low energy cosmic rays associated with solar flares. The exact composition of primary cosmic rays, outside the Earth's atmosphere, is dependent on which part of the energy spectrum is observed. However, in general, almost 90% of all the incoming cosmic rays are protons, about 9% are helium nuclei (alpha particles) and about 1% are electrons. The remaining fraction is made up of the other heavier nuclei which are abundant end products of star’s nuclear synthesis. Secondary cosmic rays consist of the other nuclei which are not abundant nuclear synthesis end products, or products of the Big Bang, primarily lithium, beryllium and boron. These light nuclei appear in cosmic rays in much greater abundance (about 1:100 particles) than in solar atmospheres, where their abundance is about 10-7 that of helium.
This abundance difference is a result of the way secondary cosmic rays are formed. When the heavy nuclei components of primary cosmic rays, namely the carbon and oxygen nuclei, collide with interstellar matter, they break up into lighter nuclei (in a process termed cosmic ray spallation), into lithium, beryllium and boron. It is found that the energy spectra of Li, Be and B falls off somewhat steeper than that of carbon or oxygen, indicating that less cosmic ray spallation occurs for the higher energy nuclei presumably due to their escape from the galactic magnetic field. Spallation is also responsible for the abundances of Sc, Ti, V and Mn elements in cosmic rays, which are produced by collisions of Fe and Ni nuclei with interstellar matter; see Environmental radioactivity#Naturals.
In the past, it was believed that the cosmic ray flux has remained fairly constant over time. Recent research has, however, produced evidence for 1.5 to 2-fold millennium-timescale changes in the cosmic ray flux in the past forty thousand years.[4]
# Modulation
The flux (flow rate) of cosmic rays incident on the Earth’s upper atmosphere is modulated (varied) by two processes; the sun’s solar wind and the Earth's magnetic field. Solar wind is expanding magnetized plasma generated by the sun, which has the effect of decelerating the incoming particles as well as partially excluding some of the particles with energies below about 1 GeV. The amount of solar wind is not constant due to changes in solar activity over its regular eleven-year cycle. Hence the level of modulation varies in autocorrelation with solar activity. Also the Earth's magnetic field deflects some of the cosmic rays, which is confirmed by the fact that the intensity of cosmic radiation is dependent on latitude, longitude and azimuth. The cosmic flux varies from eastern and western directions due to the polarity of the Earth’s geomagnetic field and the positive charge dominance in primary cosmic rays; this is termed the east-west effect. The cosmic ray intensity at the equator is lower than at the poles as the geomagnetic cutoff value is greatest at the equator. This can be understood by the fact that charged particle tend to move in the direction of field lines and not across them. This is the reason the Aurorae occur at the poles, since the field lines curve down towards the Earth’s surface there. Finally, the longitude dependence arises from the fact that the geomagnetic dipole axis is not parallel to the Earth’s rotation axis.
This modulation which describes the change in the interstellar intensities of cosmic rays as they propagate in the heliosphere is highly energy and spatial dependent, and it is described by the Parker's Transport Equation in the heliosphere. At large radial distances, far from the Sun ~ 94 AU, there exists the region where the solar wind undergoes a transition from supersonic to subsonic speeds called the solar wind termination shock. The region between the termination shock and the heliospause (the boundary marking the end of the heliosphere) is called the heliosheath. This region acts as a barrier to cosmic rays and it decreases their intensities at lower energies by about 90% indicating that it is not only the Earth's magnetic field that protect us from cosmic ray bombardment. For more on this topic and how the barrier effects occur the agile reader is referred to Mabedle Donald Ngobeni and Marius Potgieter (2007), and Mabedle Donald Ngobeni (2006).
From modelling point of view, there is a challenge in determining the Local Interstellar spectra (LIS) due to large adiabatic energy changes these particles experience owing to the diverging solar wind in the heliosphere. However, significant progress has been made in the field of cosmic ray studies with the development of an improved state-of-the-art 2D numerical model that includes the simulation of the solar wind termination shock, drifts and the heliosheath coupled with fresh descriptions of the diffusion tensor, see Langner et al. (2004). But challenges also exist because the structure of the solar wind and the turbulent magnetic field in the heliosheath is not well understood indicating the heliosheath as the region unknown beyond. With lack of knowledge of the diffusion coefficient perpendicular to the magnetic field our knowledge of the heliosphere and from the modelling point of view is far from complete. There exist promising theories like ab initio approaches, but the drawback is that such theories produce poor compatibility with observations (Minnie, 2006) indicating their failure in describing the mechanisms influencing the cosmic rays in the heliosphere.
# Detection
The nuclei that make up cosmic rays are able to travel from their distant sources to the Earth because of the low density of matter in space. Nuclei interact strongly with other matter, so when the cosmic rays approach Earth they begin to collide with the nuclei of atmospheric gases. These collisions, in a process known as a shower, result in the production of many pions and kaons, unstable mesons which quickly decay into muons. Because muons do not interact strongly with the atmosphere and because of the relativistic effect of time dilation many of these muons are able to reach the surface of the Earth. Muons are ionizing radiation, and may easily be detected by many types of particle detectors such as bubble chambers or scintillation detectors. If several muons are observed by separated detectors at the same instant it is clear that they must have been produced in the same shower event.
## Detection by particle track-etch technique
Cosmic rays can also be detected directly when they pass through particle detectors flown aboard satellites or in high altitude balloons. In a pioneering technique developed by P. Buford Price et al., sheets of clear plastic such as 1/4 mil Lexan polycarbonate can be stacked together and exposed directly to cosmic rays in space or high altitude. When returned to the laboratory, the plastic sheets are "etched" [literally, slowly dissolved] in warm caustic sodium hydroxide solution, which slowly removes the surface material at a slow, known rate. Wherever a bare cosmic ray nucleus passes through the detector, the nuclear charge causes chemical bond breaking in the plastic. The slower the particle, the more extensive is the bond-breaking along the path; and the higher the charge [the higher the Z], the more extensive is the bond-breaking along the path. The caustic sodium hydroxide dissolves at a faster rate along the path of the damage, but thereafter dissolves at the slower base-rate along the surface of the minute hole that was drilled. The net result is a conical shaped pit in the plastic; typically with two pits per sheet [one originating from each side of the plastic]. The etch pits can be measured under a high power microscope [typically 1600X oil-immersion], and the etch rate plotted as a function of the depth in the stack of plastic. At the top of the stack, the ionization damage is less due to the higher speed. As the speed decreases due to deceleration in the stack, the ionization damage increases along the path. This generates a unique curve for each atomic nucleus of Z from 1 to 92, allowing identification of both the charge and energy [speed] of the particle that traverses the stack. This technique has been used with great success for detecting not only cosmic rays, but fission product nuclei for neutron detectors.
## Interaction with the Earth's atmosphere
When cosmic ray particles enter the Earth's atmosphere they collide with molecules, mainly oxygen and nitrogen, to produce a cascade of lighter particles, a so-called air shower. The general idea is shown in the figure which shows a cosmic ray shower produced by a high energy proton of cosmic ray origin striking an atmospheric molecule.
File:Atmospheric Collision.svg
This image is a simplified picture of an air shower: in reality, the number of particles created in an air shower event can reach in the billions, depending on the energy and chemical environment (i.e. atmospheric) of the primary particle. All of the produced particles stay within about one degree of the primary particle's path. Typical particles produced in such collisions are charged mesons (e.g. positive and negative pions and kaons); one common collision is:
<math>p + \mathrm{O}^{16} \rightarrow n + \pi</math>
Cosmic rays are also responsible for the continuous production of a number of unstable isotopes in the Earth’s atmosphere, such as carbon-14, via the reaction:
<math>n + \mathrm{N}^{14} \rightarrow p + \mathrm{C}^{14}</math>
Cosmic rays kept the level of carbon-14 in the atmosphere roughly constant (70 tons) for at least the past 100,000 years, until the beginning of aboveground nuclear weapons testing in the early 1950s. This is an important fact used in radiocarbon dating which is used in archaeology.
# Unusual cosmic rays
In 1975, a team of researchers headed by P. Buford Price at U.C. Berkeley announced the discovery[5] of a cosmic ray track in a particle detector slung under a high-altitude balloon that was significantly different from all others ever measured. Using the particle track-etch method pioneered by Price, et al., they discovered the track of a particle that had passed through 32 sheets of 1/4 mil Lexan plastic without any measurable change in ionization. Yet, the Cerenkov detector admitted only of particles less than 2/3 c [the speed of light in the clear plastic]. The charge was measured as being 137, the same as predicted by Paul Dirac who first predicted the theoretical existence of magnetic monopoles. The particle track preliminarily identified as having been caused by a magnetic monopole had been spotted by technical assistant Walter L. Wagner.[6]
A possible alternative explanation was offered by Alvarez[7]. In his paper it was demonstrated that the path of the cosmic ray event that was claimed to be due to a magnetic monopole could be reproduced by a path followed by a platinum nucleus fragmenting to osmium and then to tantalum.
# Research and experiments
There are a number of cosmic ray research initiatives. These include, but are not limited to:
- CHICOS
- PAMELA
- Alpha Magnetic Spectrometer
- MARIACHI
- Pierre Auger Observatory
- Spaceship Earth
# History
After the discovery of radioactivity by Henri Becquerel in 1896, it was generally believed that atmospheric electricity (ionization of the air) was caused only by radiation from radioactive elements in the ground or the radioactive gases (isotopes of radon) they produce. Measurements of ionization rates at increasing heights above the ground during the decade from 1900 to 1910 showed a decrease that could be explained as due to absorption of the ionizing radiation by the intervening air. In 1912 Domenico Pacini observed simultaneous variations of the rate of ionization over a lake, and over the sea. Pacini concluded that a certain part of the ionization must be due to sources other than the radioactivity of the Earth or the air[8]. Then, in 1912, Victor Hess carried three Wulf electrometers (a device to measure the rate of ion production inside a hermetically sealed container) to an altitude of 5300 meters in a free balloon flight. He found the ionization rate increased approximately fourfold over the rate at ground level. He concluded "The results of my observation are best explained by the assumption that a radiation of very great penetrating power enters our atmosphere from above." In 1913-14, Werner Kolhörster confirmed Victor Hess' results by measuring the increased ionization rate at an altitude of 9 km. Hess received the Nobel Prize in Physics in 1936 for his discovery of what came to be called "cosmic rays".
For many years it was generally believed that cosmic rays were high-energy photons (gamma rays) with some secondary electrons produced by Compton scattering of the gamma rays. Then, during the decade from 1927 to 1937 a wide variety of experimental investigations demonstrated that the primary cosmic rays are mostly positively charged particles, and the secondary radiation observed at ground level is composed primarily of a "soft component" of electrons and photons and a "hard component" of penetrating particles, muons. The muon was initially believed to be the unstable particle predicted by Hideki Yukawa in 1935 in his theory of the nuclear force. Experiments proved that the muon decays with a mean life of 2.2 microseconds into an electron and two neutrinos, but that it does not interact strongly with nuclei, so it could not be the Yukawa particle. The mystery was solved by the discovery in 1947 of the pion, which is produced directly in high-energy nuclear interactions. It decays into a muon and one neutrino with a mean life of 0.0026 microseconds. The pion→muon→electron decay sequence was observed directly in a microscopic examination of particle tracks in a special kind of photographic plate called a nuclear emulsion that had been exposed to cosmic rays at a high-altitude mountain station. In 1948, observations with nuclear emulsions carried by balloons to near the top of the atmosphere by Gottlieb and Van Allen showed that the primary cosmic particles are mostly protons with some helium nuclei (alpha particles) and a small fraction heavier nuclei.
In 1934 Bruno Rossi reported an observation of near-simultaneous discharges of two Geiger counters widely separated in a horizontal plane during a test of equipment he was using in a measurement of the so-called east-west effect. In his report on the experiment, Rossi wrote "...it seems that once in a while the recording equipment is struck by very extensive showers of particles, which causes coincidences between the counters, even placed at large distances from one another. Unfortunately, he did not have the time to study this phenomenon more closely." In 1937 Pierre Auger, unaware of Rossi's earlier report, detected the same phenomenon and investigated it in some detail. He concluded that extensive particle showers are generated by high-energy primary cosmic-ray particles that interact with air nuclei high in the atmosphere, initiating a cascade of secondary interactions that ultimately yield a shower of electrons, photons, and muons that reach ground level.
Homi J. Bhabha derived an expression for the probability of scattering positrons by electrons, a process now known as Bhabha scattering. His classic paper, jointly with Warren Heitler, published in 1937 described how primary cosmic rays from space interact with the upper atmosphere to produce particles observed at the ground level. Bhabha and Heitler explained the cosmic ray shower formation by the cascade production of gamma rays and positive and negative electron pairs. In 1938 Bhabha concluded that observations of the properties of such particles would lead to the straightforward experimental verification of Albert Einstein's theory of relativity.
Measurements of the energy and arrival directions of the ultra-high-energy primary cosmic rays by the techniques of "density sampling" and "fast timing" of extensive air showers were first carried out in 1954 by members of the Rossi Cosmic Ray Group at the Massachusetts Institute of Technology. The experiment employed eleven scintillation detectors arranged within a circle 460 meters in diameter on the grounds of the Agassiz Station of the Harvard College Observatory. From that work, and from many other experiments carried out all over the world, the energy spectrum of the primary cosmic rays is now known to extend beyond 1020 eV (past the GZK cutoff, beyond which very few cosmic rays should be observed). A huge air shower experiment called the Auger Project is currently operated at a site on the pampas of Argentina by an international consortium of physicists. Their aim is to explore the properties and arrival directions of the very highest energy primary cosmic rays. The results are expected to have important implications for particle physics and cosmology. In November, 2007 preliminary results were announced showing direction of origination of the 27 highest energy events were strongly correlated with the locations of active galactic nuclei [AGN], where bare protons are believed accelerated by strong magnetic fields associated with the large black holes at the AGN centers to energies of 1E20 eV and higher.
Three varieties of neutrino are produced when the unstable particles produced in cosmic ray showers decay. Since neutrinos interact only weakly with matter most of them simply pass through the Earth and exit the other side. They very occasionally interact, however, and these atmospheric neutrinos have been detected by several deep underground experiments. The Super-Kamiokande in Japan provided the first convincing evidence for neutrino oscillation in which one flavour of neutrino changes into another. The evidence was found in a difference in the ratio of electron neutrinos to muon neutrinos depending on the distance they have traveled through the air and earth.
# Effects
## Role in ambient radiation
Cosmic rays constitute a fraction of the annual radiation exposure of human beings on earth. For example, the average radiation exposure in Australia is 0.3 mSv due to cosmic rays, out of a total of 2.3 mSv.[1]
## Effect on electronics
Cosmic rays have sufficient energy to alter the states of elements in electronic integrated circuits, causing transient errors to occur, such as corrupted data in memory, or incorrect behavior of a CPU. This has been a problem in high-altitude electronics, such as in satellites, but as transistors become smaller it is becoming an increasing concern in ground-level equipment as well.[9]
To alleviate this problem, Intel has proposed a cosmic ray detector which could be integrated into future high-density microprocessors, allowing the processor to repeat the last command following a cosmic ray event.[10]
## Significance to space travel
Galactic cosmic rays are one of the most important barriers standing in the way of plans for interplanetary travel by crewed spacecraft. See Health threat from cosmic rays.
## Role in lightning
Cosmic rays have been implicated in the triggering of electrical breakdown in lightning. It has been proposed that essentially all lightning is triggered through a relativistic process, "runaway breakdown", seeded by cosmic ray secondaries. Subsequent development of the lightning discharge then occurs through "conventional breakdown" mechanisms.[11]
## Role in climate change
Whether cosmic rays have any role in climate change is disputed. Different groups have made different arguments regarding the role of cosmic ray forcing in climate change.
Shaviv et al. have argued that galactic cosmic ray (GCR) climate signals on geological time scales are attributable to changing positions of the galactic spiral arms of the Milky Way, and that cosmic ray flux variability is the dominant climate driver over these time periods.[12][13] They also argue that GCR flux variability plays an important role in climate variability over shorter time scales, though the relative contribution of anthropogenic factors in relation to GCR flux presently is a matter of continued debate.[14] Because of uncertainty about which GCR energies are the most important drivers of cloud cover variation (if any), and because of the paucity of historical data on cosmic ray flux at various ranges of energies, controversies remain.[15]
Henrik Svensmark et al. have argued that solar variations modulate the cosmic ray signal seen at the earth and that this would affect cloud formation and hence climate. Cosmic rays have been experimentally determined to be able to produce ultra-small aerosol particles,[16] orders of magnitude smaller than cloud condensation nuclei (CCN). Whether this mechanism is relevant to the real atmosphere is unknown; in particular, the steps from this to modulation of cloud formation and thence climate have not been established. The analogy is with the Wilson cloud chamber, however acting on a global scale, where earth's atmosphere acts as the cloud chamber and the cosmic rays catalyze the production of CCN. But unlike a cloud chamber, where the air is carefully purified, the real atmosphere always has many CCN naturally. Various proposals have been made for the mechanism by which cosmic rays might affect clouds, including ion mediated nucleation, and indirect effects on current flow density in the global electric circuit (see Tinsley 2000, and F. Yu 1999). Claims have been made of identification of GCR climate signals in atmospheric parameters such as high latitude precipitation (Todd & Kniveton), and Svensmark's annual cloud cover variations, which were said to be correlated to GCR variation.
That Svensmark's work can be extrapolated to suggest any meaningful connection with global warming is disputed:[17]
More recently a Lancaster University study produced further compelling evidence showing that modern-day climate change is not caused by changes in the Sun's activity.[19]
See-also Global warming#Solar variation.
# Cosmic rays and fiction
Because of the metaphysical connotations of the word "cosmic", the very name of these particles enables their misinterpretation by the public, giving them an aura of mysterious powers. Were they merely referred to as "high-speed protons and atomic nuclei" this might not be so.
In fiction, cosmic rays have been used as a catchall, mostly in comics (notably the Marvel Comics group the Fantastic Four), as a source for mutation and therefore the powers gained by being bombarded with them.
Also, in the book Atlas Shrugged by author Ayn Rand, Dr. Robert Stadler's research of cosmic rays is said to have contributed to Project X: a weapon of mass destruction. | https://www.wikidoc.org/index.php/Cosmic_ray | |
8ccb4ea6f040772c0c294c58f8c4900f20de5ba6 | wikidoc | Creatinine | Creatinine
# Overview
Creatinine is a break-down product of creatine phosphate in muscle, and is usually produced at a fairly constant rate by the body (depending on muscle mass).
# Physiology
Creatinine is mainly filtered by the kidney, though a small amount is actively secreted. There is little-to-no tubular reabsorption of creatinine. If the filtering of the kidney is deficient, blood levels rise. As a result, creatinine levels in blood and urine may be used to calculate creatinine clearance (ClCr), which reflects the glomerular filtration rate (GFR). The GFR is clinically important because it is a measurement of renal function. However, in cases of severe renal dysfunction, the creatinine clearance rate will be overestimated because the active secretion of creatinine will account for a larger fraction of the total creatinine cleared.
A more complete estimation of renal function can be made when interpreting the blood (plasma) concentration of creatinine along with that of urea. In the USA, urea concentration is given as blood urea nitrogen (BUN), in mg/dL. In other countries, including those of Europe, urea concentration is measured and quoted in mmol/L.
The ratio of urea to creatinine can indicate other problems besides those intrinsic to the kidney. For example, a urea level raised out of proportion to the creatinine may indicate a pre-renal problem such as dehydration.
Men tend to have higher levels of creatinine because they have more skeletal muscle than women. Vegetarians tend to have lower creatinine levels, because vegetables contain no creatinine.
# Diagnostic use
Measuring serum creatinine is a simple test and it is the most commonly used indicator of renal function. A rise in blood creatinine levels is observed only with marked damage to functioning nephrons. Therefore, this test is not suitable for detecting early stage kidney disease. A better estimation of kidney function is given by the creatinine clearance test. Creatinine clearance can be accurately calculated using serum creatinine concentration and some or all of the following variables: sex, age, weight, and race as suggested by the American Diabetes Association without a 24 hour urine collection. Some laboratories will calculate the ClCr if written on the pathology request form; and, the necessary age, sex, and weight are included in the patient information.
# Interpretation
In the United States, creatinine is typically reported in mg/dL, while in Canada and Europe μmol/litre may be used. 1 mg/dL of creatinine is 88.4 μmol/l.
The typical reference ranges are 0.5 to 1.0 mg/dL (about 45-90 μmol/l) for women and 0.7 to 1.2 mg/dL (60-110 μmol/l) for men. While a baseline serum creatinine of 2.0 mg/dL (150 μmol/l) may indicate normal kidney function in a male body builder, a serum creatinine of 0.7 mg/dL (60 μmol/l) can indicate significant renal disease in a frail old woman.
More important than absolute creatinine level is the trend of serum creatinine levels over time.
Creatinine levels may increase when ACE inhibitors (ACEI) or angiotensin-II receptor blockers (ARBs) are used in the treatment of chronic heart failure (CHF). Using both ACEI & ARB concomitantly will increase creatinine levels to a greater degree than either of the two drugs would individually. An increase of <30% is to be expected with ACEI or ARB use.
# Serum Creatinine Variability
The use of serum creatinine as a marker of glomerular filtration and kidney injury relies on certain convenience assumptions. Those assumptions include that creatinine is only filtered by the kidney, its excretion rate shows little variability among individuals and over time, and measurement is accurate and reproducible. In fact, none of the previous assumptions are true. Creatinine is actually filtered and secreted and has been shown to have significant variability with age, sex, ethnicity, and diet. For that, the trend of following renal function based on previously set reference intervals for the general population has largely been replaced by following changes in serum creatinine or creatinine clearance in an individual compared to their baseline. However, to detect pathological changes in serum creatinine one must first consider the existing variance in measurements related to biological and analytical influences.
Rosano and Brown were among the first to examine intra-individual day-to-day creatinine variability by following two individuals for the period of two months. They showed a combined analytical and biological variability of 0.18 – 0.2 mg/dL with analytical variances accounting for the most significant difference. The intra-individual variance for creatinine has been discussed in many studies with values ranging from 4.7 to 6.1% in healthy individuals. Reinhard et al showed that in patients with pre-existing renal function the variance in serum creatinine can almost reach 8.9%.
The inter-individual variance in creatinine is not as well established, although Reinhard also showed a variance of 14.4% in healthy individuals. Many laboratory factors can have a noted effect on serum creatinine measurements including calibration which can account for changes of up to 0.23 mg/dL, unexplained variance among labs (0.07 mg/dl) and unexplained variance with time (0.053 mg/dL).
# CT Scans
The creatinine level is usually measured before performing a contrast-enhanced Computed tomography (CT) scan. In a small proportion of patients the administration of iodine based contrast can cause kidney damage. This may be more likely or severe in patients with an elevated baseline serum creatinine level and, again, in rare cases may require temporary or permanent dialysis. The risk can be reduced somewhat in higher-risk patients by choosing a low-osmolality contrast medium. | Creatinine
Template:Chembox new
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Creatinine is a break-down product of creatine phosphate in muscle, and is usually produced at a fairly constant rate by the body (depending on muscle mass).
# Physiology
Creatinine is mainly filtered by the kidney, though a small amount is actively secreted. There is little-to-no tubular reabsorption of creatinine. If the filtering of the kidney is deficient, blood levels rise. As a result, creatinine levels in blood and urine may be used to calculate creatinine clearance (ClCr), which reflects the glomerular filtration rate (GFR). The GFR is clinically important because it is a measurement of renal function. However, in cases of severe renal dysfunction, the creatinine clearance rate will be overestimated because the active secretion of creatinine will account for a larger fraction of the total creatinine cleared.
A more complete estimation of renal function can be made when interpreting the blood (plasma) concentration of creatinine along with that of urea. In the USA, urea concentration is given as blood urea nitrogen (BUN), in mg/dL. In other countries, including those of Europe, urea concentration is measured and quoted in mmol/L.
The ratio of urea to creatinine can indicate other problems besides those intrinsic to the kidney. For example, a urea level raised out of proportion to the creatinine may indicate a pre-renal problem such as dehydration.
Men tend to have higher levels of creatinine because they have more skeletal muscle than women. Vegetarians tend to have lower creatinine levels, because vegetables contain no creatinine.
# Diagnostic use
Measuring serum creatinine is a simple test and it is the most commonly used indicator of renal function. A rise in blood creatinine levels is observed only with marked damage to functioning nephrons. Therefore, this test is not suitable for detecting early stage kidney disease. A better estimation of kidney function is given by the creatinine clearance test. Creatinine clearance can be accurately calculated using serum creatinine concentration and some or all of the following variables: sex, age, weight, and race as suggested by the American Diabetes Association without a 24 hour urine collection.[1] Some laboratories will calculate the ClCr if written on the pathology request form; and, the necessary age, sex, and weight are included in the patient information.
# Interpretation
In the United States, creatinine is typically reported in mg/dL, while in Canada and Europe μmol/litre may be used. 1 mg/dL of creatinine is 88.4 μmol/l.
The typical reference ranges are 0.5 to 1.0 mg/dL (about 45-90 μmol/l) for women and 0.7 to 1.2 mg/dL (60-110 μmol/l) for men. While a baseline serum creatinine of 2.0 mg/dL (150 μmol/l) may indicate normal kidney function in a male body builder, a serum creatinine of 0.7 mg/dL (60 μmol/l) can indicate significant renal disease in a frail old woman.
More important than absolute creatinine level is the trend of serum creatinine levels over time.
Creatinine levels may increase when ACE inhibitors (ACEI) or angiotensin-II receptor blockers (ARBs) are used in the treatment of chronic heart failure (CHF). Using both ACEI & ARB concomitantly will increase creatinine levels to a greater degree than either of the two drugs would individually. An increase of <30% is to be expected with ACEI or ARB use.
# Serum Creatinine Variability
The use of serum creatinine as a marker of glomerular filtration and kidney injury relies on certain convenience assumptions. Those assumptions include that creatinine is only filtered by the kidney, its excretion rate shows little variability among individuals and over time, and measurement is accurate and reproducible. In fact, none of the previous assumptions are true.[2] Creatinine is actually filtered and secreted and has been shown to have significant variability with age, sex, ethnicity, and diet.[3] For that, the trend of following renal function based on previously set reference intervals for the general population has largely been replaced by following changes in serum creatinine or creatinine clearance in an individual compared to their baseline. However, to detect pathological changes in serum creatinine one must first consider the existing variance in measurements related to biological and analytical influences.
Rosano and Brown were among the first to examine intra-individual day-to-day creatinine variability by following two individuals for the period of two months. They showed a combined analytical and biological variability of 0.18 – 0.2 mg/dL with analytical variances accounting for the most significant difference.[4] The intra-individual variance for creatinine has been discussed in many studies with values ranging from 4.7 to 6.1% in healthy individuals.[5][6][7] Reinhard et al showed that in patients with pre-existing renal function the variance in serum creatinine can almost reach 8.9%.
The inter-individual variance in creatinine is not as well established, although Reinhard also showed a variance of 14.4% in healthy individuals.[5] Many laboratory factors can have a noted effect on serum creatinine measurements including calibration which can account for changes of up to 0.23 mg/dL,[8] unexplained variance among labs (0.07 mg/dl) and unexplained variance with time (0.053 mg/dL).[9]
# CT Scans
The creatinine level is usually measured before performing a contrast-enhanced Computed tomography (CT) scan. In a small proportion of patients the administration of iodine based contrast can cause kidney damage. This may be more likely or severe in patients with an elevated baseline serum creatinine level and, again, in rare cases may require temporary or permanent dialysis. The risk can be reduced somewhat in higher-risk patients by choosing a low-osmolality contrast medium. | https://www.wikidoc.org/index.php/Cr | |
31d9b1e233313b5795d1679337b52971f8a4731c | wikidoc | Crack baby | Crack baby
Crack baby is a pejorative term for a child born to a mother who used crack cocaine during her pregnancy.
There remains some dispute as to whether cocaine use during pregnancy poses a genuine threat to the fetus. The official opinion of the National Institute on Drug Abuse of the United States warns about health risks while cautioning against stereotyping:
# Claims regarding threats to fetal and infant health
They also warn about the threat of breastfeeding: "It is likely that cocaine will reach the baby through breast milk."
The March of Dimes advises the following regarding cocaine use during pregnancy: | Crack baby
Crack baby is a pejorative term for a child born to a mother who used crack cocaine during her pregnancy.
There remains some dispute as to whether cocaine use during pregnancy poses a genuine threat to the fetus. The official opinion of the National Institute on Drug Abuse of the United States warns about health risks while cautioning against stereotyping:
## Claims regarding threats to fetal and infant health
They also warn about the threat of breastfeeding: "It is likely that cocaine will reach the baby through breast milk."
The March of Dimes advises the following regarding cocaine use during pregnancy: | https://www.wikidoc.org/index.php/Crack_baby | |
50ce792b0980b89636b614dc6b78040822d96d75 | wikidoc | Cradle cap | Cradle cap
Cradle Cap (infantile or neonatal seborrhoeic dermatitis, also known as crusta lactea, milk crust, honeycomb disease) is a yellowish, patchy, greasy, scaly and crusty skin rash that occurs on the scalp of recently born babies. It is usually not itchy, and does not bother the baby. Cradle cap most commonly begins sometime in the first 3 months. The rash is often prominent around the ear, the eyebrows or the eyelids. It may appear in other locations as well, where it is called seborrhoeic dermatitis rather than cradle cap. Some countries use the term pityriasis capitis for cradle cap. It is extremely common, with about half of all babies affected. Most of them have a mild version of the disorder. Severe cradle cap is rare.
# Causes
The cause of cradle cap is not clearly defined but it is not caused by an infection, allergy nor from poor hygiene. Possibly it has to do with overactive sebaceous glands in the skin of newborn babies, due to the mother's hormones still in the baby's circulation. The glands release a greasy substance that makes old skin cells attach to the scalp as they try to dry and fall off. There may be a relationship with skin yeasts (Pityrosporum ovale, newly renamed Malassezia furfur). Nutritionally oriented practitioners have speculated that the disorder is caused by the baby's immature digestive system being unable to absorb sufficient biotin and other vitamins of the B-complex.
# Warning signs
Home remedies are appropriate with mild cases. If the condition thickens, turns red and irritated, starts spreading, appears on other body parts, or if the baby develops a persistent diaper rash, medical intervention is recommended. Fungal infection (tinea capitis) and scabies can mimic cradle cap.
Cradle cap is occasionally linked to immune disorders. If the baby is not thriving and has other problems (e.g. diarrhoea), consult a doctor.
# Prognosis
Assurances that this condition will clear as the baby matures are very common. However, studies have shown that the condition not infrequently persists into the toddler years, and less commonly into later childhood. It tends to recur in adolescence and persists into adulthood. In an Australian study, about 15% percent of previously diagnosed children still had eczema 10 years later. Sometimes, cradle cap turns into atopic dermatitis. Rarely, it turns out to be misdiagnosed psoriasis.
# Treatment
## Scalp, behind ears, eyebrows
The common advice to apply (vegetable or mineral) oil liberally to the scalp and letting it soak in overnight or for lesser periods of time seems to conflict with the fact that Malassezia yeasts thrive in oily environments. The softened scales can then be brushed away with a soft brush, toothbrush, comb or cloth, but if not done very gently, this can worsen the condition and bring about temporary hair loss. There has been no study done on these recommendations.
Applying petroleum jelly (e.g., Vaseline) liberally overnight is another popular treatment. The softened scales either fall off during the night, or can be brushed off in the morning.
Making a paste from sodium bicarbonate (baking powder) and leaving it on the affected area for 10 minutes can also help lift the scales.
There is broad disagreement regarding the role of shampoos. Some sources warn against frequent shampooing, others recommend it. Mild baby shampoo is often recommended, while never specifying what "mild" actually means. Baby shampoos often contain detergent surfactants, perfumes, quaternium-15 and other eczemagenic irritants. Again, no studies have been performed. Switching to a shampoo with the least amount of potential irritants seems prudent.
Keratolytic (dandruff) shampoos (e.g with sulphur, selenium, zinc pyrithione, or salicylic acid) are generally not recommended as they sting eyes and may worsen the dermatitis. In stubborn cases some doctors do recommend them while others warn against the use of medicated shampoos in newborns due to systemic absorption. Dandruff shampoos often contain sodium lauryl sulphate, a noted skin irritant.
Steroid and tar preparations have also been used but have significant drawbacks. Immunomodulators (tacrolimus/Protopic, pimecrolimus/Elidel) have not been approved for babies under two years.
Ketoconazole shampoos and creams are taking first place in medical treatment of moderate to serious cradle cap. Research so far indicates that this anti-fungal medication is not absorbed into the bloodstream. Unfortunately, ketoconazole shampoo is currently made with a number of problematic irritants and allergens. Using a formulation prepared by a compounding pharmacy seems like very a good idea.
There have been several studies where cradle cap cleared swiftly and completely followed by the injection of biotin, either to the baby or the breastfeeding mother. In one study, injection of B-complex worked well also. Injection directly into the vein (rather than into the muscle) is recommended. Small amounts of oral biotin have not shown efficacy in a more recent trial, and many cradle cap compendia have since said that biotin supplementation is ineffective. This is not correct. Oral supplementation with liquid biotin is favoured by some physicians, but a well-designed study is needed to ascertain the effective dosage in oral supplementation (if there is one) or the effect of injected biotin/B-complex in a larger sample. Biotin is a very safe vitamin with no known toxicity, and well worth trying.
A Swedish study found good results from massaging the scalp with small amounts of borage oil twice a day.
Other home remedies recommended in various alternative sources and parent forums are herbal washes (e.g burdock or chamomile), aloe gel, and tea tree oil (Melaleuca oil) shampoo. Tea tree oil and aloe can be sensitizers; any worsening should be an occasion to discontinue the remedy in question. Both remedies have been tested in medical trials and found useful.
## Eyelids
Typical medical advice is to use diluted baby shampoo on a cotton swab to cleanse the eyelid. There is no agreement on the dilution, which ranges from a few drops to a half cup warm water, to a 50/50 mix. No studies have been performed on the efficacy or safety of this treatment. (Please note the problems with baby shampoo noted above.) In adults, a study comparing soap and baby shampoo to commercial eyelid scrubs found that patients strongly preferred not to put soap or shampoo on their eyelids. Baking soda has also been recommended (a teaspoonful in a cup of boiled water) and is well accepted by adults. Boiled warm water wash may help. | Cradle cap
Template:DiseaseDisorder infobox
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Cradle Cap (infantile or neonatal seborrhoeic dermatitis, also known as crusta lactea, milk crust, honeycomb disease) is a yellowish, patchy, greasy, scaly and crusty skin rash that occurs on the scalp of recently born babies. It is usually not itchy, and does not bother the baby. Cradle cap most commonly begins sometime in the first 3 months. The rash is often prominent around the ear, the eyebrows or the eyelids. It may appear in other locations as well, where it is called seborrhoeic dermatitis rather than cradle cap. Some countries use the term pityriasis capitis for cradle cap. It is extremely common, with about half of all babies affected. Most of them have a mild version of the disorder. Severe cradle cap is rare.
# Causes
The cause of cradle cap is not clearly defined but it is not caused by an infection, allergy nor from poor hygiene. Possibly it has to do with overactive sebaceous glands in the skin of newborn babies, due to the mother's hormones still in the baby's circulation. The glands release a greasy substance that makes old skin cells attach to the scalp as they try to dry and fall off. There may be a relationship with skin yeasts (Pityrosporum ovale, newly renamed Malassezia furfur). Nutritionally oriented practitioners have speculated that the disorder is caused by the baby's immature digestive system being unable to absorb sufficient biotin and other vitamins of the B-complex.
# Warning signs
Home remedies are appropriate with mild cases. If the condition thickens, turns red and irritated, starts spreading, appears on other body parts, or if the baby develops a persistent diaper rash, medical intervention is recommended. Fungal infection (tinea capitis) and scabies can mimic cradle cap.
Cradle cap is occasionally linked to immune disorders. If the baby is not thriving and has other problems (e.g. diarrhoea), consult a doctor.
# Prognosis
Assurances that this condition will clear as the baby matures are very common. However, studies have shown that the condition not infrequently persists into the toddler years, and less commonly into later childhood. It tends to recur in adolescence and persists into adulthood. In an Australian study, about 15% percent of previously diagnosed children still had eczema 10 years later. Sometimes, cradle cap turns into atopic dermatitis. Rarely, it turns out to be misdiagnosed psoriasis.
# Treatment
## Scalp, behind ears, eyebrows
The common advice to apply (vegetable or mineral) oil liberally to the scalp and letting it soak in overnight or for lesser periods of time seems to conflict with the fact that Malassezia yeasts thrive in oily environments. The softened scales can then be brushed away with a soft brush, toothbrush, comb or cloth, but if not done very gently, this can worsen the condition and bring about temporary hair loss. There has been no study done on these recommendations.
Applying petroleum jelly (e.g., Vaseline) liberally overnight is another popular treatment. The softened scales either fall off during the night, or can be brushed off in the morning.
Making a paste from sodium bicarbonate (baking powder) and leaving it on the affected area for 10 minutes can also help lift the scales.
There is broad disagreement regarding the role of shampoos. Some sources warn against frequent shampooing, others recommend it. Mild baby shampoo is often recommended, while never specifying what "mild" actually means. Baby shampoos often contain detergent surfactants, perfumes, quaternium-15 and other eczemagenic irritants. Again, no studies have been performed. Switching to a shampoo with the least amount of potential irritants seems prudent.
Keratolytic (dandruff) shampoos (e.g with sulphur, selenium, zinc pyrithione, or salicylic acid) are generally not recommended as they sting eyes and may worsen the dermatitis. In stubborn cases some doctors do recommend them while others warn against the use of medicated shampoos in newborns due to systemic absorption. Dandruff shampoos often contain sodium lauryl sulphate, a noted skin irritant.[1]
Steroid and tar preparations have also been used but have significant drawbacks. Immunomodulators (tacrolimus/Protopic, pimecrolimus/Elidel) have not been approved for babies under two years.
Ketoconazole shampoos and creams are taking first place in medical treatment of moderate to serious cradle cap. Research so far indicates that this anti-fungal medication is not absorbed into the bloodstream. Unfortunately, ketoconazole shampoo is currently made with a number of problematic irritants and allergens. Using a formulation prepared by a compounding pharmacy seems like very a good idea.
There have been several studies where cradle cap cleared swiftly and completely followed by the injection of biotin, either to the baby or the breastfeeding mother. In one study, injection of B-complex worked well also. Injection directly into the vein (rather than into the muscle) is recommended. Small amounts of oral biotin have not shown efficacy in a more recent trial, and many cradle cap compendia have since said that biotin supplementation is ineffective. This is not correct. Oral supplementation with liquid biotin is favoured by some physicians, but a well-designed study is needed to ascertain the effective dosage in oral supplementation (if there is one) or the effect of injected biotin/B-complex in a larger sample. Biotin is a very safe vitamin with no known toxicity, and well worth trying.
A Swedish study found good results from massaging the scalp with small amounts of borage oil twice a day.
Other home remedies recommended in various alternative sources and parent forums are herbal washes (e.g burdock or chamomile), aloe gel, and tea tree oil (Melaleuca oil) shampoo. Tea tree oil and aloe can be sensitizers; any worsening should be an occasion to discontinue the remedy in question. Both remedies have been tested in medical trials and found useful.
## Eyelids
Typical medical advice is to use diluted baby shampoo on a cotton swab to cleanse the eyelid. There is no agreement on the dilution, which ranges from a few drops to a half cup warm water, to a 50/50 mix. No studies have been performed on the efficacy or safety of this treatment. (Please note the problems with baby shampoo noted above.) In adults, a study comparing soap and baby shampoo to commercial eyelid scrubs found that patients strongly preferred not to put soap or shampoo on their eyelids. Baking soda has also been recommended (a teaspoonful in a cup of boiled water) and is well accepted by adults. Boiled warm water wash may help. | https://www.wikidoc.org/index.php/Cradle_Cap | |
549d0535e2d23b9772827c10f14291e6af812808 | wikidoc | Craquelure | Craquelure
In art, craquelure is the fine pattern of cracks formed on old paintings. It is sometimes used to detect forged art, as craquelure is a hard-to-forge signature of authenticity.
The precise pattern of craquelure depends upon where the picture was painted. There appear to be distinct French, Italian and Dutch "styles" of craquelure.
Craquelure can furnish a record of the environmental conditions the painting has experienced during its lifetime, and also can reveal details about the painting's history of handling, transportation, and restoration.
de:Krakelee
id:Craquelure
it:Craquelé
nl:Craquelé (materiaalkunde) | Craquelure
In art, craquelure is the fine pattern of cracks formed on old paintings. It is sometimes used to detect forged art, as craquelure is a hard-to-forge signature of authenticity.
The precise pattern of craquelure depends upon where the picture was painted. There appear to be distinct French, Italian and Dutch "styles" of craquelure.
Craquelure can furnish a record of the environmental conditions the painting has experienced during its lifetime, and also can reveal details about the painting's history of handling, transportation, and restoration.
de:Krakelee
id:Craquelure
it:Craquelé
nl:Craquelé (materiaalkunde)
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Craquelure | |
9755eb742e5445a4dc2606393b9e5013d81b0d15 | wikidoc | Cresol Red | Cresol Red
Cresol Red (full name: o-Cresolsulfonephthalein) is a triarylmethane dye frequently used for monitoring the pH in aquaria.
Cresol Red can be used in many molecular reactions instead of water. For example restriction digestion or PCR.
Cresol Red can also be used as a color marker to monitor the process of agarose gel electrophoresis and polyacrylamide gel electrophoresis. In a 1% agarose gel it runs approximately at the size of a 125 base pair (bp) DNA molecule (it depends on the concentration of buffer and other component). Bromophenol blue and xylene cyanol can also be used for this purpose. | Cresol Red
Template:Chembox new
Template:PH indicator template
Cresol Red (full name: o-Cresolsulfonephthalein) is a triarylmethane dye frequently used for monitoring the pH in aquaria.
Cresol Red can be used in many molecular reactions instead of water. For example restriction digestion or PCR.
Cresol Red can also be used as a color marker to monitor the process of agarose gel electrophoresis and polyacrylamide gel electrophoresis. In a 1% agarose gel it runs approximately at the size of a 125 base pair (bp) DNA molecule (it depends on the concentration of buffer and other component). Bromophenol blue and xylene cyanol can also be used for this purpose. | https://www.wikidoc.org/index.php/Cresol_Red | |
51123339f14c8eb362783fc271b570f05dc2f803 | wikidoc | Cretaceous | Cretaceous
The Cretaceous (Template:PronEng, usually abbreviated 'K' for its German translation "Kreide") is a geological period, reaching from the end of the Jurassic Period, (Template:Period start Expression error: Unrecognized punctuation character "[". Template:Period start error million years ago (Ma) to the beginning of the Paleocene Period, Template:Period start Expression error: Unrecognized punctuation character "[". Template:Period end error Ma. It is the youngest geological period of the Mesozoic, and at 80 million years long, the longest period of the Phanerozoic. The end of the Cretaceous defines the boundary between the Mesozoic and Cenozoic eras.
The Cretaceous (from Latin creta meaning 'chalk' ) as a separate period was first defined by a Belgian geologist Jean d'Omalius d'Halloy in 1822, using strata in the Paris Basin and named for the extensive beds of chalk (calcium carbonate deposited by the shells of marine invertebrates, principally coccoliths), found in the upper Cretaceous of continental Europe and the British Isles (including the White Cliffs of Dover).
# Dating
As with other older geologic periods, the rock beds that define the Cretaceous are well identified but the exact dates of the period's start and end are uncertain by a few million years. No great extinction or burst of diversity separated the Cretaceous from the Jurassic. However, the end of the period is most sharply defined, being placed at an iridium-rich layer found worldwide that is believed to be associated with the Chicxulub impact crater in Yucatan and the Gulf of Mexico. This layer has been tightly dated at 65.5 Ma. This bolide collision is probably responsible for the major, extensively-studied Cretaceous–Tertiary extinction event.
# Divisions
The Cretaceous is usually separated into Early and Late Cretaceous Epochs. The faunal stages from youngest to oldest are listed below; time is referred to as early or late, and the corresponding rocks are referred to as lower or upper:
# Paleogeography
During the Cretaceous, the late Paleozoic - early Mesozoic supercontinent of Pangaea completed its breakup into present day continents, although their positions were substantially different at the time. As the Atlantic Ocean widened, the convergent-margin orogenies that had begun during the Jurassic continued in the North American Cordillera, as the Nevadan orogeny was followed by the Sevier and Laramide orogenies.
Though Gondwana was still intact in the beginning of the Cretaceous, it broke up as South America, Antarctica and Australia rifted away from Africa (though India and Madagascar remained attached to each other); thus, the South Atlantic and Indian Oceans were newly formed. Such active rifting lifted great undersea mountain chains along the welts, raising eustatic sea levels worldwide. To the north of Africa the Tethys Sea continued to narrow. Broad shallow seas advanced across central North America (the Western Interior Seaway) and Europe, then receded late in the period, leaving thick marine deposits sandwiched between coal beds. At the peak of the Cretaceous transgression, one-third of Earth's present land area was submerged.
The Cretaceous is justly famous for its chalk; indeed, more chalk formed in the Cretaceous than in any other period in the Phanerozoic. Mid-ocean ridge activity — or rather, the circulation of seawater through the enlarged ridges — enriched the oceans in calcium; this made the oceans more saturated, as well as increased the bioavailability of the element for calcareous nanoplankton. These widespread carbonates and other sedimentary deposits make the Cretaceous rock record especially fine. Famous formations from North America include the rich marine fossils of Kansas's Smoky Hill Chalk Member and the terrestrial fauna of the late Cretaceous Hell Creek Formation. Other important Cretaceous exposures occur in Europe (e.g., the Weald) and China (the Yixian Formation). In the area that is now India, massive lava beds called the Deccan Traps were erupted in the very late Cretaceous and early Paleocene.
# Climate
The Berriasian epoch showed a cooling trend that had been seen in the last epoch of the Jurassic. There is evidence that snowfalls were common in the higher latitudes and the tropics became wetter than during the Triassic and Jurassic. Glaciation was however restricted to alpine glaciers on some high-latitude mountains, though seasonal snow may have existed further south.
After the end of the Berriasian, however, temperatures increased again, and these conditions were almost constant until the end of the period. This trend was due to intense volcanic activity which produced large quantities of carbon dioxide. The development of a number of mantle plumes across the widening mid-ocean ridges further pushed sea levels up, so that large areas of the continental crust were covered with shallow seas. The Tethys Sea connecting the tropical oceans east to west also helped in warming the global climate. Warm-adapted plant fossils are known from localities as far north as Alaska and Greenland, while dinosaur fossils have been found within 15 degrees of the Cretaceous south pole.
A very gentle temperature gradient from the equator to the poles meant weaker global winds, contributing to less upwelling and more stagnant oceans than today. This is evidenced by widespread black shale deposition and frequent anoxic events. Sediment cores show that tropical sea surface temperatures may have briefly been as warm as 42 °C (107 °F), 17 °C (31 °F) warmer than at present, and that they averaged around 37 °C (99 °F). Meanwhile deep ocean temperatures were as much as 15 to 20 °C (27 to 36 °F) higher than today's.
# Life
## Plants
Flowering plants (angiosperms) spread during this period, although they did not become predominant until the Campanian stage near the end of the epoch. Their evolution was aided by the appearance of bees; in fact angiosperms and insects are a good example of coevolution. The first representatives of many leafy trees, including figs, planes and magnolias, appeared in the Cretaceous. At the same time, some earlier Mesozoic gymnosperms like Conifers continued to thrive; pehuéns (Monkey Puzzle trees, Araucaria) and other conifers being notably plentiful and widespread, although other gymnosperm taxa like Bennettitales died out before the end of the period.
## Terrestrial fauna
On land, mammals were a small and still relatively minor component of the fauna. The fauna was dominated by archosaurian reptiles, especially dinosaurs, which were at their most diverse. Pterosaurs were common in the early and middle Cretaceous, but as the Cretaceous proceeded they faced growing competition from the adaptive radiation of birds, and by the end of the period only two highly specialised families remained.
The Liaoning lagerstätte (Chaomidianzi formation) in China provides a glimpse of life in the Early Cretaceous, where preserved remains of numerous types of small dinosaurs, birds, and mammals have been found. The coelurosaur dinosaurs found there represent types of the group maniraptora, which is transitional between dinosaurs and birds, and are notable for the presence of hair-like feathers.
During the Cretaceous, insects began to diversify, and the oldest known ants, termites and some lepidopterans, akin to butterflies and moths, appeared. Aphids, grasshoppers, and gall wasps appeared.
## Marine fauna
In the seas, rays, modern sharks and teleosts became common. Marine reptiles included ichthyosaurs in the early and middle of the Cretaceous, plesiosaurs throughout the entire period, and mosasaurs in the Late Cretaceous.
Baculites, a genus of straight-shelled form of ammonite, flourished in the seas. The Hesperornithiformes were flightless, marine diving birds that swam like grebes. Globotruncanid Foraminifera and echinoderms such as sea urchins and starfish (sea stars) thrived. The first radiation of the diatoms (generally siliceous, rather than calcareous) in the oceans occurred during the Cretaceous; freshwater diatoms did not appear until the Miocene. The Cretaceous was also an important interval in the evolution of bioerosion, the production of borings and scrapings in rocks, hardgrounds and shells (Taylor and Wilson, 2003).
## Extinction
There was a progressive decline in biodiversity during the Maastrichtian stage of the Cretaceous Period prior to the suggested ecological crisis induced by events at the K-T boundary. Furthermore, biodiversity required a substantial amount of time to recover from the K-T event, despite the probable existence of an abundance of vacant ecological niches.
Despite the severity of this boundary event, there was significant variability in the rate of extinction between and within different clades. Species which depended on photosynthesis declined or became extinct because of the reduction in solar energy reaching the earth's surface due to atmospheric particles blocking the sunlight. As is the case today, photosynthesizing organisms, such as phytoplankton and land plants, formed the primary part of the food chain in the late Cretaceous. Evidence suggests that herbivorous animals, which depended on plants and plankton as their food, died out as their food sources became scarce; consequently, top predators such as Tyrannosaurus rex also perished.
Coccolithophorids and molluscs, including ammonites, rudists, freshwater snails and mussels, as well as organisms whose food chain included these shell builders, became extinct or suffered heavy losses. For example, it is thought that ammonites were the principal food of mosasaurs, a group of giant marine reptiles that became extinct at the boundary.
Omnivores, insectivores and carrion-eaters survived the extinction event, perhaps because of the increased availability of their food sources. At the end of the Cretaceous there seem to have been no purely herbivorous or carnivorous mammals. Mammals and birds which survived the extinction fed on insects, larvae, worms, and snails, which in turn fed on dead plant and animal matter. Scientists theorise that these organisms survived the collapse of plant-based food chains because they fed on detritus.
In stream communities, few groups of animals became extinct. Stream communities rely less on food from living plants and more on detritus that washes in from land. This particular ecological niche buffered them from extinction. Similar, but more complex patterns have been found in the oceans. Extinction was more severe among animals living in the water column, than among animals living on or in the sea floor. Animals in the water column are almost entirely dependent on primary production from living phytoplankton, while animals living on or in the ocean floor feed on detritus or can switch to detritus feeding.
The largest air-breathing survivors of the event, crocodilians and champsosaurs, were semi-aquatic and had access to detritus. Modern crocodilians can live as scavengers and can survive for months without food, and their young are small, grow slowly, and feed largely on invertebrates and dead organisms or fragments of organisms for their first few years. These characteristics have been linked to crocodilian survival at the end of the Cretaceous.
- Numerous borings in a Cretaceous cobble, Faringdon, England; these are excellent examples of fossil bioerosion.
Numerous borings in a Cretaceous cobble, Faringdon, England; these are excellent examples of fossil bioerosion.
- Cretaceous hardground from Texas with encrusting oysters and borings. The scale bar is 1.0 cm.
Cretaceous hardground from Texas with encrusting oysters and borings. The scale bar is 1.0 cm. | Cretaceous
The Cretaceous (Template:PronEng, usually abbreviated 'K' for its German translation "Kreide") is a geological period, reaching from the end of the Jurassic Period, (Template:Period start Expression error: Unrecognized punctuation character "[". Template:Period start error million years ago (Ma) to the beginning of the Paleocene Period, Template:Period start Expression error: Unrecognized punctuation character "[". Template:Period end error Ma. It is the youngest geological period of the Mesozoic, and at 80 million years long, the longest period of the Phanerozoic. The end of the Cretaceous defines the boundary between the Mesozoic and Cenozoic eras.
The Cretaceous (from Latin creta meaning 'chalk' [1]) as a separate period was first defined by a Belgian geologist Jean d'Omalius d'Halloy in 1822, using strata in the Paris Basin[2] and named for the extensive beds of chalk (calcium carbonate deposited by the shells of marine invertebrates, principally coccoliths), found in the upper Cretaceous of continental Europe and the British Isles (including the White Cliffs of Dover).
# Dating
As with other older geologic periods, the rock beds that define the Cretaceous are well identified but the exact dates of the period's start and end are uncertain by a few million years. No great extinction or burst of diversity separated the Cretaceous from the Jurassic. However, the end of the period is most sharply defined, being placed at an iridium-rich layer found worldwide that is believed to be associated with the Chicxulub impact crater in Yucatan and the Gulf of Mexico. This layer has been tightly dated at 65.5 Ma. This bolide collision is probably responsible for the major, extensively-studied Cretaceous–Tertiary extinction event.
# Divisions
The Cretaceous is usually separated into Early and Late Cretaceous Epochs. The faunal stages from youngest to oldest are listed below; time is referred to as early or late, and the corresponding rocks are referred to as lower or upper:
# Paleogeography
During the Cretaceous, the late Paleozoic - early Mesozoic supercontinent of Pangaea completed its breakup into present day continents, although their positions were substantially different at the time. As the Atlantic Ocean widened, the convergent-margin orogenies that had begun during the Jurassic continued in the North American Cordillera, as the Nevadan orogeny was followed by the Sevier and Laramide orogenies.
Though Gondwana was still intact in the beginning of the Cretaceous, it broke up as South America, Antarctica and Australia rifted away from Africa (though India and Madagascar remained attached to each other); thus, the South Atlantic and Indian Oceans were newly formed. Such active rifting lifted great undersea mountain chains along the welts, raising eustatic sea levels worldwide. To the north of Africa the Tethys Sea continued to narrow. Broad shallow seas advanced across central North America (the Western Interior Seaway) and Europe, then receded late in the period, leaving thick marine deposits sandwiched between coal beds. At the peak of the Cretaceous transgression, one-third of Earth's present land area was submerged.[3]
The Cretaceous is justly famous for its chalk; indeed, more chalk formed in the Cretaceous than in any other period in the Phanerozoic.[4] Mid-ocean ridge activity — or rather, the circulation of seawater through the enlarged ridges — enriched the oceans in calcium; this made the oceans more saturated, as well as increased the bioavailability of the element for calcareous nanoplankton.[5] These widespread carbonates and other sedimentary deposits make the Cretaceous rock record especially fine. Famous formations from North America include the rich marine fossils of Kansas's Smoky Hill Chalk Member and the terrestrial fauna of the late Cretaceous Hell Creek Formation. Other important Cretaceous exposures occur in Europe (e.g., the Weald) and China (the Yixian Formation). In the area that is now India, massive lava beds called the Deccan Traps were erupted in the very late Cretaceous and early Paleocene.
# Climate
The Berriasian epoch showed a cooling trend that had been seen in the last epoch of the Jurassic. There is evidence that snowfalls were common in the higher latitudes and the tropics became wetter than during the Triassic and Jurassic[6]. Glaciation was however restricted to alpine glaciers on some high-latitude mountains, though seasonal snow may have existed further south.
After the end of the Berriasian, however, temperatures increased again, and these conditions were almost constant until the end of the period[7]. This trend was due to intense volcanic activity which produced large quantities of carbon dioxide. The development of a number of mantle plumes across the widening mid-ocean ridges further pushed sea levels up, so that large areas of the continental crust were covered with shallow seas. The Tethys Sea connecting the tropical oceans east to west also helped in warming the global climate. Warm-adapted plant fossils are known from localities as far north as Alaska and Greenland, while dinosaur fossils have been found within 15 degrees of the Cretaceous south pole.[8]
A very gentle temperature gradient from the equator to the poles meant weaker global winds, contributing to less upwelling and more stagnant oceans than today. This is evidenced by widespread black shale deposition and frequent anoxic events.[9] Sediment cores show that tropical sea surface temperatures may have briefly been as warm as 42 °C (107 °F), 17 °C (31 °F) warmer than at present[when?], and that they averaged around 37 °C (99 °F). Meanwhile deep ocean temperatures were as much as 15 to 20 °C (27 to 36 °F) higher than today's.[10][11]
# Life
## Plants
Flowering plants (angiosperms) spread during this period, although they did not become predominant until the Campanian stage near the end of the epoch. Their evolution was aided by the appearance of bees; in fact angiosperms and insects are a good example of coevolution. The first representatives of many leafy trees, including figs, planes and magnolias, appeared in the Cretaceous. At the same time, some earlier Mesozoic gymnosperms like Conifers continued to thrive; pehuéns (Monkey Puzzle trees, Araucaria) and other conifers being notably plentiful and widespread, although other gymnosperm taxa like Bennettitales died out before the end of the period.[citation needed]
## Terrestrial fauna
On land, mammals were a small and still relatively minor component of the fauna. The fauna was dominated by archosaurian reptiles, especially dinosaurs, which were at their most diverse. Pterosaurs were common in the early and middle Cretaceous, but as the Cretaceous proceeded they faced growing competition from the adaptive radiation of birds, and by the end of the period only two highly specialised families remained.
The Liaoning lagerstätte (Chaomidianzi formation) in China provides a glimpse of life in the Early Cretaceous, where preserved remains of numerous types of small dinosaurs, birds, and mammals have been found. The coelurosaur dinosaurs found there represent types of the group maniraptora, which is transitional between dinosaurs and birds, and are notable for the presence of hair-like feathers.
During the Cretaceous, insects began to diversify, and the oldest known ants, termites and some lepidopterans, akin to butterflies and moths, appeared. Aphids, grasshoppers, and gall wasps appeared.
## Marine fauna
In the seas, rays, modern sharks and teleosts became common. Marine reptiles included ichthyosaurs in the early and middle of the Cretaceous, plesiosaurs throughout the entire period, and mosasaurs in the Late Cretaceous.
Baculites, a genus of straight-shelled form of ammonite, flourished in the seas. The Hesperornithiformes were flightless, marine diving birds that swam like grebes. Globotruncanid Foraminifera and echinoderms such as sea urchins and starfish (sea stars) thrived. The first radiation of the diatoms (generally siliceous, rather than calcareous) in the oceans occurred during the Cretaceous; freshwater diatoms did not appear until the Miocene. The Cretaceous was also an important interval in the evolution of bioerosion, the production of borings and scrapings in rocks, hardgrounds and shells (Taylor and Wilson, 2003).
## Extinction
There was a progressive decline in biodiversity during the Maastrichtian stage of the Cretaceous Period prior to the suggested ecological crisis induced by events at the K-T boundary. Furthermore, biodiversity required a substantial amount of time to recover from the K-T event, despite the probable existence of an abundance of vacant ecological niches.[12]
Despite the severity of this boundary event, there was significant variability in the rate of extinction between and within different clades. Species which depended on photosynthesis declined or became extinct because of the reduction in solar energy reaching the earth's surface due to atmospheric particles blocking the sunlight. As is the case today, photosynthesizing organisms, such as phytoplankton and land plants, formed the primary part of the food chain in the late Cretaceous. Evidence suggests that herbivorous animals, which depended on plants and plankton as their food, died out as their food sources became scarce; consequently, top predators such as Tyrannosaurus rex also perished.[13]
Coccolithophorids and molluscs, including ammonites, rudists, freshwater snails and mussels, as well as organisms whose food chain included these shell builders, became extinct or suffered heavy losses. For example, it is thought that ammonites were the principal food of mosasaurs, a group of giant marine reptiles that became extinct at the boundary.[14]
Omnivores, insectivores and carrion-eaters survived the extinction event, perhaps because of the increased availability of their food sources. At the end of the Cretaceous there seem to have been no purely herbivorous or carnivorous mammals. Mammals and birds which survived the extinction fed on insects, larvae, worms, and snails, which in turn fed on dead plant and animal matter. Scientists theorise that these organisms survived the collapse of plant-based food chains because they fed on detritus.[15][12][16]
In stream communities, few groups of animals became extinct. Stream communities rely less on food from living plants and more on detritus that washes in from land. This particular ecological niche buffered them from extinction.[17] Similar, but more complex patterns have been found in the oceans. Extinction was more severe among animals living in the water column, than among animals living on or in the sea floor. Animals in the water column are almost entirely dependent on primary production from living phytoplankton, while animals living on or in the ocean floor feed on detritus or can switch to detritus feeding.[12]
The largest air-breathing survivors of the event, crocodilians and champsosaurs, were semi-aquatic and had access to detritus. Modern crocodilians can live as scavengers and can survive for months without food, and their young are small, grow slowly, and feed largely on invertebrates and dead organisms or fragments of organisms for their first few years. These characteristics have been linked to crocodilian survival at the end of the Cretaceous.[15]
- Numerous borings in a Cretaceous cobble, Faringdon, England; these are excellent examples of fossil bioerosion.
Numerous borings in a Cretaceous cobble, Faringdon, England; these are excellent examples of fossil bioerosion.
- Cretaceous hardground from Texas with encrusting oysters and borings. The scale bar is 1.0 cm.
Cretaceous hardground from Texas with encrusting oysters and borings. The scale bar is 1.0 cm. | https://www.wikidoc.org/index.php/Cretaceous | |
dec45c14f6ee66d0b270a176cdc4b903fbf490dc | wikidoc | Crizotinib | Crizotinib
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# Overview
Crizotinib is a tyrosine kinase inhibitor that is FDA approved for the treatment of metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK)-positive. Common adverse reactions include vision disorders, nausea, diarrhea, vomiting, constipation, edema, elevated transaminases, and fatigue.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Metastatic Non-Small Cell Lung Cancer
- Patient Selection: based on the presence of ALK positivity in tumor specimens
- Dosage: 250 mg orally twice daily until disease progression or no longer tolerated by the patient.
- Recommended dose of crizotinib in patients with severe renal impairment (creatinine clearance <30 mL/min) not requiring dialysis is 250 mg orally, once daily
### Dose Modification
- Reduce dose as below, if one or more dose reductions are necessary due to adverse reactions of Grade 3 or 4 severity, as defined by NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0:
- First dose reduction: Crizotinib 200 mg taken orally twice daily
- Second dose reduction: Crizotinib 250 mg taken orally once daily
- Permanently discontinue if unable to tolerate Crizotinib 250 mg taken once daily
Dose reduction guidelines are provided in Tables 1 and 2.
Monitor complete blood counts including differential white blood cell counts monthly and as clinically indicated, with more frequent repeat testing if Grade 3 or 4 abnormalities are observed, or if fever or infection occurs.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Crizotinib in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Crizotinib in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Crizotinib 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 Crizotinib in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Crizotinib in pediatric patients.
# Contraindications
- None
# Warnings
### Hepatotoxicity
- Drug-induced hepatotoxicity with fatal outcome occurred in 2 (0.2%) of the 1225 patients treated with crizotinib across three main clinical trials. Concurrent elevations in alanine aminotransferase (ALT) greater than three times the upper limit of normal and total bilirubin greater than two times the upper limit of normal, with normal alkaline phosphatase, occurred in 7 patients (0.6%). Additionally, elevations in ALT greater than five times the upper limit of normal occurred in 109 patients (9.2%). Eight patients (0.7%) required permanent discontinuation due to elevated transaminases.
- These laboratory findings were generally reversible upon dosing interruption.
- Transaminase elevations generally occurred within the first 2 months of treatment.
- Monitor with liver function tests including ALT and total bilirubin every 2 weeks during the first 2 months of treatment, then once a month and as clinically indicated, with more frequent repeat testing for increased liver transaminases, alkaline phosphatase, or total bilirubin in patients who develop transaminase elevations.
- Temporarily suspend, dose reduce, or permanently discontinue crizotinib as described in Table 2.
### Interstitial Lung Disease Pneumonitis
- Severe, life-threatening, or fatal interstitial lung disease (ILD)/pneumonitis can occur in patients treated with crizotinib.
- Across clinical trials (n=1225), 31 crizotinib-treated patients (2.5%) had any grade ILD, 11 patients (0.9%) had Grade 3 or 4, and 6 patients (0.5%) had fatal cases.
- These cases generally occurred within 2 months after the initiation of treatment.
- Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis.
- Exclude other potential causes of ILD/pneumonitis, and permanently discontinue crizotinib in patients diagnosed with drug-related ILD/pneumonitis.
### QT Interval Prolongation
- QTc prolongation can occur in patients treated with crizotinib. Across clinical trials (n=1225), QTc prolongation (all grades) was observed in 34 (2.7%) patients and QTc greater than 500 ms on at least 2 separate ECGs occurred in 17(1.4%) patients.
- Avoid use of crizotinib in patients with congenital long QT syndrome. Consider periodic monitoring with electrocardiograms (ECGs) and electrolytes in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, or who are taking medications that are known to prolong the QT interval.
- Permanently discontinue crizotinib in patients who develop QTc greater than 500 ms or greater than or equal to 60 ms change from baseline with Torsade de pointes or polymorphic ventricular tachycardia or signs/symptoms of serious arrhythmia.
- Withhold crizotinib in patients who develop QTc greater than 500 ms on at least 2 separate ECGs until recovery to a QTc less than or equal to 480 ms, then resume crizotinib at a reduced dose as described in Table 2.
### Bradycardia
- Symptomatic bradycardia can occur in patients receiving crizotinib.
- Across clinical trials, bradycardia with a heart rate less than 50 beats per minute occurred in 11% of 1174 patients treated with crizotinib.
- In Study 1, Grade 3 syncope occurred in 2.9% of crizotinib-treated patients and in none of the chemotherapy-treated patients.
- Avoid using crizotinib in combination with other agents known to cause bradycardia (e.g., beta-blockers, non-dihydropyridine calcium channel blockers, clonidine and digoxin) to the extent possible.
- Monitor heart rate and blood pressure regularly.
- In cases of symptomatic bradycardia that is not life-threatening, hold crizotinib until recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above, re-evaluate the use of concomitant medications, and adjust the dose of crizotinib.
- Permanently discontinue for life-threatening bradycardia due to crizotinib; however, if associated with concomitant medications known to cause bradycardia or hypotension, hold crizotinib until recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above, and if concomitant medications can be adjusted or discontinued, restart crizotinib at 250 mg once daily with frequent monitoring.
### Embryofetal Toxicity
- Crizotinib can cause fetal harm when administered to a pregnant woman based on its mechanism of action.
- In nonclinical studies in rats, crizotinib was embryotoxic and fetotoxic at exposures similar to those observed in humans at the recommended clinical dose of 250 mg twice daily.
- There are no adequate and well-controlled studies in pregnant women using crizotinib.
- If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
- Safety evaluation of crizotinib is based on more than 1200 patients with ALK-positive metastatic NSCLC who received crizotinib as monotherapy at a starting oral dose of 250 mg twice daily continuously.
- The most common adverse reactions (≥25%) of crizotinib are vision disorder, nausea, diarrhea, vomiting, constipation, edema, elevated transaminases, and fatigue.
### ALK-positive metastatic NSCLC-Study 1
- The data in Table 3 are derived from 343 patients with ALK-positive metastatic NSCLC enrolled in a randomized, multicenter, active-controlled, open-label trial (Study 1).
- Patients in the crizotinib arm (n=172) received crizotinib 250 mg orally twice daily until documented disease progression, intolerance to therapy, or the investigator determined that the patient was no longer experiencing clinical benefit.
- A total of 171 patients in the chemotherapy arm received pemetrexed 500 mg/m2 (n=99) or docetaxel 75 mg/m2 (n=72) by intravenous infusion every three weeks until documented disease progression, intolerance to therapy, or the investigator determined that the patient was no longer experiencing clinical benefit.
- Patients in the chemotherapy arm received pemetrexed unless they had received pemetrexed as part of first-line or maintenance treatment.
- The median duration of study treatment was 7.1 months for patients who received crizotinib and 2.8 months for patients who received chemotherapy.
- Across the 347 patients who were randomized to study treatment (343 received at least one dose of study treatment), the median age was 50 years; 84% of patients in the crizotinib arm and 87% of patients in the chemotherapy arm were younger than 65 years.
- A total of 57% of patients on crizotinib and 55% of chemotherapy patients were female. Forty-six percent (46%) of crizotinib-treated and 45% of chemotherapy-treated patients were from Asia.
- Serious adverse reactions were reported in 64 patients (37.2%) treated with crizotinib and 40 patients (23.4%) in the chemotherapy arm.
- The most frequent serious adverse reactions reported in patients treated with crizotinib were:
- Pneumonia (4.1%)
- Pulmonary embolism (3.5%)
- Dyspnea (2.3%)
- Interstitial lung disease (ILD; 2.9%).
- Fatal adverse reactions in crizotinib-treated patients in Study 1 occurred in 9 (5%) patients, consisting of:
- Acute respiratory distress syndrome
- Arrhythmia
- Dyspnea
- Pneumonia
- Pneumonitis
- Pulmonary embolism
- ILD
- Respiratory failure
- Sepsis
- Dose reductions due to adverse reactions were required in 16% of crizotinib-treated patients.
- The most frequent adverse reactions that led to dose reduction in the patients treated with crizotinib were alanine aminotransferase (ALT) elevation (7.6%) including some patients with concurrent aspartate aminotransferase (AST) elevation, QTc prolongation (2.9%), and neutropenia (2.3%).
- Discontinuation of therapy in crizotinib-treated patients for adverse reactions was 17.0%.
- The most frequent adverse reactions that led to discontinuation in crizotinib-treated patients were:
- ILD(1.7%)
- ALT elevation
- AST elevation (1.2%)
- Dyspnea (1.2%)
- Pulmonary embolism (1.2%)
- Tables 3 and 4 summarize common Adverse Reactions and Laboratory Abnormalities in crizotinib-treated patients.
- Additional adverse reactions occurring at an overall incidence between 1% and 30% in patients treated with crizotinib included:
- Decreased appetite (27%)
- Fatigue (27%)
- Neuropathy (19%; dysesthesia, gait disturbance, hypoesthesia, muscular weakness, neuralgia, peripheral neuropathy, parasthesia, peripheral sensory neuropathy, polyneuropathy, burning sensation in skin)
- Rash (9%),
- ILD (4%; acute respiratory distress syndrome, ILD, pneumonitis), renal cyst (4%), and hepatic failure (1%).
### ALK-positive metastatic NSCLC- Study 2
- The safety analysis population in Study 2 included 934 patients with ALK-positive metastatic NSCLC who received crizotinib in a clinical trial. *The median duration of treatment was 23 weeks.
- Dosing interruptions and reductions due to treatment-related adverse events occurred in 23% and 12% of patients, respectively.
- The rate of treatment-related adverse events resulting in permanent discontinuation was 5%.
- The most common adverse reactions (≥25%) included vision disorder (55%), nausea (51%), vomiting (46%), diarrhea (46%), edema (39%), constipation (38%), and fatigue (26%).
### Description of selected adverse drug reactions
- Most commonly:
- visual impairment
- photopsia
- blurred vision, or vitreous floaters, occurred in 691 (56%) patients across clinical trials (n=1225).
- The majority (99%) of these patients had Grade 1 or 2 visual adverse reactions.
- Across clinical studies, one patient had a treatment-related grade 3 vision abnormality.
- Based on the Visual Symptom Assessment Questionnaire (VSAQ-ALK), patients treated with crizotinib in Study 1 reported a higher incidence of visual disturbances compared to patients treated with chemotherapy. The onset of vision disorders generally started within the first week of drug administration.
- The majority of patients on the crizotinib arm in Study 1 (> 50%) reported visual disturbances; these visual disturbances occurred at a frequency of 4–7 days each week, lasted up to 1 minute, and had mild or no impact (scores 0 to 3 out of a maximum score of 10) on daily activities as captured in a patient questionnaire.
- Neuropathy, most commonly sensory in nature, occurred in 235 (19%) of 1225 patients.
- Most events (95%) were Grade 1 or Grade 2 in severity.
- Renal cysts occurred in 7 (4%) patients treated with crizotinib and 1 (1%) patient treated with chemotherapy in Study 1.
- The majority of renal cysts in crizotinib-treated patients were complex. *Local cystic invasion beyond the kidney occurred, in some cases with imaging characteristics suggestive of abscess formation. However, across clinical trials no renal abscesses were confirmed by microbiology tests.
## Postmarketing Experience
There is limited information regarding Crizotinib Postmarketing Experience in the drug label.
# Drug Interactions
### Drugs That May Increase Crizotinib Plasma Concentrations
- Coadministration of crizotinib with strong CYP3A inhibitors increases crizotinib plasma concentrations.
- Avoid concomitant use of strong CYP3A inhibitors, including but not limited to atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, and voriconazole. *Avoid grapefruit or grapefruit juice which may also increase plasma concentrations of crizotinib.
- Exercise caution with concomitant use of moderate CYP3A inhibitors.
### Drugs That May Decrease Crizotinib Plasma Concentrations
- Coadministration of crizotinib with strong CYP3A inducers decreases crizotinib plasma concentrations.
- Avoid concomitant use of strong CYP3A inducers, including but not limited to carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, and St. John's Wort.
### Drugs Whose Plasma Concentrations May Be Altered By Crizotinib
- Crizotinib inhibits CYP3A both in vitro and in vivo.
- Avoid concomitant use of CYP3A substrates with narrow therapeutic range, including but not limited to alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus in patients taking crizotinib. *If concomitant use of these CYP3A substrates with narrow therapeutic range is required in patients taking crizotinib, dose reductions of the CYP3A substrates may be required due to adverse reactions.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
- Crizotinib can cause fetal harm when administered to a pregnant woman based on its mechanism of action.
- There are no adequate and well-controlled studies of crizotinib in pregnant women.
- In nonclinical studies in rats, crizotinib was embryotoxic and fetotoxic at exposures similar to those observed in humans at the recommended clinical dose of 250 mg twice daily.
- Crizotinib was administered to pregnant rats and rabbits during organogenesis to study the effects on embryo-fetal development.
- Postimplantation loss was increased at doses ≥ 50 mg/kg/day (approximately 0.6 times the AUC at the recommended human dose) in rats.
- No teratogenic effects were observed in rats at doses up to the maternally toxic dose of 200 mg/kg/day (approximately 2.7 times the AUC at the recommended human dose) or in rabbits at doses of up to 60 mg/kg/day (approximately 1.6 times the AUC at the recommended human dose), though fetal body weights were reduced at these doses.
- Advise women of childbearing potential to avoid becoming pregnant while receiving crizotinib.
- Women of childbearing potential who are receiving this drug, or partners of women of childbearing potential receiving this drug, should use adequate contraceptive methods during therapy and for at least 90 days after completing therapy.
- If this drug is used during pregnancy, or if the patient or their partner becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Crizotinib in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Crizotinib during labor and delivery.
### Nursing Mothers
- It is not known whether crizotinib 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 crizotinib, consider whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
- The safety and efficacy of crizotinib in pediatric patients has not been established.
- Decreased bone formation in growing long bones was observed in immature rats at 150 mg/kg/day following once daily dosing for 28 days (approximately 5.4 times the AUC in adult patients at the recommended human dose).
- Other toxicities of potential concern to pediatric patients have not been evaluated in juvenile animals.
### Geriatic Use
- Of crizotinib treated patients in Study 1, 27 (16%) were 65 years or older, in Study 2, 152 (16%) were 65 years or older, and in Study 3, 16 (13%) were 65 years or older.
- No overall differences in safety or effectiveness were observed between these patients and younger patients.
### Gender
- No clinically relevant effect of gender on the exposure of crizotinib based on the population pharmacokinetic analysis from Studies 1, 2 and 3.
### Race
- No clinically relevant difference in the exposure of crizotinib between Asian patients (N=523) and non-Asian patients
### Renal Impairment
- No starting dose adjustment is needed for patients with mild (creatinine clearance 60–89 mL/min) or moderate (CLcr 30–59 mL/min) renal impairment based on a population pharmacokinetic analysis.
- Increased exposure to crizotinib occurred in patients with severe renal impairment (CLcr <30 mL/min) not requiring dialysis. Administer crizotinib at a dose of 250 mg taken orally once daily in patients with severe renal impairment not requiring dialysis
### Hepatic Impairment
- Crizotinib has not been studied in patients with hepatic impairment. As crizotinib is extensively metabolized in the liver, hepatic impairment is likely to increase plasma crizotinib concentrations.
- Clinical studies excluded patients with AST or ALT greater than 2.5 × ULN, or greater than 5 × ULN, if due to liver metastases.
- Patients with total bilirubin greater than 1.5 × ULN were also excluded. Therefore, use caution in patients with hepatic impairment
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Crizotinib in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Crizotinib in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- Monitor with liver function tests including ALT and total bilirubin every 2 weeks during the first 2 months of treatment, then once a month.
- Monitor with electrocardiograms and electrolytes in patients who have a history of or predisposition for QTc prolongation, or who are taking medications that prolong QT.
- Monitor heart rate and blood pressure regularly, as it can cause bradycardia.
- Monitor complete blood counts including differential white blood cell counts monthly.
- Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis.
# IV Compatibility
There is limited information regarding the compatibility of Crizotinib and IV administrations.
# Overdosage
- There have been no known cases of crizotinib overdose.
- There is no antidote for crizotinib.
# Pharmacology
## Mechanism of Action
- Crizotinib is an inhibitor of receptor tyrosine kinases including ALK, Hepatocyte Growth Factor Receptor (HGFR, c-Met), ROS1 (c-ros), and Recepteur d'Origine Nantais (RON).
- Translocations can affect the ALK gene resulting in the expression of oncogenic fusion proteins.
- The formation of ALK fusion proteins results in activation and dysregulation of the gene's expression and signaling which can contribute to increased cell proliferation and survival in tumors expressing these proteins.
- Crizotinib demonstrated concentration-dependent inhibition of ALK, ROS1, and c-Met phosphorylation in cell-based assays using tumor cell lines and demonstrated antitumor activity in mice bearing tumor xenografts that expressed EML4- or NPM-ALK fusion proteins or c-Met.
## Structure
- The molecular formula for crizotinib is C21H22Cl2FN5O.
- The molecular weight is 450.34 Daltons.
- Crizotinib is described chemically as (R)-3--5-pyridin-2-amine.
The chemical structure of crizotinib is shown below:
- Crizotinib is a white to pale-yellow powder with a pKa of 9.4 (piperidinium cation) and 5.6 (pyridinium cation).
- The solubility of crizotinib in aqueous media decreases over the range pH 1.6 to pH 8.2 from greater than 10 mg/mL to less than 0.1 mg/mL.
- The log of the distribution coefficient (octanol/water) at pH 7.4 is 1.65.
## Pharmacodynamics
### Cardiac Electrophysiology
- The QT interval prolongation potential of crizotinib was assessed in all patients who received crizotinib 250 mg twice daily.
- Serial ECGs in triplicate were collected following a single dose and at steady state to evaluate the effect of crizotinib on QT intervals.
- Sixteen of 1167 patients (1.4%) were found to have QTcF (corrected QT by the Fridericia method) greater than or equal to 500 msec and 51 of 1136 patients (4.4%) had an increase from baseline QTcF greater than or equal to 60 msec by automated machine-read evaluation of ECG. A pharmacokinetic/pharmacodynamic analysis suggested a concentration-dependent increase in QTcF
## Pharmacokinetics
### Absorption
- Following a single oral dose, crizotinib was absorbed with median time to achieve peak concentration of 4 to 6 hours.
- Following crizotinib 250 mg twice daily, steady state was reached within 15 days and remained stable, with a median accumulation ratio of 4.8.
- Steady-state systemic exposure (Cmin and AUC) appeared to increase in a greater than dose proportional manner over the dose range of 200–300 mg twice daily.
- The mean absolute bioavailability of crizotinib was 43% (range: 32% to 66%) following a single 250 mg oral dose.
- A high-fat meal reduced crizotinib AUCinf and Cmax by approximately 14%. crizotinib can be administered with or without food.
### Distribution
- The geometric mean volume of distribution (Vss) of crizotinib was 1,772 L following intravenous administration of a 50 mg dose, indicating extensive distribution into tissues from the plasma.
- Binding of crizotinib to human plasma proteins in vitro is 91% and is independent of drug concentration. In vitro studies suggested that crizotinib is a substrate for P-glycoprotein (P-gp). The blood-to-plasma concentration ratio is approximately 1.
### Metabolism
- Crizotinib is predominantly metabolized by CYP3A4/5.
- The primary metabolic pathways in humans were oxidation of the piperidine ring to crizotinib lactam and O-dealkylation, with subsequent Phase 2 conjugation of O-dealkylated metabolites.
### Elimination
- Following single doses of crizotinib, the mean apparent plasma terminal half-life of crizotinib was 42 hours in patients.
- Following the administration of a single 250 mg radiolabeled crizotinib dose to healthy subjects, 63% and 22% of the administered dose was recovered in feces and urine, respectively.
- Unchanged crizotinib represented approximately 53% and 2.3% of the administered dose in feces and urine, respectively.
- The mean apparent clearance (CL/F) of crizotinib was lower at steady state (60 L/h) after 250 mg twice daily than that after a single 250 mg oral dose (100 L/h), which was likely due to autoinhibition of CYP3A by crizotinib after multiple dosing.
### Drug interactions
CYP3A inhibitors:
- Coadministration of a single 150 mg oral dose of crizotinib with ketoconazole (200 mg twice daily), a strong CYP3A inhibitor, increased crizotinib AUCinf and Cmax values by approximately 3.2-fold and 1.4-fold, respectively, compared to crizotinib alone. However, the magnitude of effect of CYP3A inhibitors on steady-state crizotinib exposure has not been evaluated.
CYP3A inducers:
- Coadministration of a single 250 mg oral dose of crizotinib with rifampin (600 mg once daily), a strong CYP3A inducer, decreased crizotinib AUCinf and Cmax by 82% and 69%, respectively, compared to crizotinib alone. However, the magnitude of effect of CYP3A inducers on steady-state crizotinib exposure has not been evaluated.
Gastric pH elevating medications:
- In healthy subjects, coadministration of a single 250 mg oral dose of crizotinib following administration of esomeprazole 40 mg daily for 5 days did not result in a clinically relevant change in crizotinib exposure (AUCinf decreased by 10% and no change in Cmax).
CYP3A substrates:
- Coadministration of crizotinib (250 mg twice daily for 28 days) in patients increased the AUCinf of oral midazolam 3.7-fold compared to midazolam alone, suggesting that crizotinib is a moderate inhibitor of CYP3A.
Other CYP substrates:
- In vitro studies suggest that clinical drug-drug interactions as a result of crizotinib-mediated inhibition of the metabolism of substrates for CYP1A2, CYP2C8, CYP2C9, CYP2C19, or CYP2D6 are unlikely to occur.
- Crizotinib is an inhibitor of CYP2B6 in vitro. Therefore, crizotinib may increase plasma concentrations of coadministered drugs that are predominantly metabolized by CYP2B6.
- An in vitro study suggests that clinical drug-drug interactions as a result of crizotinib-mediated induction of the metabolism of substrates for CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP3A are unlikely to occur.
UGT substrates:
- In vitro studies suggest that clinical drug-drug interactions as a result of crizotinib-mediated inhibition of the metabolism of drugs that are substrates for UGT1A1, UGT1A4, UGT1A6, UGT1A9 or UGT2B7 are unlikely to occur.
Substrates of transporters:
- Crizotinib inhibited P-glycoprotein (P-gp) in vitro at clinically relevant concentrations. Therefore, crizotinib has the potential to increase plasma concentrations of coadministered drugs that are substrates of P-gp.
- Crizotinib inhibited the hepatic uptake transporter, organic cation transporter 1 (OCT1), and renal uptake transporter, organic cation transporter 2 (OCT2), in vitro at clinically relevant concentrations. Therefore, crizotinib has the potential to increase plasma concentrations of coadministered drugs that are substrates of OCT1 or OCT2.
- Crizotinib did not inhibit the human hepatic uptake transport proteins OATP1B1 or OATP1B3, or the renal uptake transport proteins OAT1 or OAT3 in vitro at clinically relevant concentrations.
Effect on other transport proteins:
- Crizotinib did not inhibit the hepatic efflux bile salt export pump transporter (BSEP) in vitro at clinically relevant concentrations.
### Specific populations
Hepatic Impairment:
- As crizotinib is extensively metabolized in the liver, hepatic impairment is likely to increase plasma crizotinib concentrations. However, crizotinib has not been studied in patients with hepatic impairment.
- Clinical studies excluded patients with ALT or AST greater than 2.5 × ULN or greater than 5 × ULN if due to liver metastases.
- Patients with total bilirubin greater than 1.5 × ULN were also excluded. *The population pharmacokinetic analysis using the data from Studies 1, 2 and 3 suggested that baseline total bilirubin (0.1 to 2.1 mg/dL) or AST levels (7 to 124 U/L) did not have a clinically relevant effect on the exposure of crizotinib.
Renal impairment:
- The pharmacokinetics of crizotinib were evaluated using a population pharmacokinetic analysis in patients with mild (CLcr 60–89 mL/min, N=433) and moderate (CLcr 30–59 mL/min, N=137) renal impairment enrolled in Studies 1, 2, and 3.
- Mild or moderate renal impairment has no clinically relevant effect on the exposure of crizotinib.
- A study was conducted in 7 patients with severe renal impairment (CLcr <30 mL/min) who did not require dialysis and 8 patients with normal renal function (CLcr ≥ 90 mL/min).
- All patients received a single 250 mg oral dose of crizotinib.
- The mean AUCinf for crizotinib increased by 79% and the mean Cmax increased by 34% in patients with severe renal impairment compared to those with normal renal function.
- Similar changes in AUCinf and Cmax were observed for the active metabolite of crizotinib.
Ethnicity:
- No clinically relevant difference in the exposure of crizotinib between Asian patients (N=523) and non-Asian patients (N=691).
Age:
- Age has no effect on the exposure of crizotinib based on the population pharmacokinetic analysis from Studies 1, 2 and 3.
Body weight and gender:
- No clinically relevant effect of body weight or gender on the exposure of crizotinib based on the population pharmacokinetic analysis from Studies 1, 2 and 3.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies with crizotinib have not been conducted.
- Crizotinib was genotoxic in an in vitro micronucleus assay in Chinese Hamster Ovary cultures, in an in vitro human lymphocyte chromosome aberration assay, and in in vivo rat bone marrow micronucleus assays.
- Crizotinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay.
- No specific studies with crizotinib have been conducted in animals to evaluate the effect on fertility; however, crizotinib is considered to have the potential to impair reproductive function and fertility in humans based on findings in repeat-dose toxicity studies in the rat.
- Findings observed in the male reproductive tract included testicular pachytene spermatocyte degeneration in rats given greater than or equal to 50 mg/kg/day for 28 days (greater than 1.7 times the AUC at the recommended human dose). *Findings observed in the female reproductive tract included single-cell necrosis of ovarian follicles of a rat given 500 mg/kg/day (approximately 10 times the recommended human daily dose on a mg/m2 basis) for 3 days.
# Clinical Studies
### ALK-positive metastatic NSCLC-Study 1
- The efficacy and safety of crizotinib as monotherapy for the treatment of 347 patients with metastatic ALK-positive NSCLC, previously treated with one platinum-based chemotherapy regimen, was demonstrated in a randomized, multicenter, open-label, active-controlled study (Study 1).
- The major efficacy outcome was progression-free survival (PFS) as assessed by independent radiology review (IRR).
- Additional efficacy outcomes included objective response rate (ORR) as assessed by IRR and overall survival (OS).
- Patients were randomized to receive crizotinib 250 mg orally twice daily (n=173) or chemotherapy (n=174).
- Chemotherapy consisted of pemetrexed 500 mg/m2 (if pemetrexed naïve; n=99) or docetaxel 75 mg/m2 (n=72) intravenously (IV) every 21 days. *Patients in both treatment arms continued treatment until documented disease progression, intolerance to therapy, or the investigator determined that the patient was no longer experiencing clinical benefit.
- Randomization was stratified by ECOG performance status (0–1, 2), brain metastases (present, absent), and prior EGFR tyrosine kinase inhibitor treatment (yes, no).
- Patients were required to have ALK-positive NSCLC as identified by the FDA-approved assay, Vysis ALK Break-Apart FISH Probe Kit, prior to randomization. A total of 112 (64%) patients randomized to the chemotherapy arm subsequently received crizotinib after disease progression.
- The demographic characteristics of the overall study population were 56% female, median age of 50 years, baseline ECOG performance status 0 (39%) or 1 (52%), 52% White and 45% Asian, 4% current smokers, 33% past-smokers, and 63% never smokers.
- The disease characteristics were metastatic disease in at least 95% of patients and at least 93% of patients' tumors were classified as adenocarcinoma histology.
- Study 1 demonstrated a statistically significant improvement in PFS in the patients treated with crizotinib. Table 5 and Figure 1 summarize the efficacy results.
### Single-arm studies in ALK-positive metastatic NSCLC- Studies 2 and 3
- The safety and anti-tumor activity of single-agent crizotinib in the treatment of metastatic ALK-positive NSCLC was demonstrated in two multinational, single-arm studies (Studies 2 and 3).
- The major outcome in both studies was investigator-assessed ORR according to RECIST.
- Patients in both studies received 250 mg of crizotinib orally twice daily.
- In Study 2 (n=934) the demographic characteristics were 57% female, median age of 52 years, baseline ECOG performance status of 0/1 (82%) or 2/3 (18%), 52% White and 44% Asian, 4% current smokers, 30% past-smokers, and 66% never smokers.
- The disease characteristics were 92% metastatic; 94% of the cancers were classified as adenocarcinoma histology.
- Of the 934 ALK-positive metastatic NSCLC patients who received crizotinib in Study 2, 765 were ALK-positive as identified by Vysis ALK Break-Apart FISH Probe Kit and evaluable for response; demographic characteristics were similar to that of the overall population for this study.
- The median duration of treatment was 5.5 months. Based on investigator assessments, there were 8 complete and 357 partial responses for an ORR of 48% (95% CI: 44, 51) and the median DR was 11.0 months.
- In Study 3 (n=119) the demographic characteristics were 50% female, median age of 51 years, baseline ECOG performance status of 0 (35%) or 1 (53%), 62% White and 29% Asian, less than 1% were current smokers, 27% past-smokers, and 72% never smokers.
- The disease characteristics were 96% metastatic, 98% of the cancers were classified as adenocarcinoma histology, and 13% had no prior systemic therapy for metastatic disease.
- In Study 3, 119 patients with metastatic ALK-positive NSCLC were treated with crizotinib with a median duration of treatment of 32 weeks. Based on investigator assessments, the ORR was 61% (95% CI: 52%, 70%) and the median DR was 11.1 months.
# How Supplied
### 250 mg capsules
- Hard gelatin capsule with pink opaque cap and body, printed with black ink "CRZ 250" on the body; available in:
- Bottles of 60 capsules: NDC 0069-8140-20
### 200 mg capsules
- Hard gelatin capsule with pink opaque cap and white opaque body, printed with black ink "CRZ 200" on the body; available in:
- Bottles of 60 capsules: NDC 0069-8141-20
## Storage
- Store at room temperature 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Inform patients of the symptoms of hepatotoxicity, and that they should be reported immediately.
- Advise patients to immediately report any new or worsening pulmonary symptoms.
- Inform patients that symptoms of bradycardia including dizziness, lightheadedness, and syncope can occur while taking crizotinib.
- Advise patients to report these symptoms and to inform their physician about the use of any heart or blood pressure medications.
- Inform patients that nausea, diarrhea, vomiting, and constipation are the most commonly reported gastrointestinal adverse events occurring in patients who received crizotinib.
- Nausea and vomiting began most commonly during the first few days of treatment.
- Inform patients that visual changes such as perceived flashes of light, blurry vision, light sensitivity, and floaters are commonly reported adverse events and may occur while driving or operating machinery.
- The onset of visual disorders most commonly occurs during the first week of treatment.
- Inform patients to avoid grapefruit or grapefruit juice while taking crizotinib.
- Advise patients to inform their health care providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products.
- Advise patients to take crizotinib with or without food and swallow crizotinib capsules whole.
- If a patient misses a dose, advise the patient to take it as soon as remembered unless it is less than 6 hours until the next dose, in which case, advise the patient not to take the missed dose.
- If a patient vomits after taking a dose of crizotinib, advise the patient not to take an extra dose, but to take the next dose at the regular time.
- Inform patients of childbearing potential to use adequate contraceptive methods during therapy and for at least 90 days after completing therapy. *Advise patients to inform their doctor if they or their partners are pregnant or think they may be pregnant. Also advise patients not to breastfeed while taking crizotinib.
# Precautions with Alcohol
Alcohol-Crizotinib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Crizotinib
# Look-Alike Drug Names
There is limited information regarding Crizotinib Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Crizotinib
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Stefano Giannoni [2]; Sree Teja Yelamanchili, MBBS [3]
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# Overview
Crizotinib is a tyrosine kinase inhibitor that is FDA approved for the treatment of metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK)-positive. Common adverse reactions include vision disorders, nausea, diarrhea, vomiting, constipation, edema, elevated transaminases, and fatigue.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Metastatic Non-Small Cell Lung Cancer
- Patient Selection: based on the presence of ALK positivity in tumor specimens
- Dosage: 250 mg orally twice daily until disease progression or no longer tolerated by the patient.
- Recommended dose of crizotinib in patients with severe renal impairment (creatinine clearance <30 mL/min) not requiring dialysis is 250 mg orally, once daily
### Dose Modification
- Reduce dose as below, if one or more dose reductions are necessary due to adverse reactions of Grade 3 or 4 severity, as defined by NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0:
- First dose reduction: Crizotinib 200 mg taken orally twice daily
- Second dose reduction: Crizotinib 250 mg taken orally once daily
- Permanently discontinue if unable to tolerate Crizotinib 250 mg taken once daily
Dose reduction guidelines are provided in Tables 1 and 2.
Monitor complete blood counts including differential white blood cell counts monthly and as clinically indicated, with more frequent repeat testing if Grade 3 or 4 abnormalities are observed, or if fever or infection occurs.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Crizotinib in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Crizotinib in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Crizotinib 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 Crizotinib in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Crizotinib in pediatric patients.
# Contraindications
- None
# Warnings
### Hepatotoxicity
- Drug-induced hepatotoxicity with fatal outcome occurred in 2 (0.2%) of the 1225 patients treated with crizotinib across three main clinical trials. Concurrent elevations in alanine aminotransferase (ALT) greater than three times the upper limit of normal and total bilirubin greater than two times the upper limit of normal, with normal alkaline phosphatase, occurred in 7 patients (0.6%). Additionally, elevations in ALT greater than five times the upper limit of normal occurred in 109 patients (9.2%). Eight patients (0.7%) required permanent discontinuation due to elevated transaminases.
- These laboratory findings were generally reversible upon dosing interruption.
- Transaminase elevations generally occurred within the first 2 months of treatment.
- Monitor with liver function tests including ALT and total bilirubin every 2 weeks during the first 2 months of treatment, then once a month and as clinically indicated, with more frequent repeat testing for increased liver transaminases, alkaline phosphatase, or total bilirubin in patients who develop transaminase elevations.
- Temporarily suspend, dose reduce, or permanently discontinue crizotinib as described in Table 2.
### Interstitial Lung Disease Pneumonitis
- Severe, life-threatening, or fatal interstitial lung disease (ILD)/pneumonitis can occur in patients treated with crizotinib.
- Across clinical trials (n=1225), 31 crizotinib-treated patients (2.5%) had any grade ILD, 11 patients (0.9%) had Grade 3 or 4, and 6 patients (0.5%) had fatal cases.
- These cases generally occurred within 2 months after the initiation of treatment.
- Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis.
- Exclude other potential causes of ILD/pneumonitis, and permanently discontinue crizotinib in patients diagnosed with drug-related ILD/pneumonitis.
### QT Interval Prolongation
- QTc prolongation can occur in patients treated with crizotinib. Across clinical trials (n=1225), QTc prolongation (all grades) was observed in 34 (2.7%) patients and QTc greater than 500 ms on at least 2 separate ECGs occurred in 17(1.4%) patients.
- Avoid use of crizotinib in patients with congenital long QT syndrome. Consider periodic monitoring with electrocardiograms (ECGs) and electrolytes in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, or who are taking medications that are known to prolong the QT interval.
- Permanently discontinue crizotinib in patients who develop QTc greater than 500 ms or greater than or equal to 60 ms change from baseline with Torsade de pointes or polymorphic ventricular tachycardia or signs/symptoms of serious arrhythmia.
- Withhold crizotinib in patients who develop QTc greater than 500 ms on at least 2 separate ECGs until recovery to a QTc less than or equal to 480 ms, then resume crizotinib at a reduced dose as described in Table 2.
### Bradycardia
- Symptomatic bradycardia can occur in patients receiving crizotinib.
- Across clinical trials, bradycardia with a heart rate less than 50 beats per minute occurred in 11% of 1174 patients treated with crizotinib.
- In Study 1, Grade 3 syncope occurred in 2.9% of crizotinib-treated patients and in none of the chemotherapy-treated patients.
- Avoid using crizotinib in combination with other agents known to cause bradycardia (e.g., beta-blockers, non-dihydropyridine calcium channel blockers, clonidine and digoxin) to the extent possible.
- Monitor heart rate and blood pressure regularly.
- In cases of symptomatic bradycardia that is not life-threatening, hold crizotinib until recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above, re-evaluate the use of concomitant medications, and adjust the dose of crizotinib.
- Permanently discontinue for life-threatening bradycardia due to crizotinib; however, if associated with concomitant medications known to cause bradycardia or hypotension, hold crizotinib until recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above, and if concomitant medications can be adjusted or discontinued, restart crizotinib at 250 mg once daily with frequent monitoring.
### Embryofetal Toxicity
- Crizotinib can cause fetal harm when administered to a pregnant woman based on its mechanism of action.
- In nonclinical studies in rats, crizotinib was embryotoxic and fetotoxic at exposures similar to those observed in humans at the recommended clinical dose of 250 mg twice daily.
- There are no adequate and well-controlled studies in pregnant women using crizotinib.
- If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
- Safety evaluation of crizotinib is based on more than 1200 patients with ALK-positive metastatic NSCLC who received crizotinib as monotherapy at a starting oral dose of 250 mg twice daily continuously.
- The most common adverse reactions (≥25%) of crizotinib are vision disorder, nausea, diarrhea, vomiting, constipation, edema, elevated transaminases, and fatigue.
### ALK-positive metastatic NSCLC-Study 1
- The data in Table 3 are derived from 343 patients with ALK-positive metastatic NSCLC enrolled in a randomized, multicenter, active-controlled, open-label trial (Study 1).
- Patients in the crizotinib arm (n=172) received crizotinib 250 mg orally twice daily until documented disease progression, intolerance to therapy, or the investigator determined that the patient was no longer experiencing clinical benefit.
- A total of 171 patients in the chemotherapy arm received pemetrexed 500 mg/m2 (n=99) or docetaxel 75 mg/m2 (n=72) by intravenous infusion every three weeks until documented disease progression, intolerance to therapy, or the investigator determined that the patient was no longer experiencing clinical benefit.
- Patients in the chemotherapy arm received pemetrexed unless they had received pemetrexed as part of first-line or maintenance treatment.
- The median duration of study treatment was 7.1 months for patients who received crizotinib and 2.8 months for patients who received chemotherapy.
- Across the 347 patients who were randomized to study treatment (343 received at least one dose of study treatment), the median age was 50 years; 84% of patients in the crizotinib arm and 87% of patients in the chemotherapy arm were younger than 65 years.
- A total of 57% of patients on crizotinib and 55% of chemotherapy patients were female. Forty-six percent (46%) of crizotinib-treated and 45% of chemotherapy-treated patients were from Asia.
- Serious adverse reactions were reported in 64 patients (37.2%) treated with crizotinib and 40 patients (23.4%) in the chemotherapy arm.
- The most frequent serious adverse reactions reported in patients treated with crizotinib were:
- Pneumonia (4.1%)
- Pulmonary embolism (3.5%)
- Dyspnea (2.3%)
- Interstitial lung disease (ILD; 2.9%).
- Fatal adverse reactions in crizotinib-treated patients in Study 1 occurred in 9 (5%) patients, consisting of:
- Acute respiratory distress syndrome
- Arrhythmia
- Dyspnea
- Pneumonia
- Pneumonitis
- Pulmonary embolism
- ILD
- Respiratory failure
- Sepsis
- Dose reductions due to adverse reactions were required in 16% of crizotinib-treated patients.
- The most frequent adverse reactions that led to dose reduction in the patients treated with crizotinib were alanine aminotransferase (ALT) elevation (7.6%) including some patients with concurrent aspartate aminotransferase (AST) elevation, QTc prolongation (2.9%), and neutropenia (2.3%).
- Discontinuation of therapy in crizotinib-treated patients for adverse reactions was 17.0%.
- The most frequent adverse reactions that led to discontinuation in crizotinib-treated patients were:
- ILD(1.7%)
- ALT elevation
- AST elevation (1.2%)
- Dyspnea (1.2%)
- Pulmonary embolism (1.2%)
- Tables 3 and 4 summarize common Adverse Reactions and Laboratory Abnormalities in crizotinib-treated patients.
- Additional adverse reactions occurring at an overall incidence between 1% and 30% in patients treated with crizotinib included:
- Decreased appetite (27%)
- Fatigue (27%)
- Neuropathy (19%; dysesthesia, gait disturbance, hypoesthesia, muscular weakness, neuralgia, peripheral neuropathy, parasthesia, peripheral sensory neuropathy, polyneuropathy, burning sensation in skin)
- Rash (9%),
- ILD (4%; acute respiratory distress syndrome, ILD, pneumonitis), renal cyst (4%), and hepatic failure (1%).
### ALK-positive metastatic NSCLC- Study 2
- The safety analysis population in Study 2 included 934 patients with ALK-positive metastatic NSCLC who received crizotinib in a clinical trial. *The median duration of treatment was 23 weeks.
- Dosing interruptions and reductions due to treatment-related adverse events occurred in 23% and 12% of patients, respectively.
- The rate of treatment-related adverse events resulting in permanent discontinuation was 5%.
- The most common adverse reactions (≥25%) included vision disorder (55%), nausea (51%), vomiting (46%), diarrhea (46%), edema (39%), constipation (38%), and fatigue (26%).
### Description of selected adverse drug reactions
- Most commonly:
- visual impairment
- photopsia
- blurred vision, or vitreous floaters, occurred in 691 (56%) patients across clinical trials (n=1225).
- The majority (99%) of these patients had Grade 1 or 2 visual adverse reactions.
- Across clinical studies, one patient had a treatment-related grade 3 vision abnormality.
- Based on the Visual Symptom Assessment Questionnaire (VSAQ-ALK), patients treated with crizotinib in Study 1 reported a higher incidence of visual disturbances compared to patients treated with chemotherapy. The onset of vision disorders generally started within the first week of drug administration.
- The majority of patients on the crizotinib arm in Study 1 (> 50%) reported visual disturbances; these visual disturbances occurred at a frequency of 4–7 days each week, lasted up to 1 minute, and had mild or no impact (scores 0 to 3 out of a maximum score of 10) on daily activities as captured in a patient questionnaire.
- Neuropathy, most commonly sensory in nature, occurred in 235 (19%) of 1225 patients.
- Most events (95%) were Grade 1 or Grade 2 in severity.
- Renal cysts occurred in 7 (4%) patients treated with crizotinib and 1 (1%) patient treated with chemotherapy in Study 1.
- The majority of renal cysts in crizotinib-treated patients were complex. *Local cystic invasion beyond the kidney occurred, in some cases with imaging characteristics suggestive of abscess formation. However, across clinical trials no renal abscesses were confirmed by microbiology tests.
## Postmarketing Experience
There is limited information regarding Crizotinib Postmarketing Experience in the drug label.
# Drug Interactions
### Drugs That May Increase Crizotinib Plasma Concentrations
- Coadministration of crizotinib with strong CYP3A inhibitors increases crizotinib plasma concentrations.
- Avoid concomitant use of strong CYP3A inhibitors, including but not limited to atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, and voriconazole. *Avoid grapefruit or grapefruit juice which may also increase plasma concentrations of crizotinib.
- Exercise caution with concomitant use of moderate CYP3A inhibitors.
### Drugs That May Decrease Crizotinib Plasma Concentrations
- Coadministration of crizotinib with strong CYP3A inducers decreases crizotinib plasma concentrations.
- Avoid concomitant use of strong CYP3A inducers, including but not limited to carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, and St. John's Wort.
### Drugs Whose Plasma Concentrations May Be Altered By Crizotinib
- Crizotinib inhibits CYP3A both in vitro and in vivo.
- Avoid concomitant use of CYP3A substrates with narrow therapeutic range, including but not limited to alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus in patients taking crizotinib. *If concomitant use of these CYP3A substrates with narrow therapeutic range is required in patients taking crizotinib, dose reductions of the CYP3A substrates may be required due to adverse reactions.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
- Crizotinib can cause fetal harm when administered to a pregnant woman based on its mechanism of action.
- There are no adequate and well-controlled studies of crizotinib in pregnant women.
- In nonclinical studies in rats, crizotinib was embryotoxic and fetotoxic at exposures similar to those observed in humans at the recommended clinical dose of 250 mg twice daily.
- Crizotinib was administered to pregnant rats and rabbits during organogenesis to study the effects on embryo-fetal development.
- Postimplantation loss was increased at doses ≥ 50 mg/kg/day (approximately 0.6 times the AUC at the recommended human dose) in rats.
- No teratogenic effects were observed in rats at doses up to the maternally toxic dose of 200 mg/kg/day (approximately 2.7 times the AUC at the recommended human dose) or in rabbits at doses of up to 60 mg/kg/day (approximately 1.6 times the AUC at the recommended human dose), though fetal body weights were reduced at these doses.
- Advise women of childbearing potential to avoid becoming pregnant while receiving crizotinib.
- Women of childbearing potential who are receiving this drug, or partners of women of childbearing potential receiving this drug, should use adequate contraceptive methods during therapy and for at least 90 days after completing therapy.
- If this drug is used during pregnancy, or if the patient or their partner becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Crizotinib in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Crizotinib during labor and delivery.
### Nursing Mothers
- It is not known whether crizotinib 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 crizotinib, consider whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
- The safety and efficacy of crizotinib in pediatric patients has not been established.
- Decreased bone formation in growing long bones was observed in immature rats at 150 mg/kg/day following once daily dosing for 28 days (approximately 5.4 times the AUC in adult patients at the recommended human dose).
- Other toxicities of potential concern to pediatric patients have not been evaluated in juvenile animals.
### Geriatic Use
- Of crizotinib treated patients in Study 1, 27 (16%) were 65 years or older, in Study 2, 152 (16%) were 65 years or older, and in Study 3, 16 (13%) were 65 years or older.
- No overall differences in safety or effectiveness were observed between these patients and younger patients.
### Gender
- No clinically relevant effect of gender on the exposure of crizotinib based on the population pharmacokinetic analysis from Studies 1, 2 and 3.
### Race
- No clinically relevant difference in the exposure of crizotinib between Asian patients (N=523) and non-Asian patients
### Renal Impairment
- No starting dose adjustment is needed for patients with mild (creatinine clearance [CLcr] 60–89 mL/min) or moderate (CLcr 30–59 mL/min) renal impairment based on a population pharmacokinetic analysis.
- Increased exposure to crizotinib occurred in patients with severe renal impairment (CLcr <30 mL/min) not requiring dialysis. Administer crizotinib at a dose of 250 mg taken orally once daily in patients with severe renal impairment not requiring dialysis
### Hepatic Impairment
- Crizotinib has not been studied in patients with hepatic impairment. As crizotinib is extensively metabolized in the liver, hepatic impairment is likely to increase plasma crizotinib concentrations.
- Clinical studies excluded patients with AST or ALT greater than 2.5 × ULN, or greater than 5 × ULN, if due to liver metastases.
- Patients with total bilirubin greater than 1.5 × ULN were also excluded. Therefore, use caution in patients with hepatic impairment
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Crizotinib in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Crizotinib in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- Monitor with liver function tests including ALT and total bilirubin every 2 weeks during the first 2 months of treatment, then once a month.
- Monitor with electrocardiograms and electrolytes in patients who have a history of or predisposition for QTc prolongation, or who are taking medications that prolong QT.
- Monitor heart rate and blood pressure regularly, as it can cause bradycardia.
- Monitor complete blood counts including differential white blood cell counts monthly.
- Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis.
# IV Compatibility
There is limited information regarding the compatibility of Crizotinib and IV administrations.
# Overdosage
- There have been no known cases of crizotinib overdose.
- There is no antidote for crizotinib.
# Pharmacology
## Mechanism of Action
- Crizotinib is an inhibitor of receptor tyrosine kinases including ALK, Hepatocyte Growth Factor Receptor (HGFR, c-Met), ROS1 (c-ros), and Recepteur d'Origine Nantais (RON).
- Translocations can affect the ALK gene resulting in the expression of oncogenic fusion proteins.
- The formation of ALK fusion proteins results in activation and dysregulation of the gene's expression and signaling which can contribute to increased cell proliferation and survival in tumors expressing these proteins.
- Crizotinib demonstrated concentration-dependent inhibition of ALK, ROS1, and c-Met phosphorylation in cell-based assays using tumor cell lines and demonstrated antitumor activity in mice bearing tumor xenografts that expressed EML4- or NPM-ALK fusion proteins or c-Met.
## Structure
- The molecular formula for crizotinib is C21H22Cl2FN5O.
- The molecular weight is 450.34 Daltons.
- Crizotinib is described chemically as (R)-3-[1-(2,6-Dichloro-3-fluorophenyl)ethoxy]-5-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]pyridin-2-amine.
The chemical structure of crizotinib is shown below:
- Crizotinib is a white to pale-yellow powder with a pKa of 9.4 (piperidinium cation) and 5.6 (pyridinium cation).
- The solubility of crizotinib in aqueous media decreases over the range pH 1.6 to pH 8.2 from greater than 10 mg/mL to less than 0.1 mg/mL.
- The log of the distribution coefficient (octanol/water) at pH 7.4 is 1.65.
## Pharmacodynamics
### Cardiac Electrophysiology
- The QT interval prolongation potential of crizotinib was assessed in all patients who received crizotinib 250 mg twice daily.
- Serial ECGs in triplicate were collected following a single dose and at steady state to evaluate the effect of crizotinib on QT intervals.
- Sixteen of 1167 patients (1.4%) were found to have QTcF (corrected QT by the Fridericia method) greater than or equal to 500 msec and 51 of 1136 patients (4.4%) had an increase from baseline QTcF greater than or equal to 60 msec by automated machine-read evaluation of ECG. A pharmacokinetic/pharmacodynamic analysis suggested a concentration-dependent increase in QTcF
## Pharmacokinetics
### Absorption
- Following a single oral dose, crizotinib was absorbed with median time to achieve peak concentration of 4 to 6 hours.
- Following crizotinib 250 mg twice daily, steady state was reached within 15 days and remained stable, with a median accumulation ratio of 4.8.
- Steady-state systemic exposure (Cmin and AUC) appeared to increase in a greater than dose proportional manner over the dose range of 200–300 mg twice daily.
- The mean absolute bioavailability of crizotinib was 43% (range: 32% to 66%) following a single 250 mg oral dose.
- A high-fat meal reduced crizotinib AUCinf and Cmax by approximately 14%. crizotinib can be administered with or without food.
### Distribution
- The geometric mean volume of distribution (Vss) of crizotinib was 1,772 L following intravenous administration of a 50 mg dose, indicating extensive distribution into tissues from the plasma.
- Binding of crizotinib to human plasma proteins in vitro is 91% and is independent of drug concentration. In vitro studies suggested that crizotinib is a substrate for P-glycoprotein (P-gp). The blood-to-plasma concentration ratio is approximately 1.
### Metabolism
- Crizotinib is predominantly metabolized by CYP3A4/5.
- The primary metabolic pathways in humans were oxidation of the piperidine ring to crizotinib lactam and O-dealkylation, with subsequent Phase 2 conjugation of O-dealkylated metabolites.
### Elimination
- Following single doses of crizotinib, the mean apparent plasma terminal half-life of crizotinib was 42 hours in patients.
- Following the administration of a single 250 mg radiolabeled crizotinib dose to healthy subjects, 63% and 22% of the administered dose was recovered in feces and urine, respectively.
- Unchanged crizotinib represented approximately 53% and 2.3% of the administered dose in feces and urine, respectively.
- The mean apparent clearance (CL/F) of crizotinib was lower at steady state (60 L/h) after 250 mg twice daily than that after a single 250 mg oral dose (100 L/h), which was likely due to autoinhibition of CYP3A by crizotinib after multiple dosing.
### Drug interactions
CYP3A inhibitors:
- Coadministration of a single 150 mg oral dose of crizotinib with ketoconazole (200 mg twice daily), a strong CYP3A inhibitor, increased crizotinib AUCinf and Cmax values by approximately 3.2-fold and 1.4-fold, respectively, compared to crizotinib alone. However, the magnitude of effect of CYP3A inhibitors on steady-state crizotinib exposure has not been evaluated.
CYP3A inducers:
- Coadministration of a single 250 mg oral dose of crizotinib with rifampin (600 mg once daily), a strong CYP3A inducer, decreased crizotinib AUCinf and Cmax by 82% and 69%, respectively, compared to crizotinib alone. However, the magnitude of effect of CYP3A inducers on steady-state crizotinib exposure has not been evaluated.
Gastric pH elevating medications:
- In healthy subjects, coadministration of a single 250 mg oral dose of crizotinib following administration of esomeprazole 40 mg daily for 5 days did not result in a clinically relevant change in crizotinib exposure (AUCinf decreased by 10% and no change in Cmax).
CYP3A substrates:
- Coadministration of crizotinib (250 mg twice daily for 28 days) in patients increased the AUCinf of oral midazolam 3.7-fold compared to midazolam alone, suggesting that crizotinib is a moderate inhibitor of CYP3A.
Other CYP substrates:
- In vitro studies suggest that clinical drug-drug interactions as a result of crizotinib-mediated inhibition of the metabolism of substrates for CYP1A2, CYP2C8, CYP2C9, CYP2C19, or CYP2D6 are unlikely to occur.
- Crizotinib is an inhibitor of CYP2B6 in vitro. Therefore, crizotinib may increase plasma concentrations of coadministered drugs that are predominantly metabolized by CYP2B6.
- An in vitro study suggests that clinical drug-drug interactions as a result of crizotinib-mediated induction of the metabolism of substrates for CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP3A are unlikely to occur.
UGT substrates:
- In vitro studies suggest that clinical drug-drug interactions as a result of crizotinib-mediated inhibition of the metabolism of drugs that are substrates for UGT1A1, UGT1A4, UGT1A6, UGT1A9 or UGT2B7 are unlikely to occur.
Substrates of transporters:
- Crizotinib inhibited P-glycoprotein (P-gp) in vitro at clinically relevant concentrations. Therefore, crizotinib has the potential to increase plasma concentrations of coadministered drugs that are substrates of P-gp.
- Crizotinib inhibited the hepatic uptake transporter, organic cation transporter 1 (OCT1), and renal uptake transporter, organic cation transporter 2 (OCT2), in vitro at clinically relevant concentrations. Therefore, crizotinib has the potential to increase plasma concentrations of coadministered drugs that are substrates of OCT1 or OCT2.
- Crizotinib did not inhibit the human hepatic uptake transport proteins OATP1B1 or OATP1B3, or the renal uptake transport proteins OAT1 or OAT3 in vitro at clinically relevant concentrations.
Effect on other transport proteins:
- Crizotinib did not inhibit the hepatic efflux bile salt export pump transporter (BSEP) in vitro at clinically relevant concentrations.
### Specific populations
Hepatic Impairment:
- As crizotinib is extensively metabolized in the liver, hepatic impairment is likely to increase plasma crizotinib concentrations. However, crizotinib has not been studied in patients with hepatic impairment.
- Clinical studies excluded patients with ALT or AST greater than 2.5 × ULN or greater than 5 × ULN if due to liver metastases.
- Patients with total bilirubin greater than 1.5 × ULN were also excluded. *The population pharmacokinetic analysis using the data from Studies 1, 2 and 3 suggested that baseline total bilirubin (0.1 to 2.1 mg/dL) or AST levels (7 to 124 U/L) did not have a clinically relevant effect on the exposure of crizotinib.
Renal impairment:
- The pharmacokinetics of crizotinib were evaluated using a population pharmacokinetic analysis in patients with mild (CLcr 60–89 mL/min, N=433) and moderate (CLcr 30–59 mL/min, N=137) renal impairment enrolled in Studies 1, 2, and 3.
- Mild or moderate renal impairment has no clinically relevant effect on the exposure of crizotinib.
- A study was conducted in 7 patients with severe renal impairment (CLcr <30 mL/min) who did not require dialysis and 8 patients with normal renal function (CLcr ≥ 90 mL/min).
- All patients received a single 250 mg oral dose of crizotinib.
- The mean AUCinf for crizotinib increased by 79% and the mean Cmax increased by 34% in patients with severe renal impairment compared to those with normal renal function.
- Similar changes in AUCinf and Cmax were observed for the active metabolite of crizotinib.
Ethnicity:
- No clinically relevant difference in the exposure of crizotinib between Asian patients (N=523) and non-Asian patients (N=691).
Age:
- Age has no effect on the exposure of crizotinib based on the population pharmacokinetic analysis from Studies 1, 2 and 3.
Body weight and gender:
- No clinically relevant effect of body weight or gender on the exposure of crizotinib based on the population pharmacokinetic analysis from Studies 1, 2 and 3.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies with crizotinib have not been conducted.
- Crizotinib was genotoxic in an in vitro micronucleus assay in Chinese Hamster Ovary cultures, in an in vitro human lymphocyte chromosome aberration assay, and in in vivo rat bone marrow micronucleus assays.
- Crizotinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay.
- No specific studies with crizotinib have been conducted in animals to evaluate the effect on fertility; however, crizotinib is considered to have the potential to impair reproductive function and fertility in humans based on findings in repeat-dose toxicity studies in the rat.
- Findings observed in the male reproductive tract included testicular pachytene spermatocyte degeneration in rats given greater than or equal to 50 mg/kg/day for 28 days (greater than 1.7 times the AUC at the recommended human dose). *Findings observed in the female reproductive tract included single-cell necrosis of ovarian follicles of a rat given 500 mg/kg/day (approximately 10 times the recommended human daily dose on a mg/m2 basis) for 3 days.
# Clinical Studies
### ALK-positive metastatic NSCLC-Study 1
- The efficacy and safety of crizotinib as monotherapy for the treatment of 347 patients with metastatic ALK-positive NSCLC, previously treated with one platinum-based chemotherapy regimen, was demonstrated in a randomized, multicenter, open-label, active-controlled study (Study 1).
- The major efficacy outcome was progression-free survival (PFS) as assessed by independent radiology review (IRR).
- Additional efficacy outcomes included objective response rate (ORR) as assessed by IRR and overall survival (OS).
- Patients were randomized to receive crizotinib 250 mg orally twice daily (n=173) or chemotherapy (n=174).
- Chemotherapy consisted of pemetrexed 500 mg/m2 (if pemetrexed naïve; n=99) or docetaxel 75 mg/m2 (n=72) intravenously (IV) every 21 days. *Patients in both treatment arms continued treatment until documented disease progression, intolerance to therapy, or the investigator determined that the patient was no longer experiencing clinical benefit.
- Randomization was stratified by ECOG performance status (0–1, 2), brain metastases (present, absent), and prior EGFR tyrosine kinase inhibitor treatment (yes, no).
- Patients were required to have ALK-positive NSCLC as identified by the FDA-approved assay, Vysis ALK Break-Apart FISH Probe Kit, prior to randomization. A total of 112 (64%) patients randomized to the chemotherapy arm subsequently received crizotinib after disease progression.
- The demographic characteristics of the overall study population were 56% female, median age of 50 years, baseline ECOG performance status 0 (39%) or 1 (52%), 52% White and 45% Asian, 4% current smokers, 33% past-smokers, and 63% never smokers.
- The disease characteristics were metastatic disease in at least 95% of patients and at least 93% of patients' tumors were classified as adenocarcinoma histology.
- Study 1 demonstrated a statistically significant improvement in PFS in the patients treated with crizotinib. Table 5 and Figure 1 summarize the efficacy results.
### Single-arm studies in ALK-positive metastatic NSCLC- Studies 2 and 3
- The safety and anti-tumor activity of single-agent crizotinib in the treatment of metastatic ALK-positive NSCLC was demonstrated in two multinational, single-arm studies (Studies 2 and 3).
- The major outcome in both studies was investigator-assessed ORR according to RECIST.
- Patients in both studies received 250 mg of crizotinib orally twice daily.
- In Study 2 (n=934) the demographic characteristics were 57% female, median age of 52 years, baseline ECOG performance status of 0/1 (82%) or 2/3 (18%), 52% White and 44% Asian, 4% current smokers, 30% past-smokers, and 66% never smokers.
- The disease characteristics were 92% metastatic; 94% of the cancers were classified as adenocarcinoma histology.
- Of the 934 ALK-positive metastatic NSCLC patients who received crizotinib in Study 2, 765 were ALK-positive as identified by Vysis ALK Break-Apart FISH Probe Kit and evaluable for response; demographic characteristics were similar to that of the overall population for this study.
- The median duration of treatment was 5.5 months. Based on investigator assessments, there were 8 complete and 357 partial responses for an ORR of 48% (95% CI: 44, 51) and the median DR was 11.0 months.
- In Study 3 (n=119) the demographic characteristics were 50% female, median age of 51 years, baseline ECOG performance status of 0 (35%) or 1 (53%), 62% White and 29% Asian, less than 1% were current smokers, 27% past-smokers, and 72% never smokers.
- The disease characteristics were 96% metastatic, 98% of the cancers were classified as adenocarcinoma histology, and 13% had no prior systemic therapy for metastatic disease.
- In Study 3, 119 patients with metastatic ALK-positive NSCLC were treated with crizotinib with a median duration of treatment of 32 weeks. Based on investigator assessments, the ORR was 61% (95% CI: 52%, 70%) and the median DR was 11.1 months.
# How Supplied
### 250 mg capsules
- Hard gelatin capsule with pink opaque cap and body, printed with black ink "CRZ 250" on the body; available in:
- Bottles of 60 capsules: NDC 0069-8140-20
### 200 mg capsules
- Hard gelatin capsule with pink opaque cap and white opaque body, printed with black ink "CRZ 200" on the body; available in:
- Bottles of 60 capsules: NDC 0069-8141-20
## Storage
- Store at room temperature 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Inform patients of the symptoms of hepatotoxicity, and that they should be reported immediately.
- Advise patients to immediately report any new or worsening pulmonary symptoms.
- Inform patients that symptoms of bradycardia including dizziness, lightheadedness, and syncope can occur while taking crizotinib.
- Advise patients to report these symptoms and to inform their physician about the use of any heart or blood pressure medications.
- Inform patients that nausea, diarrhea, vomiting, and constipation are the most commonly reported gastrointestinal adverse events occurring in patients who received crizotinib.
- Nausea and vomiting began most commonly during the first few days of treatment.
- Inform patients that visual changes such as perceived flashes of light, blurry vision, light sensitivity, and floaters are commonly reported adverse events and may occur while driving or operating machinery.
- The onset of visual disorders most commonly occurs during the first week of treatment.
- Inform patients to avoid grapefruit or grapefruit juice while taking crizotinib.
- Advise patients to inform their health care providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products.
- Advise patients to take crizotinib with or without food and swallow crizotinib capsules whole.
- If a patient misses a dose, advise the patient to take it as soon as remembered unless it is less than 6 hours until the next dose, in which case, advise the patient not to take the missed dose.
- If a patient vomits after taking a dose of crizotinib, advise the patient not to take an extra dose, but to take the next dose at the regular time.
- Inform patients of childbearing potential to use adequate contraceptive methods during therapy and for at least 90 days after completing therapy. *Advise patients to inform their doctor if they or their partners are pregnant or think they may be pregnant. Also advise patients not to breastfeed while taking crizotinib.
# Precautions with Alcohol
Alcohol-Crizotinib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Crizotinib[1]
# Look-Alike Drug Names
There is limited information regarding Crizotinib Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Crizotinib | |
5b909683f5367cf5638accf3aee745e8abfc57a2 | wikidoc | Crofelemer | Crofelemer
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# Overview
Crofelemer is a anti-diarrheal that is FDA approved for the treatment of non-infectious diarrhea in adult patients with HIV/AIDS. Common adverse reactions include Upper respiratory tract infection, bronchitis, cough, flatulence and increased bilirubin.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- FULYZAQ is indicated for symptomatic relief of non-infectious diarrhea in patients with HIV/AIDS on Antiretroviral therapy.
### Dosage
- The recommended dose of FULYZAQ is one 125 mg delayed-release tablet taken orally two times a day, with or without food. FULYZAQ tablets should not be crushed or chewed. Tablets should be swallowed whole.
### DOSAGE FORMS AND STRENGTHS
- FULYZAQ is a white, oval, enteric-coated 125 mg delayed-release tablet printed on one side with 125SLXP.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Crofelemer in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Crofelemer in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
The safety and effectiveness of FULYZAQ have not been established in pediatric patients less than 18 years of age.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Crofelemer in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Crofelemer in pediatric patients.
# Contraindications
- None
# Warnings
- If infectious etiologies are not considered, and FULYZAQ is initiated based on a presumptive diagnosis of non-infectious diarrhea, then there is a risk that patients with infectious etiologies will not receive the appropriate treatments, and their disease may worsen. Before starting FULYZAQ, rule out infectious etiologies of diarrhea. FULYZAQ is not indicated for the treatment of infectious diarrhea.
# 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.
- A total of 696 HIV-positive patients in three placebo-controlled trials received FULYZAQ for a mean duration of 78 days. Of the total population across the three trials, 229 patients received a dose of 125 mg twice a day for a mean duration of 141 days, 69 patients received a dose of 250 mg twice a day for a mean duration of 139 days, 102 patients received a dose of 250 mg four times a day for a mean duration of 14 days, 54 patients received a dose of 500 mg twice a day for a mean duration of 146 days, and 242 patients received a dose of 500 mg four times a day for a mean duration of 14 days.
- Adverse reactions for FULYZAQ that occurred in at least 2% of patients and at a higher incidence than placebo are provided in Table 1.
- Adverse reactions that occurred in between 1% and 2% of patients taking a 250 mg daily dose of FULYZAQ were abdominal pain, acne, increased aspartate aminotransferase, increased conjugated bilirubin, increased unconjugated blood bilirubin, constipation, depression, dermatitis, dizziness, dry mouth, dyspepsia, gastroenteritis, herpes zoster, nephrolithiasis, pain in extremity, pollakiuria, procedural pain, seasonal allergy, sinusitis and decreased white blood cell count.
- Adverse reactions were similar in patients who received doses greater than 250 mg daily.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Crofelemer in the drug label.
# Drug Interactions
- In vitro studies have shown that crofelemer has the potential to inhibit cytochrome P450 isoenzyme 3A and transporters MRP2 and OATP1A2 at concentrations expected in the gut. Due to the minimal absorption of crofelemer, it is unlikely to inhibit cytochrome P450 isoenzymes 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1 and CYP3A4 systemically .
- FULYZAQ administration did not have a clinically relevant interaction with nelfinavir, zidovudine, or lamivudine in a drug-drug interaction trial.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Reproduction studies performed with crofelemer in rats at oral doses up to 177 times the recommended daily human dose of 4.2 mg/kg revealed no evidence of impaired fertility or harm to the fetus. In pregnant rabbits, crofelemer at an oral dose of about 96 times the recommended daily human dose of 4.2 mg/kg, caused abortions and resorptions of fetuses. However, it is not clear whether these effects are related to the maternal toxicity observed. A pre- and postnatal development study performed with crofelemer in rats at oral doses of up to 177 times the recommended daily human dose of 4.2 mg/kg revealed no evidence of adverse pre- and postnatal effects in offspring. There are, however, no adequate, well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Crofelemer in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Crofelemer during labor and delivery.
### Nursing Mothers
- It is not known whether crofelemer is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from FULYZAQ, 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 safety and effectiveness of FULYZAQ have not been established in pediatric patients less than 18 years of age.
### Geriatic Use
- Clinical studies with crofelemer did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger patients.
### Gender
There is no FDA guidance on the use of Crofelemer with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Crofelemer with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Crofelemer in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Crofelemer in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Crofelemer in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Crofelemer in patients who are immunocompromised.
### CD4 Count and HIV Viral Load
- No dose modifications are recommended with respect to CD4 cell count and HIV viral load, based on the findings in subgroups of patients defined by CD4 cell count and HIV viral load.
- The safety profile of crofelemer was similar in patients with baseline CD4 cell count less than 404 cells/μL (lower limit of normal range) (N=388) and patients with baseline CD4 cell counts greater than or equal to 404 cells/μL (N=289).
- The safety profile of crofelemer was similar in patients with baseline HIV viral loads less than 400 copies/mL (N = 412) and patients with baseline HIV viral loads greater than or equal to 400 copies/mL (N = 278).
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Crofelemer in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Crofelemer in the drug label.
# Overdosage
- There has been no reported experience with overdosage of crofelemer.
# Pharmacology
## Mechanism of Action
- Crofelemer is an inhibitor of both the cyclic adenosine monophosphate (cAMP)-stimulated cystic fibrosis transmembrane conductance regulator (CFTR) chloride ion (Cl-) channel, and the calcium-activated Cl- channels (CaCC) at the luminal membrane of enterocytes. The CFTR Cl- channel and CaCC regulate Cl- and fluid secretion by intestinal epithelial cells. Crofelemer acts by blocking Cl- secretion and accompanying high volume water loss in diarrhea, normalizing the flow of Cl- and water in the GI tract.
## Structure
- FULYZAQ (crofelemer) delayed-release tablets is an anti-diarrheal, enteric-coated drug product for oral administration. It contains 125 mg of crofelemer, a botanical drug substance that is derived from the red latex of Croton lechleri Müll. Arg. Crofelemer is an oligomeric proanthocyanidin mixture primarily composed of (+)‑catechin, (‑)‑epicatechin, (+)‑gallocatechin, and (‑)‑epigallocatechin monomer units linked in random sequence, as represented below. The average degree of polymerization for the oligomers ranges between 5 and 7.5, as determined by phloroglucinol degradation.
- Inactive ingredients: microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate.
- Coating ingredients: ethylacrylate and methylacrylate copolymer dispersion, talc, triethyl citrate, and white dispersion which contains xanthan gum, titanium dioxide, propyl paraben, and methyl paraben.
## Pharmacodynamics
- Consistent with the mechanism of action of crofelemer (i.e., inhibition of CFTR and CaCC in the GI lumen), data suggest stool chloride concentrations decreased in patients treated with FULYZAQ (500 mg four times daily) (n=25) for four days relative to placebo (n=24); stool chloride concentrations decreased in both African American patients treated with FULYZAQ (n=3) relative to placebo (n=5) and non-African American patients treated with FULYZAQ (n=22) relative to placebo (n=19).
- At a dose 10 times the maximum recommended dose, crofelemer does not prolong the QTc interval to any clinically relevant extent.
## Pharmacokinetics
- The absorption of crofelemer is minimal following oral dosing in healthy adults and HIV‑positive patients and concentrations of crofelemer in plasma are below the level of quantitation (50 ng/mL). Therefore, standard pharmacokinetic parameters such as area under the curve, maximum concentration, and half-life cannot be estimated.
- The distribution of crofelemer has not been determined.
- No metabolites of crofelemer have been identified in healthy subjects or patients in clinical trials.
- The elimination route has not been identified in humans.
- Administration of crofelemer with a high-fat meal was not associated with an increase in systemic exposure of crofelemer in healthy volunteers. In the clinical trial, a single 500 mg dose of crofelemer was administered one-half hour before the morning and evening meals. Therefore, crofelemer may be administered with or without a meal.
- Results of a crossover study in healthy volunteers showed crofelemer 500 mg administered four times daily for five days had no effect on the exposure of zidovudine and nelfinavir when administered as a single dose. A 20% decrease in lamivudine exposure was also observed in the same study but was not considered to be clinically important.
## Nonclinical Toxicology
- Long-term studies in animals have not been performed to evaluate the carcinogenic potential of crofelemer.
- Crofelemer was negative in the bacterial reverse mutation assay, chromosomal aberration assay, and rat bone marrow micronucleus assay.
- Crofelemer, at oral doses of up to 738 mg/kg/day (177 times the recommended human daily dose of 4.2 mg/kg), had no effects on fertility or reproductive performance of male and female rats.
# Clinical Studies
- The efficacy of FULYZAQ 125 mg delayed-release tablets twice daily was evaluated in a randomized, double-blind, placebo-controlled (one month) and placebo-free (five month), multi-center study. The study enrolled 374 HIV-positive patients on stable Antiretroviral therapy (ART) with a history of diarrhea for one month or more. Diarrhea was defined as either persistently loose stools despite regular use of anti-diarrheal medication (ADM) (e.g., loperamide, diphenoxylate, and bismuth subsalicylate) or one or more watery bowel movements per day without regular ADM use.
- Patients were excluded if they had a positive gastrointestinal (GI) biopsy, GI culture, or stool test for multiple bacteria (Salmonella, Shigella, Campylobacter, Yersinia, Mycobacterium), bacterial toxin (Clostridium difficile), ova and parasites (Giardia, Entamoeba, Isospora, Cyclospora, Cryptosporidium, Microsporidium), or viruses (Cytomegalovirus). Patients were also excluded if they had a history of ulcerative colitis, Crohn’s disease, celiac sprue (gluten-enteropathy), chronic pancreatitis, malabsorption, or any other GI disease associated with diarrhea.
- The study had a two-stage adaptive design. In both stages, patients received placebo for 10 days (screening period) followed by randomization to crofelemer or placebo for 31 days of treatment (double-blind period). Only patients with 1 or more watery bowel movements per day on at least 5 of the last 7 days in the screening period were randomized to the double-blind period. Each stage enrolled patients separately; the dose for the second stage was selected based on an interim analysis of data from the first stage. In the first stage, patients were randomized 1:1:1:1 to one of three crofelemer dose regimens (125, 250, or 500 mg twice daily) or placebo. In the second stage, patients were randomized 1:1 to crofelemer 125 mg twice daily or placebo. The efficacy analysis was based on results from the double-blind portion of both stages.
- Each study stage also had a five month period (placebo-free period) that followed the double-blind period. Patients treated with crofelemer continued the same dose in the placebo-free period. In the first stage, patients that received placebo were re-randomized 1:1:1 to one of the three crofelemer dose regimens (125, 250, or 500 mg twice daily) in the placebo-free period. In the second stage, patients that received placebo were treated with crofelemer 125 mg twice daily in the placebo-free period.
- The median time since diagnosis of HIV was 12 years. The percentage of patients with a CD4 cell count of less than 404 was 39%. The percentage of patients with a HIV viral load greater than or equal to 1000, 400 to 999, and less than 400 HIV copies/mL was 7%, 3%, and 9%, respectively; the remainder had a viral load that was not detectable. The median time since diarrhea started was 4 years. The median number of daily watery bowel movements was 2.5 per day.
- Most patients were male (85%). The percentage of patients that were Caucasian was 46%; the percentage of patients that were African-American was 32%. The median age was 45 years with a range of 21 to 68 years.
- In the double-blind period of the study, 136 patients received crofelemer 125 mg twice daily, 54 patients received 250 mg twice daily, 47 patients received 500 mg twice daily, and 138 patients received placebo. The percentages of patients that completed the double-blind period were 92%, 100%, 85%, and 94% in the 125 mg, 250 mg, 500 mg, and placebo arms, respectively.
- Most patients received concomitant protease inhibitors (PI) during the double-blind period (Table 2). The most frequently used ARTs in each group were tenofovir/emtricitabine, ritonavir, and lopinavir/ritonavir.
- The primary efficacy endpoint was the proportion of patients with a clinical response, defined as less than or equal to 2 watery bowel movements per week during at least 2 of the 4 weeks of the placebo-controlled phase. Patients who received concomitant ADMs or opiates were counted as clinical non-responders.
- A significantly larger proportion of patients in the crofelemer 125 mg twice daily group experienced clinical response compared with patients in the placebo group (17.6% vs. 8.0%, 1‑sided p < 0.01).
- In the randomized clinical study, examination of duration of diarrhea, baseline number of daily watery bowel movements, use of protease inhibitors, CD4 cell count and age subgroups did not identify differences in the consistency of the crofelemer treatment effect among these subgroups. There were too few female subjects and subjects with an HIV viral load > 400 copies/mL to adequately assess differences in effects in these populations. Among race subgroups, there were no differences in the consistency of the crofelemer treatment effect except for the subgroup of African-Americans; crofelemer was less effective in African-Americans than non-African-Americans.
- Although the CD4 cell count and HIV viral load did not appear to change over the one month placebo-controlled period, the clinical significance of this finding is unknown because of the short duration of the placebo-controlled period.
- Of the 24 clinical responders to crofelemer (125 mg twice daily), 22 entered the placebo-free period; 16 were responding at the end of month 3, and 14 were responding at the end of month 5.
# How Supplied
- Crofelemer delayed-release tablets, 125 mg, are white, oval enteric-coated tablets printed on one side with 125SLXP. They are available in the following package size:
- Bottles of 60: NDC 65649-802-02
## Storage
- Store at 20°C-25°C (68°F-77°F); excursions permitted between 15°C-30°C (59°F-86°F). See USP Controlled Room Temperature.
# Images
## Drug Images
## Package and Label Display Panel
PACKAGE LABEL - PRINCIPAL DISPLAY - FULYZAQ 125 MG TABLETS, 60 TABLETS BOTTLE LABEL
### Ingredients and Appearance
# Patient Counseling Information
- Instruct patients that FULYZAQ tablets may be taken with or without food.
- Instruct patients that FULYZAQtablets should not be crushed or chewed. Tablets should be swallowed whole.
# Precautions with Alcohol
- Alcohol-Crofelemer interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Fulyzaq®
# Look-Alike Drug Names
There is limited information regarding the look alike drug names.
# Drug Shortage Status
# Price | Crofelemer
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rabin Bista, 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
Crofelemer is a anti-diarrheal that is FDA approved for the treatment of non-infectious diarrhea in adult patients with HIV/AIDS. Common adverse reactions include Upper respiratory tract infection, bronchitis, cough, flatulence and increased bilirubin.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- FULYZAQ is indicated for symptomatic relief of non-infectious diarrhea in patients with HIV/AIDS on Antiretroviral therapy.
### Dosage
- The recommended dose of FULYZAQ is one 125 mg delayed-release tablet taken orally two times a day, with or without food. FULYZAQ tablets should not be crushed or chewed. Tablets should be swallowed whole.
### DOSAGE FORMS AND STRENGTHS
- FULYZAQ is a white, oval, enteric-coated 125 mg delayed-release tablet printed on one side with 125SLXP.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Crofelemer in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Crofelemer in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
The safety and effectiveness of FULYZAQ have not been established in pediatric patients less than 18 years of age.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Crofelemer in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Crofelemer in pediatric patients.
# Contraindications
- None
# Warnings
- If infectious etiologies are not considered, and FULYZAQ is initiated based on a presumptive diagnosis of non-infectious diarrhea, then there is a risk that patients with infectious etiologies will not receive the appropriate treatments, and their disease may worsen. Before starting FULYZAQ, rule out infectious etiologies of diarrhea. FULYZAQ is not indicated for the treatment of infectious diarrhea.
# 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.
- A total of 696 HIV-positive patients in three placebo-controlled trials received FULYZAQ for a mean duration of 78 days. Of the total population across the three trials, 229 patients received a dose of 125 mg twice a day for a mean duration of 141 days, 69 patients received a dose of 250 mg twice a day for a mean duration of 139 days, 102 patients received a dose of 250 mg four times a day for a mean duration of 14 days, 54 patients received a dose of 500 mg twice a day for a mean duration of 146 days, and 242 patients received a dose of 500 mg four times a day for a mean duration of 14 days.
- Adverse reactions for FULYZAQ that occurred in at least 2% of patients and at a higher incidence than placebo are provided in Table 1.
- Adverse reactions that occurred in between 1% and 2% of patients taking a 250 mg daily dose of FULYZAQ were abdominal pain, acne, increased aspartate aminotransferase, increased conjugated bilirubin, increased unconjugated blood bilirubin, constipation, depression, dermatitis, dizziness, dry mouth, dyspepsia, gastroenteritis, herpes zoster, nephrolithiasis, pain in extremity, pollakiuria, procedural pain, seasonal allergy, sinusitis and decreased white blood cell count.
- Adverse reactions were similar in patients who received doses greater than 250 mg daily.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Crofelemer in the drug label.
# Drug Interactions
- In vitro studies have shown that crofelemer has the potential to inhibit cytochrome P450 isoenzyme 3A and transporters MRP2 and OATP1A2 at concentrations expected in the gut. Due to the minimal absorption of crofelemer, it is unlikely to inhibit cytochrome P450 isoenzymes 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1 and CYP3A4 systemically .
- FULYZAQ administration did not have a clinically relevant interaction with nelfinavir, zidovudine, or lamivudine in a drug-drug interaction trial.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Reproduction studies performed with crofelemer in rats at oral doses up to 177 times the recommended daily human dose of 4.2 mg/kg revealed no evidence of impaired fertility or harm to the fetus. In pregnant rabbits, crofelemer at an oral dose of about 96 times the recommended daily human dose of 4.2 mg/kg, caused abortions and resorptions of fetuses. However, it is not clear whether these effects are related to the maternal toxicity observed. A pre- and postnatal development study performed with crofelemer in rats at oral doses of up to 177 times the recommended daily human dose of 4.2 mg/kg revealed no evidence of adverse pre- and postnatal effects in offspring. There are, however, no adequate, well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Crofelemer in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Crofelemer during labor and delivery.
### Nursing Mothers
- It is not known whether crofelemer is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from FULYZAQ, 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 safety and effectiveness of FULYZAQ have not been established in pediatric patients less than 18 years of age.
### Geriatic Use
- Clinical studies with crofelemer did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger patients.
### Gender
There is no FDA guidance on the use of Crofelemer with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Crofelemer with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Crofelemer in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Crofelemer in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Crofelemer in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Crofelemer in patients who are immunocompromised.
### CD4 Count and HIV Viral Load
- No dose modifications are recommended with respect to CD4 cell count and HIV viral load, based on the findings in subgroups of patients defined by CD4 cell count and HIV viral load.
- The safety profile of crofelemer was similar in patients with baseline CD4 cell count less than 404 cells/μL (lower limit of normal range) (N=388) and patients with baseline CD4 cell counts greater than or equal to 404 cells/μL (N=289).
- The safety profile of crofelemer was similar in patients with baseline HIV viral loads less than 400 copies/mL (N = 412) and patients with baseline HIV viral loads greater than or equal to 400 copies/mL (N = 278).
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Crofelemer in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Crofelemer in the drug label.
# Overdosage
- There has been no reported experience with overdosage of crofelemer.
# Pharmacology
## Mechanism of Action
- Crofelemer is an inhibitor of both the cyclic adenosine monophosphate (cAMP)-stimulated cystic fibrosis transmembrane conductance regulator (CFTR) chloride ion (Cl-) channel, and the calcium-activated Cl- channels (CaCC) at the luminal membrane of enterocytes. The CFTR Cl- channel and CaCC regulate Cl- and fluid secretion by intestinal epithelial cells. Crofelemer acts by blocking Cl- secretion and accompanying high volume water loss in diarrhea, normalizing the flow of Cl- and water in the GI tract.
## Structure
- FULYZAQ (crofelemer) delayed-release tablets is an anti-diarrheal, enteric-coated drug product for oral administration. It contains 125 mg of crofelemer, a botanical drug substance that is derived from the red latex of Croton lechleri Müll. Arg. Crofelemer is an oligomeric proanthocyanidin mixture primarily composed of (+)‑catechin, (‑)‑epicatechin, (+)‑gallocatechin, and (‑)‑epigallocatechin monomer units linked in random sequence, as represented below. The average degree of polymerization for the oligomers ranges between 5 and 7.5, as determined by phloroglucinol degradation.
- Inactive ingredients: microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate.
- Coating ingredients: ethylacrylate and methylacrylate copolymer dispersion, talc, triethyl citrate, and white dispersion which contains xanthan gum, titanium dioxide, propyl paraben, and methyl paraben.
## Pharmacodynamics
- Consistent with the mechanism of action of crofelemer (i.e., inhibition of CFTR and CaCC in the GI lumen), data suggest stool chloride concentrations decreased in patients treated with FULYZAQ (500 mg four times daily) (n=25) for four days relative to placebo (n=24); stool chloride concentrations decreased in both African American patients treated with FULYZAQ (n=3) relative to placebo (n=5) and non-African American patients treated with FULYZAQ (n=22) relative to placebo (n=19).
- At a dose 10 times the maximum recommended dose, crofelemer does not prolong the QTc interval to any clinically relevant extent.
## Pharmacokinetics
- The absorption of crofelemer is minimal following oral dosing in healthy adults and HIV‑positive patients and concentrations of crofelemer in plasma are below the level of quantitation (50 ng/mL). Therefore, standard pharmacokinetic parameters such as area under the curve, maximum concentration, and half-life cannot be estimated.
- The distribution of crofelemer has not been determined.
- No metabolites of crofelemer have been identified in healthy subjects or patients in clinical trials.
- The elimination route has not been identified in humans.
- Administration of crofelemer with a high-fat meal was not associated with an increase in systemic exposure of crofelemer in healthy volunteers. In the clinical trial, a single 500 mg dose of crofelemer was administered one-half hour before the morning and evening meals. Therefore, crofelemer may be administered with or without a meal.
- Results of a crossover study in healthy volunteers showed crofelemer 500 mg administered four times daily for five days had no effect on the exposure of zidovudine and nelfinavir when administered as a single dose. A 20% decrease in lamivudine exposure was also observed in the same study but was not considered to be clinically important.
## Nonclinical Toxicology
- Long-term studies in animals have not been performed to evaluate the carcinogenic potential of crofelemer.
- Crofelemer was negative in the bacterial reverse mutation assay, chromosomal aberration assay, and rat bone marrow micronucleus assay.
- Crofelemer, at oral doses of up to 738 mg/kg/day (177 times the recommended human daily dose of 4.2 mg/kg), had no effects on fertility or reproductive performance of male and female rats.
# Clinical Studies
- The efficacy of FULYZAQ 125 mg delayed-release tablets twice daily was evaluated in a randomized, double-blind, placebo-controlled (one month) and placebo-free (five month), multi-center study. The study enrolled 374 HIV-positive patients on stable Antiretroviral therapy (ART) with a history of diarrhea for one month or more. Diarrhea was defined as either persistently loose stools despite regular use of anti-diarrheal medication (ADM) (e.g., loperamide, diphenoxylate, and bismuth subsalicylate) or one or more watery bowel movements per day without regular ADM use.
- Patients were excluded if they had a positive gastrointestinal (GI) biopsy, GI culture, or stool test for multiple bacteria (Salmonella, Shigella, Campylobacter, Yersinia, Mycobacterium), bacterial toxin (Clostridium difficile), ova and parasites (Giardia, Entamoeba, Isospora, Cyclospora, Cryptosporidium, Microsporidium), or viruses (Cytomegalovirus). Patients were also excluded if they had a history of ulcerative colitis, Crohn’s disease, celiac sprue (gluten-enteropathy), chronic pancreatitis, malabsorption, or any other GI disease associated with diarrhea.
- The study had a two-stage adaptive design. In both stages, patients received placebo for 10 days (screening period) followed by randomization to crofelemer or placebo for 31 days of treatment (double-blind period). Only patients with 1 or more watery bowel movements per day on at least 5 of the last 7 days in the screening period were randomized to the double-blind period. Each stage enrolled patients separately; the dose for the second stage was selected based on an interim analysis of data from the first stage. In the first stage, patients were randomized 1:1:1:1 to one of three crofelemer dose regimens (125, 250, or 500 mg twice daily) or placebo. In the second stage, patients were randomized 1:1 to crofelemer 125 mg twice daily or placebo. The efficacy analysis was based on results from the double-blind portion of both stages.
- Each study stage also had a five month period (placebo-free period) that followed the double-blind period. Patients treated with crofelemer continued the same dose in the placebo-free period. In the first stage, patients that received placebo were re-randomized 1:1:1 to one of the three crofelemer dose regimens (125, 250, or 500 mg twice daily) in the placebo-free period. In the second stage, patients that received placebo were treated with crofelemer 125 mg twice daily in the placebo-free period.
- The median time since diagnosis of HIV was 12 years. The percentage of patients with a CD4 cell count of less than 404 was 39%. The percentage of patients with a HIV viral load greater than or equal to 1000, 400 to 999, and less than 400 HIV copies/mL was 7%, 3%, and 9%, respectively; the remainder had a viral load that was not detectable. The median time since diarrhea started was 4 years. The median number of daily watery bowel movements was 2.5 per day.
- Most patients were male (85%). The percentage of patients that were Caucasian was 46%; the percentage of patients that were African-American was 32%. The median age was 45 years with a range of 21 to 68 years.
- In the double-blind period of the study, 136 patients received crofelemer 125 mg twice daily, 54 patients received 250 mg twice daily, 47 patients received 500 mg twice daily, and 138 patients received placebo. The percentages of patients that completed the double-blind period were 92%, 100%, 85%, and 94% in the 125 mg, 250 mg, 500 mg, and placebo arms, respectively.
- Most patients received concomitant protease inhibitors (PI) during the double-blind period (Table 2). The most frequently used ARTs in each group were tenofovir/emtricitabine, ritonavir, and lopinavir/ritonavir.
- The primary efficacy endpoint was the proportion of patients with a clinical response, defined as less than or equal to 2 watery bowel movements per week during at least 2 of the 4 weeks of the placebo-controlled phase. Patients who received concomitant ADMs or opiates were counted as clinical non-responders.
- A significantly larger proportion of patients in the crofelemer 125 mg twice daily group experienced clinical response compared with patients in the placebo group (17.6% vs. 8.0%, 1‑sided p < 0.01).
- In the randomized clinical study, examination of duration of diarrhea, baseline number of daily watery bowel movements, use of protease inhibitors, CD4 cell count and age subgroups did not identify differences in the consistency of the crofelemer treatment effect among these subgroups. There were too few female subjects and subjects with an HIV viral load > 400 copies/mL to adequately assess differences in effects in these populations. Among race subgroups, there were no differences in the consistency of the crofelemer treatment effect except for the subgroup of African-Americans; crofelemer was less effective in African-Americans than non-African-Americans.
- Although the CD4 cell count and HIV viral load did not appear to change over the one month placebo-controlled period, the clinical significance of this finding is unknown because of the short duration of the placebo-controlled period.
- Of the 24 clinical responders to crofelemer (125 mg twice daily), 22 entered the placebo-free period; 16 were responding at the end of month 3, and 14 were responding at the end of month 5.
# How Supplied
- Crofelemer delayed-release tablets, 125 mg, are white, oval enteric-coated tablets printed on one side with 125SLXP. They are available in the following package size:
- Bottles of 60: NDC 65649-802-02
## Storage
- Store at 20°C-25°C (68°F-77°F); excursions permitted between 15°C-30°C (59°F-86°F). See USP Controlled Room Temperature.
# Images
## Drug Images
## Package and Label Display Panel
PACKAGE LABEL - PRINCIPAL DISPLAY - FULYZAQ 125 MG TABLETS, 60 TABLETS BOTTLE LABEL
### Ingredients and Appearance
# Patient Counseling Information
- Instruct patients that FULYZAQ tablets may be taken with or without food.
- Instruct patients that FULYZAQtablets should not be crushed or chewed. Tablets should be swallowed whole.
# Precautions with Alcohol
- Alcohol-Crofelemer interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Fulyzaq®[1]
# Look-Alike Drug Names
There is limited information regarding the look alike drug names.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Crofelemer | |
d25c7e417c6115a2a255c7db3d7f6a3bfdcd048d | wikidoc | Cross-eyed | Cross-eyed
Cross-eyed may refer to:
- Strabismus, a condition in which the eyes are not properly aligned with each other, sufferers of which are often referred to as being "cross-eyed"
Esotropia, a form of strabismus in which the eyes point inwards, towards the nose
Exotropia, a form of strabismus in which the eyes point outwards away from the nose
- Esotropia, a form of strabismus in which the eyes point inwards, towards the nose
- Exotropia, a form of strabismus in which the eyes point outwards away from the nose | Cross-eyed
Cross-eyed may refer to:
- Strabismus, a condition in which the eyes are not properly aligned with each other, sufferers of which are often referred to as being "cross-eyed"
Esotropia, a form of strabismus in which the eyes point inwards, towards the nose
Exotropia, a form of strabismus in which the eyes point outwards away from the nose
- Esotropia, a form of strabismus in which the eyes point inwards, towards the nose
- Exotropia, a form of strabismus in which the eyes point outwards away from the nose
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Cross-eyed | |
bd956e9c106648ced6d7f6b9b343624067ae5c0e | wikidoc | Strabismus | Strabismus
# Overview
Strabismus (from Greek: στραβισμός strabismos, from στραβίζειν strabizein "to squint," from στραβός strabos "squinting, squint-eyed") is a condition in which the eyes are not properly aligned with each other. It typically involves a lack of coordination between the extraocular muscles that prevents bringing the gaze of each eye to the same point in space and preventing proper binocular vision, which may adversely affect depth perception. Strabismus can be either a disorder of the brain coordinating the eyes or a disorder of one or more muscles, as in any process that causes a dysfunction of the usual direction and power of the muscle or muscles.
# Pathophysiology
Strabismus can be an indication that a cranial nerve has a lesion, particularly Cranial Nerve III (Occulomotor), Cranial Nerve IV (Trochlear) or Cranial Nerve VI (Abducens). A strabismus caused by a lesion in either of these nerves results in the lack of innervation to eye muscles and results in a change of eye position. A strabismus may be a sign of increased intracranial pressure, as CN III is particularly vulnerable to damage from brain swelling.
More commonly however, squints are termed concominant (i.e. non paralytic). This means the squint is not caused by a lesion reducing innervation. The squint in this example, is caused by a refractive error in one or both eyes. This refractive error causes poor vision in one eye and so stops the brain from being able to use both eyes together.
# Differentiating Strabismus from other Diseases
## Pseudostrabismus
Pseudostrabismus is the false appearance of strabismus. It generally occurs in infants and toddlers whose bridge of the nose is wide and flat, causing the appearance of strabismus. With age, the bridge of the child's nose narrows and the folds in the corner of the eyes go away. To detect the difference between pseudostrabismus and strabismus, a Hirschberg test may be used.
# Natural History, Complications and Prognosis
## Prognosis
When strabismus is congenital or develops in infancy, it can cause amblyopia, in which the brain ignores input from the deviated eye. Strabismus can lead to a permanent weakening of vision in the strabismic eye called amblyopia (this may not always happen), sometimes referred to as lazy eye. The appearance of strabismus may also be a cosmetic problem. One study reported that 85% of adult strabismus patients "reported that they had problems with work, school and sports because of their strabismus." The same study also reported that 70% said strabismus "had a negative effect on their self-image."
# Diagnosis
During eye examinations, ophthalmologists, orthoptists, and optometrists typically use a cover test to aid in the diagnosis of strabismus. If the eye being tested is the strabismic eye, then it will fixate on the object after the "straight" eye is covered, as long as the vision in this eye is good enough. If the "straight" eye is being tested, there will be no change in fixation, as it is already fixated. Depending on the direction that the strabismic eye deviates, the direction of deviation may be assessed. Exotropic is outwards (away from the midline) and esotropic is inwards (towards the nose).
A simple screening test for strabismus is the Hirschberg test. A flashlight is shone in the patient's eye. When the patient is looking at the light, a reflection can be seen on the front surface of the pupil. If the eyes are properly aligned with one another, the reflection will be in the same spot of each eye. Therefore, if strabismus is present, the reflection from the light will not be in the same spot of each eye.
## Laterality
Strabismus may be classified as unilateral if the same eye consistently 'wanders', or alternating if either of the eyes can be seen to 'wander'. Alternation of the strabismus may occur spontaneously, with or without subjective awareness of the alternation. Alternation may also be seen following the cover test, with the previously 'wandering' eye remaining straight while the previously straight eye is now seen to be 'wandering' on removal of the cover. The cover-uncover test is used to diagnose the type of strabismus (also known as tropia) present.
## Onset
Strabismus may also be classified based on time of onset, either congenital, acquired or secondary to another pathological process, such as a cataract.
# Treatment
As with other binocular vision disorders, the primary therapeutic goal for those with strabismus is comfortable, single, clear, normal binocular vision at all distances and directions of gaze.
Whereas amblyopia, if minor and detected early, can often be corrected with use of an eyepatch on the dominant eye and/or vision therapy, the use of eyepatches is unlikely to change the angle of strabismus. Advanced strabismus is usually treated with a combination of eyeglasses or prisms, vision therapy, and surgery, depending on the underlying reason for the misalignment. Surgery attempts to align the eyes by shortening, lengthening, or changing the position of one or more of the extraocular eye muscles and is frequently the only way to achieve cosmetic improvement. Glasses affect the position by changing the person's reaction to focusing. Prisms change the way light, and therefore images, strike the eye, simulating a change in the eye position.
Early treatment of strabismus and/or amblyopia in infancy can reduce the chance of developing amblyopia and depth perception problems. Eyes that remain misaligned can still develop visual problems. Although not a cure for strabismus, prism lenses can also be used to provide some comfort for sufferers and to prevent double vision from occurring.
In adults with previously normal alignment, the onset of strabismus usually results in double vision (diplopia).
# Other Terminology
Strabismus is often incorrectly referred to as "lazy eye" (which in fact refers to the associated condition amblyopia). It is also referred to as "squint," "crossed eye," "cockeye," "codeye," and "wall eye".
Cross-eyed means that when a person with strabismus looks at an object, one eye fixates the object and the other fixates with a convergence angle less than zero, that is the optic axes overconverge. Wall-eyed means that when a person with strabismus looks at an object, one eye fixates the object and the other fixates with a convergence angle greater than zero, that is the optic axes diverge from parallel.
# Related Chapters
- Duane syndrome
- Mobius syndrome
- Orthoptics
- Pediatric ophthalmology
- Sixth (abducent) nerve palsy
- Strabismus surgery | Strabismus
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Strabismus (from Greek: στραβισμός strabismos, from στραβίζειν strabizein "to squint," from στραβός strabos "squinting, squint-eyed"[1]) is a condition in which the eyes are not properly aligned with each other.[2] It typically involves a lack of coordination between the extraocular muscles that prevents bringing the gaze of each eye to the same point in space and preventing proper binocular vision, which may adversely affect depth perception. Strabismus can be either a disorder of the brain coordinating the eyes or a disorder of one or more muscles, as in any process that causes a dysfunction of the usual direction and power of the muscle or muscles.
# Pathophysiology
Strabismus can be an indication that a cranial nerve has a lesion, particularly Cranial Nerve III (Occulomotor), Cranial Nerve IV (Trochlear) or Cranial Nerve VI (Abducens). A strabismus caused by a lesion in either of these nerves results in the lack of innervation to eye muscles and results in a change of eye position. A strabismus may be a sign of increased intracranial pressure, as CN III is particularly vulnerable to damage from brain swelling.
More commonly however, squints are termed concominant (i.e. non paralytic). This means the squint is not caused by a lesion reducing innervation. The squint in this example, is caused by a refractive error in one or both eyes. This refractive error causes poor vision in one eye and so stops the brain from being able to use both eyes together.
# Differentiating Strabismus from other Diseases
## Pseudostrabismus
Pseudostrabismus is the false appearance of strabismus. It generally occurs in infants and toddlers whose bridge of the nose is wide and flat, causing the appearance of strabismus. With age, the bridge of the child's nose narrows and the folds in the corner of the eyes go away. To detect the difference between pseudostrabismus and strabismus, a Hirschberg test may be used.
# Natural History, Complications and Prognosis
## Prognosis
When strabismus is congenital or develops in infancy, it can cause amblyopia, in which the brain ignores input from the deviated eye. Strabismus can lead to a permanent weakening of vision in the strabismic eye called amblyopia (this may not always happen), sometimes referred to as lazy eye. The appearance of strabismus may also be a cosmetic problem. One study reported that 85% of adult strabismus patients "reported that they had problems with work, school and sports because of their strabismus." The same study also reported that 70% said strabismus "had a negative effect on their self-image."[3]
# Diagnosis
During eye examinations, ophthalmologists, orthoptists, and optometrists typically use a cover test to aid in the diagnosis of strabismus. If the eye being tested is the strabismic eye, then it will fixate on the object after the "straight" eye is covered, as long as the vision in this eye is good enough. If the "straight" eye is being tested, there will be no change in fixation, as it is already fixated. Depending on the direction that the strabismic eye deviates, the direction of deviation may be assessed. Exotropic is outwards (away from the midline) and esotropic is inwards (towards the nose).
A simple screening test for strabismus is the Hirschberg test. A flashlight is shone in the patient's eye. When the patient is looking at the light, a reflection can be seen on the front surface of the pupil. If the eyes are properly aligned with one another, the reflection will be in the same spot of each eye. Therefore, if strabismus is present, the reflection from the light will not be in the same spot of each eye.
## Laterality
Strabismus may be classified as unilateral if the same eye consistently 'wanders', or alternating if either of the eyes can be seen to 'wander'. Alternation of the strabismus may occur spontaneously, with or without subjective awareness of the alternation. Alternation may also be seen following the cover test, with the previously 'wandering' eye remaining straight while the previously straight eye is now seen to be 'wandering' on removal of the cover. The cover-uncover test is used to diagnose the type of strabismus (also known as tropia) present.[2]
## Onset
Strabismus may also be classified based on time of onset, either congenital, acquired or secondary to another pathological process, such as a cataract.[2]
# Treatment
As with other binocular vision disorders, the primary therapeutic goal for those with strabismus is comfortable, single, clear, normal binocular vision at all distances and directions of gaze.[4]
Whereas amblyopia, if minor and detected early, can often be corrected with use of an eyepatch on the dominant eye and/or vision therapy, the use of eyepatches is unlikely to change the angle of strabismus. Advanced strabismus is usually treated with a combination of eyeglasses or prisms, vision therapy, and surgery, depending on the underlying reason for the misalignment. Surgery attempts to align the eyes by shortening, lengthening, or changing the position of one or more of the extraocular eye muscles and is frequently the only way to achieve cosmetic improvement. Glasses affect the position by changing the person's reaction to focusing. Prisms change the way light, and therefore images, strike the eye, simulating a change in the eye position.
Early treatment of strabismus and/or amblyopia in infancy can reduce the chance of developing amblyopia and depth perception problems. Eyes that remain misaligned can still develop visual problems. Although not a cure for strabismus, prism lenses can also be used to provide some comfort for sufferers and to prevent double vision from occurring.
In adults with previously normal alignment, the onset of strabismus usually results in double vision (diplopia).
# Other Terminology
Strabismus is often incorrectly referred to as "lazy eye" (which in fact refers to the associated condition amblyopia). It is also referred to as "squint," [5] "crossed eye," "cockeye," "codeye," and "wall eye".
Cross-eyed means that when a person with strabismus looks at an object, one eye fixates the object and the other fixates with a convergence angle less than zero, that is the optic axes overconverge. Wall-eyed means that when a person with strabismus looks at an object, one eye fixates the object and the other fixates with a convergence angle greater than zero, that is the optic axes diverge from parallel.
# Related Chapters
- Duane syndrome
- Mobius syndrome
- Orthoptics
- Pediatric ophthalmology
- Sixth (abducent) nerve palsy
- Strabismus surgery | https://www.wikidoc.org/index.php/Crossed_eyes | |
7d54cdde46d6ccb48b54e0cd43064b5e5e837d30 | wikidoc | Crotamiton | Crotamiton
# 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
Crotamiton is a pesticide that is FDA approved for the treatment of scabies (sarcoptes scabiei) and for symptomatic treatment of pruritic skin. Common adverse reactions include dermatitis, skin irritation.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- For eradication of scabies (Sarcoptes scabiei) and for symptomatic treatment of pruritic skin.
- Dosing Information
- Massage gently into affected areas until medication is completely absorbed. Repeat as needed.
- LOTION: Shake well before using.
- Dosing Information
- Thoroughly massage into the skin of the whole body from the chin down, paying particular attention to all folds and creases. A second application is advisable 24 hours later. Clothing and bed linen should be changed the next morning. A cleansing bath should be taken 48 hours after the last application.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Crotamiton in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- Dosage
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Crotamiton 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 Crotamiton in pediatric patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Crotamiton in pediatric patients.
# Contraindications
- Eurax should not be applied topically to patients who develop a sensitivity or are allergic to it or who manifest a primary irritation response to topical medications.
# Warnings
- If severe irritation or sensitization develops, treatment with this product should be discontinued and appropriate therapy instituted.
### Precautions
General
- Eurax should not be applied in the eyes or mouth because it may cause irritation. It should not be applied to acutely inflamed skin or raw or weeping surfaces until the acute inflammation has subsided.
# Adverse Reactions
## Clinical Trials Experience
- Primary irritation reactions, such as dermatitis, pruritus, and rash, and allergic sensitivity reactions have been reported in a few patients.
## Postmarketing Experience
There is limited information regarding Crotamiton Postmarketing Experience in the drug label.
# Drug Interactions
- None known.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Animal reproduction studies have not been conducted with Eurax. It is also not known whether Eurax can cause fetal harm when applied topically to a pregnant woman or can affect reproduction capacity. Eurax should be given to a pregnant woman only if clearly needed.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
- There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Crotamiton in women who are pregnant.
### Labor and Delivery
- There is no FDA guidance on use of Crotamiton during labor and delivery.
### Nursing Mothers
- There is no FDA guidance on the use of Crotamiton with respect to nursing mothers.
### Pediatric Use
- Safety and effectiveness in pediatric patients have not been established.
### Geriatic Use
- Clinical studies with Eurax (crotamiton USP) Lotion/Cream did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently than younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
### Gender
- There is no FDA guidance on the use of Crotamiton with respect to specific gender populations.
### Race
- There is no FDA guidance on the use of Crotamiton with respect to specific racial populations.
### Renal Impairment
- There is no FDA guidance on the use of Crotamiton in patients with renal impairment.
### Hepatic Impairment
- There is no FDA guidance on the use of Crotamiton in patients with hepatic impairment.
### Females of Reproductive Potential and Males
- There is no FDA guidance on the use of Crotamiton in women of reproductive potentials and males.
### Immunocompromised Patients
- There is no FDA guidance one the use of Crotamiton in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- In Scabies: Thoroughly massage into the skin of the whole body from the chin down, paying particular attention to all folds and creases. A second application is advisable 24 hours later. Clothing and bed linen should be changed the next morning. A cleansing bath should be taken 48 hours after the last application.
- In Pruritus: Massage gently into affected areas until medication is completely absorbed. Repeat as needed.
- LOTION: Shake well before using.
DIRECTIONS FOR PATIENTS WITH SCABIES:
- Take a routine bath or shower. Thoroughly massage Eurax cream or lotion into the skin from the chin to the toes including folds and creases.
- Put Eurax cream or lotion under fingernails after trimming the fingernails short, because scabies are very likely to remain there. A toothbrush can be used to apply the Eurax cream or lotion under the fingernails. Immediately after use, the toothbrush should be wrapped in paper and thrown away. *Use of the same brush in the mouth could lead to poisoning.
- A second application is advisable 24 hours later.
- A 60 gram tube or bottle is sufficient for two applications.
- Clothing and bed linen should be changed the next day. Contaminated clothing and bed linen may be dry-cleaned, or washed in the hot cycle of the washing machine.
- A cleansing bath should be taken 48 hours after the last application
### Monitoring
- There is limited information regarding Monitoring of Crotamiton in the drug label.
- Description
# IV Compatibility
- There is limited information regarding IV Compatibility of Crotamiton in the drug label.
# Overdosage
- There is no specific information on the effect of overtreatment with repeated topical applications in humans. A death was reported but cause was not confirmed.
- Accidental oral ingestion may be accompanied by burning sensation in the mouth, irritation of the buccal, esophageal and gastric mucosa, nausea, vomiting, abdominal pain.
- If accidental ingestion occurs, call your Poison Control Center.
# Pharmacology
## Mechanism of Action
- Eurax has scabicidal and antipruritic actions. The mechanisms of these actions are not known.
## Structure
- Eurax (crotamiton USP) is a scabicidal and antipruritic agent available as a cream or lotion for topical use only. Eurax provides 10% (w/w) of the synthetic, crotamiton USP, in a vanishing-cream or emollient-lotion base containing: carbomer-934, cetyl alcohol, diazolidinylurea, dimethicone, fragrance, laureth-23, magnesium aluminum silicate, magnesium nitrate, methylchloroisothiazolinone, methylisothiazolinone, petrolatum, propylene glycol, sodium hydroxide, steareth-2, and water. In addition, the cream contains glyceryl stearate.
- Crotamiton is N-ethyl-N-(o-methylphenyl)-2-butenamide and its structural formula is:
- Crotamiton USP is a colorless to slightly yellowish oil, having a faint amine-like odor. It is miscible with alcohol and with methanol. Crotamiton is a mixture of the cis and trans isomers. Its molecular weight is 203.28.
## Pharmacodynamics
There is limited information regarding Crotamiton Pharmacodynamics in the drug label.
## Pharmacokinetics
- The pharmacokinetics of crotamiton and its degree of systemic absorption following topical application have not been determined.
## Nonclinical Toxicology
Carcinogenesis and Mutagenesis and Impairment of Fertility
- Long-term carcinogenicity studies in animals have not been conducted.
# Clinical Studies
- There is limited information regarding Clinical Studies of Crotamiton in the drug label.
# How Supplied
Eurax® (crotamiton USP)
- Cream: 60 g tubes NDC 10631-091-60 (NSN 6505-00-116-0200)
- Lotion: 60 g (2 oz.) bottles NDC 10631-092-60 (NSN 6505-01-153-4423)
- 454 g (16 oz.) bottles NDC 10631-092-16
- SHAKE WELL before using.
## Storage
- Store at room temperature.
- Keep out of reach of children.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
DIRECTIONS FOR PATIENTS WITH SCABIES:
- Take a routine bath or shower. Thoroughly massage Eurax cream or lotion into the skin from the chin to the toes including folds and creases.
- Put Eurax cream or lotion under fingernails after trimming the fingernails short, because scabies are very likely to remain there. A toothbrush can be used to apply the Eurax cream or lotion under the fingernails. Immediately after use, the toothbrush should be wrapped in paper and thrown away. *Use of the same brush in the mouth could lead to poisoning.
- A second application is advisable 24 hours later.
- A 60 gram tube or bottle is sufficient for two applications.
- Clothing and bed linen should be changed the next day. Contaminated clothing and bed linen may be dry-cleaned, or washed in the hot cycle of the washing machine.
- A cleansing bath should be taken 48 hours after the last application
# Precautions with Alcohol
- Alcohol-Crotamiton interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
Eurax
# Look-Alike Drug Names
- A® — B®
# Drug Shortage Status
# Price | Crotamiton
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
Crotamiton is a pesticide that is FDA approved for the treatment of scabies (sarcoptes scabiei) and for symptomatic treatment of pruritic skin. Common adverse reactions include dermatitis, skin irritation.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- For eradication of scabies (Sarcoptes scabiei) and for symptomatic treatment of pruritic skin.
- Dosing Information
- Massage gently into affected areas until medication is completely absorbed. Repeat as needed.
- LOTION: Shake well before using.
- Dosing Information
- Thoroughly massage into the skin of the whole body from the chin down, paying particular attention to all folds and creases. A second application is advisable 24 hours later. Clothing and bed linen should be changed the next morning. A cleansing bath should be taken 48 hours after the last application.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Crotamiton in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- Dosage
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Crotamiton 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 Crotamiton in pediatric patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Crotamiton in pediatric patients.
# Contraindications
- Eurax should not be applied topically to patients who develop a sensitivity or are allergic to it or who manifest a primary irritation response to topical medications.
# Warnings
- If severe irritation or sensitization develops, treatment with this product should be discontinued and appropriate therapy instituted.
### Precautions
General
- Eurax should not be applied in the eyes or mouth because it may cause irritation. It should not be applied to acutely inflamed skin or raw or weeping surfaces until the acute inflammation has subsided.
# Adverse Reactions
## Clinical Trials Experience
- Primary irritation reactions, such as dermatitis, pruritus, and rash, and allergic sensitivity reactions have been reported in a few patients.
## Postmarketing Experience
There is limited information regarding Crotamiton Postmarketing Experience in the drug label.
# Drug Interactions
- None known.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Animal reproduction studies have not been conducted with Eurax. It is also not known whether Eurax can cause fetal harm when applied topically to a pregnant woman or can affect reproduction capacity. Eurax should be given to a pregnant woman only if clearly needed.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
- There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Crotamiton in women who are pregnant.
### Labor and Delivery
- There is no FDA guidance on use of Crotamiton during labor and delivery.
### Nursing Mothers
- There is no FDA guidance on the use of Crotamiton with respect to nursing mothers.
### Pediatric Use
- Safety and effectiveness in pediatric patients have not been established.
### Geriatic Use
- Clinical studies with Eurax (crotamiton USP) Lotion/Cream did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently than younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
### Gender
- There is no FDA guidance on the use of Crotamiton with respect to specific gender populations.
### Race
- There is no FDA guidance on the use of Crotamiton with respect to specific racial populations.
### Renal Impairment
- There is no FDA guidance on the use of Crotamiton in patients with renal impairment.
### Hepatic Impairment
- There is no FDA guidance on the use of Crotamiton in patients with hepatic impairment.
### Females of Reproductive Potential and Males
- There is no FDA guidance on the use of Crotamiton in women of reproductive potentials and males.
### Immunocompromised Patients
- There is no FDA guidance one the use of Crotamiton in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- In Scabies: Thoroughly massage into the skin of the whole body from the chin down, paying particular attention to all folds and creases. A second application is advisable 24 hours later. Clothing and bed linen should be changed the next morning. A cleansing bath should be taken 48 hours after the last application.
- In Pruritus: Massage gently into affected areas until medication is completely absorbed. Repeat as needed.
- LOTION: Shake well before using.
DIRECTIONS FOR PATIENTS WITH SCABIES:
- Take a routine bath or shower. Thoroughly massage Eurax cream or lotion into the skin from the chin to the toes including folds and creases.
- Put Eurax cream or lotion under fingernails after trimming the fingernails short, because scabies are very likely to remain there. A toothbrush can be used to apply the Eurax cream or lotion under the fingernails. Immediately after use, the toothbrush should be wrapped in paper and thrown away. *Use of the same brush in the mouth could lead to poisoning.
- A second application is advisable 24 hours later.
- A 60 gram tube or bottle is sufficient for two applications.
- Clothing and bed linen should be changed the next day. Contaminated clothing and bed linen may be dry-cleaned, or washed in the hot cycle of the washing machine.
- A cleansing bath should be taken 48 hours after the last application
### Monitoring
- There is limited information regarding Monitoring of Crotamiton in the drug label.
- Description
# IV Compatibility
- There is limited information regarding IV Compatibility of Crotamiton in the drug label.
# Overdosage
- There is no specific information on the effect of overtreatment with repeated topical applications in humans. A death was reported but cause was not confirmed.
- Accidental oral ingestion may be accompanied by burning sensation in the mouth, irritation of the buccal, esophageal and gastric mucosa, nausea, vomiting, abdominal pain.
- If accidental ingestion occurs, call your Poison Control Center.
# Pharmacology
## Mechanism of Action
- Eurax has scabicidal and antipruritic actions. The mechanisms of these actions are not known.
## Structure
- Eurax (crotamiton USP) is a scabicidal and antipruritic agent available as a cream or lotion for topical use only. Eurax provides 10% (w/w) of the synthetic, crotamiton USP, in a vanishing-cream or emollient-lotion base containing: carbomer-934, cetyl alcohol, diazolidinylurea, dimethicone, fragrance, laureth-23, magnesium aluminum silicate, magnesium nitrate, methylchloroisothiazolinone, methylisothiazolinone, petrolatum, propylene glycol, sodium hydroxide, steareth-2, and water. In addition, the cream contains glyceryl stearate.
- Crotamiton is N-ethyl-N-(o-methylphenyl)-2-butenamide and its structural formula is:
- Crotamiton USP is a colorless to slightly yellowish oil, having a faint amine-like odor. It is miscible with alcohol and with methanol. Crotamiton is a mixture of the cis and trans isomers. Its molecular weight is 203.28.
## Pharmacodynamics
There is limited information regarding Crotamiton Pharmacodynamics in the drug label.
## Pharmacokinetics
- The pharmacokinetics of crotamiton and its degree of systemic absorption following topical application have not been determined.
## Nonclinical Toxicology
Carcinogenesis and Mutagenesis and Impairment of Fertility
- Long-term carcinogenicity studies in animals have not been conducted.
# Clinical Studies
- There is limited information regarding Clinical Studies of Crotamiton in the drug label.
# How Supplied
Eurax® (crotamiton USP)
- Cream: 60 g tubes NDC 10631-091-60 (NSN 6505-00-116-0200)
- Lotion: 60 g (2 oz.) bottles NDC 10631-092-60 (NSN 6505-01-153-4423)
- 454 g (16 oz.) bottles NDC 10631-092-16
- SHAKE WELL before using.
## Storage
- Store at room temperature.
- Keep out of reach of children.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
DIRECTIONS FOR PATIENTS WITH SCABIES:
- Take a routine bath or shower. Thoroughly massage Eurax cream or lotion into the skin from the chin to the toes including folds and creases.
- Put Eurax cream or lotion under fingernails after trimming the fingernails short, because scabies are very likely to remain there. A toothbrush can be used to apply the Eurax cream or lotion under the fingernails. Immediately after use, the toothbrush should be wrapped in paper and thrown away. *Use of the same brush in the mouth could lead to poisoning.
- A second application is advisable 24 hours later.
- A 60 gram tube or bottle is sufficient for two applications.
- Clothing and bed linen should be changed the next day. Contaminated clothing and bed linen may be dry-cleaned, or washed in the hot cycle of the washing machine.
- A cleansing bath should be taken 48 hours after the last application
# Precautions with Alcohol
- Alcohol-Crotamiton interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
Eurax
# Look-Alike Drug Names
- A® — B®[1]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Crotamiton | |
df23bfb3d3330456473f8bd19769843a34849f80 | wikidoc | Crustacean | Crustacean
The crustaceans (Crustacea) are a large group of arthropods, comprising approximately 52,000 described species , and are usually treated as a subphylum . They include various familiar animals, such as lobsters, crabs, shrimp, crayfish and barnacles. The majority of them are aquatic, living in either fresh water or marine environments, but a few groups have adapted to terrestrial life, such as terrestrial crabs, terrestrial hermit crabs and woodlice. The majority of crustaceans are also motile, moving about independently, although a few taxa are parasitic and live attached to their hosts (including sea lice, fish lice, whale lice, tongue worms, and Cymothoa exigua, all of which may be referred to as "crustacean lice"), and adult barnacles live a sessile life — they are attached headfirst to the substrate and cannot move independently.
The scientific study of crustaceans is known as carcinology. Other names for carcinology are malacostracology, crustaceology and crustalogy, and a scientist who works in carcinology is a carcinologist, crustaceologist or crustalogist.
# Structure of crustaceans
Crustaceans have three distinct body parts: head, thorax, and abdomen (or pleon), although the head and thorax may fuse to form a cephalothorax, an excellent example of tagmatization. The head bears two pairs of antennae, one pair of compound eyes and three pairs of mouthparts. The thorax and pleon bear a number of lateral appendages, including the gills, and the tail ends with a telson. Smaller crustaceans respire through their body surface by diffusion , and larger crustaceans respire with gills or, as shown by Birgus latro, with abdominal lungs . Both systems (diffusion and gills) were being used by various crustaceans as early as the Middle Cambrian .
In common with other arthropods, crustaceans have a stiff exoskeleton, which must be shed to allow the animal to grow (ecdysis or moulting). Various parts of the exoskeleton may be fused together; this is particularly noticeable in the carapace, the thick dorsal shield seen on many crustaceans. Crustacean appendages are typically biramous, meaning they are divided into two parts; this includes the second pair of antennae, but not the first, which is uniramous. There is some doubt whether this is a derived state, as had been traditionally assumed, or whether it may be a primitive state, with the branching of the limbs being lost in all extant arthropod groups except the crustaceans. One piece of evidence supporting the latter view is the biramous nature of trilobite limbs .
Despite their diversity of form, crustaceans are united by the special larval form known as the nauplius.
Although a few are hermaphroditic, most crustaceans have separate sexes, which are distinguished by appendages on the abdomen called swimmerets or, more technically, pleopods. The first (and sometimes the second) pair of pleopods are specialised in the male for sperm transfer. Many terrestrial crustaceans (such as the Christmas Island red crab) mate seasonally and return to the sea to release the eggs. Others, such as woodlice lay their eggs on land, albeit in damp conditions. In many decapods, the females retain the eggs until they hatch into free-swimming larvae.
# Taxonomy
Although the classification of crustaceans has been quite variable, the system used by Martin and Davis is the most authoritative, and largely supersedes earlier works.
Six classes of crustaceans are generally recognised:
- Branchiopoda — including brine shrimp (Artemia) and Triops (Notostraca)
- Remipedia — a small class restricted to deep caves connected to salt water, called anchialine caves
- Cephalocarida — horseshoe shrimp
- Maxillopoda — various groups, including barnacles and copepods. It contains Mystacocarida and Branchiura, which are sometimes treated as their own classes.
- Ostracoda — small animals with bivalve shells
- Malacostraca — the largest class, with the largest and most familiar animals, such as crabs, lobsters, shrimp, krill and woodlice.
The exact relationships of the Crustacea to other taxa are not yet entirely clear. Under the Pancrustacea hypothesis , Crustacea and Hexapoda (insects and allies) are sister groups. Studies using DNA sequences tend to show a paraphyletic Crustacea, with the insects (but not necessarily other hexapods) nested within that clade.
# Fossil record
Those crustaceans that have soft exoskeletons reinforced with calcium carbonate, such as crabs and lobsters, tend to preserve well as fossils, but many crustaceans have only thin exoskeletons. Most of the fossils known are from coral reef or shallow sea floor environments, but many crustaceans live in open seas, on deep sea floors or in burrows. Crustaceans tend, therefore, to be more rare in the fossil record than trilobites. Some crustaceans are reasonably common in Cretaceous and Caenozoic rocks, but barnacles have a particularly poor fossil record, with very few specimens from before the Mesozoic era.
The Late Jurassic lithographic limestones of Solnhofen, Bavaria, which are famous as the home of Archaeopteryx, are relatively rich in decapod crustaceans, such as Eryon (an eryonoid), Aeger (a prawn) or Pseudastacus (a lobster). The "lobster bed" of the Greensand formation from the Cretaceous period, which occurs at Atherfield on the Isle of Wight, contains many well preserved examples of the small glypheoid lobster Mecochirus magna. Crabs have been found at a number of sites, such as the Cretaceous Gault clay and the Eocene London clay.
# Consumption
Many crustaceans are consumed by humans, and nearly 10,000,000 tons were produced in 2005 . The vast majority of this output is of decapod crustaceans: crabs, lobsters, shrimp and prawns. Over 70% by weight of all crustaceans caught for consumption are shrimp and prawns, and over 80% is produced in Asia, with China alone producing nearly half the world's total. Non-decapod crustaceans are not widely consumed, with only 130,000 tons of krill being caught, despite krill having one of the greatest biomasses on the planet. | Crustacean
The crustaceans (Crustacea) are a large group of arthropods, comprising approximately 52,000 described species [1], and are usually treated as a subphylum [2]. They include various familiar animals, such as lobsters, crabs, shrimp, crayfish and barnacles. The majority of them are aquatic, living in either fresh water or marine environments, but a few groups have adapted to terrestrial life, such as terrestrial crabs, terrestrial hermit crabs and woodlice. The majority of crustaceans are also motile, moving about independently, although a few taxa are parasitic and live attached to their hosts (including sea lice, fish lice, whale lice, tongue worms, and Cymothoa exigua, all of which may be referred to as "crustacean lice"), and adult barnacles live a sessile life — they are attached headfirst to the substrate and cannot move independently.
The scientific study of crustaceans is known as carcinology. Other names for carcinology are malacostracology, crustaceology and crustalogy, and a scientist who works in carcinology is a carcinologist, crustaceologist or crustalogist.
# Structure of crustaceans
Crustaceans have three distinct body parts: head, thorax, and abdomen (or pleon), although the head and thorax may fuse to form a cephalothorax, an excellent example of tagmatization. The head bears two pairs of antennae, one pair of compound eyes and three pairs of mouthparts. The thorax and pleon bear a number of lateral appendages, including the gills, and the tail ends with a telson. Smaller crustaceans respire through their body surface by diffusion [3], and larger crustaceans respire with gills or, as shown by Birgus latro, with abdominal lungs [4]. Both systems (diffusion and gills) were being used by various crustaceans as early as the Middle Cambrian [5].
In common with other arthropods, crustaceans have a stiff exoskeleton, which must be shed to allow the animal to grow (ecdysis or moulting). Various parts of the exoskeleton may be fused together; this is particularly noticeable in the carapace, the thick dorsal shield seen on many crustaceans. Crustacean appendages are typically biramous, meaning they are divided into two parts; this includes the second pair of antennae, but not the first, which is uniramous. There is some doubt whether this is a derived state, as had been traditionally assumed, or whether it may be a primitive state, with the branching of the limbs being lost in all extant arthropod groups except the crustaceans. One piece of evidence supporting the latter view is the biramous nature of trilobite limbs [6].
Despite their diversity of form, crustaceans are united by the special larval form known as the nauplius.
Although a few are hermaphroditic, most crustaceans have separate sexes, which are distinguished by appendages on the abdomen called swimmerets or, more technically, pleopods. The first (and sometimes the second) pair of pleopods are specialised in the male for sperm transfer. Many terrestrial crustaceans (such as the Christmas Island red crab) mate seasonally and return to the sea to release the eggs. Others, such as woodlice lay their eggs on land, albeit in damp conditions. In many decapods, the females retain the eggs until they hatch into free-swimming larvae.
# Taxonomy
Although the classification of crustaceans has been quite variable, the system used by Martin and Davis [1] is the most authoritative, and largely supersedes earlier works.
Six classes of crustaceans are generally recognised:
- Branchiopoda — including brine shrimp (Artemia) and Triops (Notostraca)
- Remipedia — a small class restricted to deep caves connected to salt water, called anchialine caves
- Cephalocarida — horseshoe shrimp
- Maxillopoda — various groups, including barnacles and copepods. It contains Mystacocarida and Branchiura, which are sometimes treated as their own classes.
- Ostracoda — small animals with bivalve shells
- Malacostraca — the largest class, with the largest and most familiar animals, such as crabs, lobsters, shrimp, krill and woodlice.
The exact relationships of the Crustacea to other taxa are not yet entirely clear. Under the Pancrustacea hypothesis [7], Crustacea and Hexapoda (insects and allies) are sister groups. Studies using DNA sequences tend to show a paraphyletic Crustacea, with the insects (but not necessarily other hexapods) nested within that clade.
# Fossil record
Those crustaceans that have soft exoskeletons reinforced with calcium carbonate, such as crabs and lobsters, tend to preserve well as fossils, but many crustaceans have only thin exoskeletons. Most of the fossils known are from coral reef or shallow sea floor environments, but many crustaceans live in open seas, on deep sea floors or in burrows. Crustaceans tend, therefore, to be more rare in the fossil record than trilobites. Some crustaceans are reasonably common in Cretaceous and Caenozoic rocks, but barnacles have a particularly poor fossil record, with very few specimens from before the Mesozoic era.
The Late Jurassic lithographic limestones of Solnhofen, Bavaria, which are famous as the home of Archaeopteryx, are relatively rich in decapod crustaceans, such as Eryon (an eryonoid), Aeger (a prawn) or Pseudastacus (a lobster). The "lobster bed" of the Greensand formation from the Cretaceous period, which occurs at Atherfield on the Isle of Wight, contains many well preserved examples of the small glypheoid lobster Mecochirus magna. Crabs have been found at a number of sites, such as the Cretaceous Gault clay and the Eocene London clay.
# Consumption
Many crustaceans are consumed by humans, and nearly 10,000,000 tons were produced in 2005 [8]. The vast majority of this output is of decapod crustaceans: crabs, lobsters, shrimp and prawns. Over 70% by weight of all crustaceans caught for consumption are shrimp and prawns, and over 80% is produced in Asia, with China alone producing nearly half the world's total. Non-decapod crustaceans are not widely consumed, with only 130,000 tons of krill being caught, despite krill having one of the greatest biomasses on the planet. | https://www.wikidoc.org/index.php/Crustacean | |
51ef1c46cdf8cf01fee4efd7a06526fe5963cd84 | wikidoc | Cryogenics | Cryogenics
# Overview
In physics or engineering, cryogenics is the study of the production of very low temperatures (below –150 °C, –238 °F or 123 K) and the behavior of materials at those temperatures. (Rather than the familiar temperature scales of Fahrenheit and Celsius, cryogenicists use the Kelvin (and formerly Rankine) scales.)
# Definitions and distinctions
The terms cryogenics, cryobiology and cryonics are frequently confused. Other new terms with the prefix cryo- have also been introduced.
# Etymology
The word cryogenics means "the production of freezing cold"; however the term is used today as a synonym for the low-temperature state. It is not well-defined at what point on the temperature scale refrigeration ends and cryogenics begins. The workers at the National Institute of Standards and Technology at Boulder, Colorado have chosen to consider the field of cryogenics as that involving temperatures below –180 °C (93.15 K). This is a logical dividing line, since the normal boiling points of the so-called permanent gases (such as helium, hydrogen, neon, nitrogen, oxygen, and normal air) lie below -180 °C while the Freon refrigerants, hydrogen sulfide, and other common refrigerants have boiling points above -180 °C.
# Industrial application
Liquefied gases, such as liquid nitrogen and liquid helium, are used in many cryogenic applications. Liquid nitrogen is the most commonly used element in cryogenics and is legally purchasable around the world. Liquid helium is also commonly used and allows for the lowest attainable temperatures to be reached.
These liquids are held in either special containers known as Dewar flasks, which are generally about six feet tall (1.8 m) and three feet (91.5 cm) in diameter, or giant tanks in larger commercial operations. Dewar flasks are named after their inventor, James Dewar, the man who first liquefied hydrogen. Museums typically display smaller vacuum flasks fitted in a protective casing.
Cryogenic transfer pumps are the pumps used on LNG piers to transfer Liquefied Natural Gas from LNG Carriers to LNG storage tanks.
## Cryogenic processing
The field of cryogenics advanced during World War II when scientists found that metals frozen to low temperatures showed more resistance to wear. Based on this theory of cryogenic hardening, the commercial cryogenic processing industry was founded in 1966 by Ed Busch. With a background in the heat treating industry, Busch founded a company in Detroit called CryoTech in 1966. Though CryoTech later merged with 300 Below to create the largest and oldest commercial cryogenics company in the world, they originally experimented with the possibility of increasing the life of metal tools to anywhere between 200%-400% of the original life expectancy using cryogenic tempering instead of heat treating. This evolved in the late 1990s into the treatment of other parts (that did more than just increase the life of a product) such as musical instruments or amplifier valves (improved sound quality), brass instruments (improved tonal characteristics), baseball bats (greater sweet spot), golf clubs (greater sweet spot), racing engines (greater performance under stress), firearms (less warping after continuous shooting), knives, razor blades, brake rotors and even pantyhose. The theory was based on how heat-treating metal works (the temperatures are lowered to room temperature from a high degree causing certain strength increases in the molecular structure to occur) and supposed that continuing the descent would allow for further strength increases. Using liquid nitrogen, CryoTech formulated the first early version of the cryogenic processor. Unfortunately for the newly-born industry, the results were unstable, as components sometimes experienced thermal shock when they were cooled too fast. Some components in early tests even shattered because of the ultra-low temperatures. In the late twentieth century, the field improved significantly with the rise of applied research, which coupled microprocessor based industrial controls to the cryogenic processor in order to create more stable results.
Cryogens, like liquid nitrogen, are further used for specialty chilling and freezing applications. Some chemical reactions, like those used to produce the active ingredients for the popular statin drugs, must occur at low temperatures of approximately -100 °C. Special cryogenic chemical reactors are used to remove reaction heat and provide a low temperature environment. The freezing of foods and biotechnology products, like vaccines, requires nitrogen in blast freezing or immersion freezing systems. Certain soft or elastic materials become hard and brittle at very low temperatures, which makes cryogenic milling (grinding) an option for some materials that cannot easily be milled at higher temperatures.
## Fuels
Another use of cryogenics is cryogenic fuels. Cryogenic fuels, mainly hydrogen, have been used as rocket fuels. (Oxygen is used as an oxidizer of hydrogen, but oxygen is not, strictly speaking, a fuel.) For example, NASA's workhorse space shuttle uses cryogenic hydrogen fuel as its primary means of getting into orbit, as did all of the rockets built for the Soviet space program by Sergei Korolev. (This was a bone of contention between him and rival engine designer Valentin Glushko, who felt that cryogenic fuels were impractical for large-scale rockets such as the ill-fated N-1 rocket spacecraft.)
Russian aircraft manufacturer Tupolev is currently researching a version of its popular design Tu-154 with a cryogenic fuel system, known as the Tu-155. The plane uses a fuel referred to as liquefied natural gas or LNG, and made its first flight in 1989.
# Production
Cryogenic cooling of devices and material is usually achieved via the use of liquid nitrogen, liquid helium, or a cryocompressor (which uses high pressure helium lines).
# Detectors
Cryogenic temperatures, usually well below 77 K (-196 °C) are required to operate cryogenic detectors. | Cryogenics
# Overview
In physics or engineering, cryogenics is the study of the production of very low temperatures (below –150 °C, –238 °F or 123 K) and the behavior of materials at those temperatures. (Rather than the familiar temperature scales of Fahrenheit and Celsius, cryogenicists use the Kelvin (and formerly Rankine) scales.)
# Definitions and distinctions
The terms cryogenics, cryobiology and cryonics are frequently confused. Other new terms with the prefix cryo- have also been introduced.
# Etymology
The word cryogenics means "the production of freezing cold"; however the term is used today as a synonym for the low-temperature state. It is not well-defined at what point on the temperature scale refrigeration ends and cryogenics begins. The workers at the National Institute of Standards and Technology at Boulder, Colorado have chosen to consider the field of cryogenics as that involving temperatures below –180 °C (93.15 K). This is a logical dividing line, since the normal boiling points of the so-called permanent gases (such as helium, hydrogen, neon, nitrogen, oxygen, and normal air) lie below -180 °C while the Freon refrigerants, hydrogen sulfide, and other common refrigerants have boiling points above -180 °C.
# Industrial application
Liquefied gases, such as liquid nitrogen and liquid helium, are used in many cryogenic applications. Liquid nitrogen is the most commonly used element in cryogenics and is legally purchasable around the world. Liquid helium is also commonly used and allows for the lowest attainable temperatures to be reached.
These liquids are held in either special containers known as Dewar flasks, which are generally about six feet tall (1.8 m) and three feet (91.5 cm) in diameter, or giant tanks in larger commercial operations. Dewar flasks are named after their inventor, James Dewar, the man who first liquefied hydrogen. Museums typically display smaller vacuum flasks fitted in a protective casing.
Cryogenic transfer pumps are the pumps used on LNG piers to transfer Liquefied Natural Gas from LNG Carriers to LNG storage tanks.
## Cryogenic processing
The field of cryogenics advanced during World War II when scientists found that metals frozen to low temperatures showed more resistance to wear. Based on this theory of cryogenic hardening, the commercial cryogenic processing industry was founded in 1966 by Ed Busch. With a background in the heat treating industry, Busch founded a company in Detroit called CryoTech in 1966. Though CryoTech later merged with 300 Below to create the largest and oldest commercial cryogenics company in the world, they originally experimented with the possibility of increasing the life of metal tools to anywhere between 200%-400% of the original life expectancy using cryogenic tempering instead of heat treating. This evolved in the late 1990s into the treatment of other parts (that did more than just increase the life of a product) such as musical instruments or amplifier valves (improved sound quality), brass instruments (improved tonal characteristics), baseball bats (greater sweet spot), golf clubs (greater sweet spot), racing engines (greater performance under stress), firearms (less warping after continuous shooting), knives, razor blades, brake rotors and even pantyhose. The theory was based on how heat-treating metal works (the temperatures are lowered to room temperature from a high degree causing certain strength increases in the molecular structure to occur) and supposed that continuing the descent would allow for further strength increases. Using liquid nitrogen, CryoTech formulated the first early version of the cryogenic processor. Unfortunately for the newly-born industry, the results were unstable, as components sometimes experienced thermal shock when they were cooled too fast. Some components in early tests even shattered because of the ultra-low temperatures. In the late twentieth century, the field improved significantly with the rise of applied research, which coupled microprocessor based industrial controls to the cryogenic processor in order to create more stable results.
Cryogens, like liquid nitrogen, are further used for specialty chilling and freezing applications. Some chemical reactions, like those used to produce the active ingredients for the popular statin drugs, must occur at low temperatures of approximately -100 °C. Special cryogenic chemical reactors are used to remove reaction heat and provide a low temperature environment. The freezing of foods and biotechnology products, like vaccines, requires nitrogen in blast freezing or immersion freezing systems. Certain soft or elastic materials become hard and brittle at very low temperatures, which makes cryogenic milling (grinding) an option for some materials that cannot easily be milled at higher temperatures.
## Fuels
Another use of cryogenics is cryogenic fuels. Cryogenic fuels, mainly hydrogen, have been used as rocket fuels. (Oxygen is used as an oxidizer of hydrogen, but oxygen is not, strictly speaking, a fuel.) For example, NASA's workhorse space shuttle uses cryogenic hydrogen fuel as its primary means of getting into orbit, as did all of the rockets built for the Soviet space program by Sergei Korolev. (This was a bone of contention between him and rival engine designer Valentin Glushko, who felt that cryogenic fuels were impractical for large-scale rockets such as the ill-fated N-1 rocket spacecraft.)
Russian aircraft manufacturer Tupolev is currently researching a version of its popular design Tu-154 with a cryogenic fuel system, known as the Tu-155. The plane uses a fuel referred to as liquefied natural gas or LNG, and made its first flight in 1989.
# Production
Cryogenic cooling of devices and material is usually achieved via the use of liquid nitrogen, liquid helium, or a cryocompressor (which uses high pressure helium lines).
# Detectors
Cryogenic temperatures, usually well below 77 K (-196 °C) are required to operate cryogenic detectors. | https://www.wikidoc.org/index.php/Cryogen | |
8939d08f20828f8120343186f26e61618a437c66 | wikidoc | Cryogenine | Cryogenine
Cryogenine is the name for two different unrelated chemical compounds:
Cryogenine is a name for the antipyretic medication phenicarbazide (1-phenylsemicarbazide).
Cryogenine is also the name for the biphenylquinolizidine lactone alkaloid, also known as vertine or
(10α)-4,5-dimethoxy-2-hydroxylythran-12-one, from Heimia salicifolia and Heimia myrtifolia. This compound has anticholinergic properties and produces mild euphoria as well as aching of the muscles when taken in pure form in large doses.
The freebase form melts at 250-251 °C and is soluble in moderatly polar organic solvents such as chloroform, methylene chloride, benzene, and methanol, but is insoluble in water and petroleum ether.
In the development of thin layer chromatography plates with diazotized p-nitroaniline spray, vertine produces a purple spot (as does sinicuichine, another biphenylquinolizidine lactone alkaloid found in the Heimias).
# See Also
- Sinicuichi
- List of Entheogens | Cryogenine
Cryogenine is the name for two different unrelated chemical compounds:
Cryogenine is a name for the antipyretic medication phenicarbazide (1-phenylsemicarbazide).[1]
Cryogenine is also the name for the biphenylquinolizidine lactone alkaloid, also known as vertine or
(10α)-4,5-dimethoxy-2-hydroxylythran-12-one, from Heimia salicifolia and Heimia myrtifolia. This compound has anticholinergic properties and produces mild euphoria as well as aching of the muscles when taken in pure form in large doses.
The freebase form melts at 250-251 °C and is soluble in moderatly polar organic solvents such as chloroform, methylene chloride, benzene, and methanol, but is insoluble in water and petroleum ether.
In the development of thin layer chromatography plates with diazotized p-nitroaniline spray, vertine produces a purple spot (as does sinicuichine, another biphenylquinolizidine lactone alkaloid found in the Heimias).
# See Also
- Sinicuichi
- List of Entheogens | https://www.wikidoc.org/index.php/Cryogenine | |
c07758593627d11bcfff9042ea33a4670ef75fbe | wikidoc | Crystallin | Crystallin
# Overview
In biology, a crystallin is a water-soluble structural protein found in the lens of the eye, accounting for the transparency of the structure. It has also been identified in other places such as the heart
and aggressive breast cancer tumors
Since it has been shown that lens injury may promote nerve regeneration,
crystallin has been an area of neural research. So far, it has been demonstrated that crystallin ß b2 (crybb2) may be a neurite promoting factor
# Function
The main function of crystallins at least in the lens (anatomy) of the eye is probably to increase the refractive index while not obstructing light. However, this is not their only function. It is becoming increasingly clear that crystallins may have a several metabolic and regulatory functions, both within the lens and in other parts of the body .
## Enzyme activity
Interestingly and perhaps excitingly from an evolutionary perspective, some crystallins are active enzymes. A number of crystallins are related to the serine and tyrosine proteases, and others to quinone oxidoreductases. Whether these crystallins are products of a happy accident of evolution, in that these particular enzymes happened to be transparent, or whether the enzymatic activity is a part of the protective machinery of the lens, is an active research topic.
# Classification
Crystallins from a vertebrate eye lens are classified into three types: alpha, beta and gamma crystallins. These distinctions are based on the order in which they elute from a gel filtration chromatography column. These are also called ubiquitous crystallins. Beta- and gamma-crystallins are similar in sequence, structure and domains topology, and thus have been grouped together as a protein superfamily called βγ-Crystallins. The α-crystallin superfamily and βγ-crystallins compose the major superfamily of proteins present in the crystalline lens.
In addition to these crystallins there are other taxon-specific crystallins which are only found in the lens of some organisms; these include delta, epsilon, tau, and iota-crystallins. For example, alpha, beta, and delta crystallins are found in avian and reptilian lenses, and the alpha, beta, and gamma families are found in the lenses of all other vertebrates. | Crystallin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
In biology, a crystallin is a water-soluble structural protein found in the lens of the eye, accounting for the transparency of the structure. It has also been identified in other places such as the heart
[1]
and aggressive breast cancer tumors
[2].
Since it has been shown that lens injury may promote nerve regeneration[3],
crystallin has been an area of neural research. So far, it has been demonstrated that crystallin ß b2 (crybb2) may be a neurite promoting factor
[4].
# Function
The main function of crystallins at least in the lens (anatomy) of the eye is probably to increase the refractive index while not obstructing light. However, this is not their only function. It is becoming increasingly clear that crystallins may have a several metabolic and regulatory functions, both within the lens and in other parts of the body [5].
## Enzyme activity
Interestingly and perhaps excitingly from an evolutionary perspective, some crystallins are active enzymes.[6][7] A number of crystallins are related to the serine and tyrosine proteases, and others to quinone oxidoreductases. Whether these crystallins are products of a happy accident of evolution, in that these particular enzymes happened to be transparent, or whether the enzymatic activity is a part of the protective machinery of the lens, is an active research topic.[8]
# Classification
Crystallins from a vertebrate eye lens are classified into three types: alpha, beta and gamma crystallins. These distinctions are based on the order in which they elute from a gel filtration chromatography column. These are also called ubiquitous crystallins. Beta- and gamma-crystallins are similar in sequence, structure and domains topology, and thus have been grouped together as a protein superfamily called βγ-Crystallins. The α-crystallin superfamily and βγ-crystallins compose the major superfamily of proteins present in the crystalline lens.
In addition to these crystallins there are other taxon-specific crystallins which are only found in the lens of some organisms; these include delta, epsilon, tau, and iota-crystallins. For example, alpha, beta, and delta crystallins are found in avian and reptilian lenses, and the alpha, beta, and gamma families are found in the lenses of all other vertebrates.
# External links
- Graw J (1997). "The crystallins: genes, proteins and diseases". Biol Chem. 378 (11): 1331–48. PMID 9426193..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}
- Crystallins at the US National Library of Medicine Medical Subject Headings (MeSH)
- Lens Crystallin Crystal Structures by Christine Slingsby, Birkbeck Colleg | https://www.wikidoc.org/index.php/Crystallin | |
cdea916d541c70e9817bee9f36404851f4cde7e8 | wikidoc | Ctenophore | Ctenophore
# Overview
The phylum Ctenophora, commonly known as Comb Jellies, is a phylum classically grouped with Cnidaria in the Coelenterata infrakingdom. The phylum includes the sea gooseberry (Pleurobrachia pileus) and Venus' girdle (Cestum veneris). The word ctenophore (pronounced without the c, Template:IPA) comes from Greek, kteno-, kteis, "comb" and -phore, meaning "bearer". It comes via the New Latin ctenophorus in the 19th century.
Despite their appearance, they are zoologically not true jellyfish, not least because they lack the characteristic cnidocytes. There are more than 100 described species of ctenophore spread throughout the world's oceans, which form a considerable proportion of the entire plankton biomass. A few species, such as the sea gooseberry, native to the North Sea, have reached such high populations that they clog fishermen's nets, while of other species only a few examples are known. The fragile makeup of ctenophora makes research into their way of life extremely difficult; for this reason data on their lifespan are not available, but it is known that ctenophora begin to reproduce at an early age and so can be assumed to have a short generation cycle.
# Anatomy and morphology
## Body
Ctenophora are generally colourless, but they can have red, orange, or even black colour in certain species. The most common species are often only a few centimetres long. The exceptions are the species of the genus Cestum, which can reach up to one and a half metres.
The species which live in deep waters, such as the red tortuga, can appear brightly-coloured, although usually with pigments that absorb blue light, making them appear dark in the sea. A deep-sea species informally called the “Tortugas Red” is bright red in colour, presumably to absorb blue-light from its prey and the environment. Like many other ctenophores, can give off light by means of bioluminescence. One species, Eurhamphaea vexilligera, can give off an exudate of red ink which glows blue in the dark, perhaps to dissuade predators.
Ctenophora have an interesting form of symmetry, with many bilateral components, but a few asymmetrical structures such as the anal pores near the statocyst and sometimes the proportions of their auricles (ciliated lobe-like structures).
Ctenophorans are diploblastic (having only two body layers). The body consists of two transparent cell layers, which make up its outer skin (ectoderm) and inner skin (gastroderm). The ectoderm, made up of two cell layers, is mostly covered by a protective layer of slime, excreted by special glands. The gastroderm surrounds a cavity which serves as a stomach and is only accessible by the mouth opening, connected by a long, narrow gullet. Captured quarry is pre-digested in the gullet by strong enzymes and fully decomposed in the stomach. There is no separate exit from the stomach apart from two 'anal pores', which despite their name appear to be only moderately used for excretion, so indigestible waste is principally expelled via the mouth.
The space between the inner and outer skin is taken up by the mesoglea, a thick, transparent, jelly-like layer made from collagen and connective tissue, pervaded by numerous small canals, which are used for transport and storage of nutrients. The position of the canals varies from species to species, but they mostly run directly underneath the tissues that they serve. The extracellular net of structural protein is kept upright by special cells similar to amoebas.
The mesogloea may also play a role in the lift of the creatures. Cilia found in the canals of the digestive system may serve to pump water in or out of the mesogloea, when osmotic water pressure changes, perhaps because the creature has swum out of saline sea water into coastal brackish water. Ctenophora do not possess a specific circulatory system, neither do they have any organs for breathing; gas exchange and the excretion of waste products of cell metabolism such as ammonia occur over the body's entire surface through simple diffusion. The body is pervaded by a simple net of neurons without a 'brain'. These nerves are concentrated around the mouth, tentacles, 'combs' and statocysts and are connected with the muscular cells found in the mesogloea and the inner cellular layer of the ectoderm.
## Statocysts
The statocyst is a specialised system of the ctenophore that serves as a balancing organ and also controls its movement. It can be found on the end of the body opposite the oral opening and is formed by a collection of a few hundred calcareous cells balanced on four horizontal groups of serpentine flagella, known as the statolith. As outside influences cause the ctenophore to change its position, the statolith puts more pressure on one of the four flagella groups than on the other three. This sensation is transmitted to the ectoderm, which is propagated along eight long "comb rows" (ctenes). The ctenes are formed from rows of cilia, which coalesce with one another in groups of hundreds and form ctenes or comb plates about 2-5 millimetres long. By erecting these ctenes in succession, the ctenophore can use them as an oar, which, when the eight ctenes are properly synchronised, allow it to propel itself through the water. A ciliary group of the statocyst is needed for every quadrant and controls two ctenes as a pacemaker. The rhythm is carried automatically, and the signal is propagated mechanically, and not by nerve impulses.
Whether gravity acting on the statocyst raises or lowers the stroke frequency depends on the "disposition" or geotaxis of the ctenophore; the ctenophore can alter the beat frequency of different comb rows to either swim upward or downward in the water column. The "disposition" of the ctenophore is determined by sensations handled by the nerve net, in association with the ambient light levels.
## Tentacles
Many species have two opposing retractable tentacles emerging somewhere near the midpoint of the body, which are used to catch prey. From these central tentacles branch additional filaments called tentilla, which unlike in Cnidaria do not contain stinging cells, but colloblasts or "lasso cells". These cells burst open when prey comes in contact with the tentacle. Sticky threads released from each of the colloblasts will then capture the food. The colloblasts, like the tentacle, are regularly fully regenerated.
Not all varieties rely mainly on tentacles. Some like Beroe engulf gelatinous prey directly, and others instead use their muscular mouth lobes to catch food, with oral tentacles serving a secondary entangling function.
## Regeneration
Ctenophora are capable of extraordinary regeneration; even if half of the creature is destroyed, often the remaining half can rebuild itself. The same is true of single organs such as the statoliths, which can be regenerated even after being completely lost.
## Movement
Many Ctenophora simply let themselves drift with the current. They can however also swim, sometimes quite rapidly, by means of the strokes of their cilia. They are the largest animal to use their cilia for movement and can reach speeds of about five centimetres a second. A possible evolutionary advantage is that constant strokes do not cause vibrations that would alert prey or predators.
Some varieties also flap their oral lobes during escape swimming, while others move by undulating their body or creeping like flatworms.
# Distribution
## As an invasive species
Although ctenophores are generally hardly noticeable and their influence on an ecosystem is ostensibly very low, they can still do significant damage when they occur in non-native waters. The North Atlantic species Mnemiopsis leidyi was brought by ships' ballast water into the Black Sea and spread rapidly. Within ten years the anchovy fishing industry around the sea had collapsed, as the newly introduced species fed on the same plankton as the anchovy larvae. The biomass of ctenophora in the Black Sea reached a million tons at the highest point of its development.
Through the similarly sudden appearance in 1997 of another ctenophore, Beroe ovata, which feeds on Mnemiopsis leidyi, the balance was somewhat restored; since then the Black Sea has been occupied by both foreign species. The same scenario with the same species has now begun to be played out in the Caspian Sea, and Mnemiopsis was also reported from the North Sea in 2006.
The same scenario is now to wait in the Baltic Sea, where Finnish scientists have found that M. gardeni have survived the winter and spread very quickly. A recent expedition found over 600 ctenophore per cubic meter in the larger depths of the Baltic Sea.
# Ecology and life history
## Habitat
All Ctenophora live in the sea, where they live in depths of up to four kilometres. As plankton they are largely subject to movement of ocean currents, although various species are particular to certain habitats. They can be found in abundance in the tropic and to the both poles.
The most well-known species live as plankton in the ocean layers near the surface. However, as they are largely transparent, extremely fragile and rarely grow longer than a few centimetres, they are unknown to most people. On the coast Pleurobrachia species (called sea gooseberries) are encountered most frequently by beachgoers. Bolinopsis, Mnemiopsis and the tentacle-less Beroe can also be found fairly frequently.
About 35 species live on the sea bed. These species are ordered in the taxon of platyctenidae, due to their flattened forms which more closely resemble slugs or flatworms than jellyfish.
The ctenophore Mertensia ovum is one of the most predominant members of plankton in arctic waters.
## Community Ecology
Ctenophora are predators which use their tentacles to catch plankton, larvae, worms, crustaceans, Cnidaria, other Ctenophora, and sometimes small fish. When their tentacles are loaded with food, they can be retracted and wiped off. The food is then carried into the stomach either by mucus or inner cilia. The species of the genus Haeckelia feed almost exclusively on cnidaria, but do not digest their cnidocytes; instead they build them into their own tentacles as 'kleptocnidae'. This 'theft' baffled zoologists for a long time as they falsely assumed ctenophora were also capable of forming cnidocytes. Parasitism has only been observed in a single genus, Lampea, which is parasitic on salps when too small to engulf them entirely.
Among the species that prey on ctenophora are cnidaria, sea turtles, various fish such as mackerels and lumpfish, seabirds and other ctenophora.
## Life History
Ctenophora reproduce sexually, with the exception of some species of the order Platyctenida that reproduce asexually. Almost all ctenophores are hermaphroditic or monoecious, possessing both male and female reproductive organs, which lie directly under the 'combs' near the small channels of the mesogloea. The tropical lobate Ocyropsis is one genus with separate sexes. With almost all species, when triggered by outside lighting conditions, the gametes are discharged into the surrounding water through small openings in the ectoderm, the gonopores, where external fertilisation takes place. Self-fertilization is somewhat rare. The platyctene Tjalfiella tristoma, is viviparous; that is, the young grow in a brood chamber.
Certain species of Ctenophores, like Beroe ovata, have a special method of preventing polyspermy. After several sperm pronuclei have entered the egg, the egg pronucleus goes through a process where it migrates around the cell and finally chooses which sperm pronucleus it wants to fuse with, rejecting others because of signals indicating close relationship or lack of fitness.
After the fertilised eggs have divided twice, the ctenophore's later radial body symmetry has already been set. They develop into a free-floating cydippid state, which looks very similar between all ctenophora and sometimes is labeled as a larva, although in many cases this already represents a miniature version of what the creature will grow up to be. Among some groups such as lobates and platyctenids, the cydippid and adult forms do differentiate morphologically, so that the 'larva' label is more appropriate.
# Etymology and Taxonomic history
## Early classification
Sailors have observed ctenophores since ancient times. However, the first recorded sighting only came in 1671, made by a ship's doctor. The Swedish taxonomist Carl von Linné classified them with other 'primitive' invertebrates such as sea sponges (Porifera) or cnidaria as 'zoophytes' ("animal plants"), alluding to the passive, "plant-like" character of the creatures. The French zoologist Georges Cuvier supported this classification. Only in the 19th century were ctenophora recognised as a standalone taxon.
## Historical phylum
The initial classification of ctenophora has been disputed. According to cladistics, currently the leading ordering method, ctenophora are more closely related to the reflectively symmetrical bilateria than cnidaria. The fact that they have two opposing tentacles, breaking their radial symmetry and making them reflectively symmetrical, supports this, although certain structures give them a rotational or biradial symmetry. They differ from cnidaria in their possession of true muscle tissue, sticky colloblasts in place of cnidocytes, and their 'combs'. Another important sign of ctenophore's relationship with bilateria is the form of their spermatozoa. These consist in both groups of a single, large acrosome and a subacrosomic perforation disc. Cnidarian spermatozoa, in contrast, possess several acrosomic vesicles.
For this reason the 'classical' grouping of Coelenterata stands opposite the alternative taxon of acrosomata:
Alternative 1: Coelenterata
- Eumetazoa
Bilateria
Coelenterata
Cnidaria
Ctenophora
- Bilateria
- Coelenterata
Cnidaria
Ctenophora
- Cnidaria
- Ctenophora
Alternative 2: Acrosomata
- Eumetazoa
Cnidaria
Acrosomata
Bilateria
Ctenophora
- Cnidaria
- Acrosomata
Bilateria
Ctenophora
- Bilateria
- Ctenophora
In addition it has been suggested that ctenophora have a close relationship with flatworms, due to the similarities between flatworms and the flattened ctenophora of the order Platyctenida are one of the justifications for this. Some zoologists consider this resemblance superficial, and not indicative of a close relationship.
The soft bodies of ctenophores, which have no hard parts whatsoever, makes fossilisation generally very improbable, meaning that the phylogeny of ctenophora fossils is very sparsely documented. The sole fossil records, of Archaeocydippida hunsrueckiana and Paleoctenophora brasseli, date from the Devonian Period; enough details remained in the fine-grained schist of Hunsrück to make identification possible. It is disputed whether the species Maotianoascus octonarius, known from the Chengjiang Fauna of the lower Cambrian Period, is a member of the ctenophore phylum, while three species, Ctenorhabdotus capulus, Fasciculus vesanus and Xanioascus canadensis, are known from the Cambrian Burgess Shale.
## Classification
Currently about a hundred species are known, which are traditionally split into the classes of Tentaculata (also known as Tentaculifera) and Nuda (also known as Atentaculata).
- The Tentaculata make up by far the largest number of species; as their name implies, they possess tentacles, although these are sometimes vestigial. They are divided into the following six orders:
Cydippida, which includes the sea gooseberry (Pleurobrachia pileus)
Platyctenida
Ganeshida (probably larval form)
Thalassocalycida
Lobata
Cestida, which includes the Venus' belt (Cestum veneris)
- Cydippida, which includes the sea gooseberry (Pleurobrachia pileus)
- Platyctenida
- Ganeshida (probably larval form)
- Thalassocalycida
- Lobata
- Cestida, which includes the Venus' belt (Cestum veneris)
- The Nuda class contains only a single order, Beroida, to which the melon jelly (Beroe gracilis) belongs. As again the name of the taxon implies, they are distinguished by the complete absence of tentacles.
Due to the continued uncertainty over the ordering of ctenophora it is currently unclear whether the above divisions correctly reflect the actual phylogeny of the taxon. Molecular genetic studies indicate that cydipidda is a polyphyletic group, i.e. it does not include all the descendents of their common ancestor, and so the overall classification of the group needs to be revised.
The following diagram shows the putative phylogeny of ctenophora on the basis of morphologic and molecular genetic data (RNA):
The above details are however still in doubt. For the time being the phylogeny of ctenophora must be regarded as unsettled.
# Bibliography
- Much of this article is based on a translation of the corresponding German-language Wikipedia article, retrieved on 5 April 2006.
- D. T. Anderson, Invertebrate Zoology, 2nd ed, Oxford Univ. Press, 2001, Ch. 3, p. 54, ISBN 0-19-551368-1
- R. S. K. Barnes, P. Calow, P. J. W. Olive, D. W. Golding, J. I. Spicer, The invertebrates – a synthesis, 3rd ed, Blackwell, 2001, ch. 3.4.3, p. 63, ISBN 0-632-04761-5
- R. C. Brusca, G. J. Brusca, Invertebrates, 2nd Ed, Sinauer Associates, 2003, ch. 9, p. 269, ISBN 0-87893-097-3
- J. Moore, An Introduction to the Invertebrates, Cambridge Univ. Press, 2001, ch. 5.4, p. 65, ISBN 0-521-77914-6
- E. E. Ruppert, R. S. Fox, R. P. Barnes, Invertebrate Zoology – A functional evolutionary approach, Brooks/Cole 2004, ch. 8, p. 181, ISBN 0-03-025982-7
- W. Schäfer, Ctenophora, Rippenquallen, in W. Westheide and R. Rieger: Spezielle Zoologie Band 1, Gustav Fischer Verlag, Stuttgart 1996
- Bruno Wenzel, Glastiere des Meeres. Rippenquallen (Acnidaria), 1958, ISBN 3-7403-0189-9
## Scientific literature
- Harbison, G. R. 1985. On the classification and evolution of the Ctenophora. pp 78-100 in The Origins and Relationships of Lower Invertebrates. (S. C. Morris, J. D. George, R. Gibson and H. M. Platt, eds.). Oxford University Press, Oxford.
- M. Q. Martindale, J. Q. Henry, Ctenophora, in S. F. Gilbert, A. M. Raunio, Embryology: Constructing the Organism, Sinauer, 1997, p. 87
- C.E. Mills. Internet 1998-present. Phylum Ctenophora: list of all valid species names. Web page established March 1998, last updated (see date at end of page).
- M. Podar, S. H. D. Haddock, M. L. Sogin, G. R. Harbison, A molecular phylogenetic framework for the phylum Ctenophora using 18S rRNA genes, Molecular Phylogenetics and Evolution, 21, 2001, p. 218
- T. A. Shiganova, Invasion of the Black Sea by the ctenophore Mnemiopsis leidyi and recent changes in pelagic community structure, Fisheries Oceanography, 1998, p. 305
- G. D. Stanley, W. Stürmer, The first fossil ctenophore from the lower devonian of West Germany, Nature 303, 1983, p. 518 | Ctenophore
# Overview
The phylum Ctenophora, commonly known as Comb Jellies, is a phylum classically grouped with Cnidaria in the Coelenterata infrakingdom. The phylum includes the sea gooseberry (Pleurobrachia pileus) and Venus' girdle (Cestum veneris). The word ctenophore (pronounced without the c, Template:IPA) comes from Greek, kteno-, kteis, "comb" and -phore, meaning "bearer". It comes via the New Latin ctenophorus in the 19th century.
Despite their appearance, they are zoologically not true jellyfish, not least because they lack the characteristic cnidocytes. There are more than 100 described species of ctenophore spread throughout the world's oceans, which form a considerable proportion of the entire plankton biomass. A few species, such as the sea gooseberry, native to the North Sea, have reached such high populations that they clog fishermen's nets, while of other species only a few examples are known. The fragile makeup of ctenophora makes research into their way of life extremely difficult; for this reason data on their lifespan are not available, but it is known that ctenophora begin to reproduce at an early age and so can be assumed to have a short generation cycle.
# Anatomy and morphology
## Body
Ctenophora are generally colourless, but they can have red, orange, or even black colour in certain species. The most common species are often only a few centimetres long. The exceptions are the species of the genus Cestum, which can reach up to one and a half metres.
The species which live in deep waters, such as the red tortuga, can appear brightly-coloured, although usually with pigments that absorb blue light, making them appear dark in the sea. A deep-sea species informally called the “Tortugas Red” is bright red in colour, presumably to absorb blue-light from its prey and the environment. Like many other ctenophores, can give off light by means of bioluminescence. One species, Eurhamphaea vexilligera, can give off an exudate of red ink which glows blue in the dark, perhaps to dissuade predators.
Ctenophora have an interesting form of symmetry, with many bilateral components, but a few asymmetrical structures such as the anal pores near the statocyst and sometimes the proportions of their auricles (ciliated lobe-like structures).
Ctenophorans are diploblastic (having only two body layers). The body consists of two transparent cell layers, which make up its outer skin (ectoderm) and inner skin (gastroderm). The ectoderm, made up of two cell layers, is mostly covered by a protective layer of slime, excreted by special glands. The gastroderm surrounds a cavity which serves as a stomach and is only accessible by the mouth opening, connected by a long, narrow gullet. Captured quarry is pre-digested in the gullet by strong enzymes and fully decomposed in the stomach. There is no separate exit from the stomach apart from two 'anal pores', which despite their name appear to be only moderately used for excretion, so indigestible waste is principally expelled via the mouth.
The space between the inner and outer skin is taken up by the mesoglea, a thick, transparent, jelly-like layer made from collagen and connective tissue, pervaded by numerous small canals, which are used for transport and storage of nutrients. The position of the canals varies from species to species, but they mostly run directly underneath the tissues that they serve. The extracellular net of structural protein is kept upright by special cells similar to amoebas.
The mesogloea may also play a role in the lift of the creatures. Cilia found in the canals of the digestive system may serve to pump water in or out of the mesogloea, when osmotic water pressure changes, perhaps because the creature has swum out of saline sea water into coastal brackish water. Ctenophora do not possess a specific circulatory system, neither do they have any organs for breathing; gas exchange and the excretion of waste products of cell metabolism such as ammonia occur over the body's entire surface through simple diffusion. The body is pervaded by a simple net of neurons without a 'brain'. These nerves are concentrated around the mouth, tentacles, 'combs' and statocysts and are connected with the muscular cells found in the mesogloea and the inner cellular layer of the ectoderm.
## Statocysts
The statocyst is a specialised system of the ctenophore that serves as a balancing organ and also controls its movement. It can be found on the end of the body opposite the oral opening and is formed by a collection of a few hundred calcareous cells balanced on four horizontal groups of serpentine flagella, known as the statolith. As outside influences cause the ctenophore to change its position, the statolith puts more pressure on one of the four flagella groups than on the other three. This sensation is transmitted to the ectoderm, which is propagated along eight long "comb rows" (ctenes). The ctenes are formed from rows of cilia, which coalesce with one another in groups of hundreds and form ctenes or comb plates about 2-5 millimetres long. By erecting these ctenes in succession, the ctenophore can use them as an oar, which, when the eight ctenes are properly synchronised, allow it to propel itself through the water. A ciliary group of the statocyst is needed for every quadrant and controls two ctenes as a pacemaker. The rhythm is carried automatically, and the signal is propagated mechanically, and not by nerve impulses.
Whether gravity acting on the statocyst raises or lowers the stroke frequency depends on the "disposition" or geotaxis of the ctenophore; the ctenophore can alter the beat frequency of different comb rows to either swim upward or downward in the water column. The "disposition" of the ctenophore is determined by sensations handled by the nerve net, in association with the ambient light levels.
## Tentacles
Many species have two opposing retractable tentacles emerging somewhere near the midpoint of the body, which are used to catch prey. From these central tentacles branch additional filaments called tentilla, which unlike in Cnidaria do not contain stinging cells, but colloblasts or "lasso cells". These cells burst open when prey comes in contact with the tentacle. Sticky threads released from each of the colloblasts will then capture the food. The colloblasts, like the tentacle, are regularly fully regenerated.
Not all varieties rely mainly on tentacles. Some like Beroe engulf gelatinous prey directly, and others instead use their muscular mouth lobes to catch food, with oral tentacles serving a secondary entangling function.
## Regeneration
Ctenophora are capable of extraordinary regeneration; even if half of the creature is destroyed, often the remaining half can rebuild itself. The same is true of single organs such as the statoliths, which can be regenerated even after being completely lost.
## Movement
Many Ctenophora simply let themselves drift with the current. They can however also swim, sometimes quite rapidly, by means of the strokes of their cilia. They are the largest animal to use their cilia for movement and can reach speeds of about five centimetres a second. A possible evolutionary advantage is that constant strokes do not cause vibrations that would alert prey or predators.
Some varieties also flap their oral lobes during escape swimming, while others move by undulating their body or creeping like flatworms.
# Distribution
## As an invasive species
Although ctenophores are generally hardly noticeable and their influence on an ecosystem is ostensibly very low, they can still do significant damage when they occur in non-native waters. The North Atlantic species Mnemiopsis leidyi was brought by ships' ballast water into the Black Sea and spread rapidly. Within ten years the anchovy fishing industry around the sea had collapsed, as the newly introduced species fed on the same plankton as the anchovy larvae. The biomass of ctenophora in the Black Sea reached a million tons at the highest point of its development.
Through the similarly sudden appearance in 1997 of another ctenophore, Beroe ovata, which feeds on Mnemiopsis leidyi, the balance was somewhat restored; since then the Black Sea has been occupied by both foreign species. The same scenario with the same species has now begun to be played out in the Caspian Sea, and Mnemiopsis was also reported from the North Sea in 2006.
The same scenario is now to wait in the Baltic Sea, where Finnish scientists have found that M. gardeni have survived the winter and spread very quickly. A recent expedition found over 600 ctenophore per cubic meter in the larger depths of the Baltic Sea.[1]
# Ecology and life history
## Habitat
All Ctenophora live in the sea, where they live in depths of up to four kilometres. As plankton they are largely subject to movement of ocean currents, although various species are particular to certain habitats. They can be found in abundance in the tropic and to the both poles.
The most well-known species live as plankton in the ocean layers near the surface. However, as they are largely transparent, extremely fragile and rarely grow longer than a few centimetres, they are unknown to most people. On the coast Pleurobrachia species (called sea gooseberries) are encountered most frequently by beachgoers. Bolinopsis, Mnemiopsis and the tentacle-less Beroe can also be found fairly frequently.
About 35 species live on the sea bed. These species are ordered in the taxon of platyctenidae, due to their flattened forms which more closely resemble slugs or flatworms than jellyfish.
The ctenophore Mertensia ovum is one of the most predominant members of plankton in arctic waters.
## Community Ecology
Ctenophora are predators which use their tentacles to catch plankton, larvae, worms, crustaceans, Cnidaria, other Ctenophora, and sometimes small fish. When their tentacles are loaded with food, they can be retracted and wiped off. The food is then carried into the stomach either by mucus or inner cilia. The species of the genus Haeckelia feed almost exclusively on cnidaria, but do not digest their cnidocytes; instead they build them into their own tentacles as 'kleptocnidae'. This 'theft' baffled zoologists for a long time as they falsely assumed ctenophora were also capable of forming cnidocytes. Parasitism has only been observed in a single genus, Lampea, which is parasitic on salps when too small to engulf them entirely.
Among the species that prey on ctenophora are cnidaria, sea turtles, various fish such as mackerels and lumpfish, seabirds and other ctenophora.
## Life History
Ctenophora reproduce sexually, with the exception of some species of the order Platyctenida that reproduce asexually. Almost all ctenophores are hermaphroditic or monoecious, possessing both male and female reproductive organs, which lie directly under the 'combs' near the small channels of the mesogloea. The tropical lobate Ocyropsis is one genus with separate sexes. With almost all species, when triggered by outside lighting conditions, the gametes are discharged into the surrounding water through small openings in the ectoderm, the gonopores, where external fertilisation takes place. Self-fertilization is somewhat rare. The platyctene Tjalfiella tristoma, is viviparous; that is, the young grow in a brood chamber.
Certain species of Ctenophores, like Beroe ovata, have a special method of preventing polyspermy. After several sperm pronuclei have entered the egg, the egg pronucleus goes through a process where it migrates around the cell and finally chooses which sperm pronucleus it wants to fuse with, rejecting others because of signals indicating close relationship or lack of fitness.
After the fertilised eggs have divided twice, the ctenophore's later radial body symmetry has already been set. They develop into a free-floating cydippid state, which looks very similar between all ctenophora and sometimes is labeled as a larva, although in many cases this already represents a miniature version of what the creature will grow up to be. Among some groups such as lobates and platyctenids, the cydippid and adult forms do differentiate morphologically, so that the 'larva' label is more appropriate.
# Etymology and Taxonomic history
## Early classification
Sailors have observed ctenophores since ancient times. However, the first recorded sighting only came in 1671, made by a ship's doctor. The Swedish taxonomist Carl von Linné classified them with other 'primitive' invertebrates such as sea sponges (Porifera) or cnidaria as 'zoophytes' ("animal plants"), alluding to the passive, "plant-like" character of the creatures. The French zoologist Georges Cuvier supported this classification. Only in the 19th century were ctenophora recognised as a standalone taxon.
## Historical phylum
The initial classification of ctenophora has been disputed. According to cladistics, currently the leading ordering method, ctenophora are more closely related to the reflectively symmetrical bilateria than cnidaria. The fact that they have two opposing tentacles, breaking their radial symmetry and making them reflectively symmetrical, supports this, although certain structures give them a rotational or biradial symmetry. They differ from cnidaria in their possession of true muscle tissue, sticky colloblasts in place of cnidocytes, and their 'combs'. Another important sign of ctenophore's relationship with bilateria is the form of their spermatozoa. These consist in both groups of a single, large acrosome and a subacrosomic perforation disc. Cnidarian spermatozoa, in contrast, possess several acrosomic vesicles.
For this reason the 'classical' grouping of Coelenterata stands opposite the alternative taxon of acrosomata:
Alternative 1: Coelenterata
- Eumetazoa
Bilateria
Coelenterata
Cnidaria
Ctenophora
- Bilateria
- Coelenterata
Cnidaria
Ctenophora
- Cnidaria
- Ctenophora
Alternative 2: Acrosomata
- Eumetazoa
Cnidaria
Acrosomata
Bilateria
Ctenophora
- Cnidaria
- Acrosomata
Bilateria
Ctenophora
- Bilateria
- Ctenophora
In addition it has been suggested that ctenophora have a close relationship with flatworms, due to the similarities between flatworms and the flattened ctenophora of the order Platyctenida are one of the justifications for this. Some zoologists consider this resemblance superficial, and not indicative of a close relationship.
The soft bodies of ctenophores, which have no hard parts whatsoever, makes fossilisation generally very improbable, meaning that the phylogeny of ctenophora fossils is very sparsely documented. The sole fossil records, of Archaeocydippida hunsrueckiana and Paleoctenophora brasseli, date from the Devonian Period; enough details remained in the fine-grained schist of Hunsrück to make identification possible. It is disputed whether the species Maotianoascus octonarius, known from the Chengjiang Fauna of the lower Cambrian Period, is a member of the ctenophore phylum, while three species, Ctenorhabdotus capulus, Fasciculus vesanus and Xanioascus canadensis, are known from the Cambrian Burgess Shale.
## Classification
Currently about a hundred species are known, which are traditionally split into the classes of Tentaculata (also known as Tentaculifera) and Nuda (also known as Atentaculata).
- The Tentaculata make up by far the largest number of species; as their name implies, they possess tentacles, although these are sometimes vestigial. They are divided into the following six orders:
Cydippida, which includes the sea gooseberry (Pleurobrachia pileus)
Platyctenida
Ganeshida (probably larval form)
Thalassocalycida
Lobata
Cestida, which includes the Venus' belt (Cestum veneris)
- Cydippida, which includes the sea gooseberry (Pleurobrachia pileus)
- Platyctenida
- Ganeshida (probably larval form)
- Thalassocalycida
- Lobata
- Cestida, which includes the Venus' belt (Cestum veneris)
- The Nuda class contains only a single order, Beroida, to which the melon jelly (Beroe gracilis) belongs. As again the name of the taxon implies, they are distinguished by the complete absence of tentacles.
Due to the continued uncertainty over the ordering of ctenophora it is currently unclear whether the above divisions correctly reflect the actual phylogeny of the taxon. Molecular genetic studies indicate that cydipidda is a polyphyletic group, i.e. it does not include all the descendents of their common ancestor, and so the overall classification of the group needs to be revised.
The following diagram shows the putative phylogeny of ctenophora on the basis of morphologic and molecular genetic data (RNA):
The above details are however still in doubt. For the time being the phylogeny of ctenophora must be regarded as unsettled.
# Bibliography
- Much of this article is based on a translation of the corresponding German-language Wikipedia article, retrieved on 5 April 2006.
- D. T. Anderson, Invertebrate Zoology, 2nd ed, Oxford Univ. Press, 2001, Ch. 3, p. 54, ISBN 0-19-551368-1
- R. S. K. Barnes, P. Calow, P. J. W. Olive, D. W. Golding, J. I. Spicer, The invertebrates – a synthesis, 3rd ed, Blackwell, 2001, ch. 3.4.3, p. 63, ISBN 0-632-04761-5
- R. C. Brusca, G. J. Brusca, Invertebrates, 2nd Ed, Sinauer Associates, 2003, ch. 9, p. 269, ISBN 0-87893-097-3
- J. Moore, An Introduction to the Invertebrates, Cambridge Univ. Press, 2001, ch. 5.4, p. 65, ISBN 0-521-77914-6
- E. E. Ruppert, R. S. Fox, R. P. Barnes, Invertebrate Zoology – A functional evolutionary approach, Brooks/Cole 2004, ch. 8, p. 181, ISBN 0-03-025982-7
- W. Schäfer, Ctenophora, Rippenquallen, in W. Westheide and R. Rieger: Spezielle Zoologie Band 1, Gustav Fischer Verlag, Stuttgart 1996
- Bruno Wenzel, Glastiere des Meeres. Rippenquallen (Acnidaria), 1958, ISBN 3-7403-0189-9
## Scientific literature
- Harbison, G. R. 1985. On the classification and evolution of the Ctenophora. pp 78-100 in The Origins and Relationships of Lower Invertebrates. (S. C. Morris, J. D. George, R. Gibson and H. M. Platt, eds.). Oxford University Press, Oxford.
- M. Q. Martindale, J. Q. Henry, Ctenophora, in S. F. Gilbert, A. M. Raunio, Embryology: Constructing the Organism, Sinauer, 1997, p. 87
- C.E. Mills. Internet 1998-present. Phylum Ctenophora: list of all valid species names. Web page established March 1998, last updated (see date at end of page).
- M. Podar, S. H. D. Haddock, M. L. Sogin, G. R. Harbison, A molecular phylogenetic framework for the phylum Ctenophora using 18S rRNA genes, Molecular Phylogenetics and Evolution, 21, 2001, p. 218
- T. A. Shiganova, Invasion of the Black Sea by the ctenophore Mnemiopsis leidyi and recent changes in pelagic community structure, Fisheries Oceanography, 1998, p. 305
- G. D. Stanley, W. Stürmer, The first fossil ctenophore from the lower devonian of West Germany, Nature 303, 1983, p. 518 | https://www.wikidoc.org/index.php/Ctenophore | |
f873e49313fc60bd4e601cf51ca2010be89186e8 | wikidoc | Daptomycin | Daptomycin
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# Overview
Daptomycin is an antibacterial agent that is FDA approved for the treatment of complicated skin and skin structure infections (cSSSI), staphylococcus aureus bloodstream infections (bacteremia), including those with right-sided infective endocarditis. Common adverse reactions include diarrhea, vomiting, and pain in throat.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Complicated skin and skin structure infections (cSSSI) caused by susceptible isolates of the following Gram-positive bacteria: Staphylococcus aureus (including methicillin-resistant isolates), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae subsp. equisimilis, and Enterococcus faecalis (vancomycin-susceptible isolates only).
- Dosing Information
- CUBICIN 4 mg/kg should be administered intravenously in 0.9% sodium chloride injection once every 24 hours for 7 to 14 days.
- Staphylococcus aureus bloodstream infections (bacteremia), including those with right-sided infective endocarditis, caused by methicillin-susceptible and methicillin-resistant isolates.
- Dosing Information
- CUBICIN 6 mg/kg should be administered intravenously in 0.9% sodium chloride injection once every 24 hours for 2 to 6 weeks. There are limited safety data for the use of CUBICIN for more than 28 days of therapy. In the Phase 3 trial, there were a total of 14 patients who were treated with CUBICIN for more than 28 days.
- Administration Duration
- CUBICIN should be administered intravenously either by injection over a two (2) minute period or by infusion over a thirty (30) minute period.
- Patients with Renal Impairment
- The recommended dosage regimen for patients with creatinine clearance (CLCR) <30 mL/min, including patients on hemodialysis or continuous ambulatory peritoneal dialysis (CAPD), is 4 mg/kg (cSSSI) or 6 mg/kg (S. aureus bloodstream infections) once every 48 hours (Table 1). When possible, CUBICIN should be administered following the completion of hemodialysis on hemodialysis days.
- Preparation of CUBICIN for Administration
- CUBICIN is supplied in single-use vials, each containing 500 mg daptomycin as a sterile, lyophilized powder. The contents of a CUBICIN vial should be reconstituted, using aseptic technique, to 50 mg/mL as follows:
- Note: To minimize foaming, AVOID vigorous agitation or shaking of the vial during or after reconstitution.
- Remove the polypropylene flip-off cap from the CUBICIN vial to expose the central portion of the rubber stopper.
- Slowly transfer 10 mL of 0.9% sodium chloride injection through the center of the rubber stopper into the CUBICIN vial, pointing the transfer needle toward the wall of the vial.
- Ensure that all of the CUBICIN powder is wetted by gently rotating the vial.
- Allow the wetted product to stand undisturbed for 10 minutes.
- Gently rotate or swirl the vial contents for a few minutes, as needed, to obtain a completely reconstituted solution.
- For intravenous (IV) injection over a period of 2 minutes, administer the appropriate volume of the reconstituted CUBICIN (concentration of 50 mg/mL).
- For IV infusion over a period of 30 minutes, the appropriate volume of the reconstituted CUBICIN (concentration of 50 mg/mL) should be further diluted, using aseptic technique, into a 50 mL IV infusion bag containing 0.9% sodium chloride injection.
- Parenteral drug products should be inspected visually for particulate matter prior to administration.
- No preservative or bacteriostatic agent is present in this product. Aseptic technique must be used in the preparation of final IV solution.
- Stability studies have shown that the reconstituted solution is stable in the vial for 12 hours at room temperature and up to 48 hours if stored under refrigeration at 2 to 8°C (36 to 46°F).
- The diluted solution is stable in the infusion bag for 12 hours at room temperature and 48 hours if stored under refrigeration. The combined storage time (reconstituted solution in vial and diluted solution in infusion bag) should not exceed 12 hours at room temperature or 48 hours under refrigeration.
- CUBICIN vials are for single use only.
- Dosage Forms And Strengths
- 500 mg daptomycin as a sterile, pale yellow to light brown lyophilized powder for reconstitution in a single-use vial.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Daptomycin in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- Daptomycin high-dose (6 mg/kg or greater) or low-dose (less than 6 mg/kg)
- Dosing Information
- Daptomycin 5 mg/kg once daily and for a median of 22 days
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Daptomycin in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Daptomycin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Daptomycin in pediatric patients.
# Contraindications
- CUBICIN is contraindicated in patients with known hypersensitivity to daptomycin.
# Warnings
### Precautions
- Anaphylaxis/Hypersensitivity Reactions
- Anaphylaxis/hypersensitivity reactions have been reported with the use of antibacterial agents, including CUBICIN, and may be life-threatening.
- If an allergic reaction to CUBICIN occurs, discontinue the drug and institute appropriate therapy.
- Myopathy and Rhabdomyolysis
- Myopathy, defined as muscle aching or muscle weakness in conjunction with increases in creatine phosphokinase (CPK) values to greater than 10 times the upper limit of normal (ULN), has been reported with the use of CUBICIN. Rhabdomyolysis, with or without acute renal failure, has been reported.
- Patients receiving CUBICIN should be monitored for the development of muscle pain or weakness, particularly of the distal extremities. In patients who receive CUBICIN, CPK levels should be monitored weekly, and more frequently in patients who received recent prior or concomitant therapy with an HMG-CoA reductase inhibitor or in whom elevations in CPK occur during treatment with CUBICIN.
- In patients with renal impairment, both renal function and CPK should be monitored more frequently than once weekly.
- In Phase 1 studies and Phase 2 clinical trials, CPK elevations appeared to be more frequent when CUBICIN was dosed more than once daily.
- Therefore, CUBICIN should not be dosed more frequently than once a day.
- CUBICIN should be discontinued in patients with unexplained signs and symptoms of myopathy in conjunction with CPK elevations to levels >1,000 U/L (~5× ULN), and in patients without reported symptoms who have marked elevations in CPK, with levels >2,000 U/L (≥10× ULN). In addition, consideration should be given to suspending agents associated with rhabdomyolysis, such as HMG-CoA reductase inhibitors, temporarily in patients receiving CUBICIN.
- Eosinophilic Pneumonia
- Eosinophilic pneumonia has been reported in patients receiving CUBICIN. In reported cases associated with CUBICIN, patients developed fever, dyspnea with hypoxic respiratory insufficiency, and diffuse pulmonary infiltrates. In general, patients developed eosinophilic pneumonia 2 to 4 weeks after starting CUBICIN and improved when CUBICIN was discontinued and steroid therapy was initiated. Recurrence of eosinophilic pneumonia upon re-exposure has been reported. Patients who develop these signs and symptoms while receiving CUBICIN should undergo prompt medical evaluation, and CUBICIN should be discontinued immediately. Treatment with systemic steroids is recommended.
- Peripheral Neuropathy
- Cases of peripheral neuropathy have been reported during the CUBICIN postmarketing experience. Therefore, physicians should be alert to signs and symptoms of peripheral neuropathy in patients receiving CUBICIN.
- Clostridium difficile–Associated Diarrhea
- Clostridium difficile–associated diarrhea (CDAD) has been reported with the use of nearly all systemic antibacterial agents, including CUBICIN, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon, leading to overgrowth of C. difficile.
- C. difficile produces toxins A and B, which contribute to the development of CDAD. Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, since these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary because CDAD has been reported to occur more than 2 months after the administration of antibacterial agents.
- If CDAD is suspected or confirmed, ongoing antibacterial use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
- Persisting or Relapsing S. aureus Bacteremia/Endocarditis
- Patients with persisting or relapsing S. aureus bacteremia/endocarditis or poor clinical response should have repeat blood cultures. If a blood culture is positive for S. aureus, minimum inhibitory concentration (MIC) susceptibility testing of the isolate should be performed using a standardized procedure, and diagnostic evaluation of the patient should be performed to rule out sequestered foci of infection. Appropriate surgical intervention (e.g., debridement, removal of prosthetic devices, valve replacement surgery) and/or consideration of a change in antibacterial regimen may be required.
- Failure of treatment due to persisting or relapsing S. aureus bacteremia/endocarditis may be due to reduced daptomycin susceptibility (as evidenced by increasing MIC of the S. aureus isolate).
- Decreased Efficacy in Patients with Moderate Baseline Renal Impairment
- Limited data are available from the two Phase 3 complicated skin and skin structure infection (cSSSI) trials regarding clinical efficacy of CUBICIN treatment in patients with creatinine clearance (CLCR) <50 mL/min; only 31/534 (6%) patients treated with CUBICIN in the intent-to-treat (ITT) population had a baseline CLCR <50 mL/min. Table 2 shows the number of patients by renal function and treatment group who were clinical successes in the Phase 3 cSSSI trials.
- In a subgroup analysis of the ITT population in the Phase 3 S. aureus bacteremia/endocarditis trial, clinical success rates, as determined by a treatment-blinded Adjudication Committee, in the CUBICIN-treated patients were lower in patients with baseline CLCR <50 mL/min (see Table 3). A decrease of the magnitude shown in Table 3 was not observed in comparator-treated patients.
- Consider these data when selecting antibacterial therapy for use in patients with baseline moderate to severe renal impairment.
- Drug-Laboratory Test Interactions
- Clinically relevant plasma concentrations of daptomycin have been observed to cause a significant concentration-dependent false prolongation of prothrombin time (PT) and elevation of International Normalized Ratio (INR) when certain recombinant thromboplastin reagents are utilized for the assay.
- Non-Susceptible Microorganisms
- The use of antibacterials may promote the overgrowth of non-susceptible microorganisms. If superinfection occurs during therapy, appropriate measures should be taken.
- Prescribing CUBICIN in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
# Adverse Reactions
## Clinical Trials Experience
- Clinical trials enrolled 1,864 patients treated with CUBICIN and 1,416 treated with comparator.
- In Phase 3 complicated skin and skin structure infection (cSSSI) trials, CUBICIN was discontinued in 15/534 (2.8%) patients due to an adverse reaction, while comparator was discontinued in 17/558 (3.0%) patients.
- The rates of the most common adverse reactions, organized by body system, observed in cSSSI (4 mg/kg CUBICIN) patients are displayed in Table 4.
- Drug-related adverse reactions (possibly or probably drug-related) that occurred in <1% of patients receiving CUBICIN in the cSSSI trials are as follows:
- Fatigue, weakness, rigors, flushing, hypersensitivity.
- Supraventricular arrhythmia.
- Abdominal distension, stomatitis, jaundice, increased serum lactate dehydrogenase.
- Leukocytosis, thrombocytopenia, thrombocytosis, eosinophilia, increased International Normalized Ratio (INR).
- Hypomagnesemia, increased serum bicarbonate, electrolyte disturbance.
- Myalgia, muscle cramps, muscle weakness, arthralgia.
- Vertigo, mental status change, paresthesia.
- Taste disturbance, eye irritation.
- In the S. aureus bacteremia/endocarditis trial, CUBICIN was discontinued in 20/120 (16.7%) patients due to an adverse reaction, while comparator was discontinued in 21/116 (18.1%) patients.
- Serious Gram-negative infections (including bloodstream infections) were reported in 10/120 (8.3%) CUBICIN-treated patients and 0/115 comparator-treated patients. Comparator-treated patients received dual therapy that included initial gentamicin for 4 days. Infections were reported during treatment and during early and late follow-up. Gram-negative infections included cholangitis, alcoholic pancreatitis, sternal osteomyelitis/mediastinitis, bowel infarction, recurrent Crohn's disease, recurrent line sepsis, and recurrent urosepsis caused by a number of different Gram-negative bacteria.
- The rates of the most common adverse reactions, organized by System Organ Class (SOC), observed in S. aureus bacteremia/endocarditis (6 mg/kg CUBICIN) patients are displayed in Table 5.
- The following reactions, not included above, were reported as possibly or probably drug-related in the CUBICIN-treated group:
Eosinophilia, lymphadenopathy, thrombocythemia, thrombocytopenia
Atrial fibrillation, atrial flutter, cardiac arrest
Tinnitus
Blurred vision
Dry mouth, epigastric discomfort, gingival pain, hypoesthesia oral
Candidal infection NOS, vaginal candidiasis, fungemia, oral candidiasis, urinary tract infection fungal
Blood phosphorous increased, blood alkaline phosphatase increased, INR increased, liver function test abnormal, alanine aminotransferase increased, aspartate aminotransferase increased, prothrombin time prolonged
Appetite decreased NOS
Myalgia
Dyskinesia, paresthesia
Hallucination NOS
Proteinuria, renal impairment NOS
Pruritus generalized, vesicular rash
- In Phase 3 trials of community-acquired pneumonia (CAP), the death rate and rates of serious cardiorespiratory adverse events were higher in CUBICIN-treated patients than in comparator-treated patients. These differences were due to lack of therapeutic effectiveness of CUBICIN in the treatment of CAP in patients experiencing these adverse events.
- In Phase 3 cSSSI trials of CUBICIN at a dose of 4 mg/kg, elevations in CPK were reported as clinical adverse events in 15/534 (2.8%) CUBICIN-treated patients, compared with 10/558 (1.8%) comparator-treated patients. Of the 534 patients treated with CUBICIN, 1 (0.2%) had symptoms of muscle pain or weakness associated with CPK elevations to greater than 4 times the upper limit of normal (ULN). The symptoms resolved within 3 days and CPK returned to normal within 7 to 10 days after treatment was discontinued. Table 6 summarizes the CPK shifts from Baseline through End of Therapy in the cSSSI trials.
- In the S. aureus bacteremia/endocarditis trial, at a dose of 6 mg/kg, 11/120 (9.2%) CUBICIN-treated patients, including two patients with baseline CPK levels >500 U/L, had CPK elevations to levels >500 U/L, compared with 1/116 (0.9%) comparator-treated patients. Of the 11 CUBICIN-treated patients, 4 had prior or concomitant treatment with an HMG-CoA reductase inhibitor. Three of these 11 CUBICIN-treated patients discontinued therapy due to CPK elevation, while the one comparator-treated patient did not discontinue therapy.
## Postmarketing Experience
- The following adverse reactions have been identified during postapproval use of CUBICIN. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency reliably or establish a causal relationship to drug exposure.
- Anaphylaxis; hypersensitivity reactions, including angioedema, drug rash with eosinophilia and systemic symptoms (DRESS syndrome), pruritus, hives, shortness of breath, difficulty swallowing, truncal erythema, and pulmonary eosinophilia.
- Clostridium difficile–associated diarrhea.
- Myoglobin increased; rhabdomyolysis (some reports involved patients treated concurrently with CUBICIN and HMG-CoA reductase inhibitors).
- Cough, eosinophilic pneumonia.
- Peripheral neuropathy.
- Serious skin reactions, including Stevens-Johnson syndrome and vesiculobullous rash (with or without mucous membrane involvement).
- Nausea, vomiting.
# Drug Interactions
- In healthy subjects, concomitant administration of CUBICIN and simvastatin had no effect on plasma trough concentrations of simvastatin, and there were no reports of skeletal myopathy.
- However, inhibitors of HMG-CoA reductase may cause myopathy, which is manifested as muscle pain or weakness associated with elevated levels of creatine phosphokinase (CPK). In the Phase 3 S. aureus bacteremia/endocarditis trial, some patients who received prior or concomitant treatment with an HMG-CoA reductase inhibitor developed elevated CPK. Experience with the coadministration of HMG-CoA reductase inhibitors and CUBICIN in patients is limited; therefore, consideration should be given to suspending use of HMG-CoA reductase inhibitors temporarily in patients receiving CUBICIN.
- Clinically relevant plasma concentrations of daptomycin have been observed to cause a significant concentration-dependent false prolongation of prothrombin time (PT) and elevation of International Normalized Ratio (INR) when certain recombinant thromboplastin reagents are utilized for the assay. The possibility of an erroneously elevated PT/INR result due to interaction with a recombinant thromboplastin reagent may be minimized by drawing specimens for PT or INR testing near the time of trough plasma concentrations of daptomycin. However, sufficient daptomycin concentrations may be present at trough to cause interaction.
- If confronted with an abnormally high PT/INR result in a patient being treated with CUBICIN, it is recommended that clinicians:
- Repeat the assessment of PT/INR, requesting that the specimen be drawn just prior to the next CUBICIN dose (i.e., at trough concentration). If the PT/INR value obtained at trough remains substantially elevated above what would otherwise be expected, consider evaluating PT/INR utilizing an alternative method.
- Evaluate for other causes of abnormally elevated PT/INR results.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category B
- There are no adequate and well-controlled trials of CUBICIN in pregnant women. Embryofetal development studies performed in rats and rabbits at doses of up to 75 mg/kg (2 and 4 times the 6 mg/kg human dose, respectively, on a body surface area basis) revealed no evidence of harm to the fetus due to daptomycin. Because animal reproduction studies are not always predictive of human response, CUBICIN should be used during pregnancy only if the potential benefit outweighs the possible risk.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Daptomycin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Daptomycin during labor and delivery.
### Nursing Mothers
- Daptomycin is present in human milk but is poorly bioavailable orally. In a single case study, CUBICIN was administered daily for 28 days to a nursing mother at an IV dose of 6.7 mg/kg/day, and samples of the patient's breast milk were collected over a 24-hour period on day 27. The highest measured concentration of daptomycin in the breast milk was 0.045 mcg/mL1. The calculated maximum daily CUBICIN dose to the infant (assuming mean milk consumption of 150 mL/kg/day) was 0.1% of the maternal dose of 6.7 mg/kg/day. Caution should be exercised when CUBICIN is administered to a nursing woman.
### Pediatric Use
There is no FDA guidance on the use of Daptomycin with respect to pediatric patients.
### Geriatic Use
- Of the 534 patients treated with CUBICIN in Phase 3 controlled clinical trials of complicated skin and skin structure infections (cSSSI), 27% were 65 years of age or older and 12% were 75 years of age or older. Of the 120 patients treated with CUBICIN in the Phase 3 controlled clinical trial of S. aureus bacteremia/endocarditis, 25% were 65 years of age or older and 16% were 75 years of age or older. In Phase 3 clinical trials of cSSSI and S. aureus bacteremia/endocarditis, clinical success rates were lower in patients ≥65 years of age than in patients <65 years of age. In addition, treatment-emergent adverse events were more common in patients ≥65 years of age than in patients <65 years of age.
- The exposure of daptomycin was higher in healthy elderly subjects than in healthy young subjects. However, no adjustment of CUBICIN dosage is warranted for elderly patients with creatinine clearance (CLCR) ≥30 mL/min.
### Gender
There is no FDA guidance on the use of Daptomycin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Daptomycin with respect to specific racial populations.
### Renal Impairment
- Daptomycin is eliminated primarily by the kidneys; therefore, a modification of CUBICIN dosage interval is recommended for patients with CLCR <30 mL/min, including patients receiving hemodialysis or continuous ambulatory peritoneal dialysis (CAPD). In patients with renal impairment, both renal function and creatine phosphokinase (CPK) should be monitored more frequently than once weekly
### Hepatic Impairment
There is no FDA guidance on the use of Daptomycin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Daptomycin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Daptomycin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
### Monitoring
- Patients receiving CUBICIN should be monitored for the development of muscle pain or weakness, particularly of the distal extremities. In patients who receive CUBICIN, CPK levels should be monitored weekly, and more frequently in patients who received recent prior or concomitant therapy with an HMG-CoA reductase inhibitor or in whom elevations in CPK occur during treatment with CUBICIN.
- In patients with renal impairment, both renal function and creatine phosphokinase (CPK) should be monitored more frequently than once weekly
# IV Compatibility
CUBICIN is compatible with 0.9% sodium chloride injection and lactated Ringer's injection.
# Overdosage
## Acute Overdose
- In the event of overdosage, supportive care is advised with maintenance of glomerular filtration. Daptomycin is cleared slowly from the body by hemodialysis (approximately 15% of the administered dose is removed over 4 hours) and by peritoneal dialysis (approximately 11% of the administered dose is removed over 48 hours). The use of high-flux dialysis membranes during 4 hours of hemodialysis may increase the percentage of dose removed compared with that removed by low-flux membranes.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Daptomycin in the drug label.
# Pharmacology
## Mechanism of Action
- Daptomycin is an antibacterial drug. The mechanism of action of daptomycin is distinct from that of any other antibacterial. Daptomycin binds to bacterial cell membranes and causes a rapid depolarization of membrane potential. This loss of membrane potential causes inhibition of DNA, RNA, and protein synthesis, which results in bacterial cell death.
## Structure
- CUBICIN contains daptomycin, a cyclic lipopeptide antibacterial agent derived from the fermentation of Streptomyces roseosporus. The chemical name is N-decanoyl-L-tryptophyl-D-asparaginyl-L-aspartyl-L-threonylglycyl-L-ornithyl-L-aspartyl-D-alanyl-L-aspartylglycyl-D-seryl-threo-3-methyl-L-glutamyl-3-anthraniloyl-L-alanine ε1-lactone. The chemical structure is:
- The empirical formula is C72H101N17O26; the molecular weight is 1620.67. CUBICIN is supplied in a single-use vial as a sterile, preservative-free, pale yellow to light brown, lyophilized cake containing approximately 500 mg of daptomycin for intravenous (IV) use following reconstitution with 0.9% sodium chloride injection. The only inactive ingredient is sodium hydroxide, which is used in minimal quantities for pH adjustment. Freshly reconstituted solutions of CUBICIN range in color from pale yellow to light brown.
## Pharmacodynamics
- Based on animal models of infection, the antimicrobial activity of daptomycin appears to correlate with the AUC/MIC (area under the concentration-time curve/minimum inhibitory concentration) ratio for certain pathogens, including S. aureus. The principal pharmacokinetic/pharmacodynamic parameter best associated with clinical and microbiological cure has not been elucidated in clinical trials with CUBICIN.
## Pharmacokinetics
- CUBICIN Administered over a 30-Minute Period
- The mean and standard deviation (SD) pharmacokinetic parameters of daptomycin at steady-state following intravenous (IV) administration of CUBICIN over a 30-minute period at 4 to 12 mg/kg q24h to healthy young adults are summarized in Table 7
- Daptomycin pharmacokinetics were generally linear and time-independent at CUBICIN doses of 4 to 12 mg/kg q24h administered by IV infusion over a 30-minute period for up to 14 days. Steady-state trough concentrations were achieved by the third daily dose. The mean (SD) steady-state trough concentrations attained following the administration of 4, 6, 8, 10, and 12 mg/kg q24h were 5.9 (1.6), 6.7 (1.6), 10.3 (5.5), 12.9 (2.9), and 13.7 (5.2) mcg/mL, respectively.
- CUBICIN Administered over a 2-Minute Period
- Following IV administration of CUBICIN over a 2-minute period to healthy volunteers at doses of 4 mg/kg (N=8) and 6 mg/kg (N=12), the mean (SD) steady-state systemic exposure (AUC) values were 475 (71) and 701 (82) mcgh/mL, respectively. Values for maximum plasma concentration (Cmax) at the end of the 2-minute period could not be determined adequately in this study. However, using pharmacokinetic parameters from 14 healthy volunteers who received a single dose of CUBICIN 6 mg/kg IV administered over a 30-minute period in a separate study, steady-state Cmax values were simulated for CUBICIN 4 and 6 mg/kg IV administered over a 2-minute period. The simulated mean (SD) steady-state Cmax values were 77.7 (8.1) and 116.6 (12.2) mcg/mL, respectively.
- Distribution
- Daptomycin is reversibly bound to human plasma proteins, primarily to serum albumin, in a concentration-independent manner. The overall mean binding ranges from 90 to 93%.
- In clinical studies, mean serum protein binding in subjects with creatinine clearance (CLCR) ≥30 mL/min was comparable to that observed in healthy subjects with normal renal function. However, there was a trend toward decreasing serum protein binding among subjects with CLCR <30 mL/min (88%), including those receiving hemodialysis (86%) and continuous ambulatory peritoneal dialysis (CAPD) (84%). The protein binding of daptomycin in subjects with moderate hepatic impairment (Child-Pugh Class B) was similar to that in healthy adult subjects.
- The volume of distribution at steady-state (Vss) of daptomycin in healthy adult subjects was approximately 0.1 L/kg and was independent of dose.
- Metabolism
- In in vitro studies, daptomycin was not metabolized by human liver microsomes.
- In 5 healthy adults after infusion of radiolabeled 14C-daptomycin, the plasma total radioactivity was similar to the concentration determined by microbiological assay. Inactive metabolites were detected in urine, as determined by the difference between total radioactive concentrations and microbiologically active concentrations. In a separate study, no metabolites were observed in plasma on Day 1 following the administration of CUBICIN at 6 mg/kg to subjects. Minor amounts of three oxidative metabolites and one unidentified compound were detected in urine. The site of metabolism has not been identified.
- Excretion
- Daptomycin is excreted primarily by the kidneys. In a mass balance study of 5 healthy subjects using radiolabeled daptomycin, approximately 78% of the administered dose was recovered from urine based on total radioactivity (approximately 52% of the dose based on microbiologically active concentrations), and 5.7% of the administered dose was recovered from feces (collected for up to 9 days) based on total radioactivity.
- Specific Populations
- Renal Impairment
- Population-derived pharmacokinetic parameters were determined for infected patients (complicated skin and skin structure infections and S. aureus bacteremia) and noninfected subjects with various degrees of renal function (Table 8). Total plasma clearance (CLT), elimination half-life (t1/2), and volume of distribution at steady-state (Vss) in patients with cSSSI were similar to those in patients with S. aureus bacteremia. Following administration of CUBICIN 4 mg/kg q24h by IV infusion over a 30-minute period, the mean CLT was 9%, 22%, and 46% lower among subjects and patients with mild (CLCR 50–80 mL/min), moderate (CLCR 30–80 mL/min). The mean steady-state systemic exposure (AUC), t1/2, and Vss increased with decreasing renal function, although the mean AUC for patients with CLCR 30–80 mL/min was not markedly different from the mean AUC for patients with normal renal function. The mean AUC for patients with CLCR <30 mL/min and for patients on dialysis (CAPD and hemodialysis dosed post-dialysis) was approximately 2 and 3 times higher, respectively, than for patients with normal renal function. The mean Cmax ranged from 60 to 70 mcg/mL in patients with CLCR ≥30 mL/min, while the mean Cmax for patients with CLCR <30 mL/min ranged from 41 to 58 mcg/mL. After administration of CUBICIN 6 mg/kg q24h by IV infusion over a 30-minute period, the mean Cmax ranged from 80 to 114 mcg/mL in patients with mild to moderate renal impairment and was similar to that of patients with normal renal function.
- Because renal excretion is the primary route of elimination, adjustment of CUBICIN dosage interval is necessary in patients with severe renal impairment (CLCR <30 mL/min).
- Hepatic Impairment
- The pharmacokinetics of daptomycin were evaluated in 10 subjects with moderate hepatic impairment (Child-Pugh Class B) and compared with those in healthy volunteers (N=9) matched for gender, age, and weight. The pharmacokinetics of daptomycin were not altered in subjects with moderate hepatic impairment. No dosage adjustment is warranted when CUBICIN is administered to patients with mild to moderate hepatic impairment. The pharmacokinetics of daptomycin in patients with severe hepatic impairment (Child-Pugh Class C) have not been evaluated.
- Gender
- No clinically significant gender-related differences in daptomycin pharmacokinetics have been observed. No dosage adjustment is warranted based on gender when CUBICIN is administered.
- Geriatric
- The pharmacokinetics of daptomycin were evaluated in 12 healthy elderly subjects (≥75 years of age) and 11 healthy young controls (18 to 30 years of age). Following administration of a single 4 mg/kg dose of CUBICIN by IV infusion over a 30-minute period, the mean total clearance of daptomycin was approximately 35% lower and the mean AUC0-∞ was approximately 58% higher in elderly subjects than in healthy young subjects. There were no differences in Cmax.
- Obesity
- The pharmacokinetics of daptomycin were evaluated in 6 moderately obese (Body Mass Index 25 to 39.9 kg/m2) and 6 extremely obese (BMI ≥40 kg/m2) subjects and controls matched for age, gender, and renal function. Following administration of CUBICIN by IV infusion over a 30-minute period as a single 4 mg/kg dose based on total body weight, the total plasma clearance of daptomycin normalized to total body weight was approximately 15% lower in moderately obese subjects and 23% lower in extremely obese subjects than in nonobese controls. The AUC0-∞ of daptomycin was approximately 30% higher in moderately obese subjects and 31% higher in extremely obese subjects than in nonobese controls. The differences were most likely due to differences in the renal clearance of daptomycin. No adjustment of CUBICIN dosage is warranted in obese patients.
- Pediatric
- The pharmacokinetics of daptomycin in pediatric populations (<18 years of age) have not been established.
- Drug-Drug Interactions
- In Vitro Studies
- In vitro studies with human hepatocytes indicate that daptomycin does not inhibit or induce the activities of the following human cytochrome P450 isoforms: 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4. It is unlikely that daptomycin will inhibit or induce the metabolism of drugs metabolized by the P450 system.
- Aztreonam
- In a study in which 15 healthy adult subjects received a single dose of CUBICIN 6 mg/kg IV and a combination dose of CUBICIN 6 mg/kg IV and aztreonam 1 g IV, administered over a 30-minute period, the Cmax and AUC0-∞ of daptomycin were not significantly altered by aztreonam.
- Tobramycin
- In a study in which 6 healthy adult males received a single dose of CUBICIN 2 mg/kg IV, tobramycin 1 mg/kg IV, and both in combination, administered over a 30-minute period, the mean Cmax and AUC0-∞ of daptomycin were 12.7% and 8.7% higher, respectively, when CUBICIN was coadministered with tobramycin. The mean Cmax and AUC0-∞ of tobramycin were 10.7% and 6.6% lower, respectively, when tobramycin was coadministered with CUBICIN. These differences were not statistically significant. The interaction between daptomycin and tobramycin with a clinical dose of CUBICIN is unknown.
- Warfarin
- In 16 healthy subjects, administration of CUBICIN 6 mg/kg q24h by IV infusion over a 30-minute period for 5 days, with coadministration of a single oral dose of warfarin (25 mg) on the 5th day, had no significant effect on the pharmacokinetics of either drug and did not significantly alter the INR (International Normalized Ratio).
- Simvastatin
- In 20 healthy subjects on a stable daily dose of simvastatin 40 mg, administration of CUBICIN 4 mg/kg q24h by IV infusion over a 30-minute period for 14 days (N=10) had no effect on plasma trough concentrations of simvastatin and was not associated with a higher incidence of adverse events, including skeletal myopathy, than in subjects receiving placebo once daily (N=10).
- Probenecid
- Concomitant administration of probenecid (500 mg 4 times daily) and a single dose of CUBICIN 4 mg/kg by IV infusion over a 30-minute period did not significantly alter the Cmax or AUC0-∞ of daptomycin.
- Daptomycin belongs to the cyclic lipopeptide class of antibacterials. Daptomycin has clinical utility in the treatment of infections caused by aerobic, Gram-positive bacteria. The in vitro spectrum of activity of daptomycin encompasses most clinically relevant Gram-positive pathogenic bacteria.
- Daptomycin exhibits rapid, concentration-dependent bactericidal activity against Gram-positive bacteria in vitro. This has been demonstrated both by time-kill curves and by MBC/MIC (minimum bactericidal concentration/minimum inhibitory concentration) ratios using broth dilution methodology. Daptomycin maintained bactericidal activity in vitro against stationary phase S. aureus in simulated endocardial vegetations. The clinical significance of this is not known.
- Mechanism of Action
- The mechanism of action of daptomycin is distinct from that of any other antibacterial. Daptomycin binds to bacterial cell membranes and causes a rapid depolarization of membrane potential. This loss of membrane potential causes inhibition of DNA, RNA, and protein synthesis, which results in bacterial cell death.
- Mechanism of Resistance
- The mechanism(s) of daptomycin resistance is not fully understood. Currently, there are no known transferable elements that confer resistance to daptomycin.
- Complicated Skin and Skin Structure Infection (cSSSI) Trials
- The emergence of daptomycin non-susceptible isolates occurred in 2 infected patients across the set of Phase 2 and pivotal Phase 3 clinical trials of cSSSI. In one case, a non-susceptible S. aureus was isolated from a patient in a Phase 2 trial who received CUBICIN at less than the protocol-specified dose for the initial 5 days of therapy. In the second case, a non-susceptible Enterococcus faecalis was isolated from a patient with an infected chronic decubitus ulcer who was enrolled in a salvage trial.
- S. aureus Bacteremia/Endocarditis and Other Post-Approval Trials
- In subsequent clinical trials, non-susceptible isolates were recovered. S. aureus was isolated from a patient in a compassionate-use trial and from 7 patients in the S. aureus bacteremia/endocarditis trial. An E. faecium was isolated from a patient in a vancomycin-resistant enterococci trial.
- Interactions with Other Antibacterials
- In vitro studies have investigated daptomycin interactions with other antibacterials. Antagonism, as determined by kill curve studies, has not been observed. In vitro synergistic interactions of daptomycin with aminoglycosides, β-lactam antibacterials, and rifampin have been shown against some isolates of staphylococci (including some methicillin-resistant isolates) and enterococci (including some vancomycin-resistant isolates).
- Activity In Vitro and In Vivo
- Daptomycin has been shown to be active against most isolates of the following Gram-positive bacteria both in vitro and in clinical infections, as described in Indications and Usage (1).
Gram-Positive Bacteria
Enterococcus faecalis (vancomycin-susceptible isolates only)
Staphylococcus aureus (including methicillin-resistant isolates)
Streptococcus agalactiae
Streptococcus dysgalactiae subsp. equisimilis
Streptococcus pyogenes
- Gram-Positive Bacteria
Enterococcus faecalis (vancomycin-susceptible isolates only)
Staphylococcus aureus (including methicillin-resistant isolates)
Streptococcus agalactiae
Streptococcus dysgalactiae subsp. equisimilis
Streptococcus pyogenes
- Enterococcus faecalis (vancomycin-susceptible isolates only)
- Staphylococcus aureus (including methicillin-resistant isolates)
- Streptococcus agalactiae
- Streptococcus dysgalactiae subsp. equisimilis
- Streptococcus pyogenes
- The following in vitro data are available, but their clinical significance is unknown. At least 90% of the following Gram-positive bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for daptomycin versus the bacterial genus (Table 9). However, the efficacy of CUBICIN in treating clinical infections due to these bacteria has not been established in adequate and well-controlled clinical trials.
- Gram-Positive Bacteria
Corynebacterium jeikeium
Enterococcus faecalis (vancomycin-resistant isolates)
Enterococcus faecium (including vancomycin-resistant isolates)
Staphylococcus epidermidis (including methicillin-resistant isolates)
Staphylococcus haemolyticus
- Gram-Positive Bacteria
Corynebacterium jeikeium
Enterococcus faecalis (vancomycin-resistant isolates)
Enterococcus faecium (including vancomycin-resistant isolates)
Staphylococcus epidermidis (including methicillin-resistant isolates)
Staphylococcus haemolyticus
- Corynebacterium jeikeium
- Enterococcus faecalis (vancomycin-resistant isolates)
- Enterococcus faecium (including vancomycin-resistant isolates)
- Staphylococcus epidermidis (including methicillin-resistant isolates)
- Staphylococcus haemolyticus
- Susceptibility Testing Methods
- When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility tests for antimicrobial drug products used in resident hospitals to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting an antibacterial drug product for treatment.
- Dilution Techniques
- Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized broth test method2,3 with the broth adjusted to a calcium content of 50 mg/L. The use of the agar dilution method is not recommended with daptomycin3. The MICs should be interpreted according to the criteria listed in Table 9.
- A report of "Susceptible" indicates that the antimicrobial is likely to inhibit the growth of the pathogen if the antimicrobial compound reaches the concentration at the infection site necessary to inhibit growth of the pathogen.
- Diffusion Technique
- Quantitative methods that require measurement of zone diameters have not been shown to provide reproducible estimates of the susceptibility of bacteria to daptomycin. The use of the disk diffusion method is not recommended with daptomycin.
- Quality Control
- Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test2,3. Standard daptomycin powder should provide the ranges of MIC values noted in
## Nonclinical Toxicology
- Long-term carcinogenicity studies in animals have not been conducted to evaluate the carcinogenic potential of CUBICIN. However, neither mutagenic nor clastogenic potential was found in a battery of genotoxicity tests, including the Ames assay, a mammalian cell gene mutation assay, a test for chromosomal aberrations in Chinese hamster ovary cells, an in vivo micronucleus assay, an in vitro DNA repair assay, and an in vivo sister chromatid exchange assay in Chinese hamsters.
- Daptomycin did not affect the fertility or reproductive performance of male and female rats when administered intravenously at doses up to 150 mg/kg/day, which is approximately 9 times the estimated human exposure level based upon AUCs.
- Adult Animals
- In animals, daptomycin administration has been associated with effects on skeletal muscle. However, there were no changes in cardiac or smooth muscle. Skeletal muscle effects were characterized by microscopic degenerative/regenerative changes and variable elevations in creatine phosphokinase (CPK). No fibrosis or rhabdomyolysis was evident in repeat-dose studies up to the highest doses tested in rats (150 mg/kg/day) and dogs (100 mg/kg/day). The degree of skeletal myopathy showed no increase when treatment was extended from 1 month to up to 6 months. Severity was dose-dependent. All muscle effects, including microscopic changes, were fully reversible within 30 days following the cessation of dosing.
- In adult animals, effects on peripheral nerve (characterized by axonal degeneration and frequently accompanied by significant losses of patellar reflex, gag reflex, and pain perception) were observed at daptomycin doses higher than those associated with skeletal myopathy. Deficits in the dogs' patellar reflexes were seen within 2 weeks after the start of treatment at 40 mg/kg/day (9 times the human Cmax at the 6 mg/kg/day dose), with some clinical improvement noted within 2 weeks after the cessation of dosing. However, at 75 mg/kg/day for 1 month, 7 of 8 dogs failed to regain full patellar reflex responses within a 3-month recovery period. In a separate study in dogs receiving doses of 75 and 100 mg/kg/day for 2 weeks, minimal residual histological changes were noted at 6 months after the cessation of dosing. However, recovery of peripheral nerve function was evident.
- Tissue distribution studies in rats showed that daptomycin is retained in the kidney but appears to penetrate the blood-brain barrier only minimally following single and multiple doses.
- Juvenile Animals
- Target organs of daptomycin-related effects in 7-week-old juvenile dogs were skeletal muscle and nerve, the same target organs as in adult dogs. In juvenile dogs, nerve effects were noted at lower daptomycin blood concentrations than in adult dogs following 28 days of dosing. In contrast to adult dogs, juvenile dogs also showed evidence of effects in nerves of the spinal cord as well as peripheral nerves after 28 days of dosing. No nerve effects were noted in juvenile dogs following 14 days of dosing at doses up to 75 mg/kg/day.
- Administration of daptomycin to 7-week-old juvenile dogs for 28 days at doses of 50 mg/kg/day produced minimal degenerative effects on the peripheral nerve and spinal cord in several animals, with no corresponding clinical signs. A dose of 150 mg/kg/day for 28 days produced minimal degeneration in the peripheral nerve and spinal cord as well as minimal to mild degeneration of the skeletal muscle in a majority of animals, accompanied by slight to severe muscle weakness evident in most dogs. Following a 28-day recovery phase, microscopic examination revealed recovery of the skeletal muscle and the ulnar nerve effects, but nerve degeneration in the sciatic nerve and spinal cord was still observed in all 150 mg/kg/day dogs.
- Following once-daily administration of daptomycin to juvenile dogs for 28 days, microscopic effects in nerve tissue were noted at a Cmax value of 417 mcg/mL, which is approximately 3-fold less than the Cmax value associated with nerve effects in adult dogs treated once daily with daptomycin for 28 days (1308 mcg/mL).
# Clinical Studies
- Adult patients with clinically documented complicated skin and skin structure infections (cSSSI) (Table 11) were enrolled in two randomized, multinational, multicenter, investigator-blinded trials comparing CUBICIN (4 mg/kg IV q24h) with either vancomycin (1 g IV q12h) or an anti-staphylococcal semi-synthetic penicillin (i.e., nafcillin, oxacillin, cloxacillin, or flucloxacillin; 4 to 12 g IV per day). Patients could switch to oral therapy after a minimum of 4 days of IV treatment if clinical improvement was demonstrated. Patients known to have bacteremia at baseline were excluded. Patients with creatinine clearance (CLCR) between 30 and 70 mL/min were to receive a lower dose of CUBICIN as specified in the protocol; however, the majority of patients in this subpopulation did not have the dose of CUBICIN adjusted.
- One trial was conducted primarily in the United States and South Africa (study 9801), and the second was conducted at non-US sites only (study 9901). The two trials were similar in design but differed in patient characteristics, including history of diabetes and peripheral vascular disease. There were a total of 534 patients treated with CUBICIN and 558 treated with comparator in the two trials. The majority (89.7%) of patients received IV medication exclusively.
- The efficacy endpoints in both trials were the clinical success rates in the intent-to-treat (ITT) population and in the clinically evaluable (CE) population. In study 9801, clinical success rates in the ITT population were 62.5% (165/264) in patients treated with CUBICIN and 60.9% (162/266) in patients treated with comparator drugs. Clinical success rates in the CE population were 76.0% (158/208) in patients treated with CUBICIN and 76.7% (158/206) in patients treated with comparator drugs. In study 9901, clinical success rates in the ITT population were 80.4% (217/270) in patients treated with CUBICIN and 80.5% (235/292) in patients treated with comparator drugs. Clinical success rates in the CE population were 89.9% (214/238) in patients treated with CUBICIN and 90.4% (226/250) in patients treated with comparator drugs.
- The success rates by pathogen for microbiologically evaluable patients are presented in Table 12.
- The efficacy of CUBICIN in the treatment of patients with S. aureus bacteremia was demonstrated in a randomized, controlled, multinational, multicenter, open-label trial. In this trial, adult patients with at least one positive blood culture for S. aureus obtained within 2 calendar days prior to the first dose of study drug and irrespective of source were enrolled and randomized to either CUBICIN (6 mg/kg IV q24h) or standard of care . Of the patients in the comparator group, 93% received initial gentamicin for a median of 4 days, compared with 1 patient (<1%) in the CUBICIN group. Patients with prosthetic heart valves, intravascular foreign material that was not planned for removal within 4 days after the first dose of study medication, severe neutropenia, known osteomyelitis, polymicrobial bloodstream infections, creatinine clearance <30 mL/min, and pneumonia were excluded.
- Upon entry, patients were classified for likelihood of endocarditis using the modified Duke criteria (Possible, Definite, or Not Endocarditis). *Echocardiography, including a transesophageal echocardiogram (TEE), was performed within 5 days following study enrollment. The choice of comparator agent was based on the oxacillin susceptibility of the S. aureus isolate. The duration of study treatment was based on the investigator's clinical diagnosis. Final diagnoses and outcome assessments at Test of Cure (6 weeks after the last treatment dose) were made by a treatment-blinded Adjudication Committee, using protocol-specified clinical definitions and a composite primary efficacy endpoint (clinical and microbiological success) at the Test of Cure visit.
- A total of 246 patients ≥18 years of age (124 CUBICIN, 122 comparator) with S. aureus bacteremia were randomized from 48 centers in the US and Europe. In the ITT population, 120 patients received CUBICIN and 115 received comparator (62 received an anti-staphylococcal semi-synthetic penicillin and 53 received vancomycin). Thirty-five patients treated with an anti-staphylococcal semi-synthetic penicillin received vancomycin initially for 1 to 3 days, pending final susceptibility results for the S. aureus isolates. The median age among the 235 patients in the ITT population was 53 years (range: 21 to 91 years); 30/120 (25%) in the CUBICIN group and 37/115 (32%) in the comparator group were ≥65 years of age. *Of the 235 ITT patients, there were 141 (60%) males and 156 (66%) Caucasians across the two treatment groups. In addition, 176 (75%) of the ITT population had systemic inflammatory response syndrome (SIRS) at baseline and 85 (36%) had surgical procedures within 30 days prior to onset of the S. aureus bacteremia. Eighty-nine patients (38%) had bacteremia caused by methicillin-resistant S. aureus (MRSA). Entry diagnosis was based on the modified Duke criteria and comprised 37 (16%) Definite, 144 (61%) Possible, and 54 (23%) Not Endocarditis. Of the 37 patients with an entry diagnosis of Definite Endocarditis, all (100%) had a final diagnosis of infective endocarditis, and of the 144 patients with an entry diagnosis of Possible Endocarditis, 15 (10%) had a final diagnosis of infective endocarditis as assessed by the Adjudication Committee. Of the 54 patients with an entry diagnosis of Not Endocarditis, 1 (2%) had a final diagnosis of infective endocarditis as assessed by the Adjudication Committee.
- In the ITT population, there were 182 patients with bacteremia and 53 patients with infective endocarditis as assessed by the Adjudication Committee, including 35 with right-sided endocarditis and 18 with left-sided endocarditis. The 182 patients with bacteremia comprised 121 with complicated S. aureus bacteremia and 61 with uncomplicated S. aureus bacteremia.
- Complicated bacteremia was defined as S. aureus isolated from blood cultures obtained on at least 2 different calendar days, and/or metastatic foci of infection (deep tissue involvement), and classification of the patient as not having endocarditis according to the modified Duke criteria. Uncomplicated bacteremia was defined as S. aureus isolated from blood culture(s) obtained on a single calendar day, no metastatic foci of infection, no infection of prosthetic material, and classification of the patient as not having endocarditis according to the modified Duke criteria. The definition of right-sided infective endocarditis (RIE) used in the clinical trial was Definite or Possible Endocarditis according to the modified Duke criteria and no echocardiographic evidence of predisposing pathology or active involvement of either the mitral or aortic valve. Complicated RIE comprised patients who were not intravenous drug users, had a positive blood culture for MRSA, serum creatinine ≥2.5 mg/dL, or evidence of extrapulmonary sites of infection. Patients who were intravenous drug users, had a positive blood culture for methicillin-susceptible S. aureus (MSSA), had serum creatinine <2.5 mg/dL, and were without evidence of extrapulmonary sites of infection were considered to have uncomplicated RIE.
- The coprimary efficacy endpoints in the trial were the Adjudication Committee success rates at the Test of Cure visit (6 weeks after the last treatment dose) in the ITT and Per Protocol (PP) populations. The overall Adjudication Committee success rates in the ITT population were 44.2% (53/120) in patients treated with CUBICIN and 41.7% (48/115) in patients treated with comparator (difference = 2.4% ). The success rates in the PP population were 54.4% (43/79) in patients treated with CUBICIN and 53.3% (32/60) in patients treated with comparator (difference = 1.1% ).
- Adjudication Committee success rates are shown in Table 13.
- Eighteen (18/120) patients in the CUBICIN arm and 19/116 patients in the comparator arm died during the trial. These comprise 3/28 CUBICIN-treated patients and 8/26 comparator-treated patients with endocarditis, as well as 15/92 CUBICIN-treated patients and 11/90 comparator-treated patients with bacteremia. Among patients with persisting or relapsing S. aureus infections, 8/19 CUBICIN-treated patients and 7/11 comparator-treated patients died.
- Overall, there was no difference in time to clearance of S. aureus bacteremia between CUBICIN and comparator. The median time to clearance in patients with MSSA was 4 days and in patients with MRSA was 8 days.
- Failure of treatment due to persisting or relapsing S. aureus infections was assessed by the Adjudication Committee in 19/120 (16%) CUBICIN-treated patients (12 with MRSA and 7 with MSSA) and 11/115 (10%) comparator-treated patients (9 with MRSA treated with vancomycin and 2 with MSSA treated with an anti-staphylococcal semi-synthetic penicillin). Among all failures, isolates from 6 CUBICIN-treated patients and 1 vancomycin-treated patient developed increasing MICs (reduced susceptibility) by central laboratory testing during or following therapy. Most patients who failed due to persisting or relapsing S. aureus infection had deep-seated infection and did not receive necessary surgical intervention.
# How Supplied
- CUBICIN (daptomycin for injection) is supplied as a sterile pale yellow to light brown lyophilized cake in a single-use 10 mL vial containing 500 mg of daptomycin: Package of 1 (NDC 67919-011-01).
- Store original packages at refrigerated temperatures, 2 to 8°C (36 to 46°F); avoid excessive heat.
## Storage
There is limited information regarding Daptomycin Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients should be advised that allergic reactions, including serious allergic reactions, could occur and that serious reactions require immediate treatment. Patients should report any previous allergic reactions to CUBICIN.
- Patients should be advised to report muscle pain or weakness, especially in the forearms and lower legs, as well as tingling or numbness.
- Patients should be advised to report any symptoms of cough, breathlessness, or fever.
- Diarrhea is a common problem caused by antibacterials that usually ends when the antibacterial is discontinued. Sometimes after starting treatment with antibacterials, patients can develop watery and bloody stools (with or without stomach cramps and fever), even as late as 2 or more months after having received the last dose of the antibacterial. If this occurs, patients should contact their physician as soon as possible.
- Patients should be counseled that antibacterial drugs, including CUBICIN, should be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When CUBICIN is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be administered exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by CUBICIN or other antibacterial drugs in the future.
# Precautions with Alcohol
- Alcohol-Daptomycin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Cubicin®
# Look-Alike Drug Names
- DAPTOmycin® — DACTINomycin®
# Drug Shortage Status
# Price | Daptomycin
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
Daptomycin is an antibacterial agent that is FDA approved for the treatment of complicated skin and skin structure infections (cSSSI), staphylococcus aureus bloodstream infections (bacteremia), including those with right-sided infective endocarditis. Common adverse reactions include diarrhea, vomiting, and pain in throat.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Complicated skin and skin structure infections (cSSSI) caused by susceptible isolates of the following Gram-positive bacteria: Staphylococcus aureus (including methicillin-resistant isolates), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae subsp. equisimilis, and Enterococcus faecalis (vancomycin-susceptible isolates only).
- Dosing Information
- CUBICIN 4 mg/kg should be administered intravenously in 0.9% sodium chloride injection once every 24 hours for 7 to 14 days.
- Staphylococcus aureus bloodstream infections (bacteremia), including those with right-sided infective endocarditis, caused by methicillin-susceptible and methicillin-resistant isolates.
- Dosing Information
- CUBICIN 6 mg/kg should be administered intravenously in 0.9% sodium chloride injection once every 24 hours for 2 to 6 weeks. There are limited safety data for the use of CUBICIN for more than 28 days of therapy. In the Phase 3 trial, there were a total of 14 patients who were treated with CUBICIN for more than 28 days.
- Administration Duration
- CUBICIN should be administered intravenously either by injection over a two (2) minute period or by infusion over a thirty (30) minute period.
- Patients with Renal Impairment
- The recommended dosage regimen for patients with creatinine clearance (CLCR) <30 mL/min, including patients on hemodialysis or continuous ambulatory peritoneal dialysis (CAPD), is 4 mg/kg (cSSSI) or 6 mg/kg (S. aureus bloodstream infections) once every 48 hours (Table 1). When possible, CUBICIN should be administered following the completion of hemodialysis on hemodialysis days.
- Preparation of CUBICIN for Administration
- CUBICIN is supplied in single-use vials, each containing 500 mg daptomycin as a sterile, lyophilized powder. The contents of a CUBICIN vial should be reconstituted, using aseptic technique, to 50 mg/mL as follows:
- Note: To minimize foaming, AVOID vigorous agitation or shaking of the vial during or after reconstitution.
- Remove the polypropylene flip-off cap from the CUBICIN vial to expose the central portion of the rubber stopper.
- Slowly transfer 10 mL of 0.9% sodium chloride injection through the center of the rubber stopper into the CUBICIN vial, pointing the transfer needle toward the wall of the vial.
- Ensure that all of the CUBICIN powder is wetted by gently rotating the vial.
- Allow the wetted product to stand undisturbed for 10 minutes.
- Gently rotate or swirl the vial contents for a few minutes, as needed, to obtain a completely reconstituted solution.
- For intravenous (IV) injection over a period of 2 minutes, administer the appropriate volume of the reconstituted CUBICIN (concentration of 50 mg/mL).
- For IV infusion over a period of 30 minutes, the appropriate volume of the reconstituted CUBICIN (concentration of 50 mg/mL) should be further diluted, using aseptic technique, into a 50 mL IV infusion bag containing 0.9% sodium chloride injection.
- Parenteral drug products should be inspected visually for particulate matter prior to administration.
- No preservative or bacteriostatic agent is present in this product. Aseptic technique must be used in the preparation of final IV solution.
- Stability studies have shown that the reconstituted solution is stable in the vial for 12 hours at room temperature and up to 48 hours if stored under refrigeration at 2 to 8°C (36 to 46°F).
- The diluted solution is stable in the infusion bag for 12 hours at room temperature and 48 hours if stored under refrigeration. The combined storage time (reconstituted solution in vial and diluted solution in infusion bag) should not exceed 12 hours at room temperature or 48 hours under refrigeration.
- CUBICIN vials are for single use only.
- Dosage Forms And Strengths
- 500 mg daptomycin as a sterile, pale yellow to light brown lyophilized powder for reconstitution in a single-use vial.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Daptomycin in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- Daptomycin high-dose (6 mg/kg or greater) or low-dose (less than 6 mg/kg)[1]
- Dosing Information
- Daptomycin 5 mg/kg once daily and for a median of 22 days[2]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Daptomycin in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Daptomycin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Daptomycin in pediatric patients.
# Contraindications
- CUBICIN is contraindicated in patients with known hypersensitivity to daptomycin.
# Warnings
### Precautions
- Anaphylaxis/Hypersensitivity Reactions
- Anaphylaxis/hypersensitivity reactions have been reported with the use of antibacterial agents, including CUBICIN, and may be life-threatening.
- If an allergic reaction to CUBICIN occurs, discontinue the drug and institute appropriate therapy.
- Myopathy and Rhabdomyolysis
- Myopathy, defined as muscle aching or muscle weakness in conjunction with increases in creatine phosphokinase (CPK) values to greater than 10 times the upper limit of normal (ULN), has been reported with the use of CUBICIN. Rhabdomyolysis, with or without acute renal failure, has been reported.
- Patients receiving CUBICIN should be monitored for the development of muscle pain or weakness, particularly of the distal extremities. In patients who receive CUBICIN, CPK levels should be monitored weekly, and more frequently in patients who received recent prior or concomitant therapy with an HMG-CoA reductase inhibitor or in whom elevations in CPK occur during treatment with CUBICIN.
- In patients with renal impairment, both renal function and CPK should be monitored more frequently than once weekly.
- In Phase 1 studies and Phase 2 clinical trials, CPK elevations appeared to be more frequent when CUBICIN was dosed more than once daily.
- Therefore, CUBICIN should not be dosed more frequently than once a day.
- CUBICIN should be discontinued in patients with unexplained signs and symptoms of myopathy in conjunction with CPK elevations to levels >1,000 U/L (~5× ULN), and in patients without reported symptoms who have marked elevations in CPK, with levels >2,000 U/L (≥10× ULN). In addition, consideration should be given to suspending agents associated with rhabdomyolysis, such as HMG-CoA reductase inhibitors, temporarily in patients receiving CUBICIN.
- Eosinophilic Pneumonia
- Eosinophilic pneumonia has been reported in patients receiving CUBICIN. In reported cases associated with CUBICIN, patients developed fever, dyspnea with hypoxic respiratory insufficiency, and diffuse pulmonary infiltrates. In general, patients developed eosinophilic pneumonia 2 to 4 weeks after starting CUBICIN and improved when CUBICIN was discontinued and steroid therapy was initiated. Recurrence of eosinophilic pneumonia upon re-exposure has been reported. Patients who develop these signs and symptoms while receiving CUBICIN should undergo prompt medical evaluation, and CUBICIN should be discontinued immediately. Treatment with systemic steroids is recommended.
- Peripheral Neuropathy
- Cases of peripheral neuropathy have been reported during the CUBICIN postmarketing experience. Therefore, physicians should be alert to signs and symptoms of peripheral neuropathy in patients receiving CUBICIN.
- Clostridium difficile–Associated Diarrhea
- Clostridium difficile–associated diarrhea (CDAD) has been reported with the use of nearly all systemic antibacterial agents, including CUBICIN, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon, leading to overgrowth of C. difficile.
- C. difficile produces toxins A and B, which contribute to the development of CDAD. Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, since these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary because CDAD has been reported to occur more than 2 months after the administration of antibacterial agents.
- If CDAD is suspected or confirmed, ongoing antibacterial use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
- Persisting or Relapsing S. aureus Bacteremia/Endocarditis
- Patients with persisting or relapsing S. aureus bacteremia/endocarditis or poor clinical response should have repeat blood cultures. If a blood culture is positive for S. aureus, minimum inhibitory concentration (MIC) susceptibility testing of the isolate should be performed using a standardized procedure, and diagnostic evaluation of the patient should be performed to rule out sequestered foci of infection. Appropriate surgical intervention (e.g., debridement, removal of prosthetic devices, valve replacement surgery) and/or consideration of a change in antibacterial regimen may be required.
- Failure of treatment due to persisting or relapsing S. aureus bacteremia/endocarditis may be due to reduced daptomycin susceptibility (as evidenced by increasing MIC of the S. aureus isolate).
- Decreased Efficacy in Patients with Moderate Baseline Renal Impairment
- Limited data are available from the two Phase 3 complicated skin and skin structure infection (cSSSI) trials regarding clinical efficacy of CUBICIN treatment in patients with creatinine clearance (CLCR) <50 mL/min; only 31/534 (6%) patients treated with CUBICIN in the intent-to-treat (ITT) population had a baseline CLCR <50 mL/min. Table 2 shows the number of patients by renal function and treatment group who were clinical successes in the Phase 3 cSSSI trials.
- In a subgroup analysis of the ITT population in the Phase 3 S. aureus bacteremia/endocarditis trial, clinical success rates, as determined by a treatment-blinded Adjudication Committee, in the CUBICIN-treated patients were lower in patients with baseline CLCR <50 mL/min (see Table 3). A decrease of the magnitude shown in Table 3 was not observed in comparator-treated patients.
- Consider these data when selecting antibacterial therapy for use in patients with baseline moderate to severe renal impairment.
- Drug-Laboratory Test Interactions
- Clinically relevant plasma concentrations of daptomycin have been observed to cause a significant concentration-dependent false prolongation of prothrombin time (PT) and elevation of International Normalized Ratio (INR) when certain recombinant thromboplastin reagents are utilized for the assay.
- Non-Susceptible Microorganisms
- The use of antibacterials may promote the overgrowth of non-susceptible microorganisms. If superinfection occurs during therapy, appropriate measures should be taken.
- Prescribing CUBICIN in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
# Adverse Reactions
## Clinical Trials Experience
- Clinical trials enrolled 1,864 patients treated with CUBICIN and 1,416 treated with comparator.
- In Phase 3 complicated skin and skin structure infection (cSSSI) trials, CUBICIN was discontinued in 15/534 (2.8%) patients due to an adverse reaction, while comparator was discontinued in 17/558 (3.0%) patients.
- The rates of the most common adverse reactions, organized by body system, observed in cSSSI (4 mg/kg CUBICIN) patients are displayed in Table 4.
- Drug-related adverse reactions (possibly or probably drug-related) that occurred in <1% of patients receiving CUBICIN in the cSSSI trials are as follows:
- Fatigue, weakness, rigors, flushing, hypersensitivity.
- Supraventricular arrhythmia.
- Abdominal distension, stomatitis, jaundice, increased serum lactate dehydrogenase.
- Leukocytosis, thrombocytopenia, thrombocytosis, eosinophilia, increased International Normalized Ratio (INR).
- Hypomagnesemia, increased serum bicarbonate, electrolyte disturbance.
- Myalgia, muscle cramps, muscle weakness, arthralgia.
- Vertigo, mental status change, paresthesia.
- Taste disturbance, eye irritation.
- In the S. aureus bacteremia/endocarditis trial, CUBICIN was discontinued in 20/120 (16.7%) patients due to an adverse reaction, while comparator was discontinued in 21/116 (18.1%) patients.
- Serious Gram-negative infections (including bloodstream infections) were reported in 10/120 (8.3%) CUBICIN-treated patients and 0/115 comparator-treated patients. Comparator-treated patients received dual therapy that included initial gentamicin for 4 days. Infections were reported during treatment and during early and late follow-up. Gram-negative infections included cholangitis, alcoholic pancreatitis, sternal osteomyelitis/mediastinitis, bowel infarction, recurrent Crohn's disease, recurrent line sepsis, and recurrent urosepsis caused by a number of different Gram-negative bacteria.
- The rates of the most common adverse reactions, organized by System Organ Class (SOC), observed in S. aureus bacteremia/endocarditis (6 mg/kg CUBICIN) patients are displayed in Table 5.
- The following reactions, not included above, were reported as possibly or probably drug-related in the CUBICIN-treated group:
Eosinophilia, lymphadenopathy, thrombocythemia, thrombocytopenia
Atrial fibrillation, atrial flutter, cardiac arrest
Tinnitus
Blurred vision
Dry mouth, epigastric discomfort, gingival pain, hypoesthesia oral
Candidal infection NOS, vaginal candidiasis, fungemia, oral candidiasis, urinary tract infection fungal
Blood phosphorous increased, blood alkaline phosphatase increased, INR increased, liver function test abnormal, alanine aminotransferase increased, aspartate aminotransferase increased, prothrombin time prolonged
Appetite decreased NOS
Myalgia
Dyskinesia, paresthesia
Hallucination NOS
Proteinuria, renal impairment NOS
Pruritus generalized, vesicular rash
- In Phase 3 trials of community-acquired pneumonia (CAP), the death rate and rates of serious cardiorespiratory adverse events were higher in CUBICIN-treated patients than in comparator-treated patients. These differences were due to lack of therapeutic effectiveness of CUBICIN in the treatment of CAP in patients experiencing these adverse events.
- In Phase 3 cSSSI trials of CUBICIN at a dose of 4 mg/kg, elevations in CPK were reported as clinical adverse events in 15/534 (2.8%) CUBICIN-treated patients, compared with 10/558 (1.8%) comparator-treated patients. Of the 534 patients treated with CUBICIN, 1 (0.2%) had symptoms of muscle pain or weakness associated with CPK elevations to greater than 4 times the upper limit of normal (ULN). The symptoms resolved within 3 days and CPK returned to normal within 7 to 10 days after treatment was discontinued. Table 6 summarizes the CPK shifts from Baseline through End of Therapy in the cSSSI trials.
- In the S. aureus bacteremia/endocarditis trial, at a dose of 6 mg/kg, 11/120 (9.2%) CUBICIN-treated patients, including two patients with baseline CPK levels >500 U/L, had CPK elevations to levels >500 U/L, compared with 1/116 (0.9%) comparator-treated patients. Of the 11 CUBICIN-treated patients, 4 had prior or concomitant treatment with an HMG-CoA reductase inhibitor. Three of these 11 CUBICIN-treated patients discontinued therapy due to CPK elevation, while the one comparator-treated patient did not discontinue therapy.
## Postmarketing Experience
- The following adverse reactions have been identified during postapproval use of CUBICIN. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency reliably or establish a causal relationship to drug exposure.
- Anaphylaxis; hypersensitivity reactions, including angioedema, drug rash with eosinophilia and systemic symptoms (DRESS syndrome), pruritus, hives, shortness of breath, difficulty swallowing, truncal erythema, and pulmonary eosinophilia.
- Clostridium difficile–associated diarrhea.
- Myoglobin increased; rhabdomyolysis (some reports involved patients treated concurrently with CUBICIN and HMG-CoA reductase inhibitors).
- Cough, eosinophilic pneumonia.
- Peripheral neuropathy.
- Serious skin reactions, including Stevens-Johnson syndrome and vesiculobullous rash (with or without mucous membrane involvement).
- Nausea, vomiting.
# Drug Interactions
- In healthy subjects, concomitant administration of CUBICIN and simvastatin had no effect on plasma trough concentrations of simvastatin, and there were no reports of skeletal myopathy.
- However, inhibitors of HMG-CoA reductase may cause myopathy, which is manifested as muscle pain or weakness associated with elevated levels of creatine phosphokinase (CPK). In the Phase 3 S. aureus bacteremia/endocarditis trial, some patients who received prior or concomitant treatment with an HMG-CoA reductase inhibitor developed elevated CPK. Experience with the coadministration of HMG-CoA reductase inhibitors and CUBICIN in patients is limited; therefore, consideration should be given to suspending use of HMG-CoA reductase inhibitors temporarily in patients receiving CUBICIN.
- Clinically relevant plasma concentrations of daptomycin have been observed to cause a significant concentration-dependent false prolongation of prothrombin time (PT) and elevation of International Normalized Ratio (INR) when certain recombinant thromboplastin reagents are utilized for the assay. The possibility of an erroneously elevated PT/INR result due to interaction with a recombinant thromboplastin reagent may be minimized by drawing specimens for PT or INR testing near the time of trough plasma concentrations of daptomycin. However, sufficient daptomycin concentrations may be present at trough to cause interaction.
- If confronted with an abnormally high PT/INR result in a patient being treated with CUBICIN, it is recommended that clinicians:
- Repeat the assessment of PT/INR, requesting that the specimen be drawn just prior to the next CUBICIN dose (i.e., at trough concentration). If the PT/INR value obtained at trough remains substantially elevated above what would otherwise be expected, consider evaluating PT/INR utilizing an alternative method.
- Evaluate for other causes of abnormally elevated PT/INR results.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category B
- There are no adequate and well-controlled trials of CUBICIN in pregnant women. Embryofetal development studies performed in rats and rabbits at doses of up to 75 mg/kg (2 and 4 times the 6 mg/kg human dose, respectively, on a body surface area basis) revealed no evidence of harm to the fetus due to daptomycin. Because animal reproduction studies are not always predictive of human response, CUBICIN should be used during pregnancy only if the potential benefit outweighs the possible risk.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Daptomycin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Daptomycin during labor and delivery.
### Nursing Mothers
- Daptomycin is present in human milk but is poorly bioavailable orally. In a single case study, CUBICIN was administered daily for 28 days to a nursing mother at an IV dose of 6.7 mg/kg/day, and samples of the patient's breast milk were collected over a 24-hour period on day 27. The highest measured concentration of daptomycin in the breast milk was 0.045 mcg/mL1. The calculated maximum daily CUBICIN dose to the infant (assuming mean milk consumption of 150 mL/kg/day) was 0.1% of the maternal dose of 6.7 mg/kg/day. Caution should be exercised when CUBICIN is administered to a nursing woman.
### Pediatric Use
There is no FDA guidance on the use of Daptomycin with respect to pediatric patients.
### Geriatic Use
- Of the 534 patients treated with CUBICIN in Phase 3 controlled clinical trials of complicated skin and skin structure infections (cSSSI), 27% were 65 years of age or older and 12% were 75 years of age or older. Of the 120 patients treated with CUBICIN in the Phase 3 controlled clinical trial of S. aureus bacteremia/endocarditis, 25% were 65 years of age or older and 16% were 75 years of age or older. In Phase 3 clinical trials of cSSSI and S. aureus bacteremia/endocarditis, clinical success rates were lower in patients ≥65 years of age than in patients <65 years of age. In addition, treatment-emergent adverse events were more common in patients ≥65 years of age than in patients <65 years of age.
- The exposure of daptomycin was higher in healthy elderly subjects than in healthy young subjects. However, no adjustment of CUBICIN dosage is warranted for elderly patients with creatinine clearance (CLCR) ≥30 mL/min.
### Gender
There is no FDA guidance on the use of Daptomycin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Daptomycin with respect to specific racial populations.
### Renal Impairment
- Daptomycin is eliminated primarily by the kidneys; therefore, a modification of CUBICIN dosage interval is recommended for patients with CLCR <30 mL/min, including patients receiving hemodialysis or continuous ambulatory peritoneal dialysis (CAPD). In patients with renal impairment, both renal function and creatine phosphokinase (CPK) should be monitored more frequently than once weekly
### Hepatic Impairment
There is no FDA guidance on the use of Daptomycin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Daptomycin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Daptomycin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
### Monitoring
- Patients receiving CUBICIN should be monitored for the development of muscle pain or weakness, particularly of the distal extremities. In patients who receive CUBICIN, CPK levels should be monitored weekly, and more frequently in patients who received recent prior or concomitant therapy with an HMG-CoA reductase inhibitor or in whom elevations in CPK occur during treatment with CUBICIN.
- In patients with renal impairment, both renal function and creatine phosphokinase (CPK) should be monitored more frequently than once weekly
# IV Compatibility
CUBICIN is compatible with 0.9% sodium chloride injection and lactated Ringer's injection.
# Overdosage
## Acute Overdose
- In the event of overdosage, supportive care is advised with maintenance of glomerular filtration. Daptomycin is cleared slowly from the body by hemodialysis (approximately 15% of the administered dose is removed over 4 hours) and by peritoneal dialysis (approximately 11% of the administered dose is removed over 48 hours). The use of high-flux dialysis membranes during 4 hours of hemodialysis may increase the percentage of dose removed compared with that removed by low-flux membranes.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Daptomycin in the drug label.
# Pharmacology
## Mechanism of Action
- Daptomycin is an antibacterial drug. The mechanism of action of daptomycin is distinct from that of any other antibacterial. Daptomycin binds to bacterial cell membranes and causes a rapid depolarization of membrane potential. This loss of membrane potential causes inhibition of DNA, RNA, and protein synthesis, which results in bacterial cell death.
## Structure
- CUBICIN contains daptomycin, a cyclic lipopeptide antibacterial agent derived from the fermentation of Streptomyces roseosporus. The chemical name is N-decanoyl-L-tryptophyl-D-asparaginyl-L-aspartyl-L-threonylglycyl-L-ornithyl-L-aspartyl-D-alanyl-L-aspartylglycyl-D-seryl-threo-3-methyl-L-glutamyl-3-anthraniloyl-L-alanine ε1-lactone. The chemical structure is:
- The empirical formula is C72H101N17O26; the molecular weight is 1620.67. CUBICIN is supplied in a single-use vial as a sterile, preservative-free, pale yellow to light brown, lyophilized cake containing approximately 500 mg of daptomycin for intravenous (IV) use following reconstitution with 0.9% sodium chloride injection. The only inactive ingredient is sodium hydroxide, which is used in minimal quantities for pH adjustment. Freshly reconstituted solutions of CUBICIN range in color from pale yellow to light brown.
## Pharmacodynamics
- Based on animal models of infection, the antimicrobial activity of daptomycin appears to correlate with the AUC/MIC (area under the concentration-time curve/minimum inhibitory concentration) ratio for certain pathogens, including S. aureus. The principal pharmacokinetic/pharmacodynamic parameter best associated with clinical and microbiological cure has not been elucidated in clinical trials with CUBICIN.
## Pharmacokinetics
- CUBICIN Administered over a 30-Minute Period
- The mean and standard deviation (SD) pharmacokinetic parameters of daptomycin at steady-state following intravenous (IV) administration of CUBICIN over a 30-minute period at 4 to 12 mg/kg q24h to healthy young adults are summarized in Table 7
- Daptomycin pharmacokinetics were generally linear and time-independent at CUBICIN doses of 4 to 12 mg/kg q24h administered by IV infusion over a 30-minute period for up to 14 days. Steady-state trough concentrations were achieved by the third daily dose. The mean (SD) steady-state trough concentrations attained following the administration of 4, 6, 8, 10, and 12 mg/kg q24h were 5.9 (1.6), 6.7 (1.6), 10.3 (5.5), 12.9 (2.9), and 13.7 (5.2) mcg/mL, respectively.
- CUBICIN Administered over a 2-Minute Period
- Following IV administration of CUBICIN over a 2-minute period to healthy volunteers at doses of 4 mg/kg (N=8) and 6 mg/kg (N=12), the mean (SD) steady-state systemic exposure (AUC) values were 475 (71) and 701 (82) mcg•h/mL, respectively. Values for maximum plasma concentration (Cmax) at the end of the 2-minute period could not be determined adequately in this study. However, using pharmacokinetic parameters from 14 healthy volunteers who received a single dose of CUBICIN 6 mg/kg IV administered over a 30-minute period in a separate study, steady-state Cmax values were simulated for CUBICIN 4 and 6 mg/kg IV administered over a 2-minute period. The simulated mean (SD) steady-state Cmax values were 77.7 (8.1) and 116.6 (12.2) mcg/mL, respectively.
- Distribution
- Daptomycin is reversibly bound to human plasma proteins, primarily to serum albumin, in a concentration-independent manner. The overall mean binding ranges from 90 to 93%.
- In clinical studies, mean serum protein binding in subjects with creatinine clearance (CLCR) ≥30 mL/min was comparable to that observed in healthy subjects with normal renal function. However, there was a trend toward decreasing serum protein binding among subjects with CLCR <30 mL/min (88%), including those receiving hemodialysis (86%) and continuous ambulatory peritoneal dialysis (CAPD) (84%). The protein binding of daptomycin in subjects with moderate hepatic impairment (Child-Pugh Class B) was similar to that in healthy adult subjects.
- The volume of distribution at steady-state (Vss) of daptomycin in healthy adult subjects was approximately 0.1 L/kg and was independent of dose.
- Metabolism
- In in vitro studies, daptomycin was not metabolized by human liver microsomes.
- In 5 healthy adults after infusion of radiolabeled 14C-daptomycin, the plasma total radioactivity was similar to the concentration determined by microbiological assay. Inactive metabolites were detected in urine, as determined by the difference between total radioactive concentrations and microbiologically active concentrations. In a separate study, no metabolites were observed in plasma on Day 1 following the administration of CUBICIN at 6 mg/kg to subjects. Minor amounts of three oxidative metabolites and one unidentified compound were detected in urine. The site of metabolism has not been identified.
- Excretion
- Daptomycin is excreted primarily by the kidneys. In a mass balance study of 5 healthy subjects using radiolabeled daptomycin, approximately 78% of the administered dose was recovered from urine based on total radioactivity (approximately 52% of the dose based on microbiologically active concentrations), and 5.7% of the administered dose was recovered from feces (collected for up to 9 days) based on total radioactivity.
- Specific Populations
- Renal Impairment
- Population-derived pharmacokinetic parameters were determined for infected patients (complicated skin and skin structure infections [cSSSI] and S. aureus bacteremia) and noninfected subjects with various degrees of renal function (Table 8). Total plasma clearance (CLT), elimination half-life (t1/2), and volume of distribution at steady-state (Vss) in patients with cSSSI were similar to those in patients with S. aureus bacteremia. Following administration of CUBICIN 4 mg/kg q24h by IV infusion over a 30-minute period, the mean CLT was 9%, 22%, and 46% lower among subjects and patients with mild (CLCR 50–80 mL/min), moderate (CLCR 30–<50 mL/min), and severe (CLCR <30 mL/min) renal impairment, respectively, than in those with normal renal function (CLCR >80 mL/min). The mean steady-state systemic exposure (AUC), t1/2, and Vss increased with decreasing renal function, although the mean AUC for patients with CLCR 30–80 mL/min was not markedly different from the mean AUC for patients with normal renal function. The mean AUC for patients with CLCR <30 mL/min and for patients on dialysis (CAPD and hemodialysis dosed post-dialysis) was approximately 2 and 3 times higher, respectively, than for patients with normal renal function. The mean Cmax ranged from 60 to 70 mcg/mL in patients with CLCR ≥30 mL/min, while the mean Cmax for patients with CLCR <30 mL/min ranged from 41 to 58 mcg/mL. After administration of CUBICIN 6 mg/kg q24h by IV infusion over a 30-minute period, the mean Cmax ranged from 80 to 114 mcg/mL in patients with mild to moderate renal impairment and was similar to that of patients with normal renal function.
- Because renal excretion is the primary route of elimination, adjustment of CUBICIN dosage interval is necessary in patients with severe renal impairment (CLCR <30 mL/min).
- Hepatic Impairment
- The pharmacokinetics of daptomycin were evaluated in 10 subjects with moderate hepatic impairment (Child-Pugh Class B) and compared with those in healthy volunteers (N=9) matched for gender, age, and weight. The pharmacokinetics of daptomycin were not altered in subjects with moderate hepatic impairment. No dosage adjustment is warranted when CUBICIN is administered to patients with mild to moderate hepatic impairment. The pharmacokinetics of daptomycin in patients with severe hepatic impairment (Child-Pugh Class C) have not been evaluated.
- Gender
- No clinically significant gender-related differences in daptomycin pharmacokinetics have been observed. No dosage adjustment is warranted based on gender when CUBICIN is administered.
- Geriatric
- The pharmacokinetics of daptomycin were evaluated in 12 healthy elderly subjects (≥75 years of age) and 11 healthy young controls (18 to 30 years of age). Following administration of a single 4 mg/kg dose of CUBICIN by IV infusion over a 30-minute period, the mean total clearance of daptomycin was approximately 35% lower and the mean AUC0-∞ was approximately 58% higher in elderly subjects than in healthy young subjects. There were no differences in Cmax.
- Obesity
- The pharmacokinetics of daptomycin were evaluated in 6 moderately obese (Body Mass Index [BMI] 25 to 39.9 kg/m2) and 6 extremely obese (BMI ≥40 kg/m2) subjects and controls matched for age, gender, and renal function. Following administration of CUBICIN by IV infusion over a 30-minute period as a single 4 mg/kg dose based on total body weight, the total plasma clearance of daptomycin normalized to total body weight was approximately 15% lower in moderately obese subjects and 23% lower in extremely obese subjects than in nonobese controls. The AUC0-∞ of daptomycin was approximately 30% higher in moderately obese subjects and 31% higher in extremely obese subjects than in nonobese controls. The differences were most likely due to differences in the renal clearance of daptomycin. No adjustment of CUBICIN dosage is warranted in obese patients.
- Pediatric
- The pharmacokinetics of daptomycin in pediatric populations (<18 years of age) have not been established.
- Drug-Drug Interactions
- In Vitro Studies
- In vitro studies with human hepatocytes indicate that daptomycin does not inhibit or induce the activities of the following human cytochrome P450 isoforms: 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4. It is unlikely that daptomycin will inhibit or induce the metabolism of drugs metabolized by the P450 system.
- Aztreonam
- In a study in which 15 healthy adult subjects received a single dose of CUBICIN 6 mg/kg IV and a combination dose of CUBICIN 6 mg/kg IV and aztreonam 1 g IV, administered over a 30-minute period, the Cmax and AUC0-∞ of daptomycin were not significantly altered by aztreonam.
- Tobramycin
- In a study in which 6 healthy adult males received a single dose of CUBICIN 2 mg/kg IV, tobramycin 1 mg/kg IV, and both in combination, administered over a 30-minute period, the mean Cmax and AUC0-∞ of daptomycin were 12.7% and 8.7% higher, respectively, when CUBICIN was coadministered with tobramycin. The mean Cmax and AUC0-∞ of tobramycin were 10.7% and 6.6% lower, respectively, when tobramycin was coadministered with CUBICIN. These differences were not statistically significant. The interaction between daptomycin and tobramycin with a clinical dose of CUBICIN is unknown.
- Warfarin
- In 16 healthy subjects, administration of CUBICIN 6 mg/kg q24h by IV infusion over a 30-minute period for 5 days, with coadministration of a single oral dose of warfarin (25 mg) on the 5th day, had no significant effect on the pharmacokinetics of either drug and did not significantly alter the INR (International Normalized Ratio).
- Simvastatin
- In 20 healthy subjects on a stable daily dose of simvastatin 40 mg, administration of CUBICIN 4 mg/kg q24h by IV infusion over a 30-minute period for 14 days (N=10) had no effect on plasma trough concentrations of simvastatin and was not associated with a higher incidence of adverse events, including skeletal myopathy, than in subjects receiving placebo once daily (N=10).
- Probenecid
- Concomitant administration of probenecid (500 mg 4 times daily) and a single dose of CUBICIN 4 mg/kg by IV infusion over a 30-minute period did not significantly alter the Cmax or AUC0-∞ of daptomycin.
- Daptomycin belongs to the cyclic lipopeptide class of antibacterials. Daptomycin has clinical utility in the treatment of infections caused by aerobic, Gram-positive bacteria. The in vitro spectrum of activity of daptomycin encompasses most clinically relevant Gram-positive pathogenic bacteria.
- Daptomycin exhibits rapid, concentration-dependent bactericidal activity against Gram-positive bacteria in vitro. This has been demonstrated both by time-kill curves and by MBC/MIC (minimum bactericidal concentration/minimum inhibitory concentration) ratios using broth dilution methodology. Daptomycin maintained bactericidal activity in vitro against stationary phase S. aureus in simulated endocardial vegetations. The clinical significance of this is not known.
- Mechanism of Action
- The mechanism of action of daptomycin is distinct from that of any other antibacterial. Daptomycin binds to bacterial cell membranes and causes a rapid depolarization of membrane potential. This loss of membrane potential causes inhibition of DNA, RNA, and protein synthesis, which results in bacterial cell death.
- Mechanism of Resistance
- The mechanism(s) of daptomycin resistance is not fully understood. Currently, there are no known transferable elements that confer resistance to daptomycin.
- Complicated Skin and Skin Structure Infection (cSSSI) Trials
- The emergence of daptomycin non-susceptible isolates occurred in 2 infected patients across the set of Phase 2 and pivotal Phase 3 clinical trials of cSSSI. In one case, a non-susceptible S. aureus was isolated from a patient in a Phase 2 trial who received CUBICIN at less than the protocol-specified dose for the initial 5 days of therapy. In the second case, a non-susceptible Enterococcus faecalis was isolated from a patient with an infected chronic decubitus ulcer who was enrolled in a salvage trial.
- S. aureus Bacteremia/Endocarditis and Other Post-Approval Trials
- In subsequent clinical trials, non-susceptible isolates were recovered. S. aureus was isolated from a patient in a compassionate-use trial and from 7 patients in the S. aureus bacteremia/endocarditis trial. An E. faecium was isolated from a patient in a vancomycin-resistant enterococci trial.
- Interactions with Other Antibacterials
- In vitro studies have investigated daptomycin interactions with other antibacterials. Antagonism, as determined by kill curve studies, has not been observed. In vitro synergistic interactions of daptomycin with aminoglycosides, β-lactam antibacterials, and rifampin have been shown against some isolates of staphylococci (including some methicillin-resistant isolates) and enterococci (including some vancomycin-resistant isolates).
- Activity In Vitro and In Vivo
- Daptomycin has been shown to be active against most isolates of the following Gram-positive bacteria both in vitro and in clinical infections, as described in Indications and Usage (1).
Gram-Positive Bacteria
Enterococcus faecalis (vancomycin-susceptible isolates only)
Staphylococcus aureus (including methicillin-resistant isolates)
Streptococcus agalactiae
Streptococcus dysgalactiae subsp. equisimilis
Streptococcus pyogenes
- Gram-Positive Bacteria
Enterococcus faecalis (vancomycin-susceptible isolates only)
Staphylococcus aureus (including methicillin-resistant isolates)
Streptococcus agalactiae
Streptococcus dysgalactiae subsp. equisimilis
Streptococcus pyogenes
- Enterococcus faecalis (vancomycin-susceptible isolates only)
- Staphylococcus aureus (including methicillin-resistant isolates)
- Streptococcus agalactiae
- Streptococcus dysgalactiae subsp. equisimilis
- Streptococcus pyogenes
- The following in vitro data are available, but their clinical significance is unknown. At least 90% of the following Gram-positive bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for daptomycin versus the bacterial genus (Table 9). However, the efficacy of CUBICIN in treating clinical infections due to these bacteria has not been established in adequate and well-controlled clinical trials.
- Gram-Positive Bacteria
Corynebacterium jeikeium
Enterococcus faecalis (vancomycin-resistant isolates)
Enterococcus faecium (including vancomycin-resistant isolates)
Staphylococcus epidermidis (including methicillin-resistant isolates)
Staphylococcus haemolyticus
- Gram-Positive Bacteria
Corynebacterium jeikeium
Enterococcus faecalis (vancomycin-resistant isolates)
Enterococcus faecium (including vancomycin-resistant isolates)
Staphylococcus epidermidis (including methicillin-resistant isolates)
Staphylococcus haemolyticus
- Corynebacterium jeikeium
- Enterococcus faecalis (vancomycin-resistant isolates)
- Enterococcus faecium (including vancomycin-resistant isolates)
- Staphylococcus epidermidis (including methicillin-resistant isolates)
- Staphylococcus haemolyticus
- Susceptibility Testing Methods
- When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility tests for antimicrobial drug products used in resident hospitals to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting an antibacterial drug product for treatment.
- Dilution Techniques
- Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized broth test method2,3 with the broth adjusted to a calcium content of 50 mg/L. The use of the agar dilution method is not recommended with daptomycin3. The MICs should be interpreted according to the criteria listed in Table 9.
- A report of "Susceptible" indicates that the antimicrobial is likely to inhibit the growth of the pathogen if the antimicrobial compound reaches the concentration at the infection site necessary to inhibit growth of the pathogen.
- Diffusion Technique
- Quantitative methods that require measurement of zone diameters have not been shown to provide reproducible estimates of the susceptibility of bacteria to daptomycin. The use of the disk diffusion method is not recommended with daptomycin.
- Quality Control
- Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test2,3. Standard daptomycin powder should provide the ranges of MIC values noted in
## Nonclinical Toxicology
- Long-term carcinogenicity studies in animals have not been conducted to evaluate the carcinogenic potential of CUBICIN. However, neither mutagenic nor clastogenic potential was found in a battery of genotoxicity tests, including the Ames assay, a mammalian cell gene mutation assay, a test for chromosomal aberrations in Chinese hamster ovary cells, an in vivo micronucleus assay, an in vitro DNA repair assay, and an in vivo sister chromatid exchange assay in Chinese hamsters.
- Daptomycin did not affect the fertility or reproductive performance of male and female rats when administered intravenously at doses up to 150 mg/kg/day, which is approximately 9 times the estimated human exposure level based upon AUCs.
- Adult Animals
- In animals, daptomycin administration has been associated with effects on skeletal muscle. However, there were no changes in cardiac or smooth muscle. Skeletal muscle effects were characterized by microscopic degenerative/regenerative changes and variable elevations in creatine phosphokinase (CPK). No fibrosis or rhabdomyolysis was evident in repeat-dose studies up to the highest doses tested in rats (150 mg/kg/day) and dogs (100 mg/kg/day). The degree of skeletal myopathy showed no increase when treatment was extended from 1 month to up to 6 months. Severity was dose-dependent. All muscle effects, including microscopic changes, were fully reversible within 30 days following the cessation of dosing.
- In adult animals, effects on peripheral nerve (characterized by axonal degeneration and frequently accompanied by significant losses of patellar reflex, gag reflex, and pain perception) were observed at daptomycin doses higher than those associated with skeletal myopathy. Deficits in the dogs' patellar reflexes were seen within 2 weeks after the start of treatment at 40 mg/kg/day (9 times the human Cmax at the 6 mg/kg/day dose), with some clinical improvement noted within 2 weeks after the cessation of dosing. However, at 75 mg/kg/day for 1 month, 7 of 8 dogs failed to regain full patellar reflex responses within a 3-month recovery period. In a separate study in dogs receiving doses of 75 and 100 mg/kg/day for 2 weeks, minimal residual histological changes were noted at 6 months after the cessation of dosing. However, recovery of peripheral nerve function was evident.
- Tissue distribution studies in rats showed that daptomycin is retained in the kidney but appears to penetrate the blood-brain barrier only minimally following single and multiple doses.
- Juvenile Animals
- Target organs of daptomycin-related effects in 7-week-old juvenile dogs were skeletal muscle and nerve, the same target organs as in adult dogs. In juvenile dogs, nerve effects were noted at lower daptomycin blood concentrations than in adult dogs following 28 days of dosing. In contrast to adult dogs, juvenile dogs also showed evidence of effects in nerves of the spinal cord as well as peripheral nerves after 28 days of dosing. No nerve effects were noted in juvenile dogs following 14 days of dosing at doses up to 75 mg/kg/day.
- Administration of daptomycin to 7-week-old juvenile dogs for 28 days at doses of 50 mg/kg/day produced minimal degenerative effects on the peripheral nerve and spinal cord in several animals, with no corresponding clinical signs. A dose of 150 mg/kg/day for 28 days produced minimal degeneration in the peripheral nerve and spinal cord as well as minimal to mild degeneration of the skeletal muscle in a majority of animals, accompanied by slight to severe muscle weakness evident in most dogs. Following a 28-day recovery phase, microscopic examination revealed recovery of the skeletal muscle and the ulnar nerve effects, but nerve degeneration in the sciatic nerve and spinal cord was still observed in all 150 mg/kg/day dogs.
- Following once-daily administration of daptomycin to juvenile dogs for 28 days, microscopic effects in nerve tissue were noted at a Cmax value of 417 mcg/mL, which is approximately 3-fold less than the Cmax value associated with nerve effects in adult dogs treated once daily with daptomycin for 28 days (1308 mcg/mL).
# Clinical Studies
- Adult patients with clinically documented complicated skin and skin structure infections (cSSSI) (Table 11) were enrolled in two randomized, multinational, multicenter, investigator-blinded trials comparing CUBICIN (4 mg/kg IV q24h) with either vancomycin (1 g IV q12h) or an anti-staphylococcal semi-synthetic penicillin (i.e., nafcillin, oxacillin, cloxacillin, or flucloxacillin; 4 to 12 g IV per day). Patients could switch to oral therapy after a minimum of 4 days of IV treatment if clinical improvement was demonstrated. Patients known to have bacteremia at baseline were excluded. Patients with creatinine clearance (CLCR) between 30 and 70 mL/min were to receive a lower dose of CUBICIN as specified in the protocol; however, the majority of patients in this subpopulation did not have the dose of CUBICIN adjusted.
- One trial was conducted primarily in the United States and South Africa (study 9801), and the second was conducted at non-US sites only (study 9901). The two trials were similar in design but differed in patient characteristics, including history of diabetes and peripheral vascular disease. There were a total of 534 patients treated with CUBICIN and 558 treated with comparator in the two trials. The majority (89.7%) of patients received IV medication exclusively.
- The efficacy endpoints in both trials were the clinical success rates in the intent-to-treat (ITT) population and in the clinically evaluable (CE) population. In study 9801, clinical success rates in the ITT population were 62.5% (165/264) in patients treated with CUBICIN and 60.9% (162/266) in patients treated with comparator drugs. Clinical success rates in the CE population were 76.0% (158/208) in patients treated with CUBICIN and 76.7% (158/206) in patients treated with comparator drugs. In study 9901, clinical success rates in the ITT population were 80.4% (217/270) in patients treated with CUBICIN and 80.5% (235/292) in patients treated with comparator drugs. Clinical success rates in the CE population were 89.9% (214/238) in patients treated with CUBICIN and 90.4% (226/250) in patients treated with comparator drugs.
- The success rates by pathogen for microbiologically evaluable patients are presented in Table 12.
- The efficacy of CUBICIN in the treatment of patients with S. aureus bacteremia was demonstrated in a randomized, controlled, multinational, multicenter, open-label trial. In this trial, adult patients with at least one positive blood culture for S. aureus obtained within 2 calendar days prior to the first dose of study drug and irrespective of source were enrolled and randomized to either CUBICIN (6 mg/kg IV q24h) or standard of care [an anti-staphylococcal semi-synthetic penicillin 2 g IV q4h (nafcillin, oxacillin, cloxacillin, or flucloxacillin) or vancomycin 1 g IV q12h, each with initial gentamicin 1 mg/kg IV every 8 hours for first 4 days]. Of the patients in the comparator group, 93% received initial gentamicin for a median of 4 days, compared with 1 patient (<1%) in the CUBICIN group. Patients with prosthetic heart valves, intravascular foreign material that was not planned for removal within 4 days after the first dose of study medication, severe neutropenia, known osteomyelitis, polymicrobial bloodstream infections, creatinine clearance <30 mL/min, and pneumonia were excluded.
- Upon entry, patients were classified for likelihood of endocarditis using the modified Duke criteria (Possible, Definite, or Not Endocarditis). *Echocardiography, including a transesophageal echocardiogram (TEE), was performed within 5 days following study enrollment. The choice of comparator agent was based on the oxacillin susceptibility of the S. aureus isolate. The duration of study treatment was based on the investigator's clinical diagnosis. Final diagnoses and outcome assessments at Test of Cure (6 weeks after the last treatment dose) were made by a treatment-blinded Adjudication Committee, using protocol-specified clinical definitions and a composite primary efficacy endpoint (clinical and microbiological success) at the Test of Cure visit.
- A total of 246 patients ≥18 years of age (124 CUBICIN, 122 comparator) with S. aureus bacteremia were randomized from 48 centers in the US and Europe. In the ITT population, 120 patients received CUBICIN and 115 received comparator (62 received an anti-staphylococcal semi-synthetic penicillin and 53 received vancomycin). Thirty-five patients treated with an anti-staphylococcal semi-synthetic penicillin received vancomycin initially for 1 to 3 days, pending final susceptibility results for the S. aureus isolates. The median age among the 235 patients in the ITT population was 53 years (range: 21 to 91 years); 30/120 (25%) in the CUBICIN group and 37/115 (32%) in the comparator group were ≥65 years of age. *Of the 235 ITT patients, there were 141 (60%) males and 156 (66%) Caucasians across the two treatment groups. In addition, 176 (75%) of the ITT population had systemic inflammatory response syndrome (SIRS) at baseline and 85 (36%) had surgical procedures within 30 days prior to onset of the S. aureus bacteremia. Eighty-nine patients (38%) had bacteremia caused by methicillin-resistant S. aureus (MRSA). Entry diagnosis was based on the modified Duke criteria and comprised 37 (16%) Definite, 144 (61%) Possible, and 54 (23%) Not Endocarditis. Of the 37 patients with an entry diagnosis of Definite Endocarditis, all (100%) had a final diagnosis of infective endocarditis, and of the 144 patients with an entry diagnosis of Possible Endocarditis, 15 (10%) had a final diagnosis of infective endocarditis as assessed by the Adjudication Committee. Of the 54 patients with an entry diagnosis of Not Endocarditis, 1 (2%) had a final diagnosis of infective endocarditis as assessed by the Adjudication Committee.
- In the ITT population, there were 182 patients with bacteremia and 53 patients with infective endocarditis as assessed by the Adjudication Committee, including 35 with right-sided endocarditis and 18 with left-sided endocarditis. The 182 patients with bacteremia comprised 121 with complicated S. aureus bacteremia and 61 with uncomplicated S. aureus bacteremia.
- Complicated bacteremia was defined as S. aureus isolated from blood cultures obtained on at least 2 different calendar days, and/or metastatic foci of infection (deep tissue involvement), and classification of the patient as not having endocarditis according to the modified Duke criteria. Uncomplicated bacteremia was defined as S. aureus isolated from blood culture(s) obtained on a single calendar day, no metastatic foci of infection, no infection of prosthetic material, and classification of the patient as not having endocarditis according to the modified Duke criteria. The definition of right-sided infective endocarditis (RIE) used in the clinical trial was Definite or Possible Endocarditis according to the modified Duke criteria and no echocardiographic evidence of predisposing pathology or active involvement of either the mitral or aortic valve. Complicated RIE comprised patients who were not intravenous drug users, had a positive blood culture for MRSA, serum creatinine ≥2.5 mg/dL, or evidence of extrapulmonary sites of infection. Patients who were intravenous drug users, had a positive blood culture for methicillin-susceptible S. aureus (MSSA), had serum creatinine <2.5 mg/dL, and were without evidence of extrapulmonary sites of infection were considered to have uncomplicated RIE.
- The coprimary efficacy endpoints in the trial were the Adjudication Committee success rates at the Test of Cure visit (6 weeks after the last treatment dose) in the ITT and Per Protocol (PP) populations. The overall Adjudication Committee success rates in the ITT population were 44.2% (53/120) in patients treated with CUBICIN and 41.7% (48/115) in patients treated with comparator (difference = 2.4% [95% CI −10.2, 15.1]). The success rates in the PP population were 54.4% (43/79) in patients treated with CUBICIN and 53.3% (32/60) in patients treated with comparator (difference = 1.1% [95% CI −15.6, 17.8]).
- Adjudication Committee success rates are shown in Table 13.
- Eighteen (18/120) patients in the CUBICIN arm and 19/116 patients in the comparator arm died during the trial. These comprise 3/28 CUBICIN-treated patients and 8/26 comparator-treated patients with endocarditis, as well as 15/92 CUBICIN-treated patients and 11/90 comparator-treated patients with bacteremia. Among patients with persisting or relapsing S. aureus infections, 8/19 CUBICIN-treated patients and 7/11 comparator-treated patients died.
- Overall, there was no difference in time to clearance of S. aureus bacteremia between CUBICIN and comparator. The median time to clearance in patients with MSSA was 4 days and in patients with MRSA was 8 days.
- Failure of treatment due to persisting or relapsing S. aureus infections was assessed by the Adjudication Committee in 19/120 (16%) CUBICIN-treated patients (12 with MRSA and 7 with MSSA) and 11/115 (10%) comparator-treated patients (9 with MRSA treated with vancomycin and 2 with MSSA treated with an anti-staphylococcal semi-synthetic penicillin). Among all failures, isolates from 6 CUBICIN-treated patients and 1 vancomycin-treated patient developed increasing MICs (reduced susceptibility) by central laboratory testing during or following therapy. Most patients who failed due to persisting or relapsing S. aureus infection had deep-seated infection and did not receive necessary surgical intervention.
# How Supplied
- CUBICIN (daptomycin for injection) is supplied as a sterile pale yellow to light brown lyophilized cake in a single-use 10 mL vial containing 500 mg of daptomycin: Package of 1 (NDC 67919-011-01).
- Store original packages at refrigerated temperatures, 2 to 8°C (36 to 46°F); avoid excessive heat.
## Storage
There is limited information regarding Daptomycin Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients should be advised that allergic reactions, including serious allergic reactions, could occur and that serious reactions require immediate treatment. Patients should report any previous allergic reactions to CUBICIN.
- Patients should be advised to report muscle pain or weakness, especially in the forearms and lower legs, as well as tingling or numbness.
- Patients should be advised to report any symptoms of cough, breathlessness, or fever.
- Diarrhea is a common problem caused by antibacterials that usually ends when the antibacterial is discontinued. Sometimes after starting treatment with antibacterials, patients can develop watery and bloody stools (with or without stomach cramps and fever), even as late as 2 or more months after having received the last dose of the antibacterial. If this occurs, patients should contact their physician as soon as possible.
- Patients should be counseled that antibacterial drugs, including CUBICIN, should be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When CUBICIN is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be administered exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by CUBICIN or other antibacterial drugs in the future.
# Precautions with Alcohol
- Alcohol-Daptomycin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Cubicin®[4]
# Look-Alike Drug Names
- DAPTOmycin® — DACTINomycin®
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Cubicin | |
9f401f8832a93e1b4b964f67b00613b578c36d37 | wikidoc | Curry Tree | Curry Tree
The Curry Tree or Curry-leaf Tree (Murraya koenigii; syn. Bergera koenigii, Chalcas koenigii) is a tropical to sub-tropical tree in the family Rutaceae, which is native to India.
# Description
It is a small tree, growing 4-6 m tall, with a trunk up to 40 cm diameter. The leaves are pinnate, with 11-21 leaflets, each leaflet 2-4 cm long and 1-2 cm broad. The flowers are small white, and fragrant. The small black, shiny berries are edible, but their seeds are poisonous.
The species name commemorates the botanist Johann Gerhard Koenig.
# Uses
Its leaves are highly aromatic and are used as a herb. Their form is small and narrow and they somewhat resemble the leaves of the Neem tree; therefore they are also referred to as Kari Baavu (translated to Black Neem) in the Kannada language and Karivepaku in Telugu, again translating to the same meaning. In Tamil and Malayalam it is known as Karuveppilai, ilai meaning leaves and veppilai meaning Neem leaf. Other names include Kari Patta (Hindi), Bhursunga Patra (Oriya), Kadhi Limb (Marathi), Limda(Gujarati) and Karapincha (Sinhalese).
They are commonly used as seasoning in Indian and Sri Lankan cooking, much like bay leaves and especially in curries with fish or coconut milk. In their fresh form, they have a short shelf life though they may be stored in a freezer for quite some time. They are also available dried, though the aroma is inferior.
Various biological activities of Murraya koenigii include antidiabetic , antioxidant , antimicrobial, anti-inflammatory, hepatoprotective, anti-hypercholesterolemic etc., | Curry Tree
The Curry Tree or Curry-leaf Tree (Murraya koenigii; syn. Bergera koenigii, Chalcas koenigii) is a tropical to sub-tropical tree in the family Rutaceae, which is native to India.
## Description
It is a small tree, growing 4-6 m tall, with a trunk up to 40 cm diameter. The leaves are pinnate, with 11-21 leaflets, each leaflet 2-4 cm long and 1-2 cm broad. The flowers are small white, and fragrant. The small black, shiny berries are edible, but their seeds are poisonous.
The species name commemorates the botanist Johann Gerhard Koenig.
## Uses
Its leaves are highly aromatic and are used as a herb. Their form is small and narrow and they somewhat resemble the leaves of the Neem tree; therefore they are also referred to as Kari Baavu (translated to Black Neem) in the Kannada language and Karivepaku in Telugu, again translating to the same meaning. In Tamil and Malayalam it is known as Karuveppilai, ilai meaning leaves and veppilai meaning Neem leaf. Other names include Kari Patta (Hindi), Bhursunga Patra (Oriya), Kadhi Limb (Marathi), Limda(Gujarati) and Karapincha (Sinhalese).
They are commonly used as seasoning in Indian and Sri Lankan cooking, much like bay leaves and especially in curries with fish or coconut milk. In their fresh form, they have a short shelf life though they may be stored in a freezer for quite some time. They are also available dried, though the aroma is inferior.
Various biological activities of Murraya koenigii include antidiabetic [2], antioxidant [3], antimicrobial, anti-inflammatory, hepatoprotective, anti-hypercholesterolemic etc., | https://www.wikidoc.org/index.php/Curry_Tree | |
de9cc1e11bda6aa269cf701846e806d751872094 | wikidoc | Cyclotides | Cyclotides
Cyclotides are small disulfide rich peptides isolated from plants (1). Typically containing 28-37 amino acids, they are characterized by their head-to-tail cyclised peptide backbone and the interlocking arrangement of their three disulfide bonds. These combined features have been termed the cyclic cystine knot (CCK) motif (Figure 1). To date, over 100 cyclotides have been isolated and characterized from species of the Rubiaceae, Violaceae and Cucurbitaceae plant families.
# Cyclotide structure
Cyclotides have a well-defined three-dimensional structure as a result of their interlocking disulfide bonds and cyclic peptide backbone. Backbone loops and selected residues are labeled on the structure to help orientation. The amino acid sequence (single letter amino acid representation) for this peptide is indicated on the sequence diagram to the right. One of the interesting features of cyclic peptides is that knowledge of the peptide sequence does not reveal the ancestral head and tail; knowledge of the gene sequence is required for this (2). In the case of kalata B1 the indicated glycine (G) and asparagine (N) amino acids are the terminal residues that are linked in a peptide bond to cyclise the peptide.
# Biological significance
Cyclotides have been reported to have a wide range of biological activities, including anti-HIV, insecticidal, anti-tumour, antifouling, anti-microbial, hemolytic, neurotensin antagonism, trypsin inhibition, and uterotonic activities (3-5). An ability to induce uterine contractions was what prompted the initial discovery of kalata B1 (6).
The potent insecticidal activity of cyclotides kalata B1 and kalata B2 has prompted the belief that cyclotides act as plant host-defence agents (Figure 2). The observations that dozens or more cyclotides may be present in a single plant and the cyclotide architecture comprises a conserved core onto which a series of hypervariable loops is displayed suggest that, cyclotides may be able to target many pests/pathogens simultaneously.
# A Serendipitous Discovery
During a Red Cross relief mission in the Congo during the 1960s, a Norwegian doctor, Lorents Gran, noted that during labor African women used a medicinal tea made from the leaves of the plant Oldenlandia affinis (Figure 3) to induce labor and facilitate childbirth (8). The active ingredient was later determined to be a peptide, named kalata B1, after the traditional name for the native medicine, kalata-kalata. Although in vivo studies in rats confirmed the uterotonic activity of the purified peptide, it was another 20 years before the cyclic cystine knot motif and structure of the purified peptide were elucidated (9).
# Cyclotide amino-acid sequences
Analysis of the suite of known cyclotides reveals many sequence homologies that are important for understanding their unique physico-chemical properties and bioactivities. Table 1 presents a selection of cyclotides.
The cyclotides fall into two main structural subfamilies. Moebius cyclotides, the less common of the two, contain a cis-proline in loop 5 that induces a local 180º backbone twist (hence likening it to a Möbius strip, whereas bracelet cyclotides do not. There is smaller variation in sequences within these subfamilies than between them. A third subfamily of cyclotides are trypsin inhibitors and are more homologous to a family of non-cyclic trypsin inhibitors from squash plants known as knottins (10) than they are to the other cyclotides.
It is convenient to discuss sequences in terms of the backbone segments, or loops, between successive cysteine residues. The six cysteine residues are absolutely conserved throughout the cyclotide suite and presumably contribute to the preservation of the CCK motif. Although the cysteines appear essential to maintaining the overall fold, several other residues that are highly conserved in cyclotides are thought to provide additional stability (11).
Throughout the known cyclotides loop 1 is the most conserved. Apart from the six cysteine residues, the glutamic acid and serine/threonine residues of loop 1 are the only residues to have 100% identity across the bracelet and Möbius subfamilies. Furthermore the remaining residue of this loop exhibits only a conservative change i.e. glycine/alanine. This loop is believed to play an important role in stabilizing the cyclotide structure through hydrogen bonding with residues from loops 3 and 5.
Loops 2-6 also have highly conserved features, including the ubiquitous presence of just a single amino acid in loop 4 that is likely involved in sidechain-sidechain hydrogen bonding. Other conserved residues include a hydroxyl-containing residue in loop 3, a glycine residue in the final position of loop 3, a basic and a proline residue in the penultimate position in loop 5 of bracelet and Möbius cyclotides respectively, and an asparagine (or occasionally aspartic acid) residue at the putative cyclisation (2,7,12) point in loop 6. It is of interest to note that not only are certain residues highly conserved, but the backbone and side chain angles are as well.
With recent screening programs suggesting that the number of cyclotide sequences may soon reach the thousands (13), a database, CyBase, has been developed that offers the opportunity for comparisons of sequences and activity data for cyclotides. Several other families of circular proteins are known in bacteria, plants and animals and are also included in CyBase (14).
# Biosynthesis of cyclotides
Plants are a rich source of cyclic peptides, with the vast majority of these molecules being produced via non-ribosomal biosynthetic pathways. In contrast, the cyclotides are gene-coded products generated via processing of a larger precursor protein (2). The gene for the first such precursor is Oak1 (Oldenlandia affinis kalata clone number 1), which was shown to be responsible for the synthesis of kalata B1 (7). Figure 4 illustrates the generic configuration of the precursor protein, which consist of an endoplasmic reticulum signal sequence, a non-conserved pro-region, a highly conserved region known as the N-terminal repeat (NTR), the mature cyclotide domain and finally a short hydrophobic C-terminal tail. The cyclotide domain may contain either one cyclotide sequence, as in the case of Oak1, or multiple copies separated by additional NTR sequences as seen for Oak2 and Oak4. In precursor proteins containing multiple cyclotide domains these can either be all identical sequences, as is the case for Oak4, or they can be different cyclotides as in Oak2 which contains sequences corresponding to kalata B3 and B6.
# Applications
The remarkable stability of cyclotides means that they have an exciting range of potential applications centred on either their intrinsic biological activities or the possibility of using the CCK motif as a scaffold for stabilizing biologically active epitopes (16). Interest in these has recently intensified with the publications of a chemical methodology capable of synthetically producing cyclotides with high yields (17), and the amenability of the CCK framework to amino-acid substitutions (18). But for molecules to be useful in a therapeutic setting they require useful biopharmaceutical characteristics such as resistance to proteolysis and membrane permeability. A recent study on related cystine knot proteins as drug candidates showed that cystine knots do permeate well through rat small intestinal mucosa relative to non-cystine knot peptide drugs such as insulin and bacitracin (19). Furthermore, enzymatic digestion of cystine knot peptide drugs was associated with only a few proteases and it was suggested that this limitation may be overcome by mutating out particular cleavage sites. Thus, certain cystine knot proteins satisfy the basic criteria for drug delivery and represent exciting novel candidates as scaffolds for peptide drug delivery (19). The diverse range of intrinsic activities of cyclotides also continues to hold promise for a wide range of applications in the agricultural fields. | Cyclotides
Cyclotides are small disulfide rich peptides isolated from plants (1). Typically containing 28-37 amino acids, they are characterized by their head-to-tail cyclised peptide backbone and the interlocking arrangement of their three disulfide bonds. These combined features have been termed the cyclic cystine knot (CCK) motif (Figure 1). To date, over 100 cyclotides have been isolated and characterized from species of the Rubiaceae, Violaceae and Cucurbitaceae plant families.
# Cyclotide structure
Cyclotides have a well-defined three-dimensional structure as a result of their interlocking disulfide bonds and cyclic peptide backbone. Backbone loops and selected residues are labeled on the structure to help orientation. The amino acid sequence (single letter amino acid representation) for this peptide is indicated on the sequence diagram to the right. One of the interesting features of cyclic peptides is that knowledge of the peptide sequence does not reveal the ancestral head and tail; knowledge of the gene sequence is required for this (2). In the case of kalata B1 the indicated glycine (G) and asparagine (N) amino acids are the terminal residues that are linked in a peptide bond to cyclise the peptide.
# Biological significance
Cyclotides have been reported to have a wide range of biological activities, including anti-HIV, insecticidal, anti-tumour, antifouling, anti-microbial, hemolytic, neurotensin antagonism, trypsin inhibition, and uterotonic activities (3-5). An ability to induce uterine contractions was what prompted the initial discovery of kalata B1 (6).
The potent insecticidal activity of cyclotides kalata B1 and kalata B2 has prompted the belief that cyclotides act as plant host-defence agents (Figure 2). The observations that dozens or more cyclotides may be present in a single plant and the cyclotide architecture comprises a conserved core onto which a series of hypervariable loops is displayed suggest that, cyclotides may be able to target many pests/pathogens simultaneously.
# A Serendipitous Discovery
During a Red Cross relief mission in the Congo during the 1960s, a Norwegian doctor, Lorents Gran, noted that during labor African women used a medicinal tea made from the leaves of the plant Oldenlandia affinis (Figure 3) to induce labor and facilitate childbirth (8). The active ingredient was later determined to be a peptide, named kalata B1, after the traditional name for the native medicine, kalata-kalata. Although in vivo studies in rats confirmed the uterotonic activity of the purified peptide, it was another 20 years before the cyclic cystine knot motif and structure of the purified peptide were elucidated (9).
# Cyclotide amino-acid sequences
Analysis of the suite of known cyclotides reveals many sequence homologies that are important for understanding their unique physico-chemical properties and bioactivities. Table 1 presents a selection of cyclotides.
The cyclotides fall into two main structural subfamilies. Moebius cyclotides, the less common of the two, contain a cis-proline in loop 5 that induces a local 180º backbone twist (hence likening it to a Möbius strip, whereas bracelet cyclotides do not. There is smaller variation in sequences within these subfamilies than between them. A third subfamily of cyclotides are trypsin inhibitors and are more homologous to a family of non-cyclic trypsin inhibitors from squash plants known as knottins (10) than they are to the other cyclotides.
It is convenient to discuss sequences in terms of the backbone segments, or loops, between successive cysteine residues. The six cysteine residues are absolutely conserved throughout the cyclotide suite and presumably contribute to the preservation of the CCK motif. Although the cysteines appear essential to maintaining the overall fold, several other residues that are highly conserved in cyclotides are thought to provide additional stability (11).
Throughout the known cyclotides loop 1 is the most conserved. Apart from the six cysteine residues, the glutamic acid and serine/threonine residues of loop 1 are the only residues to have 100% identity across the bracelet and Möbius subfamilies. Furthermore the remaining residue of this loop exhibits only a conservative change i.e. glycine/alanine. This loop is believed to play an important role in stabilizing the cyclotide structure through hydrogen bonding with residues from loops 3 and 5.
Loops 2-6 also have highly conserved features, including the ubiquitous presence of just a single amino acid in loop 4 that is likely involved in sidechain-sidechain hydrogen bonding. Other conserved residues include a hydroxyl-containing residue in loop 3, a glycine residue in the final position of loop 3, a basic and a proline residue in the penultimate position in loop 5 of bracelet and Möbius cyclotides respectively, and an asparagine (or occasionally aspartic acid) residue at the putative cyclisation (2,7,12) point in loop 6. It is of interest to note that not only are certain residues highly conserved, but the backbone and side chain angles are as well.
With recent screening programs suggesting that the number of cyclotide sequences may soon reach the thousands (13), a database, CyBase, has been developed that offers the opportunity for comparisons of sequences and activity data for cyclotides. Several other families of circular proteins are known in bacteria, plants and animals and are also included in CyBase (14).
# Biosynthesis of cyclotides
Plants are a rich source of cyclic peptides, with the vast majority of these molecules being produced via non-ribosomal biosynthetic pathways. In contrast, the cyclotides are gene-coded products generated via processing of a larger precursor protein (2). The gene for the first such precursor is Oak1 (Oldenlandia affinis kalata clone number 1), which was shown to be responsible for the synthesis of kalata B1 (7). Figure 4 illustrates the generic configuration of the precursor protein, which consist of an endoplasmic reticulum signal sequence, a non-conserved pro-region, a highly conserved region known as the N-terminal repeat (NTR), the mature cyclotide domain and finally a short hydrophobic C-terminal tail. The cyclotide domain may contain either one cyclotide sequence, as in the case of Oak1, or multiple copies separated by additional NTR sequences as seen for Oak2 and Oak4. In precursor proteins containing multiple cyclotide domains these can either be all identical sequences, as is the case for Oak4, or they can be different cyclotides as in Oak2 which contains sequences corresponding to kalata B3 and B6.
# Applications
The remarkable stability of cyclotides means that they have an exciting range of potential applications centred on either their intrinsic biological activities or the possibility of using the CCK motif as a scaffold for stabilizing biologically active epitopes (16). Interest in these has recently intensified with the publications of a chemical methodology capable of synthetically producing cyclotides with high yields (17), and the amenability of the CCK framework to amino-acid substitutions (18). But for molecules to be useful in a therapeutic setting they require useful biopharmaceutical characteristics such as resistance to proteolysis and membrane permeability. A recent study on related cystine knot proteins as drug candidates showed that cystine knots do permeate well through rat small intestinal mucosa relative to non-cystine knot peptide drugs such as insulin and bacitracin (19). Furthermore, enzymatic digestion of cystine knot peptide drugs was associated with only a few proteases and it was suggested that this limitation may be overcome by mutating out particular cleavage sites. Thus, certain cystine knot proteins satisfy the basic criteria for drug delivery and represent exciting novel candidates as scaffolds for peptide drug delivery (19). The diverse range of intrinsic activities of cyclotides also continues to hold promise for a wide range of applications in the agricultural fields. | https://www.wikidoc.org/index.php/Cyclotides | |
dab90c6fd1cd46f27de3af32fc925296b865e301 | wikidoc | Cyfluthrin | Cyfluthrin
# Overview
Cyfluthrin is a synthetic pyrethroid insecticide and common household pesticide. It is a complex organic compound and the commercial product is sold as a mixture of isomers. Like most pyrethroids, it is highly toxic to fish, invertebrates, and insects, but it is far less toxic to humans. It is generally supplied as a 10-25% liquid concentrate for commercial use and is diluted prior to spraying onto agricultural crops and outbuildings.
# Safety
In rats, the Template:LD50s are 500, 800 (oral), and 600 (skin) mg/kg.
Excessive exposure can cause nausea, headache, muscle weakness, salivation, shortness of breath and seizures. In humans, it is deactivated by enzymatic hydrolysis to several carboxylic acid metabolites, whose urinary excretion half-lives are in a range of 5–7 hours. Worker exposure to the chemical can be monitored by measurement of the urinary metabolites, while severe overdosage may be confirmed by quantification of cyfluthrin in blood or plasma.
Health and safety risks are controlled by right to know laws that exist in most developed countries. Cyfluthrin is regulated in the US by the EPA.
# Commercial use
Cyfluthrin is used in insecticidal sprays such as Temprid (Bayer) which uses a combination of (beta-) cyfluthrin and imidacloprid. | Cyfluthrin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Cyfluthrin is a synthetic pyrethroid insecticide and common household pesticide. It is a complex organic compound and the commercial product is sold as a mixture of isomers. Like most pyrethroids, it is highly toxic to fish, invertebrates, and insects, but it is far less toxic to humans.[1] It is generally supplied as a 10-25% liquid concentrate for commercial use and is diluted prior to spraying onto agricultural crops and outbuildings.
# Safety
In rats, the Template:LD50s are 500, 800 (oral), and 600 (skin) mg/kg.[1]
Excessive exposure can cause nausea, headache, muscle weakness, salivation, shortness of breath and seizures. In humans, it is deactivated by enzymatic hydrolysis to several carboxylic acid metabolites, whose urinary excretion half-lives are in a range of 5–7 hours. Worker exposure to the chemical can be monitored by measurement of the urinary metabolites, while severe overdosage may be confirmed by quantification of cyfluthrin in blood or plasma.[2]
Health and safety risks are controlled by right to know laws that exist in most developed countries. Cyfluthrin is regulated in the US by the EPA.[3]
# Commercial use
Cyfluthrin is used in insecticidal sprays such as Temprid (Bayer) which uses a combination of (beta-) cyfluthrin and imidacloprid. | https://www.wikidoc.org/index.php/Cyfluthrin | |
7fedbc989b57c039de02a2af9a5b545242fed0ee | wikidoc | Duloxetine | Duloxetine
# 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
Duloxetine is a serotonin-norepinephrine reuptake inhibitor that is FDA approved for the treatment of major depressive disorder, generalized anxiety disorder, diabetic peripheral neuropathic pain, fibromyalgia and chronic musculoskeletal pain. There is a Black Box Warning for this drug as shown here. Common adverse reactions include nausea, dry mouth, somnolence, constipation, decreased appetite, and hyperhidrosis.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Duloxetine should be swallowed whole and should not be chewed or crushed, nor should the capsule be opened and its contents sprinkled on food or mixed with liquids. All of these might affect the enteric coating. Duloxetine can be given without regard to meals.
- Duloxetine should be administered at a total dose of 40 mg/day (given as 20 mg twice daily) to 60 mg/day (given either once daily or as 30 mg twice daily). For some patients, it may be desirable to start at 30 mg once daily for 1 week, to allow patients to adjust to the medication before increasing to 60 mg once daily. While a 120 mg/day dose was shown to be effective, there is no evidence that doses greater than 60 mg/day confer any additional benefits. The safety of doses above 120 mg/day has not been adequately evaluated.
- For most patients, the recommended starting dose for Duloxetine is 60 mg administered once daily. For some patients, it may be desirable to start at 30 mg once daily for 1 week, to allow patients to adjust to the medication before increasing to 60 mg once daily. While a 120 mg once daily dose was shown to be effective, there is no evidence that doses greater than 60 mg/day confer additional benefit. Nevertheless, if a decision is made to increase the dose beyond 60 mg once daily, dose increases should be in increments of 30 mg once daily. The safety of doses above 120 mg once daily has not been adequately evaluated.
- The recommended dose for Duloxetine is 60 mg administered once daily. There is no evidence that doses higher than 60 mg confer additional significant benefit and the higher dose is clearly less well tolerated. For patients for whom tolerability is a concern, a lower starting dose may be considered.
- Since diabetes is frequently complicated by renal disease, a lower starting dose and gradual increase in dose should be considered for patients with renal impairment.
- The recommended dose for Duloxetine is 60 mg administered once daily. Treatment should begin at 30 mg once daily for 1 week, to allow patients to adjust to the medication before increasing to 60 mg once daily. Some patients may respond to the starting dose. There is no evidence that doses greater than 60 mg/day confer additional benefit, even in patients who do not respond to a 60 mg dose, and higher doses are associated with a higher rate of adverse reactions.
- The recommended dose for Duloxetine is 60 mg once daily. Dosing may be started at 30 mg for one week, to allow patients to adjust to the medication before increasing to 60 mg once daily. There is no evidence that higher doses confer additional benefit, even in patients who do not respond to a 60 mg dose, and higher doses are associated with a higher rate of adverse reactions.
- It is generally agreed that acute episodes of major depression require several months or longer of sustained pharmacologic therapy. Maintenance of efficacy in MDD was demonstrated with Duloxetine as monotherapy. Duloxetine should be administered at a total dose of 60 mg once daily. Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment.
- It is generally agreed that episodes of generalized anxiety disorder require several months or longer of sustained pharmacological therapy. Maintenance of efficacy in GAD was demonstrated with Duloxetine as monotherapy. Duloxetine should be administered in a dose range of 60-120 mg once daily. Patients should be periodically reassessed to determine the continued need for maintenance treatment and the appropriate dose for such treatment.
- As the progression of diabetic peripheral neuropathy is highly variable and management of pain is empirical, the effectiveness of Duloxetine must be assessed individually. Efficacy beyond 12 weeks has not been systematically studied in placebo-controlled trials.
- Fibromyalgia is recognized as a chronic condition. The efficacy of Duloxetine in the management of fibromyalgia has been demonstrated in placebo-controlled studies up to 3 months. The efficacy of Duloxetine was not demonstrated in longer studies; however, continued treatment should be based on individual patient response.
- The efficacy of Duloxetine has not been established in placebo-controlled studies beyond 13 weeks.
- Hepatic Insufficiency
- It is recommended that Duloxetine should ordinarily not be administered to patients with any hepatic insufficiency.
- Severe Renal Impairment
- Duloxetine is not recommended for patients with end-stage renal disease or severe renal impairment (estimated creatinine clearance <30 mL/min).
- Elderly Patients
- No dose adjustment is recommended for elderly patients on the basis of age. As with any drug, caution should be exercised in treating the elderly. When individualizing the dosage in elderly patients, extra care should be taken when increasing the dose.
- Pregnant Women
- There are no adequate and well-controlled studies in pregnant women; therefore, Duloxetine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Lilly maintains a pregnancy registry to monitor the pregnancy outcomes of women exposed to Duloxetine while pregnant. Healthcare providers are encouraged to register any patient who is exposed to Duloxetine during pregnancy by calling the Duloxetine Pregnancy Registry at 1-866-814-6975 or by visiting www.cymbaltapregnancyregistry.com
- Nursing Mothers
- Because the safety of duloxetine in infants is not known, nursing while on Duloxetine is not recommended.
- Symptoms associated with discontinuation of Duloxetine and other SSRIs and SNRIs have been reported. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible
- At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with Duloxetine. Conversely, at least 5 days should be allowed after stopping Duloxetine before starting an MAOI intended to treat psychiatric disorders.
- Do not start Duloxetine in a patient who is being treated with linezolid or intravenous methylene blue because there is an 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 Duloxetine therapy 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, Duloxetine should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for 5 days or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with Duloxetine 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 Duloxetine is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use.
- Duloxetine is available as delayed release capsules:
- 20 mg opaque green capsules imprinted with “Lilly 3235 20mg”
- 30 mg opaque white and blue capsules imprinted with “Lilly 3240 30mg”
- 60 mg opaque green and blue capsules imprinted with “Lilly 3270 60mg”
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Duloxetine in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- 30 mg daily for the first week followed by 60 mg/day for 4 weeks
- Dosing Information
- 40 mg orally twice daily
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Duloxetine is not approved for use in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Duloxetine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Duloxetine in pediatric patients.
# Contraindications
- Monoamine Oxidase Inhibitors (MAOIs)
- The use of MAOIs intended to treat psychiatric disorders with Duloxetine or within 5 days of stopping treatment with Duloxetine is contraindicated because of an increased risk of serotonin syndrome. The use of Duloxetine within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated.
- Starting Duloxetine 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.
- Uncontrolled Narrow-Angle Glaucoma
- In clinical trials, Duloxetine use was associated with an increased risk of mydriasis; therefore, its use should be avoided in patients with uncontrolled narrow-angle glaucoma.
# Warnings
### Precautions
- Suicidal Thoughts and Behaviors in Adolescents and Young Adults
- Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment.
- Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.
- The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk of 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 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.
- If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that discontinuation can be associated with certain symptoms.
- Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for Duloxetine 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 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 Cymbalta (duloxetine) is not approved for use in treating bipolar depression.
- Hepatotoxicity
- There have been reports of hepatic failure, sometimes fatal, in patients treated with Cymbalta. These cases have presented as hepatitis with abdominal pain, hepatomegaly, and elevation of transaminase levels to more than twenty times the upper limit of normal with or without jaundice, reflecting a mixed or hepatocellular pattern of liver injury. Cymbalta should be discontinued in patients who develop jaundice or other evidence of clinically significant liver dysfunction and should not be resumed unless another cause can be established.
- Cases of cholestatic jaundice with minimal elevation of transaminase levels have also been reported. Other postmarketing reports indicate that elevated transaminases, bilirubin, and alkaline phosphatase have occurred in patients with chronic liver disease or cirrhosis.
- Cymbalta increased the risk of elevation of serum transaminase levels in development program clinical trials. Liver transaminase elevations resulted in the discontinuation of 0.3% (92/34,756) of Cymbalta-treated patients. In most patients, the median time to detection of the transaminase elevation was about two months. In placebo-controlled trials in any indication, for patients with normal and abnormal baseline ALT values, elevation of ALT >3 times the upper limit of normal occurred in 1.25% (144/11,496) of Duloxetine-treated patients compared to 0.45% (39/8716) of placebo-treated patients. In placebo-controlled studies using a fixed dose design, there was evidence of a dose response relationship for ALT and AST elevation of >3 times the upper limit of normal and >5 times the upper limit of normal, respectively.
- Because it is possible that duloxetine and alcohol may interact to cause liver injury or that duloxetine may aggravate pre-existing liver disease, Duloxetine should not be prescribed to patients with substantial alcohol use or evidence of chronic liver disease.
- Orthostatic Hypotension and Syncope
- Orthostatic hypotension and syncope have been reported with therapeutic doses of duloxetine. Syncope and orthostatic hypotension tend to occur within the first week of therapy but can occur at any time during duloxetine treatment, particularly after dose increases. The risk of blood pressure decreases may be greater in patients taking concomitant medications that induce orthostatic hypotension (such as antihypertensives) or are potent CYP1A2 inhibitors and in patients taking duloxetine at doses above 60 mg daily. Consideration should be given to discontinuing duloxetine in patients who experience symptomatic orthostatic hypotension and/or syncope during duloxetine therapy.
- Serotonin Syndrome
- The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including Duloxetine, 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 Duloxetine with MAOIs intended to treat psychiatric disorders is contraindicated. Duloxetine 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 Duloxetine. Duloxetine should be discontinued before initiating treatment with the MAOI.
- If concomitant use of Duloxetine 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 Duloxetine and any concomitant serotonergic agents, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.
- Abnormal Bleeding
- SSRIs and SNRIs, including duloxetine, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anti-coagulants 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 SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages.
- Patients should be cautioned about the risk of bleeding associated with the concomitant use of duloxetine and NSAIDs, aspirin, or other drugs that affect coagulation.
- Severe Skin Reactions
- Severe skin reactions, including erythema multiforme and Stevens-Johnson Syndrome (SJS), can occur with Duloxetine. The reporting rate of SJS associated with Duloxetine use exceeds the general population background incidence rate for this serious skin reaction (1 to 2 cases per million person years). The reporting rate is generally accepted to be an underestimate due to underreporting.
- Duloxetine should be discontinued at the first appearance of blisters, peeling rash, mucosal erosions, or any other sign of hypersensitivity if no other etiology can be identified.
- Discontinuation of Treatment with Duloxetine
- Discontinuation symptoms have been systematically evaluated in patients taking duloxetine. Following abrupt or tapered discontinuation in placebo-controlled clinical trials, the following symptoms occurred at 1% or greater and at a significantly higher rate in duloxetine-treated patients compared to those discontinuing from placebo: dizziness, headache, nausea, diarrhea, paresthesia, irritability, vomiting, insomnia, anxiety, hyperhidrosis, and fatigue.
- During marketing of other SSRIs and SNRIs (serotonin and norepinephrine reuptake inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. Although these events are generally self-limiting, some have been reported to be severe.
- Patients should be monitored for these symptoms when discontinuing treatment with Duloxetine. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate.
- Activation of Mania/Hypomania
- In placebo-controlled trials in patients with major depressive disorder, activation of mania or hypomania was reported in 0.1% (4/3779) of duloxetine-treated patients and 0.04% (1/2536) of placebo-treated patients. No activation of mania or hypomania was reported in GAD, fibromyalgia, or chronic musculoskeletal pain placebo-controlled trials. Activation of mania or hypomania has been reported in a small proportion of patients with mood disorders who were treated with other marketed drugs effective in the treatment of major depressive disorder. As with these other agents, Duloxetine should be used cautiously in patients with a history of mania.
- Seizures
- Duloxetine has not been systematically evaluated in patients with a seizure disorder, and such patients were excluded from clinical studies. In placebo-controlled clinical trials, seizures/convulsions occurred in 0.02% (3/12,722) of patients treated with duloxetine and 0.01% (1/9513) of patients treated with placebo. Duloxetine should be prescribed with care in patients with a history of a seizure disorder.
- Effect on Blood Pressure
- In placebo-controlled clinical trials across indications from baseline to endpoint, duloxetine treatment was associated with mean increases of 0.5 mm Hg in systolic blood pressure and 0.8 mm Hg in diastolic blood pressure compared to mean decreases of 0.6 mm Hg systolic and 0.3 mm Hg diastolic in placebo-treated patients. There was no significant difference in the frequency of sustained (3 consecutive visits) elevated blood pressure. In a clinical pharmacology study designed to evaluate the effects of duloxetine on various parameters, including blood pressure at supratherapeutic doses with an accelerated dose titration, there was evidence of increases in supine blood pressure at doses up to 200 mg twice daily. At the highest 200 mg twice daily dose, the increase in mean pulse rate was 5.0 to 6.8 beats and increases in mean blood pressure were 4.7 to 6.8 mm Hg (systolic) and 4.5 to 7 mm Hg (diastolic) up to 12 hours after dosing.
- Blood pressure should be measured prior to initiating treatment and periodically measured throughout treatment.
- Clinically Important Drug Interactions
- Both CYP1A2 and CYP2D6 are responsible for duloxetine metabolism.
- Potential for Other Drugs to Affect Duloxetine
CYP1A2 Inhibitors — Co-administration of Duloxetine with potent CYP1A2 inhibitors should be avoided.
CYP2D6 Inhibitors — Because CYP2D6 is involved in duloxetine metabolism, concomitant use of duloxetine with potent inhibitors of CYP2D6 would be expected to, and does, result in higher concentrations (on average of 60%) of duloxetine.
- CYP1A2 Inhibitors — Co-administration of Duloxetine with potent CYP1A2 inhibitors should be avoided.
- CYP2D6 Inhibitors — Because CYP2D6 is involved in duloxetine metabolism, concomitant use of duloxetine with potent inhibitors of CYP2D6 would be expected to, and does, result in higher concentrations (on average of 60%) of duloxetine.
- Potential for Duloxetine to Affect Other Drugs
Drugs Metabolized by CYP2D6 — Co-administration of Duloxetine with drugs that are extensively metabolized by CYP2D6 and that have a narrow therapeutic index, including certain antidepressants (tricyclic antidepressants , such as nortriptyline, amitriptyline, and imipramine), phenothiazines and Type 1C antiarrhythmics (e.g., propafenone, flecainide), should be approached with caution. Plasma TCA concentrations may need to be monitored and the dose of the TCA may need to be reduced if a TCA is co-administered with Duloxetine. Because of the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, Duloxetine and thioridazine should not be co-administered.
- Drugs Metabolized by CYP2D6 — Co-administration of Duloxetine with drugs that are extensively metabolized by CYP2D6 and that have a narrow therapeutic index, including certain antidepressants (tricyclic antidepressants , such as nortriptyline, amitriptyline, and imipramine), phenothiazines and Type 1C antiarrhythmics (e.g., propafenone, flecainide), should be approached with caution. Plasma TCA concentrations may need to be monitored and the dose of the TCA may need to be reduced if a TCA is co-administered with Duloxetine. Because of the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, Duloxetine and thioridazine should not be co-administered.
- Other Clinically Important Drug Interactions
- Alcohol
- Use of Duloxetine concomitantly with heavy alcohol intake may be associated with severe liver injury. For this reason, Duloxetine should not be prescribed for patients with substantial alcohol use.
- CNS Acting Drugs
- Given the primary CNS effects of Duloxetine, it should be used with caution when it is taken in combination with or substituted for other centrally acting drugs, including those with a similar mechanism of action.
- Hyponatremia
- Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including Duloxetine. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported and appeared to be reversible when Duloxetine was discontinued. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk. Discontinuation of Duloxetine should be considered 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 may lead to falls. More severe and/or acute cases have been associated with hallucination, syncope, seizure, coma, respiratory arrest, and death.
- Use in Patients with Concomitant Illness
- Clinical experience with Duloxetine in patients with concomitant systemic illnesses is limited. There is no information on the effect that alterations in gastric motility may have on the stability of Duloxetine's enteric coating. In extremely acidic conditions, Duloxetine, unprotected by the enteric coating, may undergo hydrolysis to form naphthol. Caution is advised in using Duloxetine in patients with conditions that may slow gastric emptying (e.g., some diabetics).
- Duloxetine has not been systematically evaluated in patients with a recent history of myocardial infarction or unstable coronary artery disease. Patients with these diagnoses were generally excluded from clinical studies during the product's premarketing testing.
- Hepatic Insufficiency
- Duloxetine should ordinarily not be used in patients with hepatic insufficiency.
- Severe Renal Impairment
- Duloxetine should ordinarily not be used in patients with end-stage renal disease or severe renal impairment (creatinine clearance <30 mL/min). Increased plasma concentration of duloxetine, and especially of its metabolites, occur in patients with end-stage renal disease (requiring dialysis).
- Controlled Narrow-Angle Glaucoma
- In clinical trials, Duloxetine was associated with an increased risk of mydriasis; therefore, it should be used cautiously in patients with controlled narrow-angle glaucoma.
- Glycemic Control in Patients with Diabetes
- As observed in DPNP trials, Duloxetine treatment worsens glycemic control in some patients with diabetes. In three clinical trials of Duloxetine for the management of neuropathic pain associated with diabetic peripheral neuropathy, the mean duration of diabetes was approximately 12 years, the mean baseline fasting blood glucose was 176 mg/dL, and the mean baseline hemoglobin A1c (HbA1c) was 7.8%. In the 12-week acute treatment phase of these studies, Duloxetine was associated with a small increase in mean fasting blood glucose as compared to placebo. In the extension phase of these studies, which lasted up to 52 weeks, mean fasting blood glucose increased by 12 mg/dL in the Duloxetine group and decreased by 11.5 mg/dL in the routine care group. HbA1c increased by 0.5% in the Duloxetine and by 0.2% in the routine care groups.
- Urinary Hesitation and Retention
- Duloxetine is in a class of drugs known to affect urethral resistance. If symptoms of urinary hesitation develop during treatment with Duloxetine, consideration should be given to the possibility that they might be drug-related.
- In post marketing experience, cases of urinary retention have been observed. In some instances of urinary retention associated with duloxetine use, hospitalization and/or catheterization has been needed.
- Laboratory Tests
- No specific laboratory tests are recommended.
# Adverse Reactions
## Clinical Trials Experience
- The data described below reflect exposure to duloxetine in placebo-controlled trials for MDD (N=3779), GAD (N=1018), OA (N=503), CLBP (N=600), DPNP (N=906), and FM (N=1294). The population studied was 17 to 89 years of age; 65.7%, 60.8%, 60.6%, 42.9%, and 94.4% female; and 81.8%, 72.6%, 85.3%, 74.0%, and 85.7% Caucasian for MDD, GAD, OA and CLBP, DPNP, and FM, respectively. Most patients received doses of a total of 60 to 120 mg per day.
- The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse reaction of the type listed. A reaction was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. Reactions reported during the studies were not necessarily caused by the therapy, and the frequencies do not reflect investigator impression (assessment) of causality.
- 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.
### Adverse Reactions Reported as Reasons for Discontinuation of Treatment in Placebo-Controlled Trials
- Major Depressive Disorder
- Approximately 8.4% (319/3779) of the patients who received duloxetine in placebo-controlled trials for MDD discontinued treatment due to an adverse reaction, compared with 4.6% (117/2536) of the patients receiving placebo. Nausea (duloxetine 1.1%, placebo 0.4%) was the only common adverse reaction reported as a reason for discontinuation and considered to be drug-related (i.e., discontinuation occurring in at least 1% of the duloxetine-treated patients and at a rate of at least twice that of placebo).
- Generalized Anxiety Disorder
- Approximately 13.7% (139/1018) of the patients who received duloxetine in placebo-controlled trials for GAD discontinued treatment due to an adverse reaction, compared with 5.0% (38/767) for placebo. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine 3.3%, placebo 0.4%), and dizziness (duloxetine 1.3%, placebo 0.4%).
- Diabetic Peripheral Neuropathic Pain
- Approximately 12.9% (117/906) of the patients who received duloxetine in placebo-controlled trials for DPNP discontinued treatment due to an adverse reaction, compared with 5.1% (23/448) for placebo. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine 3.5%, placebo 0.7%), dizziness (duloxetine 1.2%, placebo 0.4%), and somnolence (duloxetine 1.1%, placebo 0.0%).
- Fibromyalgia
- Approximately 17.5% (227/1294) of the patients who received duloxetine in 3 to 6 month placebo-controlled trials for FM discontinued treatment due to an adverse reaction, compared with 10.1% (96/955) for placebo. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine 2.0%, placebo 0.5%), headache (duloxetine 1.2%, placebo 0.3%), somnolence (duloxetine 1.1%, placebo 0.0%), and fatigue (duloxetine 1.1%, placebo 0.1%).
- Chronic Pain due to Osteoarthritis
- Approximately 15.7% (79/503) of the patients who received duloxetine in 13-week, placebo-controlled trials for chronic pain due to OA discontinued treatment due to an adverse reaction, compared with 7.3% (37/508) for placebo. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine 2.2%, placebo 1.0%).
- Chronic Low Back Pain
- Approximately 16.5% (99/600) of the patients who received duloxetine in 13-week, placebo-controlled trials for CLBP discontinued treatment due to an adverse reaction, compared with 6.3% (28/441) for placebo. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine 3.0%, placebo 0.7%), and somnolence (duloxetine 1.0%, placebo 0.0%).
### Most Common Adverse Reactions
- Pooled Trials for all Approved Indications
- The most commonly observed adverse reactions in Duloxetine-treated patients (incidence of at least 5% and at least twice the incidence in placebo patients) were nausea, dry mouth, somnolence, constipation, decreased appetite, and hyperhidrosis.
- Diabetic Peripheral Neuropathic Pain
- The most commonly observed adverse reactions in Duloxetine-treated patients (as defined above) were nausea, somnolence, decreased appetite, constipation, hyperhidrosis, and dry mouth.
- Fibromyalgia
- The most commonly observed adverse reactions in Duloxetine-treated patients (as defined above) were nausea, dry mouth, constipation, somnolence, decreased appetite, hyperhidrosis, and agitation.
- Chronic Pain due to Osteoarthritis
- The most commonly observed adverse reactions in Duloxetine-treated patients (as defined above) were nausea, fatigue, constipation, dry mouth, insomnia, somnolence, and dizziness.
- Chronic Low Back Pain
- The most commonly observed adverse reactions in Duloxetine-treated patients (as defined above) were nausea, dry mouth, insomnia, somnolence, constipation, dizziness, and fatigue.
### Adverse Reactions Occurring at an Incidence of 5% or More Among Duloxetine-Treated Patients in Placebo-Controlled Trials
- Table 2 gives the incidence of treatment-emergent adverse reactions in placebo-controlled trials for approved indications that occurred in 5% or more of patients treated with duloxetine and with an incidence greater than placebo.
### Adverse Reactions Occurring at an Incidence of 2% or More Among Duloxetine-Treated Patients in Placebo-Controlled Trials
- Pooled MDD and GAD Trials
- Table 3 gives the incidence of treatment-emergent adverse reactions in MDD and GAD placebo-controlled trials for approved indications that occurred in 2% or more of patients treated with duloxetine and with an incidence greater than placebo.
- DPNP, FM, OA, and CLBP
- Table 4 gives the incidence of treatment-emergent adverse events that occurred in 2% or more of patients treated with Duloxetine (determined prior to rounding) in the premarketing acute phase of DPNP, FM, OA, and CLBP placebo-controlled trials and with an incidence greater than placebo.
### Effects on Male and Female Sexual Function
- Changes in sexual desire, sexual performance and sexual satisfaction often occur as manifestations of psychiatric disorders or diabetes, but they may also be a consequence of pharmacologic treatment. Because adverse sexual reactions are presumed to be voluntarily underreported, the Arizona Sexual Experience Scale (ASEX), a validated measure designed to identify sexual side effects, was used prospectively in 4 MDD placebo-controlled trials. In these trials, as shown in Table 5 below, patients treated with Duloxetine experienced significantly more sexual dysfunction, as measured by the total score on the ASEX, than did patients treated with placebo. Gender analysis showed that this difference occurred only in males. Males treated with Duloxetine experienced more difficulty with ability to reach orgasm (ASEX Item 4) than males treated with placebo. Females did not experience more sexual dysfunction on Duloxetine than on placebo as measured by ASEX total score. Negative numbers signify an improvement from a baseline level of dysfunction, which is commonly seen in depressed patients. Physicians should routinely inquire about possible sexual side effects.
### Vital Sign Changes
- In placebo-controlled clinical trials across approved indications for change from baseline to endpoint, duloxetine treatment was associated with mean increases of 0.23 mm Hg in systolic blood pressure and 0.73 mm Hg in diastolic blood pressure compared to mean decreases of 1.09 mm Hg systolic and 0.55 mm Hg diastolic in placebo-treated patients. There was no significant difference in the frequency of sustained (3 consecutive visits) elevated blood pressure.
- Duloxetine treatment, for up to 26 weeks in placebo-controlled trials across approved indications, typically caused a small increase in heart rate for change from baseline to endpoint compared to placebo of up to 1.37 beats per minute (increase of 1.20 beats per minute in duloxetine-treated patients, decrease of 0.17 beats per minute in placebo-treated patients).
### Weight Changes
- In placebo-controlled clinical trials, MDD and GAD patients treated with Duloxetine for up to 10 weeks experienced a mean weight loss of approximately 0.5 kg, compared with a mean weight gain of approximately 0.2 kg in placebo-treated patients. In studies of DPNP, FM, OA, and CLBP, patients treated with Duloxetine for up to 26 weeks experienced a mean weight loss of approximately 0.6 kg compared with a mean weight gain of approximately 0.2 kg in placebo-treated patients. In one long-term fibromyalgia 60-week uncontrolled study, duloxetine patients had a mean weight increase of 0.7 kg. In one long-term CLBP 54-week study (13-week, placebo-controlled acute phase and 41-week, uncontrolled extension phase), duloxetine patients had a mean weight decrease of 0.6 kg in 13 weeks of acute phase compared to study entry, then a mean weight increase of 1.4 kg in 41 weeks of extension phase compared to end of acute phase.
### Laboratory Changes
- Duloxetine treatment in placebo-controlled clinical trials across approved indications, was associated with small mean increases from baseline to endpoint in ALT, AST, CPK, alkaline phosphatase; infrequent, modest, transient, abnormal values were observed for these analytes in Duloxetine-treated patients when compared with placebo-treated patients. High bicarbonate and cholesterol and abnormal (high or low) potassium were observed more frequently in duloxetine treated patients compared to placebo.
### Electrocardiogram Changes
- The effect of duloxetine 160 mg and 200 mg administered twice daily to steady state was evaluated in a randomized, double-blinded, two-way crossover study in 117 healthy female subjects. No QT interval prolongation was detected. Duloxetine appears to be associated with concentration-dependent but not clinically meaningful QT shortening.
### Other Adverse Reactions Observed During the Premarketing and Postmarketing Clinical Trial Evaluation of Duloxetine
- Following is a list of treatment-emergent adverse reactions reported by patients treated with duloxetine in clinical trials. In clinical trials of all indications, 34,756 patients were treated with duloxetine. Of these, 26.9% (9337) took duloxetine for at least 6 months, and 12.4% (4317) for at least one year. The following listing is not intended to 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.
- Reactions are categorized by body system according to the following definitions: frequent adverse reactions are those occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are those occurring in fewer than 1/1000 patients.
Frequent: palpitations; Infrequent: myocardial infarction and tachycardia.
Frequent: vertigo; Infrequent: ear pain and tinnitus.
Infrequent: hypothyroidism.
Frequent: blurred vision; Infrequent: diplopia, dry eye, and visual impairment.
Frequent: flatulence; Infrequent: dysphagia, eructation, gastritis, gastrointestinal hemorrhage, halitosis, and stomatitis; Rare: gastric ulcer.
Frequent: chills/rigors; Infrequent: falls, feeling abnormal, feeling hot and/or cold, malaise, and thirst; Rare: gait disturbance.
Infrequent: gastroenteritis and laryngitis.
Frequent: weight increased, weight decreased; Infrequent: blood cholesterol increased.
Infrequent: dehydration and hyperlipidemia; Rare: dyslipidemia.
Frequent: musculoskeletal pain; Infrequent: muscle tightness and muscle twitching.
Frequent: dysgeusia, lethargy, and parasthesia/hypoesthesia; Infrequent: disturbance in attention, dyskinesia, myoclonus, and poor quality sleep; Rare: dysarthria.
Frequent: abnormal dreams and sleep disorder; Infrequent: apathy, bruxism, disorientation/confusional state, irritability, mood swings, and suicide attempt; Rare: completed suicide.
Frequent: urinary frequency; Infrequent: dysuria, micturition urgency, nocturia, polyuria, and urine odor abnormal.
Frequent: anorgasmia/orgasm abnormal; Infrequent: menopausal symptoms, sexual dysfunction, and testicular pain; Rare: menstrual disorder.
Frequent: yawning, oropharyngeal pain; Infrequent: throat tightness.
Frequent: pruritus; Infrequent: cold sweat, dermatitis contact, erythema, increased tendency to bruise, night sweats, and photosensitivity reaction; Rare: ecchymosis.
Frequent: hot flush; Infrequent: flushing, orthostatic hypotension, and peripheral coldness.
## Postmarketing Experience
### Postmarketing Spontaneous Reports
The following adverse reactions have been identified during postapproval use of Duloxetine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Adverse reactions reported since market introduction that were temporally related to duloxetine therapy and not mentioned elsewhere in labeling include: anaphylactic reaction, aggression and anger (particularly early in treatment or after treatment discontinuation), angioneurotic edema, extrapyramidal disorder, galactorrhea, glaucoma, gynecological bleeding, hallucinations, hyperglycemia, hyperprolactinemia, hypersensitivity, hypertensive crisis, muscle spasm, rash, restless legs syndrome, seizures upon treatment discontinuation, supraventricular arrhythmia, tinnitus (upon treatment discontinuation), trismus, and urticaria.
# Drug Interactions
Both CYP1A2 and CYP2D6 are responsible for duloxetine metabolism.
- Inhibitors of CYP1A2
- When duloxetine 60 mg was co-administered with fluvoxamine 100 mg, a potent CYP1A2 inhibitor, to male subjects (n=14) duloxetine AUC was increased approximately 6-fold, the Cmax was increased about 2.5-fold, and duloxetine t1/2 was increased approximately 3-fold. Other drugs that inhibit CYP1A2 metabolism include cimetidine and quinolone antimicrobials such as ciprofloxacin and enoxacin.
- Inhibitors of CYP2D6
- Concomitant use of duloxetine (40 mg once daily) with paroxetine (20 mg once daily) increased the concentration of duloxetine AUC by about 60%, and greater degrees of inhibition are expected with higher doses of paroxetine. Similar effects would be expected with other potent CYP2D6 inhibitors (e.g., fluoxetine, quinidine).
- Dual Inhibition of CYP1A2 and CYP2D6
- Concomitant administration of duloxetine 40 mg twice daily with fluvoxamine 100 mg, a potent CYP1A2 inhibitor, to CYP2D6 poor metabolizer subjects (n=14) resulted in a 6-fold increase in duloxetine AUC and Cmax.
- Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin)
- Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding 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 or SNRIs are co-administered with warfarin. Concomitant administration of warfarin (2-9 mg once daily) under steady state conditions with duloxetine 60 or 120 mg once daily for up to 14 days in healthy subjects (n=15) did not significantly change INR from baseline (mean INR changes ranged from 0.05 to +0.07). The total warfarin (protein bound plus free drug) pharmacokinetics (AUCτ,ss, Cmax,ss or tmax,ss) for both R- and S-warfarin were not altered by duloxetine. Because of the potential effect of duloxetine on platelets, patients receiving warfarin therapy should be carefully monitored when duloxetine is initiated or discontinued.
- Lorazepam
- Under steady-state conditions for duloxetine (60 mg Q 12 hours) and lorazepam (2 mg Q 12 hours), the pharmacokinetics of duloxetine were not affected by co-administration
- Temazepam
- Under steady-state conditions for duloxetine (20 mg qhs) and temazepam (30 mg qhs), the pharmacokinetics of duloxetine were not affected by co-administration.
- Drugs that Affect Gastric Acidity
- Duloxetine has an enteric coating that resists dissolution until reaching a segment of the gastrointestinal tract where the pH exceeds 5.5. In extremely acidic conditions, Duloxetine, unprotected by the enteric coating, may undergo hydrolysis to form naphthol. Caution is advised in using Duloxetine in patients with conditions that may slow gastric emptying (e.g., some diabetics). Drugs that raise the gastrointestinal pH may lead to an earlier release of duloxetine. However, co-administration of Duloxetine with aluminum- and magnesium-containing antacids (51 mEq) or Duloxetine with famotidine, had no significant effect on the rate or extent of duloxetine absorption after administration of a 40 mg oral dose. It is unknown whether the concomitant administration of proton pump inhibitors affects duloxetine absorption.
- Drugs Metabolized by CYP1A2
- In vitro drug interaction studies demonstrate that duloxetine does not induce CYP1A2 activity. Therefore, an increase in the metabolism of CYP1A2 substrates (e.g., theophylline, caffeine) resulting from induction is not anticipated, although clinical studies of induction have not been performed. Duloxetine is an inhibitor of the CYP1A2 isoform in in vitro studies, and in two clinical studies the average (90% confidence interval) increase in theophylline AUC was 7% (1%-15%) and 20% (13%-27%) when co-administered with duloxetine (60 mg twice daily).
- Drugs Metabolized by CYP2D6
- Duloxetine is a moderate inhibitor of CYP2D6. When duloxetine was administered (at a dose of 60 mg twice daily) in conjunction with a single 50 mg dose of desipramine, a CYP2D6 substrate, the AUC of desipramine increased 3-fold.
- Drugs Metabolized by CYP2C9
- Results of in vitro studies demonstrate that duloxetine does not inhibit activity. In a clinical study, the pharmacokinetics of S-warfarin, a CYP2C9 substrate, were not significantly affected by duloxetine.
- Drugs Metabolized by CYP3A
- Results of in vitro studies demonstrate that duloxetine does not inhibit or induce CYP3A activity. Therefore, an increase or decrease in the metabolism of CYP3A substrates (e.g., oral contraceptives and other steroidal agents) resulting from induction or inhibition is not anticipated, although clinical studies have not been performed.
- Drugs Metabolized by CYP2C19
- Results of in vitro studies demonstrate that duloxetine does not inhibit CYP2C19 activity at therapeutic concentrations. Inhibition of the metabolism of CYP2C19 substrates is therefore not anticipated, although clinical studies have not been performed.
- Monoamine Oxidase Inhibitors (MAOIs)
- Serotonergic Drugs
- Alcohol
- When Duloxetine and ethanol were administered several hours apart so that peak concentrations of each would coincide, Duloxetine did not increase the impairment of mental and motor skills caused by alcohol.
- In the Duloxetine clinical trials database, three Duloxetine-treated patients had liver injury as manifested by ALT and total bilirubin elevations, with evidence of obstruction. Substantial intercurrent ethanol use was present in each of these cases, and this may have contributed to the abnormalities seen.
- CNS Drugs
- Drugs Highly Bound to Plasma Protein
- Because duloxetine is highly bound to plasma protein, administration of Duloxetine to a patient taking another drug that is highly protein bound may cause increased free concentrations of the other drug, potentially resulting in adverse reactions. However, co-administration of duloxetine (60 or 120 mg) with warfarin (2-9 mg), a highly protein-bound drug, did not result in significant changes in INR and in the pharmacokinetics of either total S-or total R-warfarin (protein bound plus free drug)
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- Teratogenic Effects
- In animal reproduction studies, duloxetine has been shown to have adverse effects on embryo/fetal and postnatal development.
- When duloxetine was administered orally to pregnant rats and rabbits during the period of organogenesis, there was no evidence of teratogenicity at doses up to 45 mg/kg/day (7 times the maximum recommended human dose and 4 times the human dose of 120 mg/day on a mg/m2 basis, in rat; 15 times the MRHD and 7 times the human dose of 120 mg/day on a mg/m2 basis in rabbit). However, fetal weights were decreased at this dose, with a no-effect dose of 10 mg/kg/day (2 times the MRHD and ≈1 times the human dose of 120 mg/day on a mg/m2 basis in rats; 3 times the MRHD and 2 times the human dose of 120 mg/day on a mg/m2 basis in rabbits).
- When duloxetine was administered orally to pregnant rats throughout gestation and lactation, the survival of pups to 1 day postpartum and pup body weights at birth and during the lactation period were decreased at a dose of 30 mg/kg/day (5 times the MRHD and 2 times the human dose of 120 mg/day on a mg/m2 basis); the no-effect dose was 10 mg/kg/day. Furthermore, behaviors consistent with increased reactivity, such as increased startle response to noise and decreased habituation of locomotor activity, were observed in pups following maternal exposure to 30 mg/kg/day. Post-weaning growth and reproductive performance of the progeny were not affected adversely by maternal duloxetine treatment.
- There are no adequate and well-controlled studies in pregnant women; therefore, duloxetine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Nonteratogenic Effects
- Neonates exposed to SSRIs or serotonin and norepinephrine reuptake inhibitors (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 SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome.
- When treating pregnant women with Duloxetine during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. The physician may consider tapering Duloxetine in the third trimester.
- Lilly maintains a pregnancy registry to monitor the pregnancy outcomes of women exposed to Duloxetine while pregnant. Healthcare providers are encouraged to register any patient who is exposed to Duloxetine during pregnancy by calling the Duloxetine Pregnancy Registry at 1-866-814-6975 or by visiting www.cymbaltapregnancyregistry.com
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Duloxetine in women who are pregnant.
### Labor and Delivery
- The effect of duloxetine on labor and delivery in humans is unknown. Duloxetine should be used during labor and delivery only if the potential benefit justifies the potential risk to the fetus.
### Nursing Mothers
- Duloxetine is excreted into the milk of lactating women. The estimated daily infant dose on a mg/kg basis is approximately 0.14% of the maternal dose. Because the safety of duloxetine in infants is not known, nursing while on Duloxetine is not recommended. However, if the physician determines that the benefit of duloxetine therapy for the mother outweighs any potential risk to the infant, no dosage adjustment is required as lactation did not influence duloxetine pharmacokinetics.
- The disposition of duloxetine was studied in 6 lactating women who were at least 12 weeks postpartum. Duloxetine 40 mg twice daily was given for 3.5 days. Like many other drugs, duloxetine is detected in breast milk, and steady state concentrations in breast milk are about one-fourth those in plasma. The amount of duloxetine in breast milk is approximately 7 μg/day while on 40 mg BID dosing. The excretion of duloxetine metabolites into breast milk was not examined. Because the safety of duloxetine in infants is not known, nursing while on Duloxetine is not recommended.
### Pediatric Use
- Efficacy was not demonstrated in two 10-week, placebo-controlled trials with 800 pediatric patients with MDD, age 7-17. Neither Duloxetine nor the active control (indicated for treatment of pediatric depression) statistically separated from placebo. Duloxetine steady state plasma concentration was comparable in children (7 - 12 years), adolescents (13 - 17 years) and adults. Duloxetine has not been studied in patients under the age of 7. Thus, safety and effectiveness in the pediatric population has not been established.
- Decreased appetite and weight loss have been observed in association with the use of SSRIs and SNRIs. Pediatric patients treated with Duloxetine in MDD clinical trials experienced a 0.2 kg mean decrease in weight at 10-weeks, compared with a mean weight gain of approximately 0.6 kg in placebo-treated patients. The proportion of patients who experienced a clinically significant decrease in weight (≥3.5%) was greater in the Duloxetine group than in the placebo group (11% and 6%, respectively). Subsequently, over the six-month uncontrolled extension period, most Duloxetine-treated patients trended toward recovery to their expected baseline weight percentile based on population data from age- and gender-matched peers. Perform regular monitoring of weight and growth in children and adolescents treated with an SNRI such as Duloxetine.
- In the 2 pediatric MDD studies, the safety findings were consistent with the known safety and tolerability profile for Duloxetine.
- Duloxetine administration to young rats from post-natal day 21 (weaning) through post-natal day 90 (adult) resulted in decreased body weights that persisted into adulthood, but recovered when drug treatment was discontinued; slightly delayed (~1.5 days) sexual maturation in females, without any effect on fertility; and a delay in learning a complex task in adulthood, which was not observed after drug treatment was discontinued. These effects were observed at the high dose of 45 mg/kg/day; the no-effect-level was 20 mg/kg/day.
### Geriatic Use
- Of the 2,418 patients in premarketing clinical studies of Duloxetine for MDD, 5.9% (143) were 65 years of age or over. Of the 1041 patients in CLBP premarketing studies, 21.2% (221) were 65 years of age or over. Of the 487 patients in OA premarketing studies, 40.5% (197) were 65 years of age or over. Of the 1,074 patients in the DPNP premarketing studies, 33% (357) were 65 years of age or over. Of the 1,761 patients in FM premarketing studies, 7.9% (140) were 65 years of age or over. Premarketing clinical studies of GAD did not include sufficient numbers of subjects age 65 or over to determine whether they respond differently from younger subjects. In the MDD, DPNP, FM, OA, and CLBP studies, no overall differences in safety or effectiveness were generally observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. SSRIs and SNRIs, including Duloxetine have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event. In a subgroup analysis of patients 65 years of age and older (N=3278) from all placebo-controlled trials, 1.1% of patients treated with duloxetine reported one or more falls, compared with 0.4% of patients treated with placebo. While many patients with falls had underlying potential risk factors for falls (e.g., medications; medical comorbidities; gait disturbances), the impact of these factors on falls is unclear. Fall with serious consequences including bone fractures and hospitalizations have been reported.
- The pharmacokinetics of duloxetine after a single dose of 40 mg were compared in healthy elderly females (65 to 77 years) and healthy middle-age females (32 to 50 years). There was no difference in the Cmax, but the AUC of duloxetine was somewhat (about 25%) higher and the half-life about 4 hours longer in the elderly females. Population pharmacokinetic analyses suggest that the typical values for clearance decrease by approximately 1% for each year of age between 25 to 75 years of age; but age as a predictive factor only accounts for a small percentage of between-patient variability. Dosage adjustment based on the age of the patient is not necessary
### Gender
There is no FDA guidance on the use of Duloxetine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Duloxetine with respect to specific racial populations.
### Renal Impairment
- Limited data are available on the effects of duloxetine in patients with end-stage renal disease (ESRD). After a single 60 mg dose of duloxetine, Cmax and AUC values were approximately 100% greater in patients with end-stage renal disease receiving chronic intermittent hemodialysis than in subjects with normal renal function. The elimination half-life, however, was similar in both groups. The AUCs of the major circulating metabolites, 4-hydroxy duloxetine glucuronide and 5-hydroxy, 6-methoxy duloxetine sulfate, largely excreted in urine, were approximately 7- to 9-fold higher and would be expected to increase further with multiple dosing. Population PK analyses suggest that mild to moderate degrees of renal dysfunction (estimated CrCl 30-80 mL/min) have no significant effect on duloxetine apparent clearance.
### Hepatic Impairment
- Patients with clinically evident hepatic insufficiency have decreased duloxetine metabolism and elimination. After a single 20 mg dose of Duloxetine, 6 cirrhotic patients with moderate liver impairment (Child-Pugh Class B) had a mean plasma duloxetine clearance about 15% that of age- and gender-matched healthy subjects, with a 5-fold increase in mean exposure (AUC). Although Cmax was similar to normals in the cirrhotic patients, the half-life was about 3 times longer.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Duloxetine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Duloxetine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- Perform regular monitoring of weight and growth in children and adolescents treated with an SNRI such as Duloxetine.
- 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 observe for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt.
# IV Compatibility
There is limited information regarding IV Compatibility of Duloxetine in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- In postmarketing experience, fatal outcomes have been reported for acute overdoses, primarily with mixed overdoses, but also with duloxetine only, at doses as low as 1000 mg. Signs and symptoms of overdose (duloxetine alone or with mixed drugs) included somnolence, coma, serotonin syndrome, seizures,syncope,tachycardia, hypotension, hypertension, and vomiting.
### Management
- There is no specific antidote to Duloxetine, but if serotonin syndrome ensues, specific treatment (such as with cyproheptadine and/or temperature control) may be considered. In case of acute overdose, treatment should consist of those general measures employed in the management of overdose with any drug.
- An adequate airway, oxygenation, and ventilation should be assured, and cardiac rhythm and vital signs should be monitored. Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion or in symptomatic patients.
- Activated charcoal may be useful in limiting absorption of duloxetine from the gastrointestinal tract. Administration of activated charcoal has been shown to decrease AUC and Cmax by an average of one-third, although some subjects had a limited effect of activated charcoal. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be beneficial.
- In managing overdose, the possibility of multiple drug involvement should be considered. A specific caution involves patients who are taking or have recently taken Duloxetine and might ingest excessive quantities of a TCA. In such a case, decreased clearance of the parent tricyclic and/or its active metabolite may increase the possibility of clinically significant sequelae and extend the time needed for close medical observation. The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians' Desk Reference (PDR).
## Chronic Overdose
There is limited information regarding Chronic Overdose of Duloxetine in the drug label.
# Pharmacology
## Mechanism of Action
- Although the exact mechanisms of the antidepressant, central pain inhibitory and anxiolytic actions of duloxetine in humans are unknown, these actions are believed to be related to its potentiation of serotonergic and noradrenergic activity in the CNS.
## Structure
- Duloxetine® (Duloxetine Delayed-Release Capsules) is a selective serotonin and norepinephrine reuptake inhibitor (SSNRI) for oral administration. Its chemical designation is (+)-(S)-N-methyl-γ-(1-naphthyloxy)-2-thiophenepropylamine hydrochloride. The empirical formula is C18H19NOSHCl, which corresponds to a molecular weight of 333.88. The structural formula is:
- Duloxetine hydrochloride is a white to slightly brownish white solid, which is slightly soluble in water.
- Each capsule contains enteric-coated pellets of 22.4, 33.7, or 67.3 mg of duloxetine hydrochloride equivalent to 20, 30, or 60 mg of duloxetine, respectively. These enteric-coated pellets are designed to prevent degradation of the drug in the acidic environment of the stomach. Inactive ingredients include FD&C Blue No. 2, gelatin, hypromellose, hydroxypropyl methylcellulose acetate succinate, sodium lauryl sulfate, sucrose, sugar spheres, talc, titanium dioxide, and triethyl citrate. The 20 and 60 mg capsules also contain iron oxide yellow.
## Pharmacodynamics
- Preclinical studies have shown that duloxetine is a potent inhibitor of neuronal serotonin and norepinephrine reuptake and a less potent inhibitor of dopamine reuptake. Duloxetine has no significant affinity for dopaminergic, adrenergic, cholinergic, histaminergic, opioid, glutamate, and GABA receptors in vitro. Duloxetine does not inhibit monoamine oxidase (MAO).
- Duloxetine is in a class of drugs known to affect urethral resistance. If symptoms of urinary hesitation develop during treatment with Duloxetine, consideration should be given to the possibility that they might be drug-related.
## Pharmacokinetics
- Duloxetine has an elimination half-life of about 12 hours (range 8 to 17 hours) and its pharmacokinetics are dose proportional over the therapeutic range. Steady-state plasma concentrations are typically achieved after 3 days of dosing. Elimination of duloxetine is mainly through hepatic metabolism involving two P450 isozymes, CYP1A2 and CYP2D6.
- Absorption and Distribution
- Orally administered duloxetine hydrochloride is well absorbed. There is a median 2 hour lag until absorption begins (Tlag), with maximal plasma concentrations (Cmax) of duloxetine occurring 6 hours post dose. Food does not affect the Cmax of duloxetine, but delays the time to reach peak concentration from 6 to 10 hours and it marginally decreases the extent of absorption (AUC) by about 10%. There is a 3 hour delay in absorption and a one-third increase in apparent clearance of duloxetine after an evening dose as compared to a morning dose.
- The apparent volume of distribution averages about 1640 L. Duloxetine is highly bound (>90%) to proteins in human plasma, binding primarily to albumin and α1-acid glycoprotein. The interaction between duloxetine and other highly protein bound drugs has not been fully evaluated. Plasma protein binding of duloxetine is not affected by renal or hepatic impairment.
- Metabolism and Elimination
- Biotransformation and disposition of duloxetine in humans have been determined following oral administration of 14C-labeled duloxetine. Duloxetine comprises about 3% of the total radiolabeled material in the plasma, indicating that it undergoes extensive metabolism to numerous metabolites. The major biotransformation pathways for duloxetine involve oxidation of the naphthyl ring followed by conjugation and further oxidation. Both CYP1A2 and CYP2D6 catalyze the oxidation of the naphthyl ring in vitro. Metabolites found in plasma include 4-hydroxy duloxetine glucuronide and 5-hydroxy, 6-methoxy duloxetine sulfate. Many additional metabolites have been identified in urine, some representing only minor pathways of elimination. Only trace (<1% of the dose) amounts of unchanged duloxetine are present in the urine. Most (about 70%) of the duloxetine dose appears in the urine as metabolites of duloxetine; about 20% is excreted in the feces. Duloxetine undergoes extensive metabolism, but the major circulating metabolites have not been shown to contribute significantly to the pharmacologic activity of duloxetine.
## Nonclinical Toxicology
- Carcinogenesis
- Duloxetine was administered in the diet to mice and rats for 2 years.
- In female mice receiving duloxetine at 140 mg/kg/day (11 times the maximum recommended human dose and 6 times the human dose of 120 mg/day on a mg/m2 basis), there was an increased incidence of hepatocellular adenomas and carcinomas. The no-effect dose was 50 mg/kg/day (4 times the MRHD and 2 times the human dose of 120 mg/day on a mg/m2 basis). Tumor incidence was not increased in male mice receiving duloxetine at doses up to 100 mg/kg/day (8 times the MRHD and 4 times the human dose of 120 mg/day on a mg/m2 basis).
- In rats, dietary doses of duloxetine up to 27 mg/kg/day in females (4 times the MRHD and 2 times the human dose of 120 mg/day on a mg/m2 basis) and up to 36 mg/kg/day in males (6 times the MRHD and 3 times the human dose of 120 mg/day on a mg/m2 basis) did not increase the incidence of tumors.
- Mutagenesis
- Duloxetine was not mutagenic in the in vitro bacterial reverse mutation assay (Ames test) and was not clastogenic in an in vivo chromosomal aberration test in mouse bone marrow cells. Additionally, duloxetine was not genotoxic in an in vitro mammalian forward gene mutation assay in mouse lymphoma cells or in an in vitro unscheduled DNA synthesis (UDS) assay in primary rat hepatocytes, and did not induce sister chromatid exchange in Chinese hamster bone marrow in vivo.
- Impairment of Fertility — Duloxetine administered orally to either male or female rats prior to and throughout mating at doses up to 45 mg/kg/day (7 times the maximum recommended human dose of 60 mg/day and 4 times the human dose of 120 mg/day on a mg/m2 basis) did not alter mating or fertility.
# Clinical Studies
- Major Depressive Disorder
- The efficacy of Duloxetine as a treatment for depression was established in 4 randomized, double-blind, placebo-controlled, fixed-dose studies in adult outpatients (18 to 83 years) meeting DSM-IV criteria for major depression. In 2 studies, patients were randomized to Duloxetine 60 mg once daily (N=123 and N=128, respectively) or placebo (N=122 and N=139, respectively) for 9 weeks; in the third study, patients were randomized to Duloxetine 20 or 40 mg twice daily (N=86 and N=91, respectively) or placebo (N=89) for 8 weeks; in the fourth study, patients were randomized to Duloxetine 40 or 60 mg twice daily (N=95 and N=93, respectively) or placebo (N=93) for 8 weeks. There is no evidence that doses greater than 60 mg/day confer additional benefits.
- In all 4 studies, Duloxetine demonstrated superiority over placebo as measured by improvement in the 17-item Hamilton Depression Rating Scale (HAMD-17) total score.
- In all of these clinical studies, analyses of the relationship between treatment outcome and age, gender, and race did not suggest any differential responsiveness on the basis of these patient characteristics.
- In another study, 533 patients meeting DSM-IV criteria for MDD received Duloxetine 60 mg once daily during an initial 12-week open-label treatment phase. Two hundred and seventy-eight patients who responded to open label treatment (defined as meeting the following criteria at weeks 10 and 12: a HAMD-17 total score ≤9, Clinical Global Impressions of Severity (CGI-S) ≤2, and not meeting the DSM-IV criteria for MDD) were randomly assigned to continuation of Duloxetine at the same dose (N=136) or to placebo (N=142) for 6 months. Patients on Duloxetine experienced a statistically significantly longer time to relapse of depression than did patients on placebo. Relapse was defined as an increase in the CGI-S score of ≥2 points compared with that obtained at week 12, as well as meeting the DSM-IV criteria for MDD at 2 consecutive visits at least 2 weeks apart, where the 2-week temporal criterion had to be satisfied at only the second visit. The effectiveness of Duloxetine in hospitalized patients with major depressive disorder has not been studied.
- Generalized Anxiety Disorder
- The efficacy of Duloxetine in the treatment of generalized anxiety disorder (GAD) was established in 1 fixed-dose randomized, double-blind, placebo-controlled trial and 2 flexible-dose randomized, double-blind, placebo-controlled trials in adult outpatients between 18 and 83 years of age meeting the DSM-IV criteria for GAD.
- In 1 flexible-dose study and in the fixed-dose study, the starting dose was 60 mg once daily where down titration to 30 mg once daily was allowed for tolerability reasons before increasing it to 60 mg once daily. Fifteen percent of patients were down titrated. One flexible-dose study had a starting dose of 30 mg once daily for 1 week before increasing it to 60 mg once daily.
- The 2 flexible-dose studies involved dose titration with Duloxetine doses ranging from 60 mg once daily to 120 mg once daily (N=168 and N=162) compared to placebo (N=159 and N=161) over a 10-week treatment period. The mean dose for completers at endpoint in the flexible-dose studies was 104.75 mg/day. The fixed-dose study evaluated Duloxetine doses of 60 mg once daily (N=168) and 120 mg once daily (N=170) compared to placebo (N=175) over a 9-week treatment period. While a 120 mg/day dose was shown to be effective, there is no evidence that doses greater than 60 mg/day confer additional benefit.
- In all 3 studies, Duloxetine demonstrated superiority over placebo as measured by greater improvement in the Hamilton Anxiety Scale (HAM-A) total score and by the Sheehan Disability Scale (SDS) global functional impairment score. The SDS is a widely used and well-validated scale that measures the extent emotional symptoms disrupt patient functioning in 3 life domains: work/school, social life/leisure activities, and family life/home responsibilities.
- In another study, 887 patients meeting DSM-IV-TR criteria for GAD received Duloxetine 60 mg to 120 mg once daily during an initial 26-week open-label treatment phase. Four hundred and twenty-nine patients who responded to open-label treatment (defined as meeting the following criteria at weeks 24 and 26: a decrease from baseline HAM-A total score by at least 50% to a score no higher than 11, and a Clinical Global Impressions of Improvement score of 1 or 2) were randomly assigned to continuation of Duloxetine at the same dose (N=216) or to placebo (N=213) and were observed for relapse. Of the patients randomized, 73% had been in a responder status for at least 10 weeks. Relapse was defined as an increase in CGI-Severity score at least 2 points to a score ≥4 and a MINI (Mini-International Neuropsychiatric Interview) diagnosis of GAD (excluding duration), or discontinuation due to lack of efficacy. Patients taking Duloxetine experienced a statistically significantly longer time to relapse of GAD than did patients taking placebo.
- Subgroup analyses did not indicate that there were any differences in treatment outcomes as a function of age or gender.
- Diabetic Peripheral Neuropathic Pain
- The efficacy of Duloxetine for the management of neuropathic pain associated with diabetic peripheral neuropathy was established in 2 randomized, 12-week, double-blind, placebo-controlled, fixed-dose studies in adult patients having diabetic peripheral neuropathic pain for at least 6 months. Study DPNP-1 and Study DPNP-2 enrolled a total of 791 patients of whom 592 (75%) completed the studies. Patients enrolled had Type I or II diabetes mellitus with a diagnosis of painful distal symmetrical sensorimotor polyneuropathy for at least 6 months. The patients had a baseline pain score of ≥4 on an 11-point scale ranging from 0 (no pain) to 10 (worst possible pain). Patients were permitted up to 4 g of acetaminophen per day as needed for pain, in addition to Duloxetine. Patients recorded their pain daily in a diary.
- Both studies compared Duloxetine 60 mg once daily or 60 mg twice daily with placebo. DPNP-1 additionally compared Duloxetine 20 mg with placebo. A total of 457 patients (342 Duloxetine, 115 placebo) were enrolled in DPNP-1 and a total of 334 patients (226 Duloxetine, 108 placebo) were enrolled in DPNP-2. Treatment with Duloxetine 60 mg one or two times a day statistically significantly improved the endpoint mean pain scores from baseline and increased the proportion of patients with at least a 50% reduction in pain scores from baseline. For various degrees of improvement in pain from baseline to study endpoint, Figures 1 and 2 show the fraction of patients achieving that degree of improvement. The figures are cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%. Patients who did not complete the study were assigned 0% improvement. Some patients experienced a decrease in pain as early as week 1, which persisted throughout the study.
- Fibromyalgia
- The efficacy of Duloxetine for the management of fibromyalgia was established in two randomized, double-blind, placebo-controlled, fixed-dose studies in adult patients meeting the American College of Rheumatology criteria for fibromyalgia (a history of widespread pain for 3 months, and pain present at 11 or more of the 18 specific tender point sites). Study FM-1 was three months in duration and enrolled female patients only. Study FM-2 was six months in duration and enrolled male and female patients. Approximately 25% of participants had a comorbid diagnosis of major depressive disorder (MDD). FM-1 and FM-2 enrolled a total of 874 patients of whom 541 (62%) completed the studies. The patients had a baseline pain score of 6.5 on an 11-point scale ranging from 0 (no pain) to 10 (worse possible pain).
- Both studies compared Duloxetine 60 mg once daily or 120 mg daily (given in divided doses in FM-1 and as a single daily dose in FM-2) with placebo. FM-2 additionally compared Duloxetine 20 mg with placebo during the initial three months of a six-month study. A total of 354 patients (234 Duloxetine, 120 placebo) were enrolled in FM-1 and a total of 520 patients (376 Duloxetine, 144 placebo) were enrolled in FM-2 (5% male, 95% female). Treatment with Duloxetine 60 mg or 120 mg daily statistically significantly improved the endpoint mean pain scores from baseline and increased the proportion of patients with at least a 50% reduction in pain score from baseline. Pain reduction was observed in patients both with and without comorbid MDD. However, the degree of pain reduction may be greater in patients with comorbid MDD. For various degrees of improvement in pain from baseline to study endpoint, Figures 3 and 4 show the fraction of patients achieving that degree of improvement. The figures are cumulative so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%. Patients who did not complete the study were assigned 0% improvement. Some patients experienced a decrease in pain as early as week 1, which persisted throughout the study. Improvement was also demonstrated on measures of function (Fibromyalgia Impact Questionnaires) and patient global impression of change (PGI). Neither study demonstrated a benefit of 120 mg compared to 60 mg, and a higher dose was associated with more adverse reactions and premature discontinuations of treatment.
- Additionally, the benefit of up-titration in non-responders to Duloxetine at 60 mg/day was evaluated in a separate study. Patients were initially treated with Duloxetine 60 mg once daily for eight weeks in open-label fashion. Subsequently, completers of this phase were randomized to double-blind treatment with Duloxetine at either 60 mg once daily or 120 mg once daily. Those patients who were considered non-responders, where response was defined as at least a 30% reduction in pain score from baseline at the end of the 8-week treatment, were no more likely to meet response criteria at the end of 60 weeks of treatment if blindly titrated to Duloxetine 120 mg as compared to those who were blindly continued on Duloxetine 60 mg.
- Chronic Musculoskeletal Pain
- Duloxetine is indicated for the management of chronic musculoskeletal pain. This has been established in studies in patients with chronic low back pain and chronic pain due to osteoarthritis.
- Studies in Chronic Low Back Pain
- The efficacy of Duloxetine in chronic low back pain (CLBP) was assessed in two double-blind, placebo-controlled, randomized clinical trials of 13-weeks duration (Study CLBP-1 and Study CLBP-2), and one of 12-weeks duration (CLBP-3). CLBP-1 and CLBP-3 demonstrated efficacy of Duloxetine in the treatment of chronic low back pain. Patients in all studies had no signs of radiculopathy or spinal stenosis.
- Study CLBP-1: Two hundred thirty-six adult patients (N=115 on Duloxetine, N=121 on placebo) enrolled and 182 (77%) completed 13-week treatment phase. After 7 weeks of treatment, Duloxetine patients with less than 30% reduction in average daily pain and who were able to tolerate duloxetine 60 mg once daily had their dose of Duloxetine, in a double-blinded fashion, increased to 120 mg once daily for the remainder of the study. Patients had a mean baseline pain rating of 6 on a numerical rating scale ranging from 0 (no pain) to 10 (worst possible pain). After 13 weeks of treatment, patients taking Duloxetine 60-120 mg daily had a significantly greater pain reduction compared to placebo. Randomization was stratified by the patients' baseline NSAIDs-use status. Subgroup analyses did not indicate that there were differences in treatment outcomes as a function of NSAIDs use.
- Study CLBP-2: Four hundred and four patients were randomized to receive fixed doses of Duloxetine daily or a matching placebo (N=59 on Duloxetine 20 mg, N=116 on Duloxetine 60 mg, N=112 on Duloxetine 120 mg, N=117 on placebo) and 267 (66%) completed the entire 13-week study. After 13 weeks of treatment, none of the three Duloxetine doses showed a statistically significant difference in pain reduction compared to placebo.
- Study CLBP-3: Four hundred and one patients were randomized to receive fixed doses of Duloxetine 60 mg daily or placebo (N=198 on Duloxetine, N=203 on placebo), and 303 (76%) completed the study. Patients had a mean baseline pain rating of 6 on a numerical rating scale ranging from 0 (no pain) to 10 (worst possible pain). After 12 weeks of treatment, patients taking Duloxetine 60 mg daily had significantly greater pain reduction compared to placebo.
- For various degrees of improvement in pain from baseline to study endpoint, Figures 5 and 6 show the fraction of patients in CLBP-1 and CLBP-3 achieving that degree of improvement. The figures are cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%. Patients who did not complete the study were assigned the value of 0% improvement.
- Studies in Chronic Pain Due to Osteoarthritis
- The efficacy of Duloxetine in chronic pain due to osteoarthritis was assessed in 2 double-blind, placebo-controlled, randomized clinical trials of 13-weeks duration (Study OA-1 and Study OA-2). All patients in both studies fulfilled the ACR clinical and radiographic criteria for classification of idiopathic osteoarthritis of the knee. Randomization was stratified by the patients' baseline NSAIDs-use status. Patients assigned to Duloxetine started treatment in both studies at a dose of 30 mg once daily for one week. After the first week, the dose of Duloxetine was increased to 60 mg once daily. After 7 weeks of treatment with Duloxetine 60 mg once daily, in OA-1 patients with sub-optimal response to treatment (<30% pain reduction) and tolerated duloxetine 60 mg once daily had their dose increased to 120 mg. However, in OA-2, all patients, regardless of their response to treatment after 7 weeks, were re-randomized to either continue receiving Duloxetine 60 mg once daily or have their dose increased to 120 mg once daily for the remainder of the study. Patients in the placebo treatment groups in both studies received a matching placebo for the entire duration of studies. For both studies, efficacy analyses were conducted using 13-week data from the combined Duloxetine 60 mg and 120 mg once daily treatment groups compared to the placebo group.
- Study OA-1: Two hundred fifty-six patients (N=128 on Duloxetine, N=128 on placebo) enrolled and 204 (80%) completed the study. Patients had a mean baseline pain rating of 6 on a numerical rating scale ranging from 0 (no pain) to 10 (worst possible pain). After 13 weeks of treatment, patients taking Duloxetine had significantly greater pain reduction. Subgroup analyses did not indicate that there were differences in treatment outcomes as a function of NSAIDs use.
- Study OA-2: Two hundred thirty-one patients (N=111 on Duloxetine, N=120 on placebo) enrolled and 173 (75%) completed the study. Patients had a mean baseline pain of 6 on a numerical rating scale ranging from 0 (no pain) to 10 (worst possible pain). After 13 weeks of treatment, patients taking Duloxetine did not show a significantly greater pain reduction.
- In Study OA-1, for various degrees of improvement in pain from baseline to study endpoint, Figure 7 shows the fraction of patients achieving that degree of improvement. The figure is cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%. Patients who did not complete the study were assigned the value of 0% improvement.
# How Supplied
- Duloxetine is available as delayed release capsules in the following strengths, colors, imprints, and presentations:
- Storage and Handling
- Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F)
## Storage
There is limited information regarding Duloxetine Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Information on Medication Guide
- Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with Duloxetine and should counsel them in its appropriate use. A patient Medication Guide is available for Duloxetine. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide before starting Duloxetine and each time their prescription is renewed, 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 Duloxetine.
- Suicidal Thoughts and Behaviors
- 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 observe 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.
- Medication Administration
- Duloxetine should be swallowed whole and should not be chewed or crushed, nor should the capsule be opened and its contents be sprinkled on food or mixed with liquids. All of these might affect the enteric coating.
- Continuing the Therapy Prescribed
- While patients may notice improvement with Duloxetine therapy in 1 to 4 weeks, they should be advised to continue therapy as directed.
- Hepatotoxicity
- Patients should be informed that severe liver problems, sometimes fatal, have been reported in patients treated with Duloxetine. Patients should be instructed to talk to their healthcare provider if they develop itching, right upper belly pain, dark urine, or yellow skin/eyes while taking Duloxetine, which may be signs of liver problems. Patients should talk to their healthcare provider about their alcohol consumption. Use of Duloxetine with heavy alcohol intake may be associated with severe liver injury.
- Alcohol
- Although Duloxetine does not increase the impairment of mental and motor skills caused by alcohol, use of Duloxetine concomitantly with heavy alcohol intake may be associated with severe liver injury. For this reason, Duloxetine should not be prescribed for patients with substantial alcohol use.
- Orthostatic Hypotension and Syncope
- Patients should be advised of the risk of orthostatic hypotension and syncope, especially during the period of initial use and subsequent dose escalation, and in association with the use of concomitant drugs that might potentiate the orthostatic effect of duloxetine.
- Serotonin Syndrome
- Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of Duloxetine and other serotonergic agents including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan and St. John's Wort.
- Patients should be advised of the signs and symptoms associated with serotonin syndrome that 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 changes (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be cautioned to seek medical care immediately if they experience these symptoms.
- Abnormal Bleeding
- Patients should be cautioned about the concomitant use of duloxetine and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding.
- Severe Skin Reactions
- Patients should be cautioned that Duloxetine may cause serious skin reactions. This may need to be treated in a hospital and may be life-threatening. Patients should be counseled to call their doctor right away or get emergency help if they have skin blisters, peeling rash, sores in their mouth, hives, or any other allergic reactions.
- Discontinuation of Treatment
- Patients should be instructed that discontinuation of Duloxetine may be associated with symptoms such as dizziness, headache, nausea, diarrhea, paresthesia, irritability, vomiting, insomnia, anxiety, hyperhidrosis, and fatigue, and should be advised not to alter their dosing regimen, or stop taking Duloxetine without consulting their physician.
- Activation of Mania or Hypomania
- Patients with depressive symptoms should be adequately screened for risk of bipolar disorder (e.g. family history of suicide, bipolar disorder, and depression) prior to initiating treatment with Duloxetine. Patients should be advised to report any signs or symptoms of a manic reaction such as greatly increased energy, severe trouble sleeping, racing thoughts, reckless behavior, talking more or faster than usual, unusually grand ideas, and excessive happiness or irritability.
- Seizures
- Patients should be advised to inform their physician if they have a history of seizure disorder.
- Effects on Blood Pressure
- Patients should be cautioned that Duloxetine may cause an increase in blood pressure.
- Concomitant Medications
- Patients should be advised to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter medications, since there is a potential for interactions.
- Hyponatremia
- Patients should be advised that hyponatremia has been reported as a result of treatment with SNRIs and SSRIs, including Duloxetine. Patients should be advised of the signs and symptoms of hyponatremia.
- Concomitant Illnesses
- Patients should be advised to inform their physicians about all of their medical conditions.
- Urinary Hesitancy and Retention
- Duloxetine is in a class of medicines that may affect urination. Patients should be instructed to consult with their healthcare provider if they develop any problems with urine flow.
- Pregnancy and Breast Feeding
- Patients should be advised to notify their physician if they
become pregnant during therapy
intend to become pregnant during therapy
are breast feeding.
- become pregnant during therapy
- intend to become pregnant during therapy
- are breast feeding.
- Interference with Psychomotor Performance
- Any psychoactive drug may impair judgment, thinking, or motor skills. Although in controlled studies Duloxetine has not been shown to impair psychomotor performance, cognitive function, or memory, it may be associated with sedation and dizziness. Therefore, patients should be cautioned about operating hazardous machinery including automobiles, until they are reasonably certain that Duloxetine therapy does not affect their ability to engage in such activities.
# Precautions with Alcohol
- Although Duloxetine does not increase the impairment of mental and motor skills caused by alcohol, use of Duloxetine concomitantly with heavy alcohol intake may be associated with severe liver injury. For this reason, Cymbalta should not be prescribed for patients with substantial alcohol use.
# Brand Names
- Cymbalta®
# Look-Alike Drug Names
- Cymbalta® — Symbyax®
- DULoxetine hydrochloride® — FLUoxetine hydrochloride®
# Drug Shortage Status
# Price | Duloxetine
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
Duloxetine is a serotonin-norepinephrine reuptake inhibitor that is FDA approved for the treatment of major depressive disorder, generalized anxiety disorder, diabetic peripheral neuropathic pain, fibromyalgia and chronic musculoskeletal pain. There is a Black Box Warning for this drug as shown here. Common adverse reactions include nausea, dry mouth, somnolence, constipation, decreased appetite, and hyperhidrosis.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Duloxetine should be swallowed whole and should not be chewed or crushed, nor should the capsule be opened and its contents sprinkled on food or mixed with liquids. All of these might affect the enteric coating. Duloxetine can be given without regard to meals.
- Duloxetine should be administered at a total dose of 40 mg/day (given as 20 mg twice daily) to 60 mg/day (given either once daily or as 30 mg twice daily). For some patients, it may be desirable to start at 30 mg once daily for 1 week, to allow patients to adjust to the medication before increasing to 60 mg once daily. While a 120 mg/day dose was shown to be effective, there is no evidence that doses greater than 60 mg/day confer any additional benefits. The safety of doses above 120 mg/day has not been adequately evaluated.
- For most patients, the recommended starting dose for Duloxetine is 60 mg administered once daily. For some patients, it may be desirable to start at 30 mg once daily for 1 week, to allow patients to adjust to the medication before increasing to 60 mg once daily. While a 120 mg once daily dose was shown to be effective, there is no evidence that doses greater than 60 mg/day confer additional benefit. Nevertheless, if a decision is made to increase the dose beyond 60 mg once daily, dose increases should be in increments of 30 mg once daily. The safety of doses above 120 mg once daily has not been adequately evaluated.
- The recommended dose for Duloxetine is 60 mg administered once daily. There is no evidence that doses higher than 60 mg confer additional significant benefit and the higher dose is clearly less well tolerated. For patients for whom tolerability is a concern, a lower starting dose may be considered.
- Since diabetes is frequently complicated by renal disease, a lower starting dose and gradual increase in dose should be considered for patients with renal impairment.
- The recommended dose for Duloxetine is 60 mg administered once daily. Treatment should begin at 30 mg once daily for 1 week, to allow patients to adjust to the medication before increasing to 60 mg once daily. Some patients may respond to the starting dose. There is no evidence that doses greater than 60 mg/day confer additional benefit, even in patients who do not respond to a 60 mg dose, and higher doses are associated with a higher rate of adverse reactions.
- The recommended dose for Duloxetine is 60 mg once daily. Dosing may be started at 30 mg for one week, to allow patients to adjust to the medication before increasing to 60 mg once daily. There is no evidence that higher doses confer additional benefit, even in patients who do not respond to a 60 mg dose, and higher doses are associated with a higher rate of adverse reactions.
- It is generally agreed that acute episodes of major depression require several months or longer of sustained pharmacologic therapy. Maintenance of efficacy in MDD was demonstrated with Duloxetine as monotherapy. Duloxetine should be administered at a total dose of 60 mg once daily. Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment.
- It is generally agreed that episodes of generalized anxiety disorder require several months or longer of sustained pharmacological therapy. Maintenance of efficacy in GAD was demonstrated with Duloxetine as monotherapy. Duloxetine should be administered in a dose range of 60-120 mg once daily. Patients should be periodically reassessed to determine the continued need for maintenance treatment and the appropriate dose for such treatment.
- As the progression of diabetic peripheral neuropathy is highly variable and management of pain is empirical, the effectiveness of Duloxetine must be assessed individually. Efficacy beyond 12 weeks has not been systematically studied in placebo-controlled trials.
- Fibromyalgia is recognized as a chronic condition. The efficacy of Duloxetine in the management of fibromyalgia has been demonstrated in placebo-controlled studies up to 3 months. The efficacy of Duloxetine was not demonstrated in longer studies; however, continued treatment should be based on individual patient response.
- The efficacy of Duloxetine has not been established in placebo-controlled studies beyond 13 weeks.
- Hepatic Insufficiency
- It is recommended that Duloxetine should ordinarily not be administered to patients with any hepatic insufficiency.
- Severe Renal Impairment
- Duloxetine is not recommended for patients with end-stage renal disease or severe renal impairment (estimated creatinine clearance <30 mL/min).
- Elderly Patients
- No dose adjustment is recommended for elderly patients on the basis of age. As with any drug, caution should be exercised in treating the elderly. When individualizing the dosage in elderly patients, extra care should be taken when increasing the dose.
- Pregnant Women
- There are no adequate and well-controlled studies in pregnant women; therefore, Duloxetine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Lilly maintains a pregnancy registry to monitor the pregnancy outcomes of women exposed to Duloxetine while pregnant. Healthcare providers are encouraged to register any patient who is exposed to Duloxetine during pregnancy by calling the Duloxetine Pregnancy Registry at 1-866-814-6975 or by visiting www.cymbaltapregnancyregistry.com
- Nursing Mothers
- Because the safety of duloxetine in infants is not known, nursing while on Duloxetine is not recommended.
- Symptoms associated with discontinuation of Duloxetine and other SSRIs and SNRIs have been reported. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible
- At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with Duloxetine. Conversely, at least 5 days should be allowed after stopping Duloxetine before starting an MAOI intended to treat psychiatric disorders.
- Do not start Duloxetine in a patient who is being treated with linezolid or intravenous methylene blue because there is an 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 Duloxetine therapy 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, Duloxetine should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for 5 days or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with Duloxetine 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 Duloxetine is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use.
- Duloxetine is available as delayed release capsules:
- 20 mg opaque green capsules imprinted with “Lilly 3235 20mg”
- 30 mg opaque white and blue capsules imprinted with “Lilly 3240 30mg”
- 60 mg opaque green and blue capsules imprinted with “Lilly 3270 60mg”
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Duloxetine in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- 30 mg daily for the first week followed by 60 mg/day for 4 weeks[1]
- Dosing Information
- 40 mg orally twice daily[2]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Duloxetine is not approved for use in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Duloxetine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Duloxetine in pediatric patients.
# Contraindications
- Monoamine Oxidase Inhibitors (MAOIs)
- The use of MAOIs intended to treat psychiatric disorders with Duloxetine or within 5 days of stopping treatment with Duloxetine is contraindicated because of an increased risk of serotonin syndrome. The use of Duloxetine within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated.
- Starting Duloxetine 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.
- Uncontrolled Narrow-Angle Glaucoma
- In clinical trials, Duloxetine use was associated with an increased risk of mydriasis; therefore, its use should be avoided in patients with uncontrolled narrow-angle glaucoma.
# Warnings
### Precautions
- Suicidal Thoughts and Behaviors in Adolescents and Young Adults
- Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment.
- Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.
- The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk of 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 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.
- If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that discontinuation can be associated with certain symptoms.
- Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for Duloxetine 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 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 Cymbalta (duloxetine) is not approved for use in treating bipolar depression.
- Hepatotoxicity
- There have been reports of hepatic failure, sometimes fatal, in patients treated with Cymbalta. These cases have presented as hepatitis with abdominal pain, hepatomegaly, and elevation of transaminase levels to more than twenty times the upper limit of normal with or without jaundice, reflecting a mixed or hepatocellular pattern of liver injury. Cymbalta should be discontinued in patients who develop jaundice or other evidence of clinically significant liver dysfunction and should not be resumed unless another cause can be established.
- Cases of cholestatic jaundice with minimal elevation of transaminase levels have also been reported. Other postmarketing reports indicate that elevated transaminases, bilirubin, and alkaline phosphatase have occurred in patients with chronic liver disease or cirrhosis.
- Cymbalta increased the risk of elevation of serum transaminase levels in development program clinical trials. Liver transaminase elevations resulted in the discontinuation of 0.3% (92/34,756) of Cymbalta-treated patients. In most patients, the median time to detection of the transaminase elevation was about two months. In placebo-controlled trials in any indication, for patients with normal and abnormal baseline ALT values, elevation of ALT >3 times the upper limit of normal occurred in 1.25% (144/11,496) of Duloxetine-treated patients compared to 0.45% (39/8716) of placebo-treated patients. In placebo-controlled studies using a fixed dose design, there was evidence of a dose response relationship for ALT and AST elevation of >3 times the upper limit of normal and >5 times the upper limit of normal, respectively.
- Because it is possible that duloxetine and alcohol may interact to cause liver injury or that duloxetine may aggravate pre-existing liver disease, Duloxetine should not be prescribed to patients with substantial alcohol use or evidence of chronic liver disease.
- Orthostatic Hypotension and Syncope
- Orthostatic hypotension and syncope have been reported with therapeutic doses of duloxetine. Syncope and orthostatic hypotension tend to occur within the first week of therapy but can occur at any time during duloxetine treatment, particularly after dose increases. The risk of blood pressure decreases may be greater in patients taking concomitant medications that induce orthostatic hypotension (such as antihypertensives) or are potent CYP1A2 inhibitors and in patients taking duloxetine at doses above 60 mg daily. Consideration should be given to discontinuing duloxetine in patients who experience symptomatic orthostatic hypotension and/or syncope during duloxetine therapy.
- Serotonin Syndrome
- The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including Duloxetine, 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 Duloxetine with MAOIs intended to treat psychiatric disorders is contraindicated. Duloxetine 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 Duloxetine. Duloxetine should be discontinued before initiating treatment with the MAOI.
- If concomitant use of Duloxetine 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 Duloxetine and any concomitant serotonergic agents, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.
- Abnormal Bleeding
- SSRIs and SNRIs, including duloxetine, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anti-coagulants 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 SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages.
- Patients should be cautioned about the risk of bleeding associated with the concomitant use of duloxetine and NSAIDs, aspirin, or other drugs that affect coagulation.
- Severe Skin Reactions
- Severe skin reactions, including erythema multiforme and Stevens-Johnson Syndrome (SJS), can occur with Duloxetine. The reporting rate of SJS associated with Duloxetine use exceeds the general population background incidence rate for this serious skin reaction (1 to 2 cases per million person years). The reporting rate is generally accepted to be an underestimate due to underreporting.
- Duloxetine should be discontinued at the first appearance of blisters, peeling rash, mucosal erosions, or any other sign of hypersensitivity if no other etiology can be identified.
- Discontinuation of Treatment with Duloxetine
- Discontinuation symptoms have been systematically evaluated in patients taking duloxetine. Following abrupt or tapered discontinuation in placebo-controlled clinical trials, the following symptoms occurred at 1% or greater and at a significantly higher rate in duloxetine-treated patients compared to those discontinuing from placebo: dizziness, headache, nausea, diarrhea, paresthesia, irritability, vomiting, insomnia, anxiety, hyperhidrosis, and fatigue.
- During marketing of other SSRIs and SNRIs (serotonin and norepinephrine reuptake inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. Although these events are generally self-limiting, some have been reported to be severe.
- Patients should be monitored for these symptoms when discontinuing treatment with Duloxetine. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate.
- Activation of Mania/Hypomania
- In placebo-controlled trials in patients with major depressive disorder, activation of mania or hypomania was reported in 0.1% (4/3779) of duloxetine-treated patients and 0.04% (1/2536) of placebo-treated patients. No activation of mania or hypomania was reported in GAD, fibromyalgia, or chronic musculoskeletal pain placebo-controlled trials. Activation of mania or hypomania has been reported in a small proportion of patients with mood disorders who were treated with other marketed drugs effective in the treatment of major depressive disorder. As with these other agents, Duloxetine should be used cautiously in patients with a history of mania.
- Seizures
- Duloxetine has not been systematically evaluated in patients with a seizure disorder, and such patients were excluded from clinical studies. In placebo-controlled clinical trials, seizures/convulsions occurred in 0.02% (3/12,722) of patients treated with duloxetine and 0.01% (1/9513) of patients treated with placebo. Duloxetine should be prescribed with care in patients with a history of a seizure disorder.
- Effect on Blood Pressure
- In placebo-controlled clinical trials across indications from baseline to endpoint, duloxetine treatment was associated with mean increases of 0.5 mm Hg in systolic blood pressure and 0.8 mm Hg in diastolic blood pressure compared to mean decreases of 0.6 mm Hg systolic and 0.3 mm Hg diastolic in placebo-treated patients. There was no significant difference in the frequency of sustained (3 consecutive visits) elevated blood pressure. In a clinical pharmacology study designed to evaluate the effects of duloxetine on various parameters, including blood pressure at supratherapeutic doses with an accelerated dose titration, there was evidence of increases in supine blood pressure at doses up to 200 mg twice daily. At the highest 200 mg twice daily dose, the increase in mean pulse rate was 5.0 to 6.8 beats and increases in mean blood pressure were 4.7 to 6.8 mm Hg (systolic) and 4.5 to 7 mm Hg (diastolic) up to 12 hours after dosing.
- Blood pressure should be measured prior to initiating treatment and periodically measured throughout treatment.
- Clinically Important Drug Interactions
- Both CYP1A2 and CYP2D6 are responsible for duloxetine metabolism.
- Potential for Other Drugs to Affect Duloxetine
CYP1A2 Inhibitors — Co-administration of Duloxetine with potent CYP1A2 inhibitors should be avoided.
CYP2D6 Inhibitors — Because CYP2D6 is involved in duloxetine metabolism, concomitant use of duloxetine with potent inhibitors of CYP2D6 would be expected to, and does, result in higher concentrations (on average of 60%) of duloxetine.
- CYP1A2 Inhibitors — Co-administration of Duloxetine with potent CYP1A2 inhibitors should be avoided.
- CYP2D6 Inhibitors — Because CYP2D6 is involved in duloxetine metabolism, concomitant use of duloxetine with potent inhibitors of CYP2D6 would be expected to, and does, result in higher concentrations (on average of 60%) of duloxetine.
- Potential for Duloxetine to Affect Other Drugs
Drugs Metabolized by CYP2D6 — Co-administration of Duloxetine with drugs that are extensively metabolized by CYP2D6 and that have a narrow therapeutic index, including certain antidepressants (tricyclic antidepressants [TCAs], such as nortriptyline, amitriptyline, and imipramine), phenothiazines and Type 1C antiarrhythmics (e.g., propafenone, flecainide), should be approached with caution. Plasma TCA concentrations may need to be monitored and the dose of the TCA may need to be reduced if a TCA is co-administered with Duloxetine. Because of the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, Duloxetine and thioridazine should not be co-administered.
- Drugs Metabolized by CYP2D6 — Co-administration of Duloxetine with drugs that are extensively metabolized by CYP2D6 and that have a narrow therapeutic index, including certain antidepressants (tricyclic antidepressants [TCAs], such as nortriptyline, amitriptyline, and imipramine), phenothiazines and Type 1C antiarrhythmics (e.g., propafenone, flecainide), should be approached with caution. Plasma TCA concentrations may need to be monitored and the dose of the TCA may need to be reduced if a TCA is co-administered with Duloxetine. Because of the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, Duloxetine and thioridazine should not be co-administered.
- Other Clinically Important Drug Interactions
- Alcohol
- Use of Duloxetine concomitantly with heavy alcohol intake may be associated with severe liver injury. For this reason, Duloxetine should not be prescribed for patients with substantial alcohol use.
- CNS Acting Drugs
- Given the primary CNS effects of Duloxetine, it should be used with caution when it is taken in combination with or substituted for other centrally acting drugs, including those with a similar mechanism of action.
- Hyponatremia
- Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including Duloxetine. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported and appeared to be reversible when Duloxetine was discontinued. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk. Discontinuation of Duloxetine should be considered 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 may lead to falls. More severe and/or acute cases have been associated with hallucination, syncope, seizure, coma, respiratory arrest, and death.
- Use in Patients with Concomitant Illness
- Clinical experience with Duloxetine in patients with concomitant systemic illnesses is limited. There is no information on the effect that alterations in gastric motility may have on the stability of Duloxetine's enteric coating. In extremely acidic conditions, Duloxetine, unprotected by the enteric coating, may undergo hydrolysis to form naphthol. Caution is advised in using Duloxetine in patients with conditions that may slow gastric emptying (e.g., some diabetics).
- Duloxetine has not been systematically evaluated in patients with a recent history of myocardial infarction or unstable coronary artery disease. Patients with these diagnoses were generally excluded from clinical studies during the product's premarketing testing.
- Hepatic Insufficiency
- Duloxetine should ordinarily not be used in patients with hepatic insufficiency.
- Severe Renal Impairment
- Duloxetine should ordinarily not be used in patients with end-stage renal disease or severe renal impairment (creatinine clearance <30 mL/min). Increased plasma concentration of duloxetine, and especially of its metabolites, occur in patients with end-stage renal disease (requiring dialysis).
- Controlled Narrow-Angle Glaucoma
- In clinical trials, Duloxetine was associated with an increased risk of mydriasis; therefore, it should be used cautiously in patients with controlled narrow-angle glaucoma.
- Glycemic Control in Patients with Diabetes
- As observed in DPNP trials, Duloxetine treatment worsens glycemic control in some patients with diabetes. In three clinical trials of Duloxetine for the management of neuropathic pain associated with diabetic peripheral neuropathy, the mean duration of diabetes was approximately 12 years, the mean baseline fasting blood glucose was 176 mg/dL, and the mean baseline hemoglobin A1c (HbA1c) was 7.8%. In the 12-week acute treatment phase of these studies, Duloxetine was associated with a small increase in mean fasting blood glucose as compared to placebo. In the extension phase of these studies, which lasted up to 52 weeks, mean fasting blood glucose increased by 12 mg/dL in the Duloxetine group and decreased by 11.5 mg/dL in the routine care group. HbA1c increased by 0.5% in the Duloxetine and by 0.2% in the routine care groups.
- Urinary Hesitation and Retention
- Duloxetine is in a class of drugs known to affect urethral resistance. If symptoms of urinary hesitation develop during treatment with Duloxetine, consideration should be given to the possibility that they might be drug-related.
- In post marketing experience, cases of urinary retention have been observed. In some instances of urinary retention associated with duloxetine use, hospitalization and/or catheterization has been needed.
- Laboratory Tests
- No specific laboratory tests are recommended.
# Adverse Reactions
## Clinical Trials Experience
- The data described below reflect exposure to duloxetine in placebo-controlled trials for MDD (N=3779), GAD (N=1018), OA (N=503), CLBP (N=600), DPNP (N=906), and FM (N=1294). The population studied was 17 to 89 years of age; 65.7%, 60.8%, 60.6%, 42.9%, and 94.4% female; and 81.8%, 72.6%, 85.3%, 74.0%, and 85.7% Caucasian for MDD, GAD, OA and CLBP, DPNP, and FM, respectively. Most patients received doses of a total of 60 to 120 mg per day.
- The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse reaction of the type listed. A reaction was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. Reactions reported during the studies were not necessarily caused by the therapy, and the frequencies do not reflect investigator impression (assessment) of causality.
- 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.
### Adverse Reactions Reported as Reasons for Discontinuation of Treatment in Placebo-Controlled Trials
- Major Depressive Disorder
- Approximately 8.4% (319/3779) of the patients who received duloxetine in placebo-controlled trials for MDD discontinued treatment due to an adverse reaction, compared with 4.6% (117/2536) of the patients receiving placebo. Nausea (duloxetine 1.1%, placebo 0.4%) was the only common adverse reaction reported as a reason for discontinuation and considered to be drug-related (i.e., discontinuation occurring in at least 1% of the duloxetine-treated patients and at a rate of at least twice that of placebo).
- Generalized Anxiety Disorder
- Approximately 13.7% (139/1018) of the patients who received duloxetine in placebo-controlled trials for GAD discontinued treatment due to an adverse reaction, compared with 5.0% (38/767) for placebo. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine 3.3%, placebo 0.4%), and dizziness (duloxetine 1.3%, placebo 0.4%).
- Diabetic Peripheral Neuropathic Pain
- Approximately 12.9% (117/906) of the patients who received duloxetine in placebo-controlled trials for DPNP discontinued treatment due to an adverse reaction, compared with 5.1% (23/448) for placebo. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine 3.5%, placebo 0.7%), dizziness (duloxetine 1.2%, placebo 0.4%), and somnolence (duloxetine 1.1%, placebo 0.0%).
- Fibromyalgia
- Approximately 17.5% (227/1294) of the patients who received duloxetine in 3 to 6 month placebo-controlled trials for FM discontinued treatment due to an adverse reaction, compared with 10.1% (96/955) for placebo. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine 2.0%, placebo 0.5%), headache (duloxetine 1.2%, placebo 0.3%), somnolence (duloxetine 1.1%, placebo 0.0%), and fatigue (duloxetine 1.1%, placebo 0.1%).
- Chronic Pain due to Osteoarthritis
- Approximately 15.7% (79/503) of the patients who received duloxetine in 13-week, placebo-controlled trials for chronic pain due to OA discontinued treatment due to an adverse reaction, compared with 7.3% (37/508) for placebo. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine 2.2%, placebo 1.0%).
- Chronic Low Back Pain
- Approximately 16.5% (99/600) of the patients who received duloxetine in 13-week, placebo-controlled trials for CLBP discontinued treatment due to an adverse reaction, compared with 6.3% (28/441) for placebo. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine 3.0%, placebo 0.7%), and somnolence (duloxetine 1.0%, placebo 0.0%).
### Most Common Adverse Reactions
- Pooled Trials for all Approved Indications
- The most commonly observed adverse reactions in Duloxetine-treated patients (incidence of at least 5% and at least twice the incidence in placebo patients) were nausea, dry mouth, somnolence, constipation, decreased appetite, and hyperhidrosis.
- Diabetic Peripheral Neuropathic Pain
- The most commonly observed adverse reactions in Duloxetine-treated patients (as defined above) were nausea, somnolence, decreased appetite, constipation, hyperhidrosis, and dry mouth.
- Fibromyalgia
- The most commonly observed adverse reactions in Duloxetine-treated patients (as defined above) were nausea, dry mouth, constipation, somnolence, decreased appetite, hyperhidrosis, and agitation.
- Chronic Pain due to Osteoarthritis
- The most commonly observed adverse reactions in Duloxetine-treated patients (as defined above) were nausea, fatigue, constipation, dry mouth, insomnia, somnolence, and dizziness.
- Chronic Low Back Pain
- The most commonly observed adverse reactions in Duloxetine-treated patients (as defined above) were nausea, dry mouth, insomnia, somnolence, constipation, dizziness, and fatigue.
### Adverse Reactions Occurring at an Incidence of 5% or More Among Duloxetine-Treated Patients in Placebo-Controlled Trials
- Table 2 gives the incidence of treatment-emergent adverse reactions in placebo-controlled trials for approved indications that occurred in 5% or more of patients treated with duloxetine and with an incidence greater than placebo.
### Adverse Reactions Occurring at an Incidence of 2% or More Among Duloxetine-Treated Patients in Placebo-Controlled Trials
- Pooled MDD and GAD Trials
- Table 3 gives the incidence of treatment-emergent adverse reactions in MDD and GAD placebo-controlled trials for approved indications that occurred in 2% or more of patients treated with duloxetine and with an incidence greater than placebo.
- DPNP, FM, OA, and CLBP
- Table 4 gives the incidence of treatment-emergent adverse events that occurred in 2% or more of patients treated with Duloxetine (determined prior to rounding) in the premarketing acute phase of DPNP, FM, OA, and CLBP placebo-controlled trials and with an incidence greater than placebo.
### Effects on Male and Female Sexual Function
- Changes in sexual desire, sexual performance and sexual satisfaction often occur as manifestations of psychiatric disorders or diabetes, but they may also be a consequence of pharmacologic treatment. Because adverse sexual reactions are presumed to be voluntarily underreported, the Arizona Sexual Experience Scale (ASEX), a validated measure designed to identify sexual side effects, was used prospectively in 4 MDD placebo-controlled trials. In these trials, as shown in Table 5 below, patients treated with Duloxetine experienced significantly more sexual dysfunction, as measured by the total score on the ASEX, than did patients treated with placebo. Gender analysis showed that this difference occurred only in males. Males treated with Duloxetine experienced more difficulty with ability to reach orgasm (ASEX Item 4) than males treated with placebo. Females did not experience more sexual dysfunction on Duloxetine than on placebo as measured by ASEX total score. Negative numbers signify an improvement from a baseline level of dysfunction, which is commonly seen in depressed patients. Physicians should routinely inquire about possible sexual side effects.
### Vital Sign Changes
- In placebo-controlled clinical trials across approved indications for change from baseline to endpoint, duloxetine treatment was associated with mean increases of 0.23 mm Hg in systolic blood pressure and 0.73 mm Hg in diastolic blood pressure compared to mean decreases of 1.09 mm Hg systolic and 0.55 mm Hg diastolic in placebo-treated patients. There was no significant difference in the frequency of sustained (3 consecutive visits) elevated blood pressure.
- Duloxetine treatment, for up to 26 weeks in placebo-controlled trials across approved indications, typically caused a small increase in heart rate for change from baseline to endpoint compared to placebo of up to 1.37 beats per minute (increase of 1.20 beats per minute in duloxetine-treated patients, decrease of 0.17 beats per minute in placebo-treated patients).
### Weight Changes
- In placebo-controlled clinical trials, MDD and GAD patients treated with Duloxetine for up to 10 weeks experienced a mean weight loss of approximately 0.5 kg, compared with a mean weight gain of approximately 0.2 kg in placebo-treated patients. In studies of DPNP, FM, OA, and CLBP, patients treated with Duloxetine for up to 26 weeks experienced a mean weight loss of approximately 0.6 kg compared with a mean weight gain of approximately 0.2 kg in placebo-treated patients. In one long-term fibromyalgia 60-week uncontrolled study, duloxetine patients had a mean weight increase of 0.7 kg. In one long-term CLBP 54-week study (13-week, placebo-controlled acute phase and 41-week, uncontrolled extension phase), duloxetine patients had a mean weight decrease of 0.6 kg in 13 weeks of acute phase compared to study entry, then a mean weight increase of 1.4 kg in 41 weeks of extension phase compared to end of acute phase.
### Laboratory Changes
- Duloxetine treatment in placebo-controlled clinical trials across approved indications, was associated with small mean increases from baseline to endpoint in ALT, AST, CPK, alkaline phosphatase; infrequent, modest, transient, abnormal values were observed for these analytes in Duloxetine-treated patients when compared with placebo-treated patients. High bicarbonate and cholesterol and abnormal (high or low) potassium were observed more frequently in duloxetine treated patients compared to placebo.
### Electrocardiogram Changes
- The effect of duloxetine 160 mg and 200 mg administered twice daily to steady state was evaluated in a randomized, double-blinded, two-way crossover study in 117 healthy female subjects. No QT interval prolongation was detected. Duloxetine appears to be associated with concentration-dependent but not clinically meaningful QT shortening.
### Other Adverse Reactions Observed During the Premarketing and Postmarketing Clinical Trial Evaluation of Duloxetine
- Following is a list of treatment-emergent adverse reactions reported by patients treated with duloxetine in clinical trials. In clinical trials of all indications, 34,756 patients were treated with duloxetine. Of these, 26.9% (9337) took duloxetine for at least 6 months, and 12.4% (4317) for at least one year. The following listing is not intended to 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.
- Reactions are categorized by body system according to the following definitions: frequent adverse reactions are those occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are those occurring in fewer than 1/1000 patients.
Frequent: palpitations; Infrequent: myocardial infarction and tachycardia.
Frequent: vertigo; Infrequent: ear pain and tinnitus.
Infrequent: hypothyroidism.
Frequent: blurred vision; Infrequent: diplopia, dry eye, and visual impairment.
Frequent: flatulence; Infrequent: dysphagia, eructation, gastritis, gastrointestinal hemorrhage, halitosis, and stomatitis; Rare: gastric ulcer.
Frequent: chills/rigors; Infrequent: falls, feeling abnormal, feeling hot and/or cold, malaise, and thirst; Rare: gait disturbance.
Infrequent: gastroenteritis and laryngitis.
Frequent: weight increased, weight decreased; Infrequent: blood cholesterol increased.
Infrequent: dehydration and hyperlipidemia; Rare: dyslipidemia.
Frequent: musculoskeletal pain; Infrequent: muscle tightness and muscle twitching.
Frequent: dysgeusia, lethargy, and parasthesia/hypoesthesia; Infrequent: disturbance in attention, dyskinesia, myoclonus, and poor quality sleep; Rare: dysarthria.
Frequent: abnormal dreams and sleep disorder; Infrequent: apathy, bruxism, disorientation/confusional state, irritability, mood swings, and suicide attempt; Rare: completed suicide.
Frequent: urinary frequency; Infrequent: dysuria, micturition urgency, nocturia, polyuria, and urine odor abnormal.
Frequent: anorgasmia/orgasm abnormal; Infrequent: menopausal symptoms, sexual dysfunction, and testicular pain; Rare: menstrual disorder.
Frequent: yawning, oropharyngeal pain; Infrequent: throat tightness.
Frequent: pruritus; Infrequent: cold sweat, dermatitis contact, erythema, increased tendency to bruise, night sweats, and photosensitivity reaction; Rare: ecchymosis.
Frequent: hot flush; Infrequent: flushing, orthostatic hypotension, and peripheral coldness.
## Postmarketing Experience
### Postmarketing Spontaneous Reports
The following adverse reactions have been identified during postapproval use of Duloxetine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Adverse reactions reported since market introduction that were temporally related to duloxetine therapy and not mentioned elsewhere in labeling include: anaphylactic reaction, aggression and anger (particularly early in treatment or after treatment discontinuation), angioneurotic edema, extrapyramidal disorder, galactorrhea, glaucoma, gynecological bleeding, hallucinations, hyperglycemia, hyperprolactinemia, hypersensitivity, hypertensive crisis, muscle spasm, rash, restless legs syndrome, seizures upon treatment discontinuation, supraventricular arrhythmia, tinnitus (upon treatment discontinuation), trismus, and urticaria.
# Drug Interactions
Both CYP1A2 and CYP2D6 are responsible for duloxetine metabolism.
- Inhibitors of CYP1A2
- When duloxetine 60 mg was co-administered with fluvoxamine 100 mg, a potent CYP1A2 inhibitor, to male subjects (n=14) duloxetine AUC was increased approximately 6-fold, the Cmax was increased about 2.5-fold, and duloxetine t1/2 was increased approximately 3-fold. Other drugs that inhibit CYP1A2 metabolism include cimetidine and quinolone antimicrobials such as ciprofloxacin and enoxacin.
- Inhibitors of CYP2D6
- Concomitant use of duloxetine (40 mg once daily) with paroxetine (20 mg once daily) increased the concentration of duloxetine AUC by about 60%, and greater degrees of inhibition are expected with higher doses of paroxetine. Similar effects would be expected with other potent CYP2D6 inhibitors (e.g., fluoxetine, quinidine).
- Dual Inhibition of CYP1A2 and CYP2D6
- Concomitant administration of duloxetine 40 mg twice daily with fluvoxamine 100 mg, a potent CYP1A2 inhibitor, to CYP2D6 poor metabolizer subjects (n=14) resulted in a 6-fold increase in duloxetine AUC and Cmax.
- Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin)
- Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding 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 or SNRIs are co-administered with warfarin. Concomitant administration of warfarin (2-9 mg once daily) under steady state conditions with duloxetine 60 or 120 mg once daily for up to 14 days in healthy subjects (n=15) did not significantly change INR from baseline (mean INR changes ranged from 0.05 to +0.07). The total warfarin (protein bound plus free drug) pharmacokinetics (AUCτ,ss, Cmax,ss or tmax,ss) for both R- and S-warfarin were not altered by duloxetine. Because of the potential effect of duloxetine on platelets, patients receiving warfarin therapy should be carefully monitored when duloxetine is initiated or discontinued.
- Lorazepam
- Under steady-state conditions for duloxetine (60 mg Q 12 hours) and lorazepam (2 mg Q 12 hours), the pharmacokinetics of duloxetine were not affected by co-administration
- Temazepam
- Under steady-state conditions for duloxetine (20 mg qhs) and temazepam (30 mg qhs), the pharmacokinetics of duloxetine were not affected by co-administration.
- Drugs that Affect Gastric Acidity
- Duloxetine has an enteric coating that resists dissolution until reaching a segment of the gastrointestinal tract where the pH exceeds 5.5. In extremely acidic conditions, Duloxetine, unprotected by the enteric coating, may undergo hydrolysis to form naphthol. Caution is advised in using Duloxetine in patients with conditions that may slow gastric emptying (e.g., some diabetics). Drugs that raise the gastrointestinal pH may lead to an earlier release of duloxetine. However, co-administration of Duloxetine with aluminum- and magnesium-containing antacids (51 mEq) or Duloxetine with famotidine, had no significant effect on the rate or extent of duloxetine absorption after administration of a 40 mg oral dose. It is unknown whether the concomitant administration of proton pump inhibitors affects duloxetine absorption.
- Drugs Metabolized by CYP1A2
- In vitro drug interaction studies demonstrate that duloxetine does not induce CYP1A2 activity. Therefore, an increase in the metabolism of CYP1A2 substrates (e.g., theophylline, caffeine) resulting from induction is not anticipated, although clinical studies of induction have not been performed. Duloxetine is an inhibitor of the CYP1A2 isoform in in vitro studies, and in two clinical studies the average (90% confidence interval) increase in theophylline AUC was 7% (1%-15%) and 20% (13%-27%) when co-administered with duloxetine (60 mg twice daily).
- Drugs Metabolized by CYP2D6
- Duloxetine is a moderate inhibitor of CYP2D6. When duloxetine was administered (at a dose of 60 mg twice daily) in conjunction with a single 50 mg dose of desipramine, a CYP2D6 substrate, the AUC of desipramine increased 3-fold.
- Drugs Metabolized by CYP2C9
- Results of in vitro studies demonstrate that duloxetine does not inhibit activity. In a clinical study, the pharmacokinetics of S-warfarin, a CYP2C9 substrate, were not significantly affected by duloxetine.
- Drugs Metabolized by CYP3A
- Results of in vitro studies demonstrate that duloxetine does not inhibit or induce CYP3A activity. Therefore, an increase or decrease in the metabolism of CYP3A substrates (e.g., oral contraceptives and other steroidal agents) resulting from induction or inhibition is not anticipated, although clinical studies have not been performed.
- Drugs Metabolized by CYP2C19
- Results of in vitro studies demonstrate that duloxetine does not inhibit CYP2C19 activity at therapeutic concentrations. Inhibition of the metabolism of CYP2C19 substrates is therefore not anticipated, although clinical studies have not been performed.
- Monoamine Oxidase Inhibitors (MAOIs)
- Serotonergic Drugs
- Alcohol
- When Duloxetine and ethanol were administered several hours apart so that peak concentrations of each would coincide, Duloxetine did not increase the impairment of mental and motor skills caused by alcohol.
- In the Duloxetine clinical trials database, three Duloxetine-treated patients had liver injury as manifested by ALT and total bilirubin elevations, with evidence of obstruction. Substantial intercurrent ethanol use was present in each of these cases, and this may have contributed to the abnormalities seen.
- CNS Drugs
- Drugs Highly Bound to Plasma Protein
- Because duloxetine is highly bound to plasma protein, administration of Duloxetine to a patient taking another drug that is highly protein bound may cause increased free concentrations of the other drug, potentially resulting in adverse reactions. However, co-administration of duloxetine (60 or 120 mg) with warfarin (2-9 mg), a highly protein-bound drug, did not result in significant changes in INR and in the pharmacokinetics of either total S-or total R-warfarin (protein bound plus free drug)
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- Teratogenic Effects
- In animal reproduction studies, duloxetine has been shown to have adverse effects on embryo/fetal and postnatal development.
- When duloxetine was administered orally to pregnant rats and rabbits during the period of organogenesis, there was no evidence of teratogenicity at doses up to 45 mg/kg/day (7 times the maximum recommended human dose [MRHD, 60 mg/day] and 4 times the human dose of 120 mg/day on a mg/m2 basis, in rat; 15 times the MRHD and 7 times the human dose of 120 mg/day on a mg/m2 basis in rabbit). However, fetal weights were decreased at this dose, with a no-effect dose of 10 mg/kg/day (2 times the MRHD and ≈1 times the human dose of 120 mg/day on a mg/m2 basis in rats; 3 times the MRHD and 2 times the human dose of 120 mg/day on a mg/m2 basis in rabbits).
- When duloxetine was administered orally to pregnant rats throughout gestation and lactation, the survival of pups to 1 day postpartum and pup body weights at birth and during the lactation period were decreased at a dose of 30 mg/kg/day (5 times the MRHD and 2 times the human dose of 120 mg/day on a mg/m2 basis); the no-effect dose was 10 mg/kg/day. Furthermore, behaviors consistent with increased reactivity, such as increased startle response to noise and decreased habituation of locomotor activity, were observed in pups following maternal exposure to 30 mg/kg/day. Post-weaning growth and reproductive performance of the progeny were not affected adversely by maternal duloxetine treatment.
- There are no adequate and well-controlled studies in pregnant women; therefore, duloxetine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Nonteratogenic Effects
- Neonates exposed to SSRIs or serotonin and norepinephrine reuptake inhibitors (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 SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome.
- When treating pregnant women with Duloxetine during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. The physician may consider tapering Duloxetine in the third trimester.
- Lilly maintains a pregnancy registry to monitor the pregnancy outcomes of women exposed to Duloxetine while pregnant. Healthcare providers are encouraged to register any patient who is exposed to Duloxetine during pregnancy by calling the Duloxetine Pregnancy Registry at 1-866-814-6975 or by visiting www.cymbaltapregnancyregistry.com
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Duloxetine in women who are pregnant.
### Labor and Delivery
- The effect of duloxetine on labor and delivery in humans is unknown. Duloxetine should be used during labor and delivery only if the potential benefit justifies the potential risk to the fetus.
### Nursing Mothers
- Duloxetine is excreted into the milk of lactating women. The estimated daily infant dose on a mg/kg basis is approximately 0.14% of the maternal dose. Because the safety of duloxetine in infants is not known, nursing while on Duloxetine is not recommended. However, if the physician determines that the benefit of duloxetine therapy for the mother outweighs any potential risk to the infant, no dosage adjustment is required as lactation did not influence duloxetine pharmacokinetics.
- The disposition of duloxetine was studied in 6 lactating women who were at least 12 weeks postpartum. Duloxetine 40 mg twice daily was given for 3.5 days. Like many other drugs, duloxetine is detected in breast milk, and steady state concentrations in breast milk are about one-fourth those in plasma. The amount of duloxetine in breast milk is approximately 7 μg/day while on 40 mg BID dosing. The excretion of duloxetine metabolites into breast milk was not examined. Because the safety of duloxetine in infants is not known, nursing while on Duloxetine is not recommended.
### Pediatric Use
- Efficacy was not demonstrated in two 10-week, placebo-controlled trials with 800 pediatric patients with MDD, age 7-17. Neither Duloxetine nor the active control (indicated for treatment of pediatric depression) statistically separated from placebo. Duloxetine steady state plasma concentration was comparable in children (7 - 12 years), adolescents (13 - 17 years) and adults. Duloxetine has not been studied in patients under the age of 7. Thus, safety and effectiveness in the pediatric population has not been established.
- Decreased appetite and weight loss have been observed in association with the use of SSRIs and SNRIs. Pediatric patients treated with Duloxetine in MDD clinical trials experienced a 0.2 kg mean decrease in weight at 10-weeks, compared with a mean weight gain of approximately 0.6 kg in placebo-treated patients. The proportion of patients who experienced a clinically significant decrease in weight (≥3.5%) was greater in the Duloxetine group than in the placebo group (11% and 6%, respectively). Subsequently, over the six-month uncontrolled extension period, most Duloxetine-treated patients trended toward recovery to their expected baseline weight percentile based on population data from age- and gender-matched peers. Perform regular monitoring of weight and growth in children and adolescents treated with an SNRI such as Duloxetine.
- In the 2 pediatric MDD studies, the safety findings were consistent with the known safety and tolerability profile for Duloxetine.
- Duloxetine administration to young rats from post-natal day 21 (weaning) through post-natal day 90 (adult) resulted in decreased body weights that persisted into adulthood, but recovered when drug treatment was discontinued; slightly delayed (~1.5 days) sexual maturation in females, without any effect on fertility; and a delay in learning a complex task in adulthood, which was not observed after drug treatment was discontinued. These effects were observed at the high dose of 45 mg/kg/day; the no-effect-level was 20 mg/kg/day.
### Geriatic Use
- Of the 2,418 patients in premarketing clinical studies of Duloxetine for MDD, 5.9% (143) were 65 years of age or over. Of the 1041 patients in CLBP premarketing studies, 21.2% (221) were 65 years of age or over. Of the 487 patients in OA premarketing studies, 40.5% (197) were 65 years of age or over. Of the 1,074 patients in the DPNP premarketing studies, 33% (357) were 65 years of age or over. Of the 1,761 patients in FM premarketing studies, 7.9% (140) were 65 years of age or over. Premarketing clinical studies of GAD did not include sufficient numbers of subjects age 65 or over to determine whether they respond differently from younger subjects. In the MDD, DPNP, FM, OA, and CLBP studies, no overall differences in safety or effectiveness were generally observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. SSRIs and SNRIs, including Duloxetine have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event. In a subgroup analysis of patients 65 years of age and older (N=3278) from all placebo-controlled trials, 1.1% of patients treated with duloxetine reported one or more falls, compared with 0.4% of patients treated with placebo. While many patients with falls had underlying potential risk factors for falls (e.g., medications; medical comorbidities; gait disturbances), the impact of these factors on falls is unclear. Fall with serious consequences including bone fractures and hospitalizations have been reported.
- The pharmacokinetics of duloxetine after a single dose of 40 mg were compared in healthy elderly females (65 to 77 years) and healthy middle-age females (32 to 50 years). There was no difference in the Cmax, but the AUC of duloxetine was somewhat (about 25%) higher and the half-life about 4 hours longer in the elderly females. Population pharmacokinetic analyses suggest that the typical values for clearance decrease by approximately 1% for each year of age between 25 to 75 years of age; but age as a predictive factor only accounts for a small percentage of between-patient variability. Dosage adjustment based on the age of the patient is not necessary
### Gender
There is no FDA guidance on the use of Duloxetine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Duloxetine with respect to specific racial populations.
### Renal Impairment
- Limited data are available on the effects of duloxetine in patients with end-stage renal disease (ESRD). After a single 60 mg dose of duloxetine, Cmax and AUC values were approximately 100% greater in patients with end-stage renal disease receiving chronic intermittent hemodialysis than in subjects with normal renal function. The elimination half-life, however, was similar in both groups. The AUCs of the major circulating metabolites, 4-hydroxy duloxetine glucuronide and 5-hydroxy, 6-methoxy duloxetine sulfate, largely excreted in urine, were approximately 7- to 9-fold higher and would be expected to increase further with multiple dosing. Population PK analyses suggest that mild to moderate degrees of renal dysfunction (estimated CrCl 30-80 mL/min) have no significant effect on duloxetine apparent clearance.
### Hepatic Impairment
- Patients with clinically evident hepatic insufficiency have decreased duloxetine metabolism and elimination. After a single 20 mg dose of Duloxetine, 6 cirrhotic patients with moderate liver impairment (Child-Pugh Class B) had a mean plasma duloxetine clearance about 15% that of age- and gender-matched healthy subjects, with a 5-fold increase in mean exposure (AUC). Although Cmax was similar to normals in the cirrhotic patients, the half-life was about 3 times longer.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Duloxetine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Duloxetine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- Perform regular monitoring of weight and growth in children and adolescents treated with an SNRI such as Duloxetine.
- 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 observe for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt.
# IV Compatibility
There is limited information regarding IV Compatibility of Duloxetine in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- In postmarketing experience, fatal outcomes have been reported for acute overdoses, primarily with mixed overdoses, but also with duloxetine only, at doses as low as 1000 mg. Signs and symptoms of overdose (duloxetine alone or with mixed drugs) included somnolence, coma, serotonin syndrome, seizures,syncope,tachycardia, hypotension, hypertension, and vomiting.
### Management
- There is no specific antidote to Duloxetine, but if serotonin syndrome ensues, specific treatment (such as with cyproheptadine and/or temperature control) may be considered. In case of acute overdose, treatment should consist of those general measures employed in the management of overdose with any drug.
- An adequate airway, oxygenation, and ventilation should be assured, and cardiac rhythm and vital signs should be monitored. Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion or in symptomatic patients.
- Activated charcoal may be useful in limiting absorption of duloxetine from the gastrointestinal tract. Administration of activated charcoal has been shown to decrease AUC and Cmax by an average of one-third, although some subjects had a limited effect of activated charcoal. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be beneficial.
- In managing overdose, the possibility of multiple drug involvement should be considered. A specific caution involves patients who are taking or have recently taken Duloxetine and might ingest excessive quantities of a TCA. In such a case, decreased clearance of the parent tricyclic and/or its active metabolite may increase the possibility of clinically significant sequelae and extend the time needed for close medical observation. The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians' Desk Reference (PDR).
## Chronic Overdose
There is limited information regarding Chronic Overdose of Duloxetine in the drug label.
# Pharmacology
## Mechanism of Action
- Although the exact mechanisms of the antidepressant, central pain inhibitory and anxiolytic actions of duloxetine in humans are unknown, these actions are believed to be related to its potentiation of serotonergic and noradrenergic activity in the CNS.
## Structure
- Duloxetine® (Duloxetine Delayed-Release Capsules) is a selective serotonin and norepinephrine reuptake inhibitor (SSNRI) for oral administration. Its chemical designation is (+)-(S)-N-methyl-γ-(1-naphthyloxy)-2-thiophenepropylamine hydrochloride. The empirical formula is C18H19NOS•HCl, which corresponds to a molecular weight of 333.88. The structural formula is:
- Duloxetine hydrochloride is a white to slightly brownish white solid, which is slightly soluble in water.
- Each capsule contains enteric-coated pellets of 22.4, 33.7, or 67.3 mg of duloxetine hydrochloride equivalent to 20, 30, or 60 mg of duloxetine, respectively. These enteric-coated pellets are designed to prevent degradation of the drug in the acidic environment of the stomach. Inactive ingredients include FD&C Blue No. 2, gelatin, hypromellose, hydroxypropyl methylcellulose acetate succinate, sodium lauryl sulfate, sucrose, sugar spheres, talc, titanium dioxide, and triethyl citrate. The 20 and 60 mg capsules also contain iron oxide yellow.
## Pharmacodynamics
- Preclinical studies have shown that duloxetine is a potent inhibitor of neuronal serotonin and norepinephrine reuptake and a less potent inhibitor of dopamine reuptake. Duloxetine has no significant affinity for dopaminergic, adrenergic, cholinergic, histaminergic, opioid, glutamate, and GABA receptors in vitro. Duloxetine does not inhibit monoamine oxidase (MAO).
- Duloxetine is in a class of drugs known to affect urethral resistance. If symptoms of urinary hesitation develop during treatment with Duloxetine, consideration should be given to the possibility that they might be drug-related.
## Pharmacokinetics
- Duloxetine has an elimination half-life of about 12 hours (range 8 to 17 hours) and its pharmacokinetics are dose proportional over the therapeutic range. Steady-state plasma concentrations are typically achieved after 3 days of dosing. Elimination of duloxetine is mainly through hepatic metabolism involving two P450 isozymes, CYP1A2 and CYP2D6.
- Absorption and Distribution
- Orally administered duloxetine hydrochloride is well absorbed. There is a median 2 hour lag until absorption begins (Tlag), with maximal plasma concentrations (Cmax) of duloxetine occurring 6 hours post dose. Food does not affect the Cmax of duloxetine, but delays the time to reach peak concentration from 6 to 10 hours and it marginally decreases the extent of absorption (AUC) by about 10%. There is a 3 hour delay in absorption and a one-third increase in apparent clearance of duloxetine after an evening dose as compared to a morning dose.
- The apparent volume of distribution averages about 1640 L. Duloxetine is highly bound (>90%) to proteins in human plasma, binding primarily to albumin and α1-acid glycoprotein. The interaction between duloxetine and other highly protein bound drugs has not been fully evaluated. Plasma protein binding of duloxetine is not affected by renal or hepatic impairment.
- Metabolism and Elimination
- Biotransformation and disposition of duloxetine in humans have been determined following oral administration of 14C-labeled duloxetine. Duloxetine comprises about 3% of the total radiolabeled material in the plasma, indicating that it undergoes extensive metabolism to numerous metabolites. The major biotransformation pathways for duloxetine involve oxidation of the naphthyl ring followed by conjugation and further oxidation. Both CYP1A2 and CYP2D6 catalyze the oxidation of the naphthyl ring in vitro. Metabolites found in plasma include 4-hydroxy duloxetine glucuronide and 5-hydroxy, 6-methoxy duloxetine sulfate. Many additional metabolites have been identified in urine, some representing only minor pathways of elimination. Only trace (<1% of the dose) amounts of unchanged duloxetine are present in the urine. Most (about 70%) of the duloxetine dose appears in the urine as metabolites of duloxetine; about 20% is excreted in the feces. Duloxetine undergoes extensive metabolism, but the major circulating metabolites have not been shown to contribute significantly to the pharmacologic activity of duloxetine.
## Nonclinical Toxicology
- Carcinogenesis
- Duloxetine was administered in the diet to mice and rats for 2 years.
- In female mice receiving duloxetine at 140 mg/kg/day (11 times the maximum recommended human dose [MRHD, 60 mg/day] and 6 times the human dose of 120 mg/day on a mg/m2 basis), there was an increased incidence of hepatocellular adenomas and carcinomas. The no-effect dose was 50 mg/kg/day (4 times the MRHD and 2 times the human dose of 120 mg/day on a mg/m2 basis). Tumor incidence was not increased in male mice receiving duloxetine at doses up to 100 mg/kg/day (8 times the MRHD and 4 times the human dose of 120 mg/day on a mg/m2 basis).
- In rats, dietary doses of duloxetine up to 27 mg/kg/day in females (4 times the MRHD and 2 times the human dose of 120 mg/day on a mg/m2 basis) and up to 36 mg/kg/day in males (6 times the MRHD and 3 times the human dose of 120 mg/day on a mg/m2 basis) did not increase the incidence of tumors.
- Mutagenesis
- Duloxetine was not mutagenic in the in vitro bacterial reverse mutation assay (Ames test) and was not clastogenic in an in vivo chromosomal aberration test in mouse bone marrow cells. Additionally, duloxetine was not genotoxic in an in vitro mammalian forward gene mutation assay in mouse lymphoma cells or in an in vitro unscheduled DNA synthesis (UDS) assay in primary rat hepatocytes, and did not induce sister chromatid exchange in Chinese hamster bone marrow in vivo.
- Impairment of Fertility — Duloxetine administered orally to either male or female rats prior to and throughout mating at doses up to 45 mg/kg/day (7 times the maximum recommended human dose of 60 mg/day and 4 times the human dose of 120 mg/day on a mg/m2 basis) did not alter mating or fertility.
# Clinical Studies
- Major Depressive Disorder
- The efficacy of Duloxetine as a treatment for depression was established in 4 randomized, double-blind, placebo-controlled, fixed-dose studies in adult outpatients (18 to 83 years) meeting DSM-IV criteria for major depression. In 2 studies, patients were randomized to Duloxetine 60 mg once daily (N=123 and N=128, respectively) or placebo (N=122 and N=139, respectively) for 9 weeks; in the third study, patients were randomized to Duloxetine 20 or 40 mg twice daily (N=86 and N=91, respectively) or placebo (N=89) for 8 weeks; in the fourth study, patients were randomized to Duloxetine 40 or 60 mg twice daily (N=95 and N=93, respectively) or placebo (N=93) for 8 weeks. There is no evidence that doses greater than 60 mg/day confer additional benefits.
- In all 4 studies, Duloxetine demonstrated superiority over placebo as measured by improvement in the 17-item Hamilton Depression Rating Scale (HAMD-17) total score.
- In all of these clinical studies, analyses of the relationship between treatment outcome and age, gender, and race did not suggest any differential responsiveness on the basis of these patient characteristics.
- In another study, 533 patients meeting DSM-IV criteria for MDD received Duloxetine 60 mg once daily during an initial 12-week open-label treatment phase. Two hundred and seventy-eight patients who responded to open label treatment (defined as meeting the following criteria at weeks 10 and 12: a HAMD-17 total score ≤9, Clinical Global Impressions of Severity (CGI-S) ≤2, and not meeting the DSM-IV criteria for MDD) were randomly assigned to continuation of Duloxetine at the same dose (N=136) or to placebo (N=142) for 6 months. Patients on Duloxetine experienced a statistically significantly longer time to relapse of depression than did patients on placebo. Relapse was defined as an increase in the CGI-S score of ≥2 points compared with that obtained at week 12, as well as meeting the DSM-IV criteria for MDD at 2 consecutive visits at least 2 weeks apart, where the 2-week temporal criterion had to be satisfied at only the second visit. The effectiveness of Duloxetine in hospitalized patients with major depressive disorder has not been studied.
- Generalized Anxiety Disorder
- The efficacy of Duloxetine in the treatment of generalized anxiety disorder (GAD) was established in 1 fixed-dose randomized, double-blind, placebo-controlled trial and 2 flexible-dose randomized, double-blind, placebo-controlled trials in adult outpatients between 18 and 83 years of age meeting the DSM-IV criteria for GAD.
- In 1 flexible-dose study and in the fixed-dose study, the starting dose was 60 mg once daily where down titration to 30 mg once daily was allowed for tolerability reasons before increasing it to 60 mg once daily. Fifteen percent of patients were down titrated. One flexible-dose study had a starting dose of 30 mg once daily for 1 week before increasing it to 60 mg once daily.
- The 2 flexible-dose studies involved dose titration with Duloxetine doses ranging from 60 mg once daily to 120 mg once daily (N=168 and N=162) compared to placebo (N=159 and N=161) over a 10-week treatment period. The mean dose for completers at endpoint in the flexible-dose studies was 104.75 mg/day. The fixed-dose study evaluated Duloxetine doses of 60 mg once daily (N=168) and 120 mg once daily (N=170) compared to placebo (N=175) over a 9-week treatment period. While a 120 mg/day dose was shown to be effective, there is no evidence that doses greater than 60 mg/day confer additional benefit.
- In all 3 studies, Duloxetine demonstrated superiority over placebo as measured by greater improvement in the Hamilton Anxiety Scale (HAM-A) total score and by the Sheehan Disability Scale (SDS) global functional impairment score. The SDS is a widely used and well-validated scale that measures the extent emotional symptoms disrupt patient functioning in 3 life domains: work/school, social life/leisure activities, and family life/home responsibilities.
- In another study, 887 patients meeting DSM-IV-TR criteria for GAD received Duloxetine 60 mg to 120 mg once daily during an initial 26-week open-label treatment phase. Four hundred and twenty-nine patients who responded to open-label treatment (defined as meeting the following criteria at weeks 24 and 26: a decrease from baseline HAM-A total score by at least 50% to a score no higher than 11, and a Clinical Global Impressions of Improvement [CGI-Improvement] score of 1 or 2) were randomly assigned to continuation of Duloxetine at the same dose (N=216) or to placebo (N=213) and were observed for relapse. Of the patients randomized, 73% had been in a responder status for at least 10 weeks. Relapse was defined as an increase in CGI-Severity score at least 2 points to a score ≥4 and a MINI (Mini-International Neuropsychiatric Interview) diagnosis of GAD (excluding duration), or discontinuation due to lack of efficacy. Patients taking Duloxetine experienced a statistically significantly longer time to relapse of GAD than did patients taking placebo.
- Subgroup analyses did not indicate that there were any differences in treatment outcomes as a function of age or gender.
- Diabetic Peripheral Neuropathic Pain
- The efficacy of Duloxetine for the management of neuropathic pain associated with diabetic peripheral neuropathy was established in 2 randomized, 12-week, double-blind, placebo-controlled, fixed-dose studies in adult patients having diabetic peripheral neuropathic pain for at least 6 months. Study DPNP-1 and Study DPNP-2 enrolled a total of 791 patients of whom 592 (75%) completed the studies. Patients enrolled had Type I or II diabetes mellitus with a diagnosis of painful distal symmetrical sensorimotor polyneuropathy for at least 6 months. The patients had a baseline pain score of ≥4 on an 11-point scale ranging from 0 (no pain) to 10 (worst possible pain). Patients were permitted up to 4 g of acetaminophen per day as needed for pain, in addition to Duloxetine. Patients recorded their pain daily in a diary.
- Both studies compared Duloxetine 60 mg once daily or 60 mg twice daily with placebo. DPNP-1 additionally compared Duloxetine 20 mg with placebo. A total of 457 patients (342 Duloxetine, 115 placebo) were enrolled in DPNP-1 and a total of 334 patients (226 Duloxetine, 108 placebo) were enrolled in DPNP-2. Treatment with Duloxetine 60 mg one or two times a day statistically significantly improved the endpoint mean pain scores from baseline and increased the proportion of patients with at least a 50% reduction in pain scores from baseline. For various degrees of improvement in pain from baseline to study endpoint, Figures 1 and 2 show the fraction of patients achieving that degree of improvement. The figures are cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%. Patients who did not complete the study were assigned 0% improvement. Some patients experienced a decrease in pain as early as week 1, which persisted throughout the study.
- Fibromyalgia
- The efficacy of Duloxetine for the management of fibromyalgia was established in two randomized, double-blind, placebo-controlled, fixed-dose studies in adult patients meeting the American College of Rheumatology criteria for fibromyalgia (a history of widespread pain for 3 months, and pain present at 11 or more of the 18 specific tender point sites). Study FM-1 was three months in duration and enrolled female patients only. Study FM-2 was six months in duration and enrolled male and female patients. Approximately 25% of participants had a comorbid diagnosis of major depressive disorder (MDD). FM-1 and FM-2 enrolled a total of 874 patients of whom 541 (62%) completed the studies. The patients had a baseline pain score of 6.5 on an 11-point scale ranging from 0 (no pain) to 10 (worse possible pain).
- Both studies compared Duloxetine 60 mg once daily or 120 mg daily (given in divided doses in FM-1 and as a single daily dose in FM-2) with placebo. FM-2 additionally compared Duloxetine 20 mg with placebo during the initial three months of a six-month study. A total of 354 patients (234 Duloxetine, 120 placebo) were enrolled in FM-1 and a total of 520 patients (376 Duloxetine, 144 placebo) were enrolled in FM-2 (5% male, 95% female). Treatment with Duloxetine 60 mg or 120 mg daily statistically significantly improved the endpoint mean pain scores from baseline and increased the proportion of patients with at least a 50% reduction in pain score from baseline. Pain reduction was observed in patients both with and without comorbid MDD. However, the degree of pain reduction may be greater in patients with comorbid MDD. For various degrees of improvement in pain from baseline to study endpoint, Figures 3 and 4 show the fraction of patients achieving that degree of improvement. The figures are cumulative so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%. Patients who did not complete the study were assigned 0% improvement. Some patients experienced a decrease in pain as early as week 1, which persisted throughout the study. Improvement was also demonstrated on measures of function (Fibromyalgia Impact Questionnaires) and patient global impression of change (PGI). Neither study demonstrated a benefit of 120 mg compared to 60 mg, and a higher dose was associated with more adverse reactions and premature discontinuations of treatment.
- Additionally, the benefit of up-titration in non-responders to Duloxetine at 60 mg/day was evaluated in a separate study. Patients were initially treated with Duloxetine 60 mg once daily for eight weeks in open-label fashion. Subsequently, completers of this phase were randomized to double-blind treatment with Duloxetine at either 60 mg once daily or 120 mg once daily. Those patients who were considered non-responders, where response was defined as at least a 30% reduction in pain score from baseline at the end of the 8-week treatment, were no more likely to meet response criteria at the end of 60 weeks of treatment if blindly titrated to Duloxetine 120 mg as compared to those who were blindly continued on Duloxetine 60 mg.
- Chronic Musculoskeletal Pain
- Duloxetine is indicated for the management of chronic musculoskeletal pain. This has been established in studies in patients with chronic low back pain and chronic pain due to osteoarthritis.
- Studies in Chronic Low Back Pain
- The efficacy of Duloxetine in chronic low back pain (CLBP) was assessed in two double-blind, placebo-controlled, randomized clinical trials of 13-weeks duration (Study CLBP-1 and Study CLBP-2), and one of 12-weeks duration (CLBP-3). CLBP-1 and CLBP-3 demonstrated efficacy of Duloxetine in the treatment of chronic low back pain. Patients in all studies had no signs of radiculopathy or spinal stenosis.
- Study CLBP-1: Two hundred thirty-six adult patients (N=115 on Duloxetine, N=121 on placebo) enrolled and 182 (77%) completed 13-week treatment phase. After 7 weeks of treatment, Duloxetine patients with less than 30% reduction in average daily pain and who were able to tolerate duloxetine 60 mg once daily had their dose of Duloxetine, in a double-blinded fashion, increased to 120 mg once daily for the remainder of the study. Patients had a mean baseline pain rating of 6 on a numerical rating scale ranging from 0 (no pain) to 10 (worst possible pain). After 13 weeks of treatment, patients taking Duloxetine 60-120 mg daily had a significantly greater pain reduction compared to placebo. Randomization was stratified by the patients' baseline NSAIDs-use status. Subgroup analyses did not indicate that there were differences in treatment outcomes as a function of NSAIDs use.
- Study CLBP-2: Four hundred and four patients were randomized to receive fixed doses of Duloxetine daily or a matching placebo (N=59 on Duloxetine 20 mg, N=116 on Duloxetine 60 mg, N=112 on Duloxetine 120 mg, N=117 on placebo) and 267 (66%) completed the entire 13-week study. After 13 weeks of treatment, none of the three Duloxetine doses showed a statistically significant difference in pain reduction compared to placebo.
- Study CLBP-3: Four hundred and one patients were randomized to receive fixed doses of Duloxetine 60 mg daily or placebo (N=198 on Duloxetine, N=203 on placebo), and 303 (76%) completed the study. Patients had a mean baseline pain rating of 6 on a numerical rating scale ranging from 0 (no pain) to 10 (worst possible pain). After 12 weeks of treatment, patients taking Duloxetine 60 mg daily had significantly greater pain reduction compared to placebo.
- For various degrees of improvement in pain from baseline to study endpoint, Figures 5 and 6 show the fraction of patients in CLBP-1 and CLBP-3 achieving that degree of improvement. The figures are cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%. Patients who did not complete the study were assigned the value of 0% improvement.
- Studies in Chronic Pain Due to Osteoarthritis
- The efficacy of Duloxetine in chronic pain due to osteoarthritis was assessed in 2 double-blind, placebo-controlled, randomized clinical trials of 13-weeks duration (Study OA-1 and Study OA-2). All patients in both studies fulfilled the ACR clinical and radiographic criteria for classification of idiopathic osteoarthritis of the knee. Randomization was stratified by the patients' baseline NSAIDs-use status. Patients assigned to Duloxetine started treatment in both studies at a dose of 30 mg once daily for one week. After the first week, the dose of Duloxetine was increased to 60 mg once daily. After 7 weeks of treatment with Duloxetine 60 mg once daily, in OA-1 patients with sub-optimal response to treatment (<30% pain reduction) and tolerated duloxetine 60 mg once daily had their dose increased to 120 mg. However, in OA-2, all patients, regardless of their response to treatment after 7 weeks, were re-randomized to either continue receiving Duloxetine 60 mg once daily or have their dose increased to 120 mg once daily for the remainder of the study. Patients in the placebo treatment groups in both studies received a matching placebo for the entire duration of studies. For both studies, efficacy analyses were conducted using 13-week data from the combined Duloxetine 60 mg and 120 mg once daily treatment groups compared to the placebo group.
- Study OA-1: Two hundred fifty-six patients (N=128 on Duloxetine, N=128 on placebo) enrolled and 204 (80%) completed the study. Patients had a mean baseline pain rating of 6 on a numerical rating scale ranging from 0 (no pain) to 10 (worst possible pain). After 13 weeks of treatment, patients taking Duloxetine had significantly greater pain reduction. Subgroup analyses did not indicate that there were differences in treatment outcomes as a function of NSAIDs use.
- Study OA-2: Two hundred thirty-one patients (N=111 on Duloxetine, N=120 on placebo) enrolled and 173 (75%) completed the study. Patients had a mean baseline pain of 6 on a numerical rating scale ranging from 0 (no pain) to 10 (worst possible pain). After 13 weeks of treatment, patients taking Duloxetine did not show a significantly greater pain reduction.
- In Study OA-1, for various degrees of improvement in pain from baseline to study endpoint, Figure 7 shows the fraction of patients achieving that degree of improvement. The figure is cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%. Patients who did not complete the study were assigned the value of 0% improvement.
# How Supplied
- Duloxetine is available as delayed release capsules in the following strengths, colors, imprints, and presentations:
- Storage and Handling
- Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F)
## Storage
There is limited information regarding Duloxetine Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Information on Medication Guide
- Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with Duloxetine and should counsel them in its appropriate use. A patient Medication Guide is available for Duloxetine. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide before starting Duloxetine and each time their prescription is renewed, 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 Duloxetine.
- Suicidal Thoughts and Behaviors
- 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 observe 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.
- Medication Administration
- Duloxetine should be swallowed whole and should not be chewed or crushed, nor should the capsule be opened and its contents be sprinkled on food or mixed with liquids. All of these might affect the enteric coating.
- Continuing the Therapy Prescribed
- While patients may notice improvement with Duloxetine therapy in 1 to 4 weeks, they should be advised to continue therapy as directed.
- Hepatotoxicity
- Patients should be informed that severe liver problems, sometimes fatal, have been reported in patients treated with Duloxetine. Patients should be instructed to talk to their healthcare provider if they develop itching, right upper belly pain, dark urine, or yellow skin/eyes while taking Duloxetine, which may be signs of liver problems. Patients should talk to their healthcare provider about their alcohol consumption. Use of Duloxetine with heavy alcohol intake may be associated with severe liver injury.
- Alcohol
- Although Duloxetine does not increase the impairment of mental and motor skills caused by alcohol, use of Duloxetine concomitantly with heavy alcohol intake may be associated with severe liver injury. For this reason, Duloxetine should not be prescribed for patients with substantial alcohol use.
- Orthostatic Hypotension and Syncope
- Patients should be advised of the risk of orthostatic hypotension and syncope, especially during the period of initial use and subsequent dose escalation, and in association with the use of concomitant drugs that might potentiate the orthostatic effect of duloxetine.
- Serotonin Syndrome
- Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of Duloxetine and other serotonergic agents including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan and St. John's Wort.
- Patients should be advised of the signs and symptoms associated with serotonin syndrome that 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 changes (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be cautioned to seek medical care immediately if they experience these symptoms.
- Abnormal Bleeding
- Patients should be cautioned about the concomitant use of duloxetine and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding.
- Severe Skin Reactions
- Patients should be cautioned that Duloxetine may cause serious skin reactions. This may need to be treated in a hospital and may be life-threatening. Patients should be counseled to call their doctor right away or get emergency help if they have skin blisters, peeling rash, sores in their mouth, hives, or any other allergic reactions.
- Discontinuation of Treatment
- Patients should be instructed that discontinuation of Duloxetine may be associated with symptoms such as dizziness, headache, nausea, diarrhea, paresthesia, irritability, vomiting, insomnia, anxiety, hyperhidrosis, and fatigue, and should be advised not to alter their dosing regimen, or stop taking Duloxetine without consulting their physician.
- Activation of Mania or Hypomania
- Patients with depressive symptoms should be adequately screened for risk of bipolar disorder (e.g. family history of suicide, bipolar disorder, and depression) prior to initiating treatment with Duloxetine. Patients should be advised to report any signs or symptoms of a manic reaction such as greatly increased energy, severe trouble sleeping, racing thoughts, reckless behavior, talking more or faster than usual, unusually grand ideas, and excessive happiness or irritability.
- Seizures
- Patients should be advised to inform their physician if they have a history of seizure disorder.
- Effects on Blood Pressure
- Patients should be cautioned that Duloxetine may cause an increase in blood pressure.
- Concomitant Medications
- Patients should be advised to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter medications, since there is a potential for interactions.
- Hyponatremia
- Patients should be advised that hyponatremia has been reported as a result of treatment with SNRIs and SSRIs, including Duloxetine. Patients should be advised of the signs and symptoms of hyponatremia.
- Concomitant Illnesses
- Patients should be advised to inform their physicians about all of their medical conditions.
- Urinary Hesitancy and Retention
- Duloxetine is in a class of medicines that may affect urination. Patients should be instructed to consult with their healthcare provider if they develop any problems with urine flow.
- Pregnancy and Breast Feeding
- Patients should be advised to notify their physician if they
become pregnant during therapy
intend to become pregnant during therapy
are breast feeding.
- become pregnant during therapy
- intend to become pregnant during therapy
- are breast feeding.
- Interference with Psychomotor Performance
- Any psychoactive drug may impair judgment, thinking, or motor skills. Although in controlled studies Duloxetine has not been shown to impair psychomotor performance, cognitive function, or memory, it may be associated with sedation and dizziness. Therefore, patients should be cautioned about operating hazardous machinery including automobiles, until they are reasonably certain that Duloxetine therapy does not affect their ability to engage in such activities.
# Precautions with Alcohol
- Although Duloxetine does not increase the impairment of mental and motor skills caused by alcohol, use of Duloxetine concomitantly with heavy alcohol intake may be associated with severe liver injury. For this reason, Cymbalta should not be prescribed for patients with substantial alcohol use.
# Brand Names
- Cymbalta®[3]
# Look-Alike Drug Names
- Cymbalta® — Symbyax®[4]
- DULoxetine hydrochloride® — FLUoxetine hydrochloride®[4]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Cymbalta | |
dea54b47cd6d5b88cc34ca2f81666957b328435b | wikidoc | Cystinosis | Cystinosis
# Overview
Cystinosis is a hereditary disorder of the renal tubules characterized by the presence of carbohydrates and amino acids in the urine, excessive urination, and low blood levels of potassium ions and phosphates. The body accumulates the amino acid cystine within cells. Excess cystine forms crystals that can build up and damage cells. These crystals negatively affect many systems in the body, especially the kidneys and eyes.
# Historical Perspective
# Classification
- Online Mendelian Inheritance in Man (OMIM) 219800 - Infantile nephropathic
- Online Mendelian Inheritance in Man (OMIM) 219900 - Adolescent nephropathic
- Online Mendelian Inheritance in Man (OMIM) 219750 - Adult nonnephropathic
# Pathophysiology
## Genetics
The cause of cystinosis is due to a mutation in the gene CTNS which codes for cystinosin, the lysosomal cystine transporter. Symptoms are first seen at about 3 to 18 months of age with profound polyuria (excessive urination), followed by poor growth, photophobia, and ultimately kidney failure by age 6 years in the nephropathic form. It is important for the child to see a biochemical geneticist and pediatric nephrologist to begin treatment with cysteamine as early as possible. Cysteamine decreases the amount of cystine stored in lysosomes and correlates with conservation of renal function and improved growth. Cysteamine eyedrops remove the cystine crystals in the cornea that can cause photophobia if left unchecked.
All forms of cystinosis (nephropathic, juvenile and ocular) are inherited as autosomal recessive traits, which means that there is a 25% recurrence risk to any couple who have had an affected child. The disease "breeds true" such that parents of a child with the juvenile variety of cystinosis will not have another child with the nephropathic form, etc. Cystinosis affects approximately 1 in 100,000 to 200,000 newborns. The incidence is higher in the province of Brittany, France, where the disorder affects 1 in 26,000 individuals.
# Causes
It is caused by abnormal transport of the amino acid cystine from lysosomes of all tissues, resulting in a massive intra-lysosomal cystine accumulation. Via an as yet unknown mechanism, lysosomal cystine appears to amplify apoptosis such that cells die inappropriately, leading to loss of renal epithelial cells, accounting for the renal Fanconi syndrome, and similar loss in other tissues can account for the short stature, retinopathy, and other features of the disease.
# Differentiating Cystinosis from Other Diseases
# Epidemiology and Demographics
# Risk Factors
# Screening
# Natural History, Complications, and Prognosis
## Natural History
## Complications
## Prognosis
# Diagnosis
## Diagnostic Criteria
## History and Symptoms
There are three distinct types of cystinosis each with slightly different symptoms: nephropathic cystinosis, intermediate cystinosis, and non-nephropathic or ocular cystinosis. Infants affected by nephropathic cystinosis initially exhibit poor growth and particular kidney problems (sometimes called renal Fanconi syndrome). The kidney problems lead to the loss of important minerals, salts, fluids, and other nutrients. The loss of nutrients not only impairs growth, but may result in soft, bowed bones (hypophosphatemic rickets), especially in the legs. The nutrient imbalances in the body lead to increased urination, thirst, dehydration, and abnormally acidic blood (acidosis). By about age two years, cystine crystals may be present in the cornea. The buildup of these crystals in the eye causes an increased sensitivity to light (photophobia). Untreated children will experience complete kidney failure by about age 10 years. Other signs and symptoms that may occur in untreated patients include muscle deterioration, blindness, inability to swallow, diabetes, and thyroid and nervous system problems.
## Physical Examination
The signs and symptoms of intermediate cystinosis are the same as nephropathic cystinosis, but they occur at a later age. Intermediate cystinosis typically begins to affect individuals from age 12 years to age 15 years. Malfunctioning kidneys and corneal crystals are the main initial features of this disorder. If intermediate cystinosis is left untreated, complete kidney failure will occur, but usually not until the late teens to mid twenties.
People with non-nephropathic or ocular cystinosis do not usually experience growth impairment or kidney malfunction. The only symptom is photophobia due to cystine crystals in the cornea.
It is currently being researched at UC San Diego, Tulane University School of Medicine, and at the National Institutes of Health in Bethesda, Maryland as well as at Robert Gordon University in Aberdeen and in Sunderland, UK.
## Laboratory Findings
## Imaging Findings
## Other Diagnostic Studies
# Treatment
## Medical Therapy
## Surgery
## Prevention | Cystinosis
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Cystinosis is a hereditary disorder of the renal tubules characterized by the presence of carbohydrates and amino acids in the urine, excessive urination, and low blood levels of potassium ions and phosphates. The body accumulates the amino acid cystine within cells. Excess cystine forms crystals that can build up and damage cells. These crystals negatively affect many systems in the body, especially the kidneys and eyes.
# Historical Perspective
# Classification
- Online Mendelian Inheritance in Man (OMIM) 219800 - Infantile nephropathic
- Online Mendelian Inheritance in Man (OMIM) 219900 - Adolescent nephropathic
- Online Mendelian Inheritance in Man (OMIM) 219750 - Adult nonnephropathic
# Pathophysiology
## Genetics
The cause of cystinosis is due to a mutation in the gene CTNS which codes for cystinosin, the lysosomal cystine transporter. Symptoms are first seen at about 3 to 18 months of age with profound polyuria (excessive urination), followed by poor growth, photophobia, and ultimately kidney failure by age 6 years in the nephropathic form. It is important for the child to see a biochemical geneticist and pediatric nephrologist to begin treatment with cysteamine as early as possible. Cysteamine decreases the amount of cystine stored in lysosomes and correlates with conservation of renal function and improved growth. Cysteamine eyedrops remove the cystine crystals in the cornea that can cause photophobia if left unchecked.
All forms of cystinosis (nephropathic, juvenile and ocular) are inherited as autosomal recessive traits, which means that there is a 25% recurrence risk to any couple who have had an affected child. The disease "breeds true" such that parents of a child with the juvenile variety of cystinosis will not have another child with the nephropathic form, etc. Cystinosis affects approximately 1 in 100,000 to 200,000 newborns. The incidence is higher in the province of Brittany, France, where the disorder affects 1 in 26,000 individuals.
# Causes
It is caused by abnormal transport of the amino acid cystine from lysosomes of all tissues, resulting in a massive intra-lysosomal cystine accumulation. Via an as yet unknown mechanism, lysosomal cystine appears to amplify apoptosis such that cells die inappropriately, leading to loss of renal epithelial cells, accounting for the renal Fanconi syndrome, and similar loss in other tissues can account for the short stature, retinopathy, and other features of the disease.
# Differentiating Cystinosis from Other Diseases
# Epidemiology and Demographics
# Risk Factors
# Screening
# Natural History, Complications, and Prognosis
## Natural History
## Complications
## Prognosis
# Diagnosis
## Diagnostic Criteria
## History and Symptoms
There are three distinct types of cystinosis each with slightly different symptoms: nephropathic cystinosis, intermediate cystinosis, and non-nephropathic or ocular cystinosis. Infants affected by nephropathic cystinosis initially exhibit poor growth and particular kidney problems (sometimes called renal Fanconi syndrome). The kidney problems lead to the loss of important minerals, salts, fluids, and other nutrients. The loss of nutrients not only impairs growth, but may result in soft, bowed bones (hypophosphatemic rickets), especially in the legs. The nutrient imbalances in the body lead to increased urination, thirst, dehydration, and abnormally acidic blood (acidosis). By about age two years, cystine crystals may be present in the cornea. The buildup of these crystals in the eye causes an increased sensitivity to light (photophobia). Untreated children will experience complete kidney failure by about age 10 years. Other signs and symptoms that may occur in untreated patients include muscle deterioration, blindness, inability to swallow, diabetes, and thyroid and nervous system problems.
## Physical Examination
The signs and symptoms of intermediate cystinosis are the same as nephropathic cystinosis, but they occur at a later age. Intermediate cystinosis typically begins to affect individuals from age 12 years to age 15 years. Malfunctioning kidneys and corneal crystals are the main initial features of this disorder. If intermediate cystinosis is left untreated, complete kidney failure will occur, but usually not until the late teens to mid twenties.
People with non-nephropathic or ocular cystinosis do not usually experience growth impairment or kidney malfunction. The only symptom is photophobia due to cystine crystals in the cornea.
It is currently being researched at UC San Diego, Tulane University School of Medicine, and at the National Institutes of Health in Bethesda, Maryland as well as at Robert Gordon University in Aberdeen and in Sunderland, UK.
## Laboratory Findings
## Imaging Findings
## Other Diagnostic Studies
# Treatment
## Medical Therapy
## Surgery
## Prevention | https://www.wikidoc.org/index.php/Cystagon | |
d1d41d77c74ec37983a3a4297beb8ef833456aad | wikidoc | Cystatin A | Cystatin A
Cystatin-A is a protein that in humans is encoded by the CSTA gene.
The cystatin superfamily encompasses proteins that contain multiple cystatin-like sequences. Some of the members are active cysteine protease inhibitors, while others have lost or perhaps never acquired this inhibitory activity. There are three inhibitory families in the superfamily, including the type 1 cystatins (stefins), type 2 cystatins, and kininogens. This gene encodes a stefin that functions as a cysteine protease inhibitor, forming tight complexes with papain and the cathepsins B, H, and L. The protein is one of the precursor proteins of cornified cell envelope in keratinocytes and plays a role in epidermal development and maintenance. Stefins have been proposed as prognostic and diagnostic tools for cancer.
# Interactions
Cystatin A has been shown to interact with Cathepsin B and CTSL1. | Cystatin A
Cystatin-A is a protein that in humans is encoded by the CSTA gene.[1][2]
The cystatin superfamily encompasses proteins that contain multiple cystatin-like sequences. Some of the members are active cysteine protease inhibitors, while others have lost or perhaps never acquired this inhibitory activity. There are three inhibitory families in the superfamily, including the type 1 cystatins (stefins), type 2 cystatins, and kininogens. This gene encodes a stefin that functions as a cysteine protease inhibitor, forming tight complexes with papain and the cathepsins B, H, and L. The protein is one of the precursor proteins of cornified cell envelope in keratinocytes and plays a role in epidermal development and maintenance. Stefins have been proposed as prognostic and diagnostic tools for cancer.[2]
# Interactions
Cystatin A has been shown to interact with Cathepsin B[3][4] and CTSL1.[4][5] | https://www.wikidoc.org/index.php/Cystatin_A | |
9e5cc9af9cdaf783a27076834bd1540ff39a0918 | wikidoc | Cystatin C | Cystatin C
Cystatin C or cystatin 3 (formerly gamma trace, post-gamma-globulin, or neuroendocrine basic polypeptide), a protein encoded by the CST3 gene, is mainly used as a biomarker of kidney function. Recently, it has been studied for its role in predicting new-onset or deteriorating cardiovascular disease. It also seems to play a role in brain disorders involving amyloid (a specific type of protein deposition), such as Alzheimer's disease.
In humans, all cells with a nucleus (cell core containing the DNA) produce cystatin C as a chain of 120 amino acids. It is found in virtually all tissues and body fluids. It is a potent inhibitor of lysosomal proteinases (enzymes from a special subunit of the cell that break down proteins) and probably one of the most important extracellular inhibitors of cysteine proteases (it prevents the breakdown of proteins outside the cell by a specific type of protein degrading enzymes). Cystatin C belongs to the type 2 cystatin gene family.
# Gene
## Transcriptions
The "four cystatin genes contain the ATA-box sequence (ATAAA) in their 5'-flanking regions; however, the CAT-box sequence (CAT), a binding site of the transcription factor, CTF, is found only in the 5'-flanking region of the S-type cystatin genes."
# Role in medicine
## Kidney function
Glomerular filtration rate (GFR), a marker of kidney health, is most accurately measured by injecting compounds such as inulin, radioisotopes such as 51chromium-EDTA, 125I-iothalamate, 99mTc-DTPA or radiocontrast agents such as iohexol, but these techniques are complicated, costly, time-consuming and have potential side-effects.
Creatinine is the most widely used biomarker of kidney function. It is inaccurate at detecting mild renal impairment, and levels can vary with muscle mass but not with protein intake. Urea levels might change with protein intake.
Formulas such as the Cockcroft and Gault formula and the MDRD formula (see Renal function) try to adjust for these variables.
Cystatin C has a low molecular weight (approximately 13.3 kilodaltons), and it is removed from the bloodstream by glomerular filtration in the kidneys. If kidney function and glomerular filtration rate decline, the blood levels of cystatin C rise. Cross-sectional studies (based on a single point in time) suggest that serum levels of cystatin C are a more precise test of kidney function (as represented by the glomerular filtration rate, GFR) than serum creatinine levels.. Longitudinal studies (following cystatin C over time) are sparse, but some show promising results.
Cystatin C levels are less dependent on age, gender, ethnicity and muscle mass compared to creatinine. Cystatin C measurements alone have not been shown to be superior to formula-adjusted estimations of kidney function. As opposed to previous claims, cystatin C has been found to be influenced by body composition.
It has been suggested that cystatin C might predict the risk of developing chronic kidney disease, thereby signaling a state of 'preclinical' kidney dysfunction.
Studies have also investigated cystatin C as a marker of kidney function in the adjustment of medication dosages.
Cystatin C levels have been reported to be altered in patients with cancer, (even subtle) thyroid dysfunction and glucocorticoid therapy in some but not all situations. Other reports have found that levels are influenced by cigarette smoking and levels of C-reactive protein. Levels seem to be increased in HIV infection, which might or might not reflect actual renal dysfunction. The role of cystatin C to monitor GFR during pregnancy remains controversial. Like creatinine, the elimination of cystatin C via routes other than the kidney increase with worsening GFR.
## Death and cardiovascular disease
Kidney dysfunction increases the risk of death and cardiovascular disease.
Several studies have found that increased levels of cystatin C are associated with the risk of death, several types of cardiovascular disease (including myocardial infarction, stroke, heart failure, peripheral arterial disease and metabolic syndrome) and healthy aging. Some studies have found cystatin C to be better in this regard than serum creatinine or creatinine-based GFR equations.
Because the association of cystatin C with long term outcomes has appeared stronger than what could be expected for GFR, it has been hypothesized that cystatin C might also be linked to mortality in a way independent of kidney function. In keeping with its housekeeping gene properties, it has been suggested that cystatin C might be influenced by the basal metabolic rate.
## Neurologic disorders
Mutations in the cystatin 3 gene are responsible for the Icelandic type of hereditary cerebral amyloid angiopathy, a condition predisposing to intracerebral haemorrhage, stroke and dementia. The condition is inherited in a dominant fashion.
Since cystatin 3 also binds amyloid β and reduces its aggregation and deposition, it is a potential target in Alzheimer's disease. Although not all studies have confirmed this, the overall evidence is in favor of a role for CST3 as a susceptibility gene for Alzheimer's disease. Cystatin C levels have been reported to be higher in subjects with Alzheimer's disease.
The role of cystatin C in multiple sclerosis and other demyelinating diseases (characterized by a loss of the myelin nerve sheath) remains controversial.
## Other roles
Cystatin C levels are decreased in atherosclerotic (so-called 'hardening' of the arteries) and aneurysmal (saccular bulging) lesions of the aorta.
Genetic and prognostic studies also suggest a role for cystatin C.
Breakdown of parts of the vessel wall in these conditions is thought to result from an imbalance between proteinases (cysteine proteases and matrix metalloproteinases, increased) and their inhibitors (such as cystatin C, decreased).
A few studies have looked at the role of cystatin C or the CST3 gene in age-related macular degeneration. Cystatin C has also been investigated as a prognostic marker in several forms of cancer. Its role in pre-eclampsia remains to be confirmed.
# Laboratory measurement
Cystatin C can be measured in a random sample of serum (the fluid in blood from which the red blood cells and clotting factors have been removed) using immunoassays such as nephelometry or particle-enhanced turbidimetry. It is a more expensive test than serum creatinine (around $2 or $3, compared to $0.02 to $0.15), which can be measured with a Jaffé reaction.
Reference values differ in many populations and with sex and age. Across different studies, the mean reference interval (as defined by the 5th and 95th percentile) was between 0.52 and 0.98 mg/L. For women, the average reference interval is 0.52 to 0.90 mg/L with a mean of 0.71 mg/L. For men, the average reference interval is 0.56 to 0.98 mg/L with a mean of 0.77 mg/L.
The normal values decrease until the first year of life, remaining relatively stable before they increase again, especially beyond age 50. Creatinine levels increase until puberty and differ according to gender from then on, making their interpretation problematic for pediatric patients.
In a large study from the United States National Health and Nutrition Examination Survey, the reference interval (as defined by the 1st and 99th percentile) was between 0.57 and 1.12 mg/L. This interval was 0.55 - 1.18 for women and 0.60 - 1.11 for men. Non-Hispanic blacks and Mexican Americans had lower normal cystatin C levels. Other studies have found that in patients with an impaired renal function, women have lower and blacks have higher cystatin C levels for the same GFR. For example, the cut-off values of cystatin C for chronic kidney disease for a 60-year-old white women would be 1.12 mg/L and 1.27 mg/L in a black man (a 13% increase). For serum creatinine values adjusted with the MDRD equation, these values would be 0.95 mg/dL to 1.46 mg/dL (a 54% increase).
Based on a threshold level of 1.09 mg/L (the 99th percentile in a population of 20- to 39-year-olds without hypertension, diabetes, microalbuminuria or macroalbuminuria or higher than stage 3 chronic kidney disease), the prevalence of increased levels of cystatin C in the United States was 9.6% in subjects of normal weight, increasing in overweight and obese individuals. In Americans aged 60 and 80 and older, serum cystatin is increased in 41% and more than 50%.
# Molecular biology
The cystatin superfamily encompasses proteins that contain multiple cystatin-like sequences. Some of the members are active cysteine protease inhibitors, while others have lost or perhaps never acquired this inhibitory activity. There are three inhibitory families in the superfamily, including the type 1 cystatins (stefins), type 2 cystatins and the kininogens. The type 2 cystatin proteins are a class of cysteine proteinase inhibitors found in a variety of human fluids and secretions, where they appear to provide protective functions. The cystatin locus on the short arm of chromosome 20 contains the majority of the type 2 cystatin genes and pseudogenes.
The CST3 gene is located in the cystatin locus and comprises 3 exons (coding regions, as opposed to introns, non-coding regions within a gene), spanning 4.3 kilo-base pairs. It encodes the most abundant extracellular inhibitor of cysteine proteases. It is found in high concentrations in biological fluids and is expressed in virtually all organs of the body (CST3 is a housekeeping gene). The highest levels are found in semen, followed by breastmilk, tears and saliva. The hydrophobic leader sequence indicates that the protein is normally secreted. There are three polymorphisms in the promoter region of the gene, resulting in two common variants. Several single nucleotide polymorphisms have been associated with altered cystatin C levels.
Cystatin C is a non-glycosylated, basic protein (isoelectric point at pH 9.3). The crystal structure of cystatin C is characterized by a short alpha helix and a long alpha helix which lies across a large antiparallel, five-stranded beta sheet. Like other type 2 cystatins, it has two disulfide bonds. Around 50% of the molecules carry a hydroxylated proline. Cystatin C forms dimers (molecule pairs) by exchanging subdomains; in the paired state, each half is made up of the long alpha helix and one beta strand of one partner, and four beta strands of the other partner.
# History
Cystatin C was first described as 'gamma-trace' in 1961 as a trace protein together with other ones (such as beta-trace) in the cerebrospinal fluid and in the urine of patients with renal failure. Grubb and Löfberg first reported its amino acid sequence. They noticed it was increased in patients with advanced renal failure. It was first proposed as a measure of glomerular filtration rate by Grubb and coworkers in 1985.
Use of serum creatinine and cystatin C was found very effective in accurately reflecting the GFR in a study reported in the July 5, 2012 issue of the New England Journal of Medicine.
# Footnotes
- ↑ "Alzforum: AlzGene". Archived from the original on 2004-12-27..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}
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- ↑ Jump up to: 4.0 4.1 Roos JF, Doust J, Tett SE, Kirkpatrick CM (March 2007). "Diagnostic accuracy of cystatin C compared to serum creatinine for the estimation of renal dysfunction in adults and children--a meta-analysis". Clin. Biochem. 40 (5–6): 383–391. doi:10.1016/j.clinbiochem.2006.10.026. PMID 17316593.
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- ↑ Strojan P, Oblak I, Svetic B, Smid L, Kos J (May 2004). "Cysteine proteinase inhibitor cystatin C in squamous cell carcinoma of the head and neck: relation to prognosis". Br. J. Cancer. 90 (10): 1961–1968. doi:10.1038/sj.bjc.6601830. PMC 2409457. PMID 15138478.
- ↑ Kos J, Krasovec M, Cimerman N, Nielsen HJ, Christensen IJ, Brünner N (February 2000). "Cysteine proteinase inhibitors stefin A, stefin B, and cystatin C in sera from patients with colorectal cancer: relation to prognosis". Clin. Cancer Res. 6 (2): 505–11. PMID 10690531.
- ↑ Strevens H, Wide-Swensson D, Grubb A, et al. (September 2003). "Serum cystatin C reflects glomerular endotheliosis in normal, hypertensive and pre-eclamptic pregnancies". BJOG. 110 (9): 825–830. doi:10.1111/j.1471-0528.2003.02051.x. PMID 14511964.
- ↑ Franceschini N, Qiu C, Barrow DA, Williams MA (2008). "Cystatin C and preeclampsia: a case control study". Ren Fail. 30 (1): 89–95. doi:10.1080/08860220701742229. PMID 18197549.
- ↑ Kristensen K, Wide-Swensson D, Schmidt C, et al. (2007). "Cystatin C, beta-2-microglobulin and beta-trace protein in pre-eclampsia". Acta Obstet Gynecol Scand. 86 (8): 921–926. doi:10.1080/00016340701318133. PMID 17653875.
- ↑ Kristensen K, Larsson I, Hansson SR (March 2007). "Increased cystatin C expression in the pre-eclamptic placenta". Mol. Hum. Reprod. 13 (3): 189–195*. doi:10.1093/molehr/gal111. PMID 17227816.
- ↑ Jump up to: 69.0 69.1 Croda-Todd MT, Soto-Montano XJ, Hernández-Cancino PA, Juárez-Aguilar E (September 2007). "Adult cystatin C reference intervals determined by nephelometric immunoassay". Clin. Biochem. 40 (13–14): 1084–1087. doi:10.1016/j.clinbiochem.2007.05.011. PMID 17624320.
- ↑ Lamb EJ, O'Riordan SE, Webb MC, Newman DJ (November 2003). "Serum cystatin C may be a better marker of renal impairment than creatinine". J Am Geriatr Soc. 51 (11): 1674–1675. doi:10.1046/j.1532-5415.2003.515244.x. PMID 14687406.
- ↑ Peake M, Whiting M (November 2006). "Measurement of serum creatinine - current status and future goals". Clin Biochem Rev. 27 (4): 173–84. PMC 1784008. PMID 17581641.
- ↑ Myers GL, Miller WG, Coresh J, et al. (January 2006). "Recommendations for improving serum creatinine measurement: a report from the Laboratory Working Group of the National Kidney Disease Education Program". Clin. Chem. 52 (1): 5–18. doi:10.1373/clinchem.2005.0525144. PMID 16332993.
- ↑ Jump up to: 73.0 73.1 73.2 Köttgen A, Selvin E, Stevens LA, Levey AS, Van Lente F, Coresh J (March 2008). "Serum cystatin C in the United States: the Third National Health and Nutrition Examination Survey (NHANES III)". Am. J. Kidney Dis. 51 (3): 385–394. doi:10.1053/j.ajkd.2007.11.019. PMID 18295054.
- ↑ Jump up to: 74.0 74.1 Finney H, Newman DJ, Thakkar H, Fell JM, Price CP (January 2000). "Reference ranges for plasma cystatin C and creatinine measurements in premature infants, neonates, and older children". Arch. Dis. Child. 82 (1): 71–75. doi:10.1136/adc.82.1.71. PMC 1718178. PMID 10630919.
- ↑ Ognibene A, Mannucci E, Caldini A, et al. (June 2006). "Cystatin C reference values and aging". Clin. Biochem. 39 (6): 658–661. doi:10.1016/j.clinbiochem.2006.03.017. PMID 16730690.
- ↑ Filler G, Bökenkamp A, Hofmann W, Le Bricon T, Martínez-Brú C, Grubb A (January 2005). "Cystatin C as a marker of GFR--history, indications, and future research". Clin. Biochem. 38 (1): 1–8. doi:10.1016/j.clinbiochem.2004.09.025. PMID 15607309.
- ↑ Shlipak MG (March 2008). "Cystatin C: research priorities targeted to clinical decision making". Am. J. Kidney Dis. 51 (3): 358–361. doi:10.1053/j.ajkd.2008.01.002. PMID 18295049.
- ↑ Muntner P, Winston J, Uribarri J, Mann D, Fox CS (April 2008). "Overweight, obesity, and elevated serum cystatin C levels in adults in the United States". Am. J. Med. 121 (4): 341–348. doi:10.1016/j.amjmed.2008.01.003. PMC 3049932. PMID 18374694.
- ↑ "Entrez Gene: CST3 cystatin C (amyloid angiopathy and cerebral hemorrhage)".
- ↑ Hwang SJ, Yang Q, Meigs JB, Pearce EN, Fox CS (2007). "A genome-wide association for kidney function and endocrine-related traits in the NHLBI's Framingham Heart Study". BMC Med. Genet. 8 Suppl 1: S10. doi:10.1186/1471-2350-8-S1-S10. PMC 1995611. PMID 17903292. Archived from the original on 2008-06-12.
- ↑ Janowski R, Kozak M, Jankowska E, et al. (April 2001). "Human cystatin C, an amyloidogenic protein, dimerizes through three-dimensional domain swapping". Nature Structural & Molecular Biology. 8 (4): 316–320. doi:10.1038/86188. PMID 11276250.
- ↑ Jump up to: 82.0 82.1 Grubb A, Löfberg H (May 1982). "Human gamma-trace, a basic microprotein: amino acid sequence and presence in the adenohypophysis". Proc. Natl. Acad. Sci. U.S.A. 79 (9): 3024–3027. doi:10.1073/pnas.79.9.3024. PMC 346341. PMID 6283552.
- ↑ Löfberg H, Grubb AO (November 1979). "Quantitation of gamma-trace in human biological fluids: indications for production in the central nervous system". Scand. J. Clin. Lab. Invest. 39 (7): 619–626. doi:10.3109/00365517909108866. PMID 119302.
- ↑ Grubb A, Simonsen O, Sturfelt G, Truedsson L, Thysell H (1985). "Serum concentration of cystatin C, factor D and beta 2-microglobulin as a measure of glomerular filtration rate". Acta Med Scand. 218 (5): 499–503. doi:10.1111/j.0954-6820.1985.tb08880.x. PMID 3911736.
- ↑ Simonsen O, Grubb A, Thysell H (April 1985). "The blood serum concentration of cystatin C (gamma-trace) as a measure of the glomerular filtration rate". Scand. J. Clin. Lab. Invest. 45 (2): 97–101. doi:10.3109/00365518509160980. PMID 3923607.
- ↑ Shlipak MG, Matsushita K, Ärnlöv J, Inker LA, Katz R, Polkinghorne KR, Rothenbacher D, Sarnak MJ, Astor BC, Coresh J, Levey AS, Gansevoort RT (2013). "Cystatin C versus creatinine in determining risk based on kidney function". NEJM. 369: 932–943. doi:10.1056/NEJMoa1214234. PMC 3993094. PMID 24004120. | Cystatin C
Cystatin C or cystatin 3 (formerly gamma trace, post-gamma-globulin, or neuroendocrine basic polypeptide),[1] a protein encoded by the CST3 gene, is mainly used as a biomarker of kidney function. Recently, it has been studied for its role in predicting new-onset or deteriorating cardiovascular disease. It also seems to play a role in brain disorders involving amyloid (a specific type of protein deposition), such as Alzheimer's disease.
In humans, all cells with a nucleus (cell core containing the DNA) produce cystatin C as a chain of 120 amino acids. It is found in virtually all tissues and body fluids. It is a potent inhibitor of lysosomal proteinases (enzymes from a special subunit of the cell that break down proteins) and probably one of the most important extracellular inhibitors of cysteine proteases (it prevents the breakdown of proteins outside the cell by a specific type of protein degrading enzymes). Cystatin C belongs to the type 2 cystatin gene family.
# Gene
## Transcriptions
The "four cystatin genes [GeneID: 1469 CST1, GeneID: 1470 CST2, GeneID: 1471 CST3, and GeneID: 1472 CST4] contain the ATA-box sequence (ATAAA) in their 5'-flanking regions; however, the CAT-box sequence (CAT), a binding site of the transcription factor, CTF, is found only in the 5'-flanking region of the S-type cystatin genes."[2]
# Role in medicine
## Kidney function
Glomerular filtration rate (GFR), a marker of kidney health, is most accurately measured by injecting compounds such as inulin, radioisotopes such as 51chromium-EDTA, 125I-iothalamate, 99mTc-DTPA or radiocontrast agents such as iohexol, but these techniques are complicated, costly, time-consuming and have potential side-effects.[3][4]
Creatinine is the most widely used biomarker of kidney function. It is inaccurate at detecting mild renal impairment, and levels can vary with muscle mass but not with protein intake. Urea levels might change with protein intake.[5]
Formulas such as the Cockcroft and Gault formula and the MDRD formula (see Renal function) try to adjust for these variables.
Cystatin C has a low molecular weight (approximately 13.3 kilodaltons), and it is removed from the bloodstream by glomerular filtration in the kidneys. If kidney function and glomerular filtration rate decline, the blood levels of cystatin C rise. Cross-sectional studies (based on a single point in time) suggest that serum levels of cystatin C are a more precise test of kidney function (as represented by the glomerular filtration rate, GFR) than serum creatinine levels.[4][6]. Longitudinal studies (following cystatin C over time) are sparse, but some show promising results.[7][8][9]
Cystatin C levels are less dependent on age, gender, ethnicity and muscle mass compared to creatinine. Cystatin C measurements alone have not been shown to be superior to formula-adjusted estimations of kidney function.[10] As opposed to previous claims, cystatin C has been found to be influenced by body composition.[11][12]
It has been suggested that cystatin C might predict the risk of developing chronic kidney disease, thereby signaling a state of 'preclinical' kidney dysfunction.[13]
Studies have also investigated cystatin C as a marker of kidney function in the adjustment of medication dosages.[14][15]
Cystatin C levels have been reported to be altered in patients with cancer,[16][17][18] (even subtle) thyroid dysfunction[19][20][21] and glucocorticoid therapy in some[22][23] but not all[24] situations. Other reports have found that levels are influenced by cigarette smoking and levels of C-reactive protein.[25] Levels seem to be increased in HIV infection, which might or might not reflect actual renal dysfunction.[26][27][28] The role of cystatin C to monitor GFR during pregnancy remains controversial.[29][30] Like creatinine, the elimination of cystatin C via routes other than the kidney increase with worsening GFR.[31]
## Death and cardiovascular disease
Kidney dysfunction increases the risk of death and cardiovascular disease.[32][33]
Several studies have found that increased levels of cystatin C are associated with the risk of death, several types of cardiovascular disease (including myocardial infarction, stroke, heart failure, peripheral arterial disease and metabolic syndrome) and healthy aging.[citation needed][clarification needed] Some studies have found cystatin C to be better in this regard than serum creatinine or creatinine-based GFR equations.[34][35][36][37][38][39][40][41][42][43][44][45]
Because the association of cystatin C with long term outcomes has appeared stronger than what could be expected for GFR, it has been hypothesized that cystatin C might also be linked to mortality in a way independent of kidney function.[46] In keeping with its housekeeping gene properties, it has been suggested that cystatin C might be influenced by the basal metabolic rate.[47]
## Neurologic disorders
Mutations in the cystatin 3 gene are responsible for the Icelandic type of hereditary cerebral amyloid angiopathy, a condition predisposing to intracerebral haemorrhage, stroke and dementia.[48][49] The condition is inherited in a dominant fashion.
Since cystatin 3 also binds amyloid β and reduces its aggregation and deposition, it is a potential target in Alzheimer's disease.[50][51] Although not all studies have confirmed this, the overall evidence is in favor of a role for CST3 as a susceptibility gene for Alzheimer's disease.[52] Cystatin C levels have been reported to be higher in subjects with Alzheimer's disease.[53]
The role of cystatin C in multiple sclerosis and other demyelinating diseases (characterized by a loss of the myelin nerve sheath) remains controversial.[54]
## Other roles
Cystatin C levels are decreased in atherosclerotic (so-called 'hardening' of the arteries) and aneurysmal (saccular bulging) lesions of the aorta.[55][56][57][58]
Genetic and prognostic studies also suggest a role for cystatin C.[59][60]
Breakdown of parts of the vessel wall in these conditions is thought to result from an imbalance between proteinases (cysteine proteases and matrix metalloproteinases, increased) and their inhibitors (such as cystatin C, decreased).
A few studies have looked at the role of cystatin C or the CST3 gene in age-related macular degeneration.[61][62] Cystatin C has also been investigated as a prognostic marker in several forms of cancer.[63][64] Its role in pre-eclampsia remains to be confirmed.[65][66][67][68]
# Laboratory measurement
Cystatin C can be measured in a random sample of serum (the fluid in blood from which the red blood cells and clotting factors have been removed) using immunoassays such as nephelometry or particle-enhanced turbidimetry.[69] It is a more expensive test than serum creatinine (around $2 or $3, compared to $0.02 to $0.15), which can be measured with a Jaffé reaction.[70][71][72]
Reference values differ in many populations and with sex and age. Across different studies, the mean reference interval (as defined by the 5th and 95th percentile) was between 0.52 and 0.98 mg/L. For women, the average reference interval is 0.52 to 0.90 mg/L with a mean of 0.71 mg/L. For men, the average reference interval is 0.56 to 0.98 mg/L with a mean of 0.77 mg/L.[69]
The normal values decrease until the first year of life, remaining relatively stable before they increase again, especially beyond age 50.[73][74][75] Creatinine levels increase until puberty and differ according to gender from then on, making their interpretation problematic for pediatric patients.[74][76]
In a large study from the United States National Health and Nutrition Examination Survey, the reference interval (as defined by the 1st and 99th percentile) was between 0.57 and 1.12 mg/L. This interval was 0.55 - 1.18 for women and 0.60 - 1.11 for men. Non-Hispanic blacks and Mexican Americans had lower normal cystatin C levels.[73] Other studies have found that in patients with an impaired renal function, women have lower and blacks have higher cystatin C levels for the same GFR.[10] For example, the cut-off values of cystatin C for chronic kidney disease for a 60-year-old white women would be 1.12 mg/L and 1.27 mg/L in a black man (a 13% increase). For serum creatinine values adjusted with the MDRD equation, these values would be 0.95 mg/dL to 1.46 mg/dL (a 54% increase).[77]
Based on a threshold level of 1.09 mg/L (the 99th percentile in a population of 20- to 39-year-olds without hypertension, diabetes, microalbuminuria or macroalbuminuria or higher than stage 3 chronic kidney disease), the prevalence of increased levels of cystatin C in the United States was 9.6% in subjects of normal weight, increasing in overweight and obese individuals.[78] In Americans aged 60 and 80 and older, serum cystatin is increased in 41% and more than 50%.[73]
# Molecular biology
The cystatin superfamily encompasses proteins that contain multiple cystatin-like sequences. Some of the members are active cysteine protease inhibitors, while others have lost or perhaps never acquired this inhibitory activity. There are three inhibitory families in the superfamily, including the type 1 cystatins (stefins), type 2 cystatins and the kininogens. The type 2 cystatin proteins are a class of cysteine proteinase inhibitors found in a variety of human fluids and secretions, where they appear to provide protective functions. The cystatin locus on the short arm of chromosome 20 contains the majority of the type 2 cystatin genes and pseudogenes.
The CST3 gene is located in the cystatin locus and comprises 3 exons (coding regions, as opposed to introns, non-coding regions within a gene), spanning 4.3 kilo-base pairs. It encodes the most abundant extracellular inhibitor of cysteine proteases. It is found in high concentrations in biological fluids and is expressed in virtually all organs of the body (CST3 is a housekeeping gene). The highest levels are found in semen, followed by breastmilk, tears and saliva. The hydrophobic leader sequence indicates that the protein is normally secreted. There are three polymorphisms in the promoter region of the gene, resulting in two common variants.[79] Several single nucleotide polymorphisms have been associated with altered cystatin C levels.[80]
Cystatin C is a non-glycosylated, basic protein (isoelectric point at pH 9.3). The crystal structure of cystatin C is characterized by a short alpha helix and a long alpha helix which lies across a large antiparallel, five-stranded beta sheet. Like other type 2 cystatins, it has two disulfide bonds. Around 50% of the molecules carry a hydroxylated proline. Cystatin C forms dimers (molecule pairs) by exchanging subdomains; in the paired state, each half is made up of the long alpha helix and one beta strand of one partner, and four beta strands of the other partner.[81]
# History
Cystatin C was first described as 'gamma-trace' in 1961 as a trace protein together with other ones (such as beta-trace) in the cerebrospinal fluid and in the urine of patients with renal failure.[82] Grubb and Löfberg first reported its amino acid sequence.[82] They noticed it was increased in patients with advanced renal failure.[83] It was first proposed as a measure of glomerular filtration rate by Grubb and coworkers in 1985.[84][85]
Use of serum creatinine and cystatin C was found very effective in accurately reflecting the GFR in a study reported in the July 5, 2012 issue of the New England Journal of Medicine.[86]
# Footnotes
- ↑ "Alzforum: AlzGene". Archived from the original on 2004-12-27..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}
- ↑ Eiichi Saitoh and Satoko Isemura (January 1, 1993). "Molecular Biology of Human Salivary Cysteine Proteinase Inhibitors" (PDF). Critical Reviews in Oral Biology and Medicine. 4 (3/4): 487–93. doi:10.1177/10454411930040033301. Retrieved 2013-06-28.
- ↑ Zahran A, El-Husseini A, Shoker A (2007). "Can cystatin C replace creatinine to estimate glomerular filtration rate? A literature review". Am. J. Nephrol. 27 (2): 197–205. doi:10.1159/000100907. PMID 17361076.
- ↑ Jump up to: 4.0 4.1 Roos JF, Doust J, Tett SE, Kirkpatrick CM (March 2007). "Diagnostic accuracy of cystatin C compared to serum creatinine for the estimation of renal dysfunction in adults and children--a meta-analysis". Clin. Biochem. 40 (5–6): 383–391. doi:10.1016/j.clinbiochem.2006.10.026. PMID 17316593.
- ↑ King AJ, Levey AS (May 1993). "Dietary protein and renal function". J. Am. Soc. Nephrol. 3 (11): 1723–37. PMID 8329667.
- ↑ Dharnidharka VR, Kwon C, Stevens G (August 2002). "Serum cystatin C is superior to serum creatinine as a marker of kidney function: a meta-analysis". Am. J. Kidney Dis. 40 (2): 221–226. doi:10.1053/ajkd.2002.34487. PMID 12148093.
- ↑ Premaratne E, MacIsaac RJ, Finch S, Panagiotopoulos S, Ekinci E, Jerums G (May 2008). "Serial measurements of cystatin C are more accurate than creatinine-based methods in detecting declining renal function in type 1 diabetes". Diabetes Care. 31 (5): 971–973. doi:10.2337/dc07-1588. PMID 18319326.
- ↑ Perkins BA, Nelson RG, Ostrander BE, et al. (May 2005). "Detection of renal function decline in patients with diabetes and normal or elevated GFR by serial measurements of serum cystatin C concentration: results of a 4-year follow-up study". J. Am. Soc. Nephrol. 16 (5): 1404–1412. doi:10.1681/ASN.2004100854. PMC 2429917. PMID 15788478.
- ↑ Corrao AM, Lisi G, Di Pasqua G, et al. (January 2006). "Serum cystatin C as a reliable marker of changes in glomerular filtration rate in children with urinary tract malformations". J. Urol. 175 (1): 303–309. doi:10.1016/S0022-5347(05)00015-7. PMID 16406933.
- ↑ Jump up to: 10.0 10.1 Stevens LA, Coresh J, Schmid CH, et al. (March 2008). "Estimating GFR using serum cystatin C alone and in combination with serum creatinine: a pooled analysis of 3,418 individuals with CKD". Am. J. Kidney Dis. 51 (3): 395–406. doi:10.1053/j.ajkd.2007.11.018. PMC 2390827. PMID 18295055.
- ↑ Shlipak MG (April 2007). "Cystatin C as a marker of glomerular filtration rate in chronic kidney disease: influence of body composition". Nat Clin Pract Nephrol. 3 (4): 188–189. doi:10.1038/ncpneph0404. PMID 17290239.
- ↑ Macdonald J, Marcora S, Jibani M, et al. (November 2006). "GFR estimation using cystatin C is not independent of body composition". Am. J. Kidney Dis. 48 (5): 712–719. doi:10.1053/j.ajkd.2006.07.001. PMID 17059990.
- ↑ Shlipak MG, Katz R, Sarnak MJ, et al. (August 2006). "Cystatin C and prognosis for cardiovascular and kidney outcomes in elderly persons without chronic kidney disease". Annals of Internal Medicine. 145 (4): 237–46. doi:10.7326/0003-4819-145-4-200608150-00003. PMID 16908914.
- ↑ Hermida J, Tutor JC (June 2006). "Serum cystatin C for the prediction of glomerular filtration rate with regard to the dose adjustment of amikacin, gentamicin, tobramycin, and vancomycin". Ther Drug Monit. 28 (3): 326–331. doi:10.1097/01.ftd.0000211805.89440.3d. PMID 16778715.
- ↑ Schück O, Teplan V, Sibová J, Stollová M (February 2004). "Predicting the glomerular filtration rate from serum creatinine, serum cystatin C and the Cockcroft and Gault formula with regard to drug dosage adjustment". Int J Clin Pharmacol Ther. 42 (2): 93–7. doi:10.5414/cpp42093. PMID 15180169.
- ↑ Demirtaş S, Akan O, Can M, Elmali E, Akan H (February 2006). "Cystatin C can be affected by nonrenal factors: a preliminary study on leukemia". Clin. Biochem. 39 (2): 115–118. doi:10.1016/j.clinbiochem.2005.10.009. PMID 16337174.
- ↑ Nakai K, Kikuchi M, Fujimoto K, et al. (April 2008). "Serum levels of cystatin C in patients with malignancy". Clin. Exp. Nephrol. 12 (2): 132–139. doi:10.1007/s10157-008-0043-8. PMID 18317874.
- ↑ Kos J, Stabuc B, Cimerman N, Brünner N (December 1998). "Serum cystatin C, a new marker of glomerular filtration rate, is increased during malignant progression". Clin. Chem. 44 (12): 2556–7. PMID 9836733.
- ↑ Fricker M, Wiesli P, Brändle M, Schwegler B, Schmid C (May 2003). "Impact of thyroid dysfunction on serum cystatin C". Kidney Int. 63 (5): 1944–1947. doi:10.1046/j.1523-1755.2003.00925.x. PMID 12675875.
- ↑ Manetti L, Pardini E, Genovesi M, et al. (April 2005). "Thyroid function differently affects serum cystatin C and creatinine concentrations". J. Endocrinol. Invest. 28 (4): 346–9. doi:10.1007/bf03347201. PMID 15966508. Archived from the original on 2008-06-08.
- ↑ Wiesli P, Schwegler B, Spinas GA, Schmid C (December 2003). "Serum cystatin C is sensitive to small changes in thyroid function". Clin. Chim. Acta. 338 (1–2): 87–90. doi:10.1016/j.cccn.2003.07.022. PMID 14637271.
- ↑ Risch L, Herklotz R, Blumberg A, Huber AR (November 2001). "Effects of glucocorticoid immunosuppression on serum cystatin C concentrations in renal transplant patients". Clin. Chem. 47 (11): 2055–9. PMID 11673383.
- ↑ Cimerman N, Brguljan PM, Krasovec M, Suskovic S, Kos J (October 2000). "Serum cystatin C, a potent inhibitor of cysteine proteinases, is elevated in asthmatic patients". Clin. Chim. Acta. 300 (1–2): 83–95. doi:10.1016/S0009-8981(00)00298-9. PMID 10958865.
- ↑ Bökenkamp A, van Wijk JA, Lentze MJ, Stoffel-Wagner B (July 2002). "Effect of corticosteroid therapy on serum cystatin C and beta2-microglobulin concentrations". Clin. Chem. 48 (7): 1123–6. PMID 12089191.
- ↑ Knight EL, Verhave JC, Spiegelman D, et al. (April 2004). "Factors influencing serum cystatin C levels other than renal function and the impact on renal function measurement". Kidney Int. 65 (4): 1416–1421. doi:10.1111/j.1523-1755.2004.00517.x. PMID 15086483.
- ↑ Odden MC, Scherzer R, Bacchetti P, et al. (November 2007). "Cystatin C level as a marker of kidney function in human immunodeficiency virus infection: the FRAM study". Arch. Intern. Med. 167 (20): 2213–2219. doi:10.1001/archinte.167.20.2213. PMC 3189482. PMID 17998494.[permanent dead link]
- ↑ Collé A, Tavera C, Prévot D, et al. (1992). "Cystatin C levels in sera of patients with human immunodeficiency virus infection. A new avidin-biotin ELISA assay for its measurement". J Immunoassay. 13 (1): 47–60. doi:10.1080/15321819208019824. PMID 1569212.
- ↑ Jaroszewicz J, Wiercinska-Drapalo A, Lapinski TW, Prokopowicz D, Rogalska M, Parfieniuk A (2006). "Does HAART improve renal function? An association between serum cystatin C concentration, HIV viral load and HAART duration". Antivir. Ther. (Lond.). 11 (5): 641–5. PMID 16964834.
- ↑ Strevens H, Wide-Swensson D, Torffvit O, Grubb A (2002). "Serum cystatin C for assessment of glomerular filtration rate in pregnant and non-pregnant women. Indications of altered filtration process in pregnancy". Scand. J. Clin. Lab. Invest. 62 (2): 141–147. doi:10.1080/003655102753611771. PMID 12004930.
- ↑ Akbari A, Lepage N, Keely E, et al. (May 2005). "Cystatin-C and beta trace protein as markers of renal function in pregnancy". BJOG. 112 (5): 575–578. doi:10.1111/j.1471-0528.2004.00492.x. PMID 15842279.
- ↑ Sjöström P, Tidman M, Jones I (2005). "Determination of the production rate and non-renal clearance of cystatin C and estimation of the glomerular filtration rate from the serum concentration of cystatin C in humans". Scand. J. Clin. Lab. Invest. 65 (2): 111–124. doi:10.1080/00365510510013523. PMID 16025834.
- ↑ Tonelli M, Wiebe N, Culleton B, et al. (July 2006). "Chronic kidney disease and mortality risk: a systematic review". J. Am. Soc. Nephrol. 17 (7): 2034–2047. doi:10.1681/ASN.2005101085. PMID 16738019.
- ↑ Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY (September 2004). "Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization". N. Engl. J. Med. 351 (13): 1296–1305. doi:10.1056/NEJMoa041031. PMID 15385656.
- ↑ Zethelius B, Berglund L, Sundström J, et al. (May 2008). "Use of multiple biomarkers to improve the prediction of death from cardiovascular causes". N. Engl. J. Med. 358 (20): 2107–2116. doi:10.1056/NEJMoa0707064. PMID 18480203.
- ↑ Shlipak MG, Sarnak MJ, Katz R, et al. (May 2005). "Cystatin C and the risk of death and cardiovascular events among elderly persons". N. Engl. J. Med. 352 (20): 2049–2060. doi:10.1056/NEJMoa043161. PMID 15901858.
- ↑ Ix JH, Shlipak MG, Chertow GM, Whooley MA (January 2007). "Association of cystatin C with mortality, cardiovascular events, and incident heart failure among persons with coronary heart disease: data from the Heart and Soul Study". Circulation. 115 (2): 173–179. doi:10.1161/CIRCULATIONAHA.106.644286. PMC 2771187. PMID 17190862.
- ↑ Deo R, Fyr CL, Fried LF, et al. (January 2008). "Kidney dysfunction and fatal cardiovascular disease--an association independent of atherosclerotic events: results from the Health, Aging, and Body Composition (Health ABC) study". Am. Heart J. 155 (1): 62–68. doi:10.1016/j.ahj.2007.08.012. PMID 18082491.
- ↑ Koenig W, Twardella D, Brenner H, Rothenbacher D (February 2005). "Plasma concentrations of cystatin C in patients with coronary heart disease and risk for secondary cardiovascular events: more than simply a marker of glomerular filtration rate". Clin. Chem. 51 (2): 321–327. doi:10.1373/clinchem.2004.041889. PMID 15563478.
- ↑ Jernberg T, Lindahl B, James S, Larsson A, Hansson LO, Wallentin L (October 2004). "Cystatin C: a novel predictor of outcome in suspected or confirmed non-ST-elevation acute coronary syndrome". Circulation. 110 (16): 2342–2348. doi:10.1161/01.CIR.0000145166.44942.E0. PMID 15477399.
- ↑ Luc G, Bard JM, Lesueur C, et al. (April 2006). "Plasma cystatin-C and development of coronary heart disease: The PRIME Study". Atherosclerosis. 185 (2): 375–380. doi:10.1016/j.atherosclerosis.2005.06.017. PMID 16046222.
- ↑ Servais A, Giral P, Bernard M, Bruckert E, Deray G, Isnard Bagnis C (May 2008). "Is serum cystatin-C a reliable marker for metabolic syndrome?". Am. J. Med. 121 (5): 426–432. doi:10.1016/j.amjmed.2008.01.040. PMID 18456039.
- ↑ Menon V, Shlipak MG, Wang X, et al. (July 2007). "Cystatin C as a risk factor for outcomes in chronic kidney disease". Annals of Internal Medicine. 147 (1): 19–27. doi:10.7326/0003-4819-147-1-200707030-00004. PMID 17606957.
- ↑ Sarnak MJ, Katz R, Fried LF, et al. (January 2008). "Cystatin C and aging success". Arch. Intern. Med. 168 (2): 147–153. doi:10.1001/archinternmed.2007.40. PMC 2871318. PMID 18227360.[permanent dead link]
- ↑ Djoussé L, Kurth T, Gaziano JM (January 2008). "Cystatin C and risk of heart failure in the Physicians' Health Study (PHS)". Am. Heart J. 155 (1): 82–86. doi:10.1016/j.ahj.2007.08.023. PMC 2179893. PMID 18082494.
- ↑ O'Hare AM, Newman AB, Katz R, et al. (2005). "Cystatin C and incident peripheral arterial disease events in the elderly: results from the Cardiovascular Health Study". Arch. Intern. Med. 165 (22): 2666–2670. doi:10.1001/archinte.165.22.2666. PMID 16344426.[permanent dead link]
- ↑ Stevens LA, Levey AS (May 2005). "Chronic kidney disease in the elderly--how to assess risk". N. Engl. J. Med. 352 (20): 2122–2124. doi:10.1056/NEJMe058035. PMID 15901867.
- ↑ Delanaye P, Cavalier E, Krzesinski JM (February 2008). "Cystatin C, renal function, and cardiovascular risk". Annals of Internal Medicine. 148 (4): 323. doi:10.7326/0003-4819-148-4-200802190-00023. PMID 18283218.
- ↑ Levy E, Lopez-Otin C, Ghiso J, Geltner D, Frangione B (May 1989). "Stroke in Icelandic patients with hereditary amyloid angiopathy is related to a mutation in the cystatin C gene, an inhibitor of cysteine proteases". J. Exp. Med. 169 (5): 1771–1778. doi:10.1084/jem.169.5.1771. PMC 2189307. PMID 2541223.
- ↑ Levy E, Jaskolski M, Grubb A (January 2006). "The role of cystatin C in cerebral amyloid angiopathy and stroke: cell biology and animal models". Brain Pathol. 16 (1): 60–70. doi:10.1111/j.1750-3639.2006.tb00562.x. PMID 16612983.
- ↑ Mi W, Pawlik M, Sastre M, et al. (December 2007). "Cystatin C inhibits amyloid-beta deposition in Alzheimer's disease mouse models". Nat. Genet. 39 (12): 1440–1442. doi:10.1038/ng.2007.29. PMID 18026100.
- ↑ Kaeser SA, Herzig MC, Coomaraswamy J, et al. (December 2007). "Cystatin C modulates cerebral beta-amyloidosis". Nat. Genet. 39 (12): 1437–1439. doi:10.1038/ng.2007.23. PMID 18026102.
- ↑ Bertram L, McQueen MB, Mullin K, Blacker D, Tanzi RE (January 2007). "Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database". Nat. Genet. 39 (1): 17–23. doi:10.1038/ng1934. PMID 17192785.
- ↑ Chuo LJ, Sheu WH, Pai MC, Kuo YM (2007). "Genotype and plasma concentration of cystatin C in patients with late-onset Alzheimer disease". Dement Geriatr Cogn Disord. 23 (4): 251–257. doi:10.1159/000100021. PMID 17310123.
- ↑ Del Boccio P, Pieragostino D, Lugaresi A, et al. (August 2007). "Cleavage of cystatin C is not associated with multiple sclerosis". Annals of Neurology. 62 (2): 201–204. doi:10.1002/ana.20968. PMID 17006926.
- ↑ Shi GP, Sukhova GK, Grubb A, et al. (November 1999). "Cystatin C deficiency in human atherosclerosis and aortic aneurysms" (PDF). J. Clin. Invest. 104 (9): 1191–1197. doi:10.1172/JCI7709. PMC 409823. PMID 10545518.
- ↑ Abisi S, Burnand KG, Waltham M, Humphries J, Taylor PR, Smith A (December 2007). "Cysteine protease activity in the wall of abdominal aortic aneurysms". J. Vasc. Surg. 46 (6): 1260–1266. doi:10.1016/j.jvs.2007.08.015. PMID 18155003.
- ↑ Abdul-Hussien H, Soekhoe RG, Weber E, et al. (March 2007). "Collagen degradation in the abdominal aneurysm: a conspiracy of matrix metalloproteinase and cysteine collagenases" (– Scholar search). Am. J. Pathol. 170 (3): 809–817. doi:10.2353/ajpath.2007.060522. PMC 1864891. PMID 17322367.[dead link]
- ↑ Gacko M, Chyczewski L, Chrostek L (1999). "Distribution, activity and concentration of cathepsin B and cystatin C in the wall of aortic aneurysm". Pol J Pathol. 50 (2): 83–6. PMID 10481531.
- ↑ Eriksson P, Jones KG, Brown LC, Greenhalgh RM, Hamsten A, Powell JT (January 2004). "Genetic approach to the role of cysteine proteases in the expansion of abdominal aortic aneurysms". Br J Surg. 91 (1): 86–89. doi:10.1002/bjs.4364. PMID 14716800.
- ↑ Lindholt JS, Erlandsen EJ, Henneberg EW (November 2001). "Cystatin C deficiency is associated with the progression of small abdominal aortic aneurysms". Br J Surg. 88 (11): 1472–1475. doi:10.1046/j.0007-1323.2001.01911.x. PMID 11683743.
- ↑ Zurdel J, Finckh U, Menzer G, Nitsch RM, Richard G (February 2002). "CST3 genotype associated with exudative age related macular degeneration". Br J Ophthalmol. 86 (2): 214–219. doi:10.1136/bjo.86.2.214. PMC 1771004. PMID 11815350.
- ↑ Im E, Kazlauskas A (March 2007). "The role of cathepsins in ocular physiology and pathology". Exp. Eye Res. 84 (3): 383–388. doi:10.1016/j.exer.2006.05.017. PMID 16893541.
- ↑ Strojan P, Oblak I, Svetic B, Smid L, Kos J (May 2004). "Cysteine proteinase inhibitor cystatin C in squamous cell carcinoma of the head and neck: relation to prognosis". Br. J. Cancer. 90 (10): 1961–1968. doi:10.1038/sj.bjc.6601830. PMC 2409457. PMID 15138478.
- ↑ Kos J, Krasovec M, Cimerman N, Nielsen HJ, Christensen IJ, Brünner N (February 2000). "Cysteine proteinase inhibitors stefin A, stefin B, and cystatin C in sera from patients with colorectal cancer: relation to prognosis". Clin. Cancer Res. 6 (2): 505–11. PMID 10690531.
- ↑ Strevens H, Wide-Swensson D, Grubb A, et al. (September 2003). "Serum cystatin C reflects glomerular endotheliosis in normal, hypertensive and pre-eclamptic pregnancies". BJOG. 110 (9): 825–830. doi:10.1111/j.1471-0528.2003.02051.x. PMID 14511964.
- ↑ Franceschini N, Qiu C, Barrow DA, Williams MA (2008). "Cystatin C and preeclampsia: a case control study". Ren Fail. 30 (1): 89–95. doi:10.1080/08860220701742229. PMID 18197549.
- ↑ Kristensen K, Wide-Swensson D, Schmidt C, et al. (2007). "Cystatin C, beta-2-microglobulin and beta-trace protein in pre-eclampsia". Acta Obstet Gynecol Scand. 86 (8): 921–926. doi:10.1080/00016340701318133. PMID 17653875.
- ↑ Kristensen K, Larsson I, Hansson SR (March 2007). "Increased cystatin C expression in the pre-eclamptic placenta". Mol. Hum. Reprod. 13 (3): 189–195*. doi:10.1093/molehr/gal111. PMID 17227816.
- ↑ Jump up to: 69.0 69.1 Croda-Todd MT, Soto-Montano XJ, Hernández-Cancino PA, Juárez-Aguilar E (September 2007). "Adult cystatin C reference intervals determined by nephelometric immunoassay". Clin. Biochem. 40 (13–14): 1084–1087. doi:10.1016/j.clinbiochem.2007.05.011. PMID 17624320.
- ↑ Lamb EJ, O'Riordan SE, Webb MC, Newman DJ (November 2003). "Serum cystatin C may be a better marker of renal impairment than creatinine". J Am Geriatr Soc. 51 (11): 1674–1675. doi:10.1046/j.1532-5415.2003.515244.x. PMID 14687406.
- ↑ Peake M, Whiting M (November 2006). "Measurement of serum creatinine - current status and future goals". Clin Biochem Rev. 27 (4): 173–84. PMC 1784008. PMID 17581641.
- ↑ Myers GL, Miller WG, Coresh J, et al. (January 2006). "Recommendations for improving serum creatinine measurement: a report from the Laboratory Working Group of the National Kidney Disease Education Program". Clin. Chem. 52 (1): 5–18. doi:10.1373/clinchem.2005.0525144. PMID 16332993.
- ↑ Jump up to: 73.0 73.1 73.2 Köttgen A, Selvin E, Stevens LA, Levey AS, Van Lente F, Coresh J (March 2008). "Serum cystatin C in the United States: the Third National Health and Nutrition Examination Survey (NHANES III)". Am. J. Kidney Dis. 51 (3): 385–394. doi:10.1053/j.ajkd.2007.11.019. PMID 18295054.
- ↑ Jump up to: 74.0 74.1 Finney H, Newman DJ, Thakkar H, Fell JM, Price CP (January 2000). "Reference ranges for plasma cystatin C and creatinine measurements in premature infants, neonates, and older children". Arch. Dis. Child. 82 (1): 71–75. doi:10.1136/adc.82.1.71. PMC 1718178. PMID 10630919.
- ↑ Ognibene A, Mannucci E, Caldini A, et al. (June 2006). "Cystatin C reference values and aging". Clin. Biochem. 39 (6): 658–661. doi:10.1016/j.clinbiochem.2006.03.017. PMID 16730690.
- ↑ Filler G, Bökenkamp A, Hofmann W, Le Bricon T, Martínez-Brú C, Grubb A (January 2005). "Cystatin C as a marker of GFR--history, indications, and future research". Clin. Biochem. 38 (1): 1–8. doi:10.1016/j.clinbiochem.2004.09.025. PMID 15607309.
- ↑ Shlipak MG (March 2008). "Cystatin C: research priorities targeted to clinical decision making". Am. J. Kidney Dis. 51 (3): 358–361. doi:10.1053/j.ajkd.2008.01.002. PMID 18295049.
- ↑ Muntner P, Winston J, Uribarri J, Mann D, Fox CS (April 2008). "Overweight, obesity, and elevated serum cystatin C levels in adults in the United States". Am. J. Med. 121 (4): 341–348. doi:10.1016/j.amjmed.2008.01.003. PMC 3049932. PMID 18374694.
- ↑ "Entrez Gene: CST3 cystatin C (amyloid angiopathy and cerebral hemorrhage)".
- ↑ Hwang SJ, Yang Q, Meigs JB, Pearce EN, Fox CS (2007). "A genome-wide association for kidney function and endocrine-related traits in the NHLBI's Framingham Heart Study". BMC Med. Genet. 8 Suppl 1: S10. doi:10.1186/1471-2350-8-S1-S10. PMC 1995611. PMID 17903292. Archived from the original on 2008-06-12.
- ↑ Janowski R, Kozak M, Jankowska E, et al. (April 2001). "Human cystatin C, an amyloidogenic protein, dimerizes through three-dimensional domain swapping". Nature Structural & Molecular Biology. 8 (4): 316–320. doi:10.1038/86188. PMID 11276250.
- ↑ Jump up to: 82.0 82.1 Grubb A, Löfberg H (May 1982). "Human gamma-trace, a basic microprotein: amino acid sequence and presence in the adenohypophysis". Proc. Natl. Acad. Sci. U.S.A. 79 (9): 3024–3027. doi:10.1073/pnas.79.9.3024. PMC 346341. PMID 6283552.
- ↑ Löfberg H, Grubb AO (November 1979). "Quantitation of gamma-trace in human biological fluids: indications for production in the central nervous system". Scand. J. Clin. Lab. Invest. 39 (7): 619–626. doi:10.3109/00365517909108866. PMID 119302.
- ↑ Grubb A, Simonsen O, Sturfelt G, Truedsson L, Thysell H (1985). "Serum concentration of cystatin C, factor D and beta 2-microglobulin as a measure of glomerular filtration rate". Acta Med Scand. 218 (5): 499–503. doi:10.1111/j.0954-6820.1985.tb08880.x. PMID 3911736.
- ↑ Simonsen O, Grubb A, Thysell H (April 1985). "The blood serum concentration of cystatin C (gamma-trace) as a measure of the glomerular filtration rate". Scand. J. Clin. Lab. Invest. 45 (2): 97–101. doi:10.3109/00365518509160980. PMID 3923607.
- ↑ Shlipak MG, Matsushita K, Ärnlöv J, Inker LA, Katz R, Polkinghorne KR, Rothenbacher D, Sarnak MJ, Astor BC, Coresh J, Levey AS, Gansevoort RT (2013). "Cystatin C versus creatinine in determining risk based on kidney function". NEJM. 369: 932–943. doi:10.1056/NEJMoa1214234. PMC 3993094. PMID 24004120.
# External links
- Cystatin: a protein that flips out! QUite Interesting PDB Structure article at PDBe
- The MEROPS online database for peptidases and their inhibitors: I25.004 | https://www.wikidoc.org/index.php/Cystatin_C | |
adfc48e16d9b08c33bfc227e2e5008d23e9cf36e | wikidoc | Cystectomy | Cystectomy
# Overview
Cystectomy is a medical term for surgical removal of all or part of the urinary bladder. It may also be rarely used to refer to the removal of a cyst, or the gallbladder. The most common condition warranting removal of the urinary bladder is bladder cancer. After the bladder has been removed, an Ileal conduit urinary diversion is necessary. An alternative to this method is to construct a pouch from a section of ileum or colon, which can act as a form of replacement bladder, storing urine until the patient desires to release it, which can be achieved by either abdominal straining or self catherisation.
Future treatment for this condition may involve a full replacement with an artificial bladder.
One of the follow-up solutions to a cystectomy is the creation of a neobladder (one form of which is named Studer's Ileal Neobladder or the Studer Pouch). A neobladder is a loop of intestine that is surgically fashioned into a pouch and placed in the location of the original bladder. It is then attached to the ureters and the urethra, thus simulating the function of the original organ. The kidneys filter the urine into the neobladder which can often be emptied by muscle control. There are side effects of this complex surgery, including partial shut down of the digestive system (in response to removal of the piece of intestine), incontinence, and the loss of the nerves that signal a full bladder. | Cystectomy
Template:Interventions infobox
# Overview
Cystectomy is a medical term for surgical removal of all or part of the urinary bladder. It may also be rarely used to refer to the removal of a cyst, or the gallbladder. The most common condition warranting removal of the urinary bladder is bladder cancer. After the bladder has been removed, an Ileal conduit urinary diversion is necessary. An alternative to this method is to construct a pouch from a section of ileum or colon, which can act as a form of replacement bladder, storing urine until the patient desires to release it, which can be achieved by either abdominal straining or self catherisation.
Future treatment for this condition may involve a full replacement with an artificial bladder.
One of the follow-up solutions to a cystectomy is the creation of a neobladder (one form of which is named Studer's Ileal Neobladder or the Studer Pouch). A neobladder is a loop of intestine that is surgically fashioned into a pouch and placed in the location of the original bladder. It is then attached to the ureters and the urethra, thus simulating the function of the original organ. The kidneys filter the urine into the neobladder which can often be emptied by muscle control. There are side effects of this complex surgery, including partial shut down of the digestive system (in response to removal of the piece of intestine), incontinence, and the loss of the nerves that signal a full bladder.
# External links
- http://blcwebcafe.org/cystectomy.asp
- http://cancer.stanfordhospital.com/forPatients/services/surgery/neobladderReconstruct/default
- http://www.jco.org/cgi/content/full/21/4/690
- Ovarian Cyst Support Group
Template:Urogenital surgical procedures
de:Zystektomie
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Cystectomy | |
c952b1a954b88fae18dd32dc158dbc3f5cf63d81 | wikidoc | Cystinuria | Cystinuria
# Overview
Cystinuria is an inherited autosomal recessive disorder and is characterized by the formation of cystine stones in the kidneys, ureter, and bladder.
Newfoundland dogs are at an increased risk for cystinuria, compared with other breeds of dogs.
# Historical Perspective
# Classification
Cystinuria is characterized by the inadequate reabsorption of cystine during the filtering process in the kidneys, thus resulting in an excessive concentration of this amino acid. Cystine will precipitate out of the urine, if the urine is neutral or acidic, and form crystals or stones in the kidneys, ureters, or bladder.
Mutations in the SLC3A1 and SLC7A9 genes cause cystinuria. The SLC3A1 and SLC7A9 genes provide instructions for producing the two parts of a transporter protein that is made primarily in the kidneys. These defects prevent proper reabsorption of basic, or positively charged amino acids such as histidine, lysine, ornithine, arginine and cystine. Normally this protein allows certain amino acids, including cystine, to be reabsorbed into the blood from the filtered fluid that will become urine. Mutations in either of these genes disrupt the ability of this transporter protein to reabsorb these amino acids, allowing them to become concentrated in the urine. As the levels of cystine in the urine increase, the crystals typical of cystinuria are able to form, resulting in kidney stones. Cystine crystals form hexagonal-shaped crystals which can be viewed upon microscopic analysis of the urine. The other amino acids that are not reabsorbed do not create crystals in urine. The disorder affects 1 in 10,000 people and is inherited in an autosomal recessive pattern.
# Pathophysiology
# Causes
# Differentiating Cystinuria from Other Diseases
# Epidemiology and Demographics
# Risk Factors
# Screening
# Natural History, Complications, and Prognosis
## Natural History
## Complications
## Prognosis
# Diagnosis
## Diagnostic Criteria
## History and Symptoms
## Physical Examination
## Laboratory Findings
## Imaging Findings
## Other Diagnostic Studies
# Treatment
## Medical Therapy
## Surgery
## Prevention | Cystinuria
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Cystinuria is an inherited autosomal recessive disorder and is characterized by the formation of cystine stones in the kidneys, ureter, and bladder.
Newfoundland dogs are at an increased risk for cystinuria, compared with other breeds of dogs.
# Historical Perspective
# Classification
Cystinuria is characterized by the inadequate reabsorption of cystine during the filtering process in the kidneys, thus resulting in an excessive concentration of this amino acid. Cystine will precipitate out of the urine, if the urine is neutral or acidic, and form crystals or stones in the kidneys, ureters, or bladder.
Mutations in the SLC3A1 and SLC7A9 genes cause cystinuria. The SLC3A1 and SLC7A9 genes provide instructions for producing the two parts of a transporter protein that is made primarily in the kidneys. These defects prevent proper reabsorption of basic, or positively charged amino acids such as histidine, lysine, ornithine, arginine and cystine.[1] Normally this protein allows certain amino acids, including cystine, to be reabsorbed into the blood from the filtered fluid that will become urine. Mutations in either of these genes disrupt the ability of this transporter protein to reabsorb these amino acids, allowing them to become concentrated in the urine. As the levels of cystine in the urine increase, the crystals typical of cystinuria are able to form, resulting in kidney stones. Cystine crystals form hexagonal-shaped crystals which can be viewed upon microscopic analysis of the urine. The other amino acids that are not reabsorbed do not create crystals in urine. The disorder affects 1 in 10,000 people and is inherited in an autosomal recessive pattern.
# Pathophysiology
# Causes
# Differentiating Cystinuria from Other Diseases
# Epidemiology and Demographics
# Risk Factors
# Screening
# Natural History, Complications, and Prognosis
## Natural History
## Complications
## Prognosis
# Diagnosis
## Diagnostic Criteria
## History and Symptoms
## Physical Examination
## Laboratory Findings
## Imaging Findings
## Other Diagnostic Studies
# Treatment
## Medical Therapy
## Surgery
## Prevention | https://www.wikidoc.org/index.php/Cystinuria | |
b6bbf9b244718e2aadafdfb22cb81e37c22476c1 | wikidoc | Cystometry | Cystometry
Cystometry, also known as flow cystometry, is a clinical diagnostic procedure used to evaluate bladder function. Specifically, it measures contractile force of the bladder when voiding. The resulting chart generated from cystometric analysis is known as a cystometrogram (CMG), which plots volume of liquid emptied from bladder against intravesical pressure.
# Use
Cystometric analysis is used to evaluate the bladder's capacity to contract and expel urine. It helps determine the source of urinary problems. A normal CMG effectively rules out primary vesical dysfunction. It is used as a component for diagnosis of various disorders including urinary tract infections, multiple sclerosis, stroke, spinal cord injury, urethral obstruction, and overactive bladder, among others.
# Procedure
The procedure is relatively short, ranging from fifteen minutes to an hour in duration. It involves the insertion of one or two catheters into an emptied bladder through the urethra. In the two catheter method, one catheter transfers liquid while the other is a manometer (pressure sensor). In the single catheter method, a specialized catheter performs both functions. An additional rectal catheter may also be placed for additional data. The bladder will then be filled with saline and the patient's awareness of the event will be queried. The patient will often be asked to note when presence of liquid is felt, when the bladder feels full, and when the urgency to void is felt. The patient is then asked to void, and both flow and pressure are recorded. These are plotted against each other to create the cystometrogram.
# Results
The primary results of cystometric analysis is the cystometrogram. The x-axis is the volume of liquid and the y-axis is the intraluminal pressure of the bladder. In normal patients, the plot is a series of spikes whose local minimums form a non-linear curve resembling an exponential growth curve. The spikes correspond to the bladder contractions associated with the micturation reflex. The curve formed by the bottom of the plot reflects the level of pressure necessary to void. In normal patients, the first couple hundred milliliters of urine flow with minimal applied pressure. Increasing pressure is necessary to void 200-300 millileters of urine. Beyond that, the pressure necessary to void additional urine rises sharply.
# Risks & Contraindications
As with any catheterization, the primary risk is of urinary tract infection. As a result, the procedure is contraindicated in any patient with an active UTI because the results may be skewed and the infection may spread.
There is also the potential for trauma to the bladder and urethtra, which may result in hematuria (blood in the urine). | Cystometry
Cystometry, also known as flow cystometry, is a clinical diagnostic procedure used to evaluate bladder function. Specifically, it measures contractile force of the bladder when voiding. The resulting chart generated from cystometric analysis is known as a cystometrogram (CMG), which plots volume of liquid emptied from bladder against intravesical pressure.
# Use
Cystometric analysis is used to evaluate the bladder's capacity to contract and expel urine. It helps determine the source of urinary problems. A normal CMG effectively rules out primary vesical dysfunction. It is used as a component for diagnosis of various disorders including urinary tract infections, multiple sclerosis, stroke, spinal cord injury, urethral obstruction, and overactive bladder, among others.[1]
# Procedure
The procedure is relatively short, ranging from fifteen minutes[2] to an hour in duration.[3] It involves the insertion of one or two catheters into an emptied bladder through the urethra. In the two catheter method, one catheter transfers liquid while the other is a manometer (pressure sensor).[4] In the single catheter method, a specialized catheter performs both functions. An additional rectal catheter may also be placed for additional data. The bladder will then be filled with saline and the patient's awareness of the event will be queried. The patient will often be asked to note when presence of liquid is felt, when the bladder feels full, and when the urgency to void is felt. The patient is then asked to void, and both flow and pressure are recorded.[3] These are plotted against each other to create the cystometrogram.
# Results
The primary results of cystometric analysis is the cystometrogram. The x-axis is the volume of liquid and the y-axis is the intraluminal pressure of the bladder. In normal patients, the plot is a series of spikes whose local minimums form a non-linear curve resembling an exponential growth curve. The spikes correspond to the bladder contractions associated with the micturation reflex. The curve formed by the bottom of the plot reflects the level of pressure necessary to void. In normal patients, the first couple hundred milliliters of urine flow with minimal applied pressure. Increasing pressure is necessary to void 200-300 millileters of urine. Beyond that, the pressure necessary to void additional urine rises sharply.[5]
# Risks & Contraindications
As with any catheterization, the primary risk is of urinary tract infection. As a result, the procedure is contraindicated in any patient with an active UTI because the results may be skewed and the infection may spread.
There is also the potential for trauma to the bladder and urethtra, which may result in hematuria (blood in the urine).[1] | https://www.wikidoc.org/index.php/Cystometry | |
05b891f9afcbff2aebe8672a181efbfffa677bee | wikidoc | Cystoscopy | Cystoscopy
Steven C. Campbell, M.D., Ph.D.
# Overview
Endoscopy of the urinary bladder via the urethra is called cystoscopy. Diagnostic cystoscopy is usually carried out with local anaesthesia. General anaesthesia is sometimes used for operative cystoscopic procedures.
When a patient has a urinary problem, the doctor may use a cystoscope to see the inside of the bladder and urethra.
The urethra is the tube that carries urine from the bladder to the outside of the body.
The cystoscope has lenses like a telescope or microscope. These lenses let the doctor focus on the inner surfaces of the urinary tract. Some cystoscopes use optical fibres (flexible glass fibres) that carry an image from the tip of the instrument to a viewing piece at the other end. The cystoscope is as thick as a pencil and has a light at the tip. Many cystoscopes have extra tubes to guide other instruments for surgical procedures to treat urinary problems.
There are two main types of cystoscopy - flexible and rigid - differing in the flexibility of the cystoscope. Flexible cystoscopy is carried out using local anaesthesia on both sexes. Typically, lidocaine gel (such as the brand name Instillagel) is used as an anaesthetic, instilled in the urethra. Rigid cystoscopy can be performed under the same conditions, but is generally carried out under general anaesthesia, particularly in male subjects, due to the pain caused by the probe.
A doctor may recommend cystoscopy for any of the following conditions:
- Interstitial Cystitis
- Frequent urinary tract infections
- Blood in the urine (hematuria)
- Loss of bladder control (incontinence) or overactive bladder
- Unusual cells found in urine sample
- Need for a bladder catheter
- Painful urination, chronic pelvic pain, or interstitial cystitis
- Urinary blockage such as from prostate enlargement, stricture, or narrowing of the urinary tract
- Stone in the urinary tract
- Unusual growth, polyp, tumor, or cancer
# Male and female urinary tracts
If a patient has a stone lodged higher in the urinary tract, the doctor may use a much finer calibre scope called a ureteroscope through the bladder and up into the ureter.
(The ureter is the tube that carries urine from the kidney to the bladder).
The doctor can then see the stone and remove it with a small basket at the end of a wire which is inserted through an extra tube in the ureteroscope.
For larger stones, the doctor may also use the extra tube in the ureteroscope to extend a flexible fiber that carries a laser beam to break the stone into smaller pieces that can then pass out of the body in the urine.
# Test Procedures
Doctors may have special instructions, but in most cases, patients are able to eat normally and return to normal activities after the test.
Patients are sometimes asked to give a urine sample before the test to check for infection.
These patients should avoid urinating for an hour before this part of the test.
Patients will have to remove their clothing covering the lower part of the body, although some doctors may prefer if the patient wears a hospital gown for the examination and covers the lower part of the body with a sterile drape.
In most cases, patients lie on their backs with their knees slightly parted. Occasionally, a patient may also need to have their knees raised.
A doctor, nurse or technician will clean the area around the urethral opening and apply a local anesthetic.
Patients receiving a ureteroscopy may receive a spinal or general anaesthetic.
The doctor will gently insert the tip of the cystoscope into the urethra and slowly glide it up into the bladder. Men will likely feel a couple of pinches as the scope passes through the prostate into the bladder.
Relaxing the pelvic muscles helps make this part of the test easier.
A sterile liquid (water, saline, or glycine solution) will flow through the cystoscope to slowly fill the bladder and stretch it so that the doctor has a better view of the bladder wall.
As the bladder reaches capacity, patients typically feel some mild discomfort and the urge to urinate.
The time from insertion of the cystoscope to removal may be only a few minutes, or it may be longer if the doctor finds a stone and decides to remove it.
Taking a biopsy (a small tissue sample for examination under a microscope) will also make the procedure last longer. In most cases, the entire examination, including preparation, will take about 15 to 20 minutes.
After the test, patients often have some burning feeling when they urinate and often see small amounts of blood in their urine. Occasionally, patients may feel some lower abdominal pains, reflecting bladder muscle spasms, but these are not common.
Common prescriptions to relieve discomfort after the test include:
- Drink 32 fluid ounces (1 L) of water over 2 hours.
- Ask your doctor if you can take a warm bath to relieve the burning feeling.
- Hold a warm, damp washcloth over the urethral opening.
Some doctors will prescribe an antibiotic to take for 1 or 2 days to prevent an infection.
However, recent trends have been to discourage this kind of prophylactic treatment (prescribing antibiotics as a preventative when there is no other evidence of infection) because it tends to increase the rate at which bacteria develop resistance to the antibiotic drug.
(If you have signs of infection - including pain, chills or fever - call your doctor.) | Cystoscopy
Template:Search infobox
Steven C. Campbell, M.D., Ph.D.
# Overview
Endoscopy of the urinary bladder via the urethra is called cystoscopy. Diagnostic cystoscopy is usually carried out with local anaesthesia. General anaesthesia is sometimes used for operative cystoscopic procedures.
When a patient has a urinary problem, the doctor may use a cystoscope to see the inside of the bladder and urethra.
The urethra is the tube that carries urine from the bladder to the outside of the body.
The cystoscope has lenses like a telescope or microscope. These lenses let the doctor focus on the inner surfaces of the urinary tract. Some cystoscopes use optical fibres (flexible glass fibres) that carry an image from the tip of the instrument to a viewing piece at the other end. The cystoscope is as thick as a pencil and has a light at the tip. Many cystoscopes have extra tubes to guide other instruments for surgical procedures to treat urinary problems.
There are two main types of cystoscopy - flexible and rigid - differing in the flexibility of the cystoscope. Flexible cystoscopy is carried out using local anaesthesia on both sexes. Typically, lidocaine gel (such as the brand name Instillagel) is used as an anaesthetic, instilled in the urethra. Rigid cystoscopy can be performed under the same conditions, but is generally carried out under general anaesthesia, particularly in male subjects, due to the pain caused by the probe.
A doctor may recommend cystoscopy for any of the following conditions:
- Interstitial Cystitis
- Frequent urinary tract infections
- Blood in the urine (hematuria)
- Loss of bladder control (incontinence) or overactive bladder
- Unusual cells found in urine sample
- Need for a bladder catheter
- Painful urination, chronic pelvic pain, or interstitial cystitis
- Urinary blockage such as from prostate enlargement, stricture, or narrowing of the urinary tract
- Stone in the urinary tract
- Unusual growth, polyp, tumor, or cancer
# Male and female urinary tracts
If a patient has a stone lodged higher in the urinary tract, the doctor may use a much finer calibre scope called a ureteroscope through the bladder and up into the ureter.
(The ureter is the tube that carries urine from the kidney to the bladder).
The doctor can then see the stone and remove it with a small basket at the end of a wire which is inserted through an extra tube in the ureteroscope.
For larger stones, the doctor may also use the extra tube in the ureteroscope to extend a flexible fiber that carries a laser beam to break the stone into smaller pieces that can then pass out of the body in the urine.
# Test Procedures
Doctors may have special instructions, but in most cases, patients are able to eat normally and return to normal activities after the test.
Patients are sometimes asked to give a urine sample before the test to check for infection.
These patients should avoid urinating for an hour before this part of the test.
Patients will have to remove their clothing covering the lower part of the body, although some doctors may prefer if the patient wears a hospital gown for the examination and covers the lower part of the body with a sterile drape.
In most cases, patients lie on their backs with their knees slightly parted. Occasionally, a patient may also need to have their knees raised.
A doctor, nurse or technician will clean the area around the urethral opening and apply a local anesthetic.
Patients receiving a ureteroscopy may receive a spinal or general anaesthetic.
The doctor will gently insert the tip of the cystoscope into the urethra and slowly glide it up into the bladder. Men will likely feel a couple of pinches as the scope passes through the prostate into the bladder.
Relaxing the pelvic muscles helps make this part of the test easier.
A sterile liquid (water, saline, or glycine solution) will flow through the cystoscope to slowly fill the bladder and stretch it so that the doctor has a better view of the bladder wall.
As the bladder reaches capacity, patients typically feel some mild discomfort and the urge to urinate.
The time from insertion of the cystoscope to removal may be only a few minutes, or it may be longer if the doctor finds a stone and decides to remove it.
Taking a biopsy (a small tissue sample for examination under a microscope) will also make the procedure last longer. In most cases, the entire examination, including preparation, will take about 15 to 20 minutes.
After the test, patients often have some burning feeling when they urinate and often see small amounts of blood in their urine. Occasionally, patients may feel some lower abdominal pains, reflecting bladder muscle spasms, but these are not common.
Common prescriptions to relieve discomfort after the test include:
- Drink 32 fluid ounces (1 L) of water over 2 hours.
- Ask your doctor if you can take a warm bath to relieve the burning feeling.
- Hold a warm, damp washcloth over the urethral opening.
Some doctors will prescribe an antibiotic to take for 1 or 2 days to prevent an infection.
However, recent trends have been to discourage this kind of prophylactic treatment (prescribing antibiotics as a preventative when there is no other evidence of infection) because it tends to increase the rate at which bacteria develop resistance to the antibiotic drug.
(If you have signs of infection - including pain, chills or fever - call your doctor.)
# External links and references
- Cystoscopy and Ureteroscopy on the National Institute of Diabetes and Digestive and Kidney Diseases website
An earlier version of this article was adapted from the public domain NIH Publication No. 01-4800, at http://www.niddk.nih.gov/health/kidney/pubs/cystoscopy/cystoscopy.htm which says, "This e-text is not copyrighted. The clearinghouse encourages users of this e-pub to duplicate and distribute as many copies as desired."
Template:Urogenital surgical procedures
de:Zystoskopie
nl:Cystoscopie
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Cystoscope | |
9063bad50c05316f89bf8b4e83060c4a6d3c6fbe | wikidoc | Cystovirus | Cystovirus
# Overview
Cystovirus is a genus of dsRNA virus, which infect certain Gram negative bacteria.
# Characteristics
All cystoviruses are distinguished by their three strands (analogous to chromosomes) of dsRNA, totalling ~14 kb in length and their protein and lipid outer layer. No other bacteriophage have any lipid in their outer coat, though the Tectiviridae and the Corticoviridae have lipids within their capsids.
Most identified cystoviruses infect Pseudomonas species, but this is likely biased due to the method of screening and enrichment . The type species is Pseudomonas phage Φ6, but there are many other members of this family. Φ7, Φ8, Φ9, Φ10, Φ11, Φ12 and Φ13 have been identified and named , but other cystoviruses have also been isolated .
Members of the Cystoviridae appear to be most closely related to the Reoviridae , but also share homology with the Totiviridae. Cystoviruses are the only bacteriophage that are more closely related to viruses of eukaryotes than to other phage. | Cystovirus
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Cystovirus is a genus of dsRNA virus, which infect certain Gram negative bacteria.
# Characteristics
All cystoviruses are distinguished by their three strands (analogous to chromosomes) of dsRNA, totalling ~14 kb in length and their protein and lipid outer layer. No other bacteriophage have any lipid in their outer coat, though the Tectiviridae and the Corticoviridae have lipids within their capsids.
Most identified cystoviruses infect Pseudomonas species, but this is likely biased due to the method of screening and enrichment [1]. The type species is Pseudomonas phage Φ6, but there are many other members of this family. Φ7, Φ8, Φ9, Φ10, Φ11, Φ12 and Φ13 have been identified and named [2], but other cystoviruses have also been isolated [1].
Members of the Cystoviridae appear to be most closely related to the Reoviridae [3], but also share homology with the Totiviridae. Cystoviruses are the only bacteriophage that are more closely related to viruses of eukaryotes than to other phage. | https://www.wikidoc.org/index.php/Cystoviridae | |
3a914227592c21b490f2c3d8e2fc633d9dbf48ac | wikidoc | Cytochrome | Cytochrome
# Overview
Cytochromes are generally membrane-bound hemoproteins that contain heme groups and carry out electron transport.
They are either found as monomeric proteins (i.e. cytochrome c) or as subunits of bigger enzymatic complexes that catalyze redox reactions. They are found in the mitochondrial inner membrane and endoplasmic reticulum of eukaryotes, in the chloroplasts of plants, in photosynthetic microorganisms, and in bacteria.
# Structure and function
The heme group is a highly conjugated ring system (which means its electrons are very mobile) surrounding a metal ion, which readily interconverts between the oxidation states. For many cytochromes the metal ion present is that of iron, which interconverts between Fe2+ (reduced) and Fe3+ (oxidized) states (electron-transfer processes) or between Fe2+ (reduced) and Fe3+ (formal, oxidized) states (oxidative processes). Cytochromes are thus capable of performing oxidation and reduction. Because the cytochromes (as well as other complexes) are held within membranes in an organized way, the redox reactions are carried out in the proper sequence for maximum efficiency.
In the process of oxidative phosphorylation, which is the principal energy-generating process undertaken by organisms which need oxygen to survive, other membrane-bound and soluble complexes and cofactors are involved in the chain of redox reactions, with the additional net effect that protons (H+) are transported across the mitochondrial inner membrane. The resulting transmembrane proton gradient is used to generate ATP, which is the universal chemical energy currency of life. ATP is consumed to drive cellular processes that require energy (such as synthesis of macromolecules, active transport of molecules across the membrane, and assembly of flagella).
# Types
Several kinds of cytochrome exist and can be distinguished by spectroscopy, exact structure of the heme group, inhibitor sensitivity, and reduction potential.
Three types of cytochrome are distinguished by their prosthetic groups:
The definition of cytochrome c is not defined in terms of the heme group. There is no "cytochrome e", but there is a cytochrome f, which is often considered a type of cytochrome c.
In mitochondria and chloroplasts, these cytochromes are often combined in electron transport and related metabolic pathways:
A completely distinct family of cytochromes are known as the cytochrome P450 oxidases, so named for the characteristic Soret peak formed by absorbance of light at wavelengths near 450 nm when the heme iron is reduced (with sodium dithionite) and complexed to carbon monoxide. These enzymes are primarily involved in steroidogenesis and detoxification. | Cytochrome
# Overview
Cytochromes are generally membrane-bound hemoproteins that contain heme groups and carry out electron transport.
They are either found as monomeric proteins (i.e. cytochrome c) or as subunits of bigger enzymatic complexes that catalyze redox reactions. They are found in the mitochondrial inner membrane and endoplasmic reticulum of eukaryotes, in the chloroplasts of plants, in photosynthetic microorganisms, and in bacteria.
# Structure and function
The heme group is a highly conjugated ring system (which means its electrons are very mobile) surrounding a metal ion, which readily interconverts between the oxidation states. For many cytochromes the metal ion present is that of iron, which interconverts between Fe2+ (reduced) and Fe3+ (oxidized) states (electron-transfer processes) or between Fe2+ (reduced) and Fe3+ (formal, oxidized) states (oxidative processes). Cytochromes are thus capable of performing oxidation and reduction. Because the cytochromes (as well as other complexes) are held within membranes in an organized way, the redox reactions are carried out in the proper sequence for maximum efficiency.
In the process of oxidative phosphorylation, which is the principal energy-generating process undertaken by organisms which need oxygen to survive, other membrane-bound and soluble complexes and cofactors are involved in the chain of redox reactions, with the additional net effect that protons (H+) are transported across the mitochondrial inner membrane. The resulting transmembrane proton gradient [(protonmotive force)] is used to generate ATP, which is the universal chemical energy currency of life. ATP is consumed to drive cellular processes that require energy (such as synthesis of macromolecules, active transport of molecules across the membrane, and assembly of flagella).
# Types
Several kinds of cytochrome exist and can be distinguished by spectroscopy, exact structure of the heme group, inhibitor sensitivity, and reduction potential.
Three types of cytochrome are distinguished by their prosthetic groups:
The definition of cytochrome c is not defined in terms of the heme group.[2] There is no "cytochrome e", but there is a cytochrome f, which is often considered a type of cytochrome c.[3]
In mitochondria and chloroplasts, these cytochromes are often combined in electron transport and related metabolic pathways:
A completely distinct family of cytochromes are known as the cytochrome P450 oxidases, so named for the characteristic Soret peak formed by absorbance of light at wavelengths near 450 nm when the heme iron is reduced (with sodium dithionite) and complexed to carbon monoxide. These enzymes are primarily involved in steroidogenesis and detoxification. | https://www.wikidoc.org/index.php/Cytochrome | |
b156bbd61eb4ae73dce97103c692e79b7e1c7e6f | wikidoc | Cytoglobin | Cytoglobin
Cytoglobin is the protein product of CYGB, a human and mammalian gene.
Cytoglobin is a globin molecule ubiquitously expressed in all tissues and most notably utilized in marine mammals. It was discovered in 2001 and named cytoglobin in 2002. It is thought to protect against hypoxia. The predicted function of cytoglobin is the transfer of oxygen from arterial blood to the brain.
# Function
Cytoglobin is a ubiquitously expressed hexacoordinate hemoglobin that may facilitate diffusion of oxygen through tissues, scavenge nitric oxide or reactive oxygen species, or serve a protective function during oxidative stress.
# Applications
CYGB expression can be used as a specific marker with which hepatic stellate cells can be distinguished from portal myofibroblasts in the damaged human liver. | Cytoglobin
Cytoglobin is the protein product of CYGB, a human and mammalian gene.[1]
Cytoglobin is a globin molecule ubiquitously expressed in all tissues and most notably utilized in marine mammals. It was discovered in 2001[2] and named cytoglobin in 2002.[3] It is thought to protect against hypoxia. The predicted function of cytoglobin is the transfer of oxygen from arterial blood to the brain.[4]
# Function
Cytoglobin is a ubiquitously expressed hexacoordinate hemoglobin that may facilitate diffusion of oxygen through tissues, scavenge nitric oxide or reactive oxygen species, or serve a protective function during oxidative stress.[1][5]
# Applications
CYGB expression can be used as a specific marker with which hepatic stellate cells can be distinguished from portal myofibroblasts in the damaged human liver.[6] | https://www.wikidoc.org/index.php/Cytoglobin | |
6c935ae5c526e16b372f5f598218a4fca0bb3af1 | wikidoc | DAPT score | DAPT score
Synonyms and keywords: Dual Antiplatelet Therapy score; DAPT (Dual Antiplatelet Therapy) score; DAPT score calculator; Dual Antiplatelet Therapy score calculator; DAPT (Dual Antiplatelet Therapy) score calculator
# Overview
The DAPT score is a clinical prediction score assessing ischemic and bleeding risks at 12 to 30 months following percutaneous coronary intervention (PCI) to inform the duration of dual antiplatelet therapy (DAPT). The score was derived from the DAPT study (ClinicalTrials.gov: NCT00977938) and initially validated in the PROTECT trial (ClinicalTrials.gov: NCT00476957).
# DAPT Score
The DAPT score is a simplified clinical prediction score designed to assess the benefit-risk tradeoff between ischemia reduction (myocardial infarction or stent thrombosis) and bleeding increase (moderate or severe hemorrhage) associated with continued thienopyridine plus aspirin versus aspirin alone at 12 to 30 months after PCI based on 11,648 patients enrolled in the DAPT study (derivation cohort) and 8,136 patients enrolled in the PROTECT trial (validation cohort). The DAPT score has been externally validated in several subsequent studies.
# DAPT Score Calculator
Shown below is the calculator for the DAPT score (check all the boxes that apply):
function calcScore(){
var age_score = 0;
if (document.getElementById('AGE1').checked == 1) {age_score += -2;}
if (document.getElementById('AGE2').checked == 1) {age_score += -1;}
if (document.getElementById('AGE3').checked == 1) {age_score += 0;}
var score = age_score + 0;
if(document.forms.checked == 1){score += 1;}
if(document.forms.checked == 1){score += 1;}
if(document.forms.checked == 1){score += 1;}
if(document.forms.checked == 1){score += 1;}
if(document.forms.checked == 1){score += 1;}
if(document.forms.checked == 1){score += 1;}
if(document.forms.checked == 1){score += 2;}
if(document.forms.checked == 1){score += 2;}
document.forms.value = score;
if(score >= 2){document.forms.value = "Benefit-risk favoring prolonged DAPT over aspirin alone";}
if(score <= 1){document.forms.value = "Benefit-risk favoring aspirin alone over prolonged DAPT";}
# Interpretation
- Score ≥2 (high score): benefit-risk favoring prolonged DAPT over aspirin alone
- Greater ischemic reduction (2.7% for prolonged DAPT vs 5.7% for aspirin alone; difference, −3.0% ; NNT=34)
- Smaller bleeding increase (1.8% for prolonged DAPT vs 1.4% for aspirin alone; difference, 0.4% )
- Score <2 (low score): benefit-risk favoring aspirin alone over prolonged DAPT
- Smaller ischemic reduction (1.7% for prolonged DAPT vs 2.3% for aspirin alone; difference, −0.7% )
- Greater bleeding increase (3.0% for prolonged DAPT vs 1.4% for aspirin alone; difference, 1.5% ; NNH=64) | DAPT score
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sadaf Sharfaei M.D.[2]
Synonyms and keywords: Dual Antiplatelet Therapy score; DAPT (Dual Antiplatelet Therapy) score; DAPT score calculator; Dual Antiplatelet Therapy score calculator; DAPT (Dual Antiplatelet Therapy) score calculator
# Overview
The DAPT score is a clinical prediction score assessing ischemic and bleeding risks at 12 to 30 months following percutaneous coronary intervention (PCI) to inform the duration of dual antiplatelet therapy (DAPT). The score was derived from the DAPT study (ClinicalTrials.gov: NCT00977938) and initially validated in the PROTECT trial (ClinicalTrials.gov: NCT00476957).
# DAPT Score
The DAPT score is a simplified clinical prediction score designed to assess the benefit-risk tradeoff between ischemia reduction (myocardial infarction or stent thrombosis) and bleeding increase (moderate or severe hemorrhage) associated with continued thienopyridine plus aspirin versus aspirin alone at 12 to 30 months after PCI based on 11,648 patients enrolled in the DAPT study (derivation cohort) and 8,136 patients enrolled in the PROTECT trial (validation cohort).[1] The DAPT score has been externally validated in several subsequent studies.[2][3][4][5][6]
# DAPT Score Calculator
Shown below is the calculator for the DAPT score (check all the boxes that apply):
function calcScore(){
var age_score = 0;
if (document.getElementById('AGE1').checked == 1) {age_score += -2;}
if (document.getElementById('AGE2').checked == 1) {age_score += -1;}
if (document.getElementById('AGE3').checked == 1) {age_score += 0;}
var score = age_score + 0;
if(document.forms["DAPTSCORE"]["input4"].checked == 1){score += 1;}
if(document.forms["DAPTSCORE"]["input5"].checked == 1){score += 1;}
if(document.forms["DAPTSCORE"]["input6"].checked == 1){score += 1;}
if(document.forms["DAPTSCORE"]["input7"].checked == 1){score += 1;}
if(document.forms["DAPTSCORE"]["input8"].checked == 1){score += 1;}
if(document.forms["DAPTSCORE"]["input9"].checked == 1){score += 1;}
if(document.forms["DAPTSCORE"]["input10"].checked == 1){score += 2;}
if(document.forms["DAPTSCORE"]["input11"].checked == 1){score += 2;}
document.forms["DAPTSCORE"]["result"].value = score;
if(score >= 2){document.forms["DAPTSCORE"]["longanswer"].value = "Benefit-risk favoring prolonged DAPT over aspirin alone";}
if(score <= 1){document.forms["DAPTSCORE"]["longanswer"].value = "Benefit-risk favoring aspirin alone over prolonged DAPT";}
}
# Interpretation
- Score ≥2 (high score): benefit-risk favoring prolonged DAPT over aspirin alone
- Greater ischemic reduction (2.7% for prolonged DAPT vs 5.7% for aspirin alone; difference, −3.0% [95% CI, −4.1% to −2.0%]; NNT=34)
- Smaller bleeding increase (1.8% for prolonged DAPT vs 1.4% for aspirin alone; difference, 0.4% [95% CI, −0.3% to 1.0%])
- Score <2 (low score): benefit-risk favoring aspirin alone over prolonged DAPT
- Smaller ischemic reduction (1.7% for prolonged DAPT vs 2.3% for aspirin alone; difference, −0.7% [95% CI, −1.4% to 0.1%])
- Greater bleeding increase (3.0% for prolonged DAPT vs 1.4% for aspirin alone; difference, 1.5% [95% CI, 0.8% to 2.3%]; NNH=64) | https://www.wikidoc.org/index.php/DAPT_(Dual_Antiplatelet_Therapy)_score | |
b7ea9f2fdef1fc16b985bfb6fc842bcd2dc82020 | wikidoc | DNA ligase | DNA ligase
DNA ligase is a specific type of enzyme, a ligase, (EC 6.5.1.1) that facilitates the joining of DNA strands together by catalyzing the formation of a phosphodiester bond. It plays a role in repairing single-strand breaks in duplex DNA in living organisms, but some forms (such as DNA ligase IV) may specifically repair double-strand breaks (i.e. a break in both complementary strands of DNA). Single-strand breaks are repaired by DNA ligase using the complementary strand of the double helix as a template, with DNA ligase creating the final phosphodiester bond to fully repair the DNA.
DNA ligase is used in both DNA repair and DNA replication (see Mammalian ligases). In addition, DNA ligase has extensive use in molecular biology laboratories for recombinant DNA experiments (see Research Applications). Purified DNA ligase is used in gene cloning to join DNA molecules together to form recombinant DNA.
# Enzymatic mechanism
The mechanism of DNA ligase is to form two covalent phosphodiester bonds between 3' hydroxyl ends of one nucleotide ("acceptor"), with the 5' phosphate end of another ("donor"). Two ATP molecules are consumed for each phosphodiester bond formed. AMP is required for the ligase reaction, which proceeds in four steps:
- Reorganization of activity site such as nicks in DNA segments or Okazaki fragments etc.
- Adenylation (addition of AMP) of a lysine residue in the active center of the enzyme, pyrophosphate is released;
- Transfer of the AMP to the 5' phosphate of the so-called donor, formation of a pyrophosphate bond;
- Formation of a phosphodiester bond between the 5' phosphate of the donor and the 3' hydroxyl of the acceptor.
Ligase will also work with blunt ends, although higher enzyme concentrations and different reaction conditions are required.
# Types
## E. coli
The E. coli DNA ligase is encoded by the lig gene. DNA ligase in E. coli, as well as most prokaryotes, uses energy gained by cleaving nicotinamide adenine dinucleotide (NAD) to create the phosphodiester bond. It does not ligate blunt-ended DNA except under conditions of molecular crowding with polyethylene glycol, and cannot join RNA to DNA efficiently.
The activity of E. coli DNA ligase can be enhanced by DNA polymerase at the right concentrations. Enhancement only works when the concentrations of the DNA polymerase 1 are much lower than the DNA fragments to be ligated. When the concentrations of Pol I DNA polymerases are higher, it has an adverse effect on E. coli DNA ligase
## T4
The DNA ligase from bacteriophage T4(Enterobacteria phage T4 is a bacteriophage that infects Escherichia coli bacteria. The T4 phage is a member of the T-even phages, a group including enterobacteriophages T2 and T6. T4 is capable of undergoing only a lytic lifecycle and not the lysogenic lifecycle.) is the ligase most-commonly used in laboratory research. It can ligate either cohesive or blunt ends of DNA, oligonucleotides, as well as RNA and RNA-DNA hybrids, but not single-stranded nucleic acids. It can also ligate blunt-ended DNA with much greater efficiency than E. coli DNA ligase. Unlike E. coli DNA ligase, T4 DNA ligase cannot utilize NAD and it has an absolute requirement for ATP as a cofactor. Some engineering has been done to improve the in vitro activity of T4 DNA ligase; one successful approach, for example, tested T4 DNA ligase fused to several alternative DNA binding proteins and found that the constructs with either p50 or NF-kB as fusion partners were over 160% more active in blunt-end ligations for cloning purposes than wild type T4 DNA ligase. A typical reaction for inserting a fragment into a plasmid vector would use about 0.01 (sticky ends) to 1 (blunt ends) units of ligase. The optimal incubation temperature for T4 DNA ligase is 16 °C.
## Mammalian
In mammals, there are four specific types of ligase.
- DNA ligase I: ligates the nascent DNA of the lagging strand after the Ribonuclease H has removed the RNA primer from the Okazaki fragments.
- DNA ligase III: complexes with DNA repair protein XRCC1 to aid in sealing DNA during the process of nucleotide excision repair and recombinant fragments. Of the all known mammalian DNA ligases, only Lig III has been found to be present in mitochondria.
- DNA ligase IV: complexes with XRCC4. It catalyzes the final step in the non-homologous end joining DNA double-strand break repair pathway. It is also required for V(D)J recombination, the process that generates diversity in immunoglobulin and T-cell receptor loci during immune system development.
- DNA ligase II: appears to be used in repair. It is formed by alternative splicing of a proteolytic fragment of DNA ligase III and does not have its own gene, therefore it is often considered to be virtually identical to DNA ligase III.
DNA ligase from eukaryotes and some microbes uses adenosine triphosphate (ATP) rather than NAD.
## Thermostable
Derived from a thermophilic bacterium, the enzyme is stable and active at much higher temperatures than conventional DNA ligases. Its half-life is 48 hours at 65°C and greater than 1 hour at 95°C. Ampligase DNA Ligase has been shown to be active for at least 500 thermal cycles (94°C/80°C) or 16 hours of cycling.10 This exceptional thermostability permits extremely high hybridization stringency and ligation specificity.
# Measurement of activity
There are at least three different units used to measure the activity of DNA ligase:
- Weiss unit - the amount of ligase that catalyzes the exchange of 1 nmole of 32P from inorganic pyrophosphate to ATP in 20 minutes at 37°C. This is the one most commonly used.
- Modrich-Lehman unit - this is rarely used, and one unit is defined as the amount of enzyme required to convert 100 nmoles of d(A-T)n to an exonuclease-III resistant form in 30 minutes under standard conditions.
- Many commercial suppliers of ligases use an arbitrary unit based on the ability of ligase to ligate cohesive ends. These units are often more subjective than quantitative and lack precision.
# Research applications
DNA ligases have become indispensable tools in modern molecular biology research for generating recombinant DNA sequences. For example, DNA ligases are used with restriction enzymes to insert DNA fragments, often genes, into plasmids.
Controlling the optimal temperature is a vital aspect of performing efficient recombination experiments involving the ligation of cohesive-ended fragments. Most experiments use T4 DNA Ligase (isolated from bacteriophage T4), which is most active at 37 °C. However, for optimal ligation efficiency with cohesive-ended fragments ("sticky ends"), the optimal enzyme temperature needs to be balanced with the melting temperature Tm of the sticky ends being ligated, the homologous pairing of the sticky ends will not be stable because the high temperature disrupts hydrogen bonding. A ligation reaction is most efficient when the sticky ends are already stably annealed, and disruption of the annealing ends would therefore result in low ligation efficiency. The shorter the overhang, the lower the Tm. It has been shown recently that T4 DNA ligase in combination with 3 M betaine and 10 % PEG 8000 can ligate XNA molecules .
Since blunt-ended DNA fragments have no cohesive ends to anneal, the melting temperature is not a factor to consider within the normal temperature range of the ligation reaction. The limiting factor in blunt end ligation is not the activity of the ligase but rather the number of alignments between DNA fragment ends that occur. The most efficient ligation temperature for blunt-ended DNA would therefore be the temperature at which the greatest number of alignments can occur. The majority of blunt-ended ligations are carried out at 14-25 °C overnight. The absence of stably annealed ends also means that the ligation efficiency is lowered, requiring a higher ligase concentration to be used.
A novel use of DNA ligase can be seen in the field of nano chemistry, specifically in DNA origami. DNA based self-assembly principles have proven useful for organizing nanoscale objects, such as biomolecules, nanomachines, nanoelectronic and photonic component. Assembly of such nano structure requires the creation of an intricate mesh of DNA molecules. Although DNA self-assembly is possible without any outside help using different substrates such as provision of catatonic surface of Aluminium foil, DNA ligase can provide the enzymatic assistance that is required to make DNA lattice structure from DNA over hangs.
# History
The first DNA ligase was purified and characterized in 1967 by the Gellert, Lehman, Richardson, and Hurwitz laboratories. It was first purified and characterized by Weiss and Richardson using a six-step chromatographic-fractionation process beginning with elimination of cell debris and addition of streptomycin, followed by several Diethylaminoethyl (DEAE)-cellulose column washes and a final phosphocellulose fractionation. The final extract contained 10% of the activity initially recorded in the E. coli media; along the process it was discovered that ATP and Mg++ were necessary to optimize the reaction. The common commercially available DNA ligases were originally discovered in bacteriophage T4, E. coli and other bacteria.
# Disorders
Genetic deficiencies in human DNA ligases have been associated with clinical syndromes marked by immunodeficiency, radiation sensitivity, and developmental abnormalities, LIG4 syndrome (Ligase IV syndrome) is a rare disease associated with mutations in DNA ligase 4 and interferes with dsDNA break-repair mechanisms. Ligase IV syndrome causes immunodeficiency in individuals and is commonly associated with microcephaly and marrow hypoplasia. A list of prevalent diseases caused by lack of or malfunctioning of DNA ligase is as follows.
## Xeroderma pigmentosum
Xeroderma pigmentosum, which is commonly known as XP, is an inherited condition characterized by an extreme sensitivity to ultraviolet (UV) rays from sunlight. This condition mostly affects the eyes and areas of skin exposed to the sun. Some affected individuals also have problems involving the nervous system.
## Ataxia-telangiectasia
Mutations in the ATM gene cause ataxia-telangiectasia. The ATM gene provides instructions for making a protein that helps control cell division and is involved in DNA repair. This protein plays an important role in the normal development and activity of several body systems, including the nervous system and immune system. The ATM protein assists cells in recognizing damaged or broken DNA strands and coordinates DNA repair by activating enzymes that fix the broken strands. Efficient repair of damaged DNA strands helps maintain the stability of the cell's genetic information. Affected children typically develop difficulty walking, problems with balance and hand coordination, involuntary jerking movements (chorea), muscle twitches (myoclonus), and disturbances in nerve function (neuropathy). The movement problems typically cause people to require wheelchair assistance by adolescence. People with this disorder also have slurred speech and trouble moving their eyes to look side-to-side (oculomotor apraxia).
## Fanconi Anemia
Fanconi anemia (FA) is a rare, inherited blood disorder that leads to bone marrow failure. FA prevents bone marrow from making enough new blood cells for the body to work normally. FA also can cause the bone marrow to make many faulty blood cells. This can lead to serious health problems, such as leukemia.
## Bloom syndrome
Bloom syndrome results in skin that is sensitive to sun exposure, and usually the development of a butterfly-shaped patch of reddened skin across the nose and cheeks. A skin rash can also appear on other areas that are typically exposed to the sun, such as the back of the hands and the forearms. Small clusters of enlarged blood vessels (telangiectases) often appear in the rash; telangiectases can also occur in the eyes. Other skin features include patches of skin that are lighter or darker than the surrounding areas (hypopigmentation or hyperpigmentation respectively). These patches appear on areas of the skin that are not exposed to the sun, and their development is not related to the rashes.
# As a drug target
In recent studies, human DNA ligase I was used in Computer-aided drug design to identify DNA ligase inhibitors as possible therapeutic agents to treat cancer. Since excessive cell growth is a hallmark of cancer development, targetes chemotherapy that disrupts the functioning of DNA ligase can impede adjuvant cancer forms. Furthermore, it has been shown that DNA ligase can be broadly divided into two categories namely, ATP dependent and NAD+ dependent. Previous research has shown that although NAD+-dependent DNA ligases have been discovered in sporadic cellular or viral niches outside the bacterial domain of life, there is no instance in which a NAD+-dependent ligase is present in a eukaryal organism. The narrow phylogenetic distribution, unique substrate specificity, and distinctive domain structure of NAD+ depandant compared with ATP-dependent human DNA ligases recommend the NAD+ ligases as targets for the development of new antibacterial drugs. | DNA ligase
DNA ligase is a specific type of enzyme, a ligase, (EC 6.5.1.1) that facilitates the joining of DNA strands together by catalyzing the formation of a phosphodiester bond. It plays a role in repairing single-strand breaks in duplex DNA in living organisms, but some forms (such as DNA ligase IV) may specifically repair double-strand breaks (i.e. a break in both complementary strands of DNA). Single-strand breaks are repaired by DNA ligase using the complementary strand of the double helix as a template,[1] with DNA ligase creating the final phosphodiester bond to fully repair the DNA.
DNA ligase is used in both DNA repair and DNA replication (see Mammalian ligases). In addition, DNA ligase has extensive use in molecular biology laboratories for recombinant DNA experiments (see Research Applications). Purified DNA ligase is used in gene cloning to join DNA molecules together to form recombinant DNA.
# Enzymatic mechanism
The mechanism of DNA ligase is to form two covalent phosphodiester bonds between 3' hydroxyl ends of one nucleotide ("acceptor"), with the 5' phosphate end of another ("donor"). Two ATP molecules are consumed for each phosphodiester bond formed. AMP is required for the ligase reaction, which proceeds in four steps:
- Reorganization of activity site such as nicks in DNA segments or Okazaki fragments etc.
- Adenylation (addition of AMP) of a lysine residue in the active center of the enzyme, pyrophosphate is released;
- Transfer of the AMP to the 5' phosphate of the so-called donor, formation of a pyrophosphate bond;
- Formation of a phosphodiester bond between the 5' phosphate of the donor and the 3' hydroxyl of the acceptor.[2]
Ligase will also work with blunt ends, although higher enzyme concentrations and different reaction conditions are required.
# Types
## E. coli
The E. coli DNA ligase is encoded by the lig gene. DNA ligase in E. coli, as well as most prokaryotes, uses energy gained by cleaving nicotinamide adenine dinucleotide (NAD) to create the phosphodiester bond.[3] It does not ligate blunt-ended DNA except under conditions of molecular crowding with polyethylene glycol, and cannot join RNA to DNA efficiently.
The activity of E. coli DNA ligase can be enhanced by DNA polymerase at the right concentrations. Enhancement only works when the concentrations of the DNA polymerase 1 are much lower than the DNA fragments to be ligated. When the concentrations of Pol I DNA polymerases are higher, it has an adverse effect on E. coli DNA ligase[4]
## T4
The DNA ligase from bacteriophage T4(Enterobacteria phage T4 is a bacteriophage that infects Escherichia coli bacteria. The T4 phage is a member of the T-even phages, a group including enterobacteriophages T2 and T6. T4 is capable of undergoing only a lytic lifecycle and not the lysogenic lifecycle.) is the ligase most-commonly used in laboratory research.[5] It can ligate either cohesive or blunt ends of DNA, oligonucleotides, as well as RNA and RNA-DNA hybrids, but not single-stranded nucleic acids. It can also ligate blunt-ended DNA with much greater efficiency than E. coli DNA ligase. Unlike E. coli DNA ligase, T4 DNA ligase cannot utilize NAD and it has an absolute requirement for ATP as a cofactor. Some engineering has been done to improve the in vitro activity of T4 DNA ligase; one successful approach, for example, tested T4 DNA ligase fused to several alternative DNA binding proteins and found that the constructs with either p50 or NF-kB as fusion partners were over 160% more active in blunt-end ligations for cloning purposes than wild type T4 DNA ligase.[6] A typical reaction for inserting a fragment into a plasmid vector would use about 0.01 (sticky ends) to 1 (blunt ends) units of ligase. The optimal incubation temperature for T4 DNA ligase is 16 °C.
## Mammalian
In mammals, there are four specific types of ligase.
- DNA ligase I: ligates the nascent DNA of the lagging strand after the Ribonuclease H has removed the RNA primer from the Okazaki fragments.
- DNA ligase III: complexes with DNA repair protein XRCC1 to aid in sealing DNA during the process of nucleotide excision repair and recombinant fragments. Of the all known mammalian DNA ligases, only Lig III has been found to be present in mitochondria.
- DNA ligase IV: complexes with XRCC4. It catalyzes the final step in the non-homologous end joining DNA double-strand break repair pathway. It is also required for V(D)J recombination, the process that generates diversity in immunoglobulin and T-cell receptor loci during immune system development.
- DNA ligase II: appears to be used in repair. It is formed by alternative splicing of a proteolytic fragment of DNA ligase III and does not have its own gene, therefore it is often considered to be virtually identical to DNA ligase III.
DNA ligase from eukaryotes and some microbes uses adenosine triphosphate (ATP) rather than NAD.[3]
## Thermostable
Derived from a thermophilic bacterium, the enzyme is stable and active at much higher temperatures than conventional DNA ligases. Its half-life is 48 hours at 65°C and greater than 1 hour at 95°C. Ampligase DNA Ligase has been shown to be active for at least 500 thermal cycles (94°C/80°C) or 16 hours of cycling.10 This exceptional thermostability permits extremely high hybridization stringency and ligation specificity.[7]
# Measurement of activity
There are at least three different units used to measure the activity of DNA ligase:[8]
- Weiss unit - the amount of ligase that catalyzes the exchange of 1 nmole of 32P from inorganic pyrophosphate to ATP in 20 minutes at 37°C. This is the one most commonly used.
- Modrich-Lehman unit - this is rarely used, and one unit is defined as the amount of enzyme required to convert 100 nmoles of d(A-T)n to an exonuclease-III resistant form in 30 minutes under standard conditions.
- Many commercial suppliers of ligases use an arbitrary unit based on the ability of ligase to ligate cohesive ends. These units are often more subjective than quantitative and lack precision.
# Research applications
DNA ligases have become indispensable tools in modern molecular biology research for generating recombinant DNA sequences. For example, DNA ligases are used with restriction enzymes to insert DNA fragments, often genes, into plasmids.
Controlling the optimal temperature is a vital aspect of performing efficient recombination experiments involving the ligation of cohesive-ended fragments. Most experiments use T4 DNA Ligase (isolated from bacteriophage T4), which is most active at 37 °C.[9] However, for optimal ligation efficiency with cohesive-ended fragments ("sticky ends"), the optimal enzyme temperature needs to be balanced with the melting temperature Tm of the sticky ends being ligated,[10] the homologous pairing of the sticky ends will not be stable because the high temperature disrupts hydrogen bonding. A ligation reaction is most efficient when the sticky ends are already stably annealed, and disruption of the annealing ends would therefore result in low ligation efficiency. The shorter the overhang, the lower the Tm. It has been shown recently that T4 DNA ligase in combination with 3 M betaine and 10 % PEG 8000 can ligate XNA molecules [11].
Since blunt-ended DNA fragments have no cohesive ends to anneal, the melting temperature is not a factor to consider within the normal temperature range of the ligation reaction. The limiting factor in blunt end ligation is not the activity of the ligase but rather the number of alignments between DNA fragment ends that occur. The most efficient ligation temperature for blunt-ended DNA would therefore be the temperature at which the greatest number of alignments can occur. The majority of blunt-ended ligations are carried out at 14-25 °C overnight. The absence of stably annealed ends also means that the ligation efficiency is lowered, requiring a higher ligase concentration to be used.[10]
A novel use of DNA ligase can be seen in the field of nano chemistry, specifically in DNA origami. DNA based self-assembly principles have proven useful for organizing nanoscale objects, such as biomolecules, nanomachines, nanoelectronic and photonic component. Assembly of such nano structure requires the creation of an intricate mesh of DNA molecules. Although DNA self-assembly is possible without any outside help using different substrates such as provision of catatonic surface of Aluminium foil, DNA ligase can provide the enzymatic assistance that is required to make DNA lattice structure from DNA over hangs.[12]
# History
The first DNA ligase was purified and characterized in 1967 by the Gellert, Lehman, Richardson, and Hurwitz laboratories.[13] It was first purified and characterized by Weiss and Richardson using a six-step chromatographic-fractionation process beginning with elimination of cell debris and addition of streptomycin, followed by several Diethylaminoethyl (DEAE)-cellulose column washes and a final phosphocellulose fractionation. The final extract contained 10% of the activity initially recorded in the E. coli media; along the process it was discovered that ATP and Mg++ were necessary to optimize the reaction. The common commercially available DNA ligases were originally discovered in bacteriophage T4, E. coli and other bacteria.[14]
# Disorders
Genetic deficiencies in human DNA ligases have been associated with clinical syndromes marked by immunodeficiency, radiation sensitivity, and developmental abnormalities, [13] LIG4 syndrome (Ligase IV syndrome) is a rare disease associated with mutations in DNA ligase 4 and interferes with dsDNA break-repair mechanisms. Ligase IV syndrome causes immunodeficiency in individuals and is commonly associated with microcephaly and marrow hypoplasia.[15] A list of prevalent diseases caused by lack of or malfunctioning of DNA ligase is as follows.
## Xeroderma pigmentosum
Xeroderma pigmentosum, which is commonly known as XP, is an inherited condition characterized by an extreme sensitivity to ultraviolet (UV) rays from sunlight. This condition mostly affects the eyes and areas of skin exposed to the sun. Some affected individuals also have problems involving the nervous system.[16]
## Ataxia-telangiectasia
Mutations in the ATM gene cause ataxia-telangiectasia. The ATM gene provides instructions for making a protein that helps control cell division and is involved in DNA repair. This protein plays an important role in the normal development and activity of several body systems, including the nervous system and immune system. The ATM protein assists cells in recognizing damaged or broken DNA strands and coordinates DNA repair by activating enzymes that fix the broken strands. Efficient repair of damaged DNA strands helps maintain the stability of the cell's genetic information. Affected children typically develop difficulty walking, problems with balance and hand coordination, involuntary jerking movements (chorea), muscle twitches (myoclonus), and disturbances in nerve function (neuropathy). The movement problems typically cause people to require wheelchair assistance by adolescence. People with this disorder also have slurred speech and trouble moving their eyes to look side-to-side (oculomotor apraxia).[17]
## Fanconi Anemia
Fanconi anemia (FA) is a rare, inherited blood disorder that leads to bone marrow failure. FA prevents bone marrow from making enough new blood cells for the body to work normally. FA also can cause the bone marrow to make many faulty blood cells. This can lead to serious health problems, such as leukemia.[18]
## Bloom syndrome
Bloom syndrome results in skin that is sensitive to sun exposure, and usually the development of a butterfly-shaped patch of reddened skin across the nose and cheeks. A skin rash can also appear on other areas that are typically exposed to the sun, such as the back of the hands and the forearms. Small clusters of enlarged blood vessels (telangiectases) often appear in the rash; telangiectases can also occur in the eyes. Other skin features include patches of skin that are lighter or darker than the surrounding areas (hypopigmentation or hyperpigmentation respectively). These patches appear on areas of the skin that are not exposed to the sun, and their development is not related to the rashes.
# As a drug target
In recent studies, human DNA ligase I was used in Computer-aided drug design to identify DNA ligase inhibitors as possible therapeutic agents to treat cancer.[19] Since excessive cell growth is a hallmark of cancer development, targetes chemotherapy that disrupts the functioning of DNA ligase can impede adjuvant cancer forms. Furthermore, it has been shown that DNA ligase can be broadly divided into two categories namely, ATP dependent and NAD+ dependent. Previous research has shown that although NAD+-dependent DNA ligases have been discovered in sporadic cellular or viral niches outside the bacterial domain of life, there is no instance in which a NAD+-dependent ligase is present in a eukaryal organism. The narrow phylogenetic distribution, unique substrate specificity, and distinctive domain structure of NAD+ depandant compared with ATP-dependent human DNA ligases recommend the NAD+ ligases as targets for the development of new antibacterial drugs.[13] | https://www.wikidoc.org/index.php/DNA_Ligase | |
42e9dae44f5615dca2b98e516526d6d0aba9aa75 | wikidoc | DNA adduct | DNA adduct
# Overview
A DNA adduct is an abnormal piece of DNA covalently-bonded to a cancer-causing chemical. This has shown to be the start of a cancerous cell, or carcinogenesis. DNA adducts in scientific experiments are used as bio-markers and as such are themselves measured to reflect quantitatively, for comparison, the amount of cancer in the subject, i.e. rats or other living animals. Under experimental conditions for study, such DNA adducts are induced by known carcinogens, of which commonly used is DMBA, chemically structured and named as 7,12-Dimethyl-benz Anthracene . For example, a scientific journal that writes "DMBA - DNA adduct" is referring to a piece of DNA that has the chemical DMBA attached to it. The presence of such adduct indicates the presence of cancer in the subject animal.
Other examples :
- acetaldehyde DNA Adducts. Note: acetaldehyde is a major component of cigarette smoke.
## DNA Damage
When a chemical bonds to DNA, the DNA becomes damaged, and proper and complete replication cannot occur to make the normal intended cell. This would be the start of a mutation, or mutagenesis, and without proper DNA repair (DNA repair happens naturally under normal circumstances), this can lead to carcinogenesis, the beginnings of cancer. | DNA adduct
# Overview
A DNA adduct is an abnormal piece of DNA covalently-bonded to a cancer-causing chemical. This has shown to be the start of a cancerous cell, or carcinogenesis. DNA adducts in scientific experiments are used as bio-markers and as such are themselves measured to reflect quantitatively, for comparison, the amount of cancer in the subject, i.e. rats or other living animals. Under experimental conditions for study, such DNA adducts are induced by known carcinogens, of which commonly used is DMBA, chemically structured and named as 7,12-Dimethyl-benz[a] Anthracene . For example, a scientific journal that writes "DMBA - DNA adduct" is referring to a piece of DNA that has the chemical DMBA attached to it. The presence of such adduct indicates the presence of cancer in the subject animal.[1]
Other examples :
- acetaldehyde DNA Adducts. Note: acetaldehyde is a major component of cigarette smoke.
## DNA Damage
When a chemical bonds to DNA, the DNA becomes damaged, and proper and complete replication cannot occur to make the normal intended cell. This would be the start of a mutation, or mutagenesis, and without proper DNA repair (DNA repair happens naturally under normal circumstances), this can lead to carcinogenesis, the beginnings of cancer.[2] | https://www.wikidoc.org/index.php/DNA_adduct | |
c365e03d1c2082261be05c9316c2f82cdfdeb3ef | wikidoc | DNA repair | DNA repair
DNA repair refers to a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as UV light can cause DNA damage, resulting in as many as 1 million individual molecular lesions per cell per day. Many of these lesions cause structural damage to the DNA molecule and can alter or eliminate the cell's ability to transcribe the gene that the affected DNA encodes. Other lesions induce potentially harmful mutations in the cell's genome, which affect the survival of its daughter cells after it undergoes mitosis. Consequently, the DNA repair process must be constantly active so it can respond rapidly to any damage in the DNA structure.
The rate of DNA repair is dependent on many factors, including the cell type, the age of the cell, and the extracellular environment. A cell that has accumulated a large amount of DNA damage, or one that no longer effectively repairs damage incurred to its DNA, can enter one of three possible states:
- an irreversible state of dormancy, known as senescence
- cell suicide, also known as apoptosis or programmed cell death
- unregulated cell division, which can lead to the formation of a tumor that is cancerous
The DNA repair ability of a cell is vital to the integrity of its genome and thus to its normal functioning and that of the organism. Many genes that were initially shown to influence lifespan have turned out to be involved in DNA damage repair and protection. Failure to correct molecular lesions in cells that form gametes can introduce mutations into the genomes of the offspring and thus influence the rate of evolution.
# DNA damage
DNA damage, due to environmental factors and normal metabolic processes inside the cell, occurs at a rate of 1,000 to 1,000,000 molecular lesions per cell per day. While this constitutes only 0.000165% of the human genome's approximately 6 billion bases (3 billion base pairs), unrepaired lesions in critical genes (such as tumor suppressor genes) can impede a cell's ability to carry out its function and appreciably increase the likelihood of tumor formation.
The vast majority of DNA damage affects the primary structure of the double helix; that is, the bases themselves are chemically modified. These modifications can in turn disrupt the molecules' regular helical structure by introducing non-native chemical bonds or bulky adducts that do not fit in the standard double helix. Unlike proteins and RNA, DNA usually lacks tertiary structure and therefore damage or disturbance does not occur at that level. DNA is, however, supercoiled and wound around "packaging" proteins called histones (in eukaryotes), and both superstructures are vulnerable to the effects of DNA damage.
## Sources of damage
DNA damage can be subdivided into two main types:
- endogenous damage such as attack by reactive oxygen species produced from normal metabolic byproducts (spontaneous mutation), especially the process of oxidative deamination;
- exogenous damage caused by external agents such as
ultraviolet radiation from the sun
-ther radiation frequencies, including x-rays and gamma rays
hydrolysis or thermal disruption
certain plant toxins
human-made mutagenic chemicals, especially aromatic compounds that act as DNA intercalating agents
cancer chemotherapy and radiotherapy
- ultraviolet radiation from the sun
- other radiation frequencies, including x-rays and gamma rays
- hydrolysis or thermal disruption
- certain plant toxins
- human-made mutagenic chemicals, especially aromatic compounds that act as DNA intercalating agents
- cancer chemotherapy and radiotherapy
The replication of damaged DNA before cell division can lead to the incorporation of wrong bases opposite damaged ones. Daughter cells that inherit these wrong bases carry mutations from which the original DNA sequence is unrecoverable (except in the rare case of a back mutation, for example, through gene conversion).
## Types of damage
There are four main types of damage to DNA due to endogenous cellular processes:
- oxidation of bases and generation of DNA strand interruptions from reactive oxygen species,
- alkylation of bases (usually methylation), such as formation of 7-methylguanine, 1-methyladenine, O6 methylguanine
- hydrolysis of bases, such as deamination, depurination and depyrimidination.
- mismatch of bases, due to errors in DNA replication, in which the wrong DNA base is stitched into place in a newly forming DNA strand, or a DNA base is skipped over or mistakenly inserted.
Damage caused by exogenous agents comes in many forms. Some examples are:
- UV light causes crosslinking between adjacent cytosine and thymine bases creating pyrimidine dimers
- Ionizing radiation such as that created by radioactive decay or in cosmic rays causes breaks in DNA strands.
- Thermal disruption at elevated temperature increases the rate of depurination (loss of purine bases from the DNA backbone) and single strand breaks. For example, hydrolytic depurination is seen in the thermophilic bacteria, which grow in hot springs at 85–250°C. The rate of depurination (300 purine residues per genome per generation) is too high in these species to be repaired by normal repair machinery, hence a possibility of an adaptive response cannot be ruled out.
- Industrial chemicals such as vinyl chloride and hydrogen peroxide, and environmental chemicals such as polycyclic hydrocarbons found in smoke, soot and tar create a huge diversity of DNA adducts- ethenobases, oxidized bases, alkylated phosphotriesters and Crosslinking of DNA just to name a few.
UV damage, alkylation/methylation, X-ray damage and oxidative damage are examples of induced damage. Spontaneous damage can include the loss of a base, deamination, sugar ring puckering and tautomeric shift.
## Nuclear versus mitochondrial DNA damage
In human cells, and eukaryotic cells in general, DNA is found in two cellular locations - inside the nucleus and inside the mitochondria. Nuclear DNA (nDNA) exists as chromatin during non-replicative stages of the cell cycle and is condensed into aggregate structures known as chromosomes during cell division. In either state the DNA is highly compacted and wound up around bead-like proteins called histones. Whenever a cell needs to express the genetic information encoded in its nDNA the required chromosomal region is unravelled, genes located therein are expressed, and then the region is condensed back to its resting conformation. Mitochondrial DNA (mtDNA) is located inside mitochondria organelles, exists in multiple copies, and is also tightly associated with a number of proteins to form a complex known as the nucleoid. Inside mitochondria, reactive oxygen species (ROS), or free radicals, byproducts of the constant production of adenosine triphosphate (ATP) via oxidative phosphorylation, create a highly oxidative environment that is known to damage mtDNA. A critical enzyme in counteracting the toxicity of these species is superoxide dismutase, which is present in both the mitochondria and cytoplasm of eukaryotic cells.
## Senescence and apoptosis
Senescence, an irreversible state in which the cell no longer divides (mitosis), is a protective response to the shortening of the chromosome ends (telomeres). The telomeres are long regions of repetitive noncoding DNA that cap chromosomes and undergo partial degradation each time a cell undergoes division (see Hayflick limit). In contrast, quiescence is a reversible state of cellular dormancy that is unrelated to genome damage (see cell cycle). Senescence in cells may serve as a functional alternative to apoptosis in cases where the physical presence of a cell for spatial reasons is required by the organism, which serves as a "last resort" mechanism to prevent a cell with damaged DNA from replicating inappropriately in the absence of pro-growth cellular signaling. Unregulated cell division can lead to the formation of a tumor (see cancer), which is potentially lethal to an organism. Therefore the induction of senescence and apoptosis is considered to be part of a strategy of protection against cancer.
# DNA repair mechanisms
Cells cannot function if DNA damage corrupts the integrity and accessibility of essential information in the genome (but cells remain superficially functional when so-called "non-essential" genes are missing or damaged). Depending on the type of damage inflicted on the DNA's double helical structure, a variety of repair strategies have evolved to restore lost information. If possible, cells use the unmodified complementary strand of the DNA or the sister chromatid as a template to losslessly recover the original information. Without access to a template, cells use an error-prone recovery mechanism known as translesion synthesis as a last resort.
Damage to DNA alters the spatial configuration of the helix and such alterations can be detected by the cell. Once damage is localized, specific DNA repair molecules are summoned to, and bind at or near the site of damage, inducing other molecules to bind and form a complex that enables the actual repair to take place. The types of molecules involved and the mechanism of repair that is mobilized depend on the type of damage that has occurred and the phase of the cell cycle that the cell is in.
## Direct reversal
Cells are known to eliminate three types of damage to their DNA by chemically reversing it. These mechanisms do not require a template, since the types of damage they counteract can only occur in one of the four bases. Such direct reversal mechanisms are specific to the type of damage incurred and do not involve breakage of the phosphodiester backbone. The formation of thymine dimers (a common type of cyclobutyl dimer) upon irradiation with UV light results in an abnormal covalent bond between adjacent thymidine bases. The photoreactivation process directly reverses this damage by the action of the enzyme photolyase, whose activation is obligately dependent on energy absorbed from blue/UV light (300–500nm wavelength) to promote catalysis. Another type of damage, methylation of guanine bases, is directly reversed by the protein methyl guanine methyl transferase (MGMT), the bacterial equivalent of which is called as ogt. This is an expensive process because each MGMT molecule can only be used once; that is, the reaction is stoichiometric rather than catalytic. A generalized response to methylating agents in bacteria is known as the adaptive response and confers a level of resistance to alkylating agents upon sustained exposure by upregulation of alkylation repair enzymes. The third type of DNA damage reversed by cells is certain methylation of the bases cytosine and adenine.
## Single strand damage
When only one of the two strands of a double helix has a defect, the other strand can be used as a template to guide the correction of the damaged strand. In order to repair damage to one of the two paired molecules of DNA, there exist a number of excision repair mechanisms that remove the damaged nucleotide and replace it with an undamaged nucleotide complementary to that found in the undamaged DNA strand.
- Base excision repair (BER), which repairs damage to a single nucleotide caused by oxidation, alkylation, hydrolysis, or deamination. The base is removed with glycosylase and ultimately replaced by repair synthesis with DNA ligase.
- Nucleotide excision repair (NER), which repairs damage affecting longer strands of 2–30 bases. This process recognizes bulky, helix-distorting changes such as thymine dimers as well as single-strand breaks (repaired with enzymes such UvrABC endonuclease). A specialized form of NER known as Transcription-Coupled Repair (TCR) deploys high-priority NER repair enzymes to genes that are being actively transcribed.
- Mismatch repair (MMR), which corrects errors of DNA replication and recombination that result in mispaired (but normal, that is non- damaged) nucleotides following DNA replication.
## Double-strand breaks
Double-strand breaks (DSBs), in which both strands in the double helix are severed, are particularly hazardous to the cell because they can lead to genome rearrangements. Two mechanisms exist to repair DSBs: non-homologous end joining (NHEJ) and recombinational repair (also known as template-assisted repair or homologous recombination repair).
In NHEJ, DNA Ligase IV, a specialized DNA Ligase that forms a complex with the cofactor XRCC4, directly joins the two ends. To guide accurate repair, NHEJ relies on short homologous sequences called microhomologies present on the single-stranded tails of the DNA ends to be joined. If these overhangs are compatible, repair is usually accurate. NHEJ can also introduce mutations during repair. Loss of damaged nucleotides at the break site can lead to deletions, and joining of nonmatching termini forms translocations. NHEJ is especially important before the cell has replicated its DNA, since there is no template available for repair by homologous recombination. There are "backup" NHEJ pathways in higher eukaryotes. Besides its role as a genome caretaker, NHEJ is required for joining hairpin-capped double-strand breaks induced during V(D)J recombination, the process that generates diversity in B-cell and T-cell receptors in the vertebrate immune system.
Recombinational repair requires the presence of an identical or nearly identical sequence to be used as a template for repair of the break. The enzymatic machinery responsible for this repair process is nearly identical to the machinery responsible for chromosomal crossover during meiosis. This pathway allows a damaged chromosome to be repaired using a sister chromatid (available in G2 after DNA replication) or a homologous chromosome as a template. DSBs caused by the replication machinery attempting to synthesize across a single-strand break or unrepaired lesion cause collapse of the replication fork and are typically repaired by recombination.
Topoisomerases introduce both single- and double-strand breaks in the course of changing the DNA's state of supercoiling, which is especially common in regions near an open replication fork. Such breaks are not considered DNA damage because they are a natural intermediate in the topoisomerase biochemical mechanism and are immediately repaired by the enzymes that created them.
A team of French researchers bombarded Deinococcus radiodurans to study the mechanism of double-strand break DNA repair in that organism. At least two copies of the genome, with random DNA breaks, can form DNA fragments through annealing. Partially overlapping fragments are then used for synthesis of homologous regions through a moving D-loop that can continue extension until they find complementary partner strands. In the final step there is crossover by means of RecA-dependent homologous recombination.
## Translesion synthesis
Translesion synthesis allows the DNA replication machinery to replicate past damaged DNA. This involves the use of specialized translesion DNA polymerases that can insert bases at the site of damage. Some mechanisms of translesion synthesis introduce mutations, but others do not. For example, Pol η mediates error-free bypass of lesions induced by UV irradiation, whereas Pol ζ introduces mutations at these sites. From the cell's perspective, the potential for introducing mutations during translesion synthesis is less dangerous than continuing the cell cycle with an incompletely replicated chromosome.
# Global response to DNA damage
Cells exposed to ionizing radiation, ultraviolet light or chemicals are prone to acquire multiple sites of bulky DNA lesions and double strand breaks. Moreover, DNA damaging agents can damage other biomolecules such as proteins, carbohydrates, lipids and RNA. The accumulation of damage, specifically double strand breaks or adducts stalling the replication forks, are among known stimulation signals for a global response to DNA damage. The global response to damage is an act directed toward the cells' own preservation and triggers multiple pathways of macromolecular repair, lesion bypass, tolerance or apoptosis. The common features of global response are induction of multiple genes, cell cycle arrest, and inhibition of cell division.
## DNA damage checkpoints
After DNA damage, cell cycle checkpoints are activated. Checkpoint activation pauses the cell cycle and gives the cell time to repair the damage before continuing to divide. DNA damage checkpoints occur at the G1/S and G2/M boundaries. An intra-S checkpoint also exists. Checkpoint activation is controlled by two master kinases, ATM and ATR. ATM responds to DNA double-strand breaks and disruptions in chromatin structure, whereas ATR primarily responds to stalled replication forks. These kinases phosphorylate downstream targets in a signal transduction cascade, eventually leading to cell cycle arrest. A class of checkpoint mediator proteins including BRCA1, MDC1, and 53BP1 has also been identified. These proteins seem to be required for transmitting the checkpoint activation signal to downstream proteins.
p53 is an important downstream target of ATM and ATR, as it is required for inducing apoptosis following DNA damage. At the G1/S checkpoint, p53 functions by deactivating the CDK2/cyclin E complex. Similarly, p21 mediates the G2/M checkpoint by deactivating the CDK1/cyclin B complex.
## The prokaryotic SOS response
The SOS response is the term used to describe changes in gene expression in Escherichia coli and other bacteria in response to DNA damage. The prokaryotic SOS system is regulated by two key proteins: LexA and RecA. The LexA homodimer is a transcriptional repressor that binds to operator sequences commonly referred to as SOS boxes. It is known that LexA regulates transcription of approximately 48 genes including the lexA and recA genes.
The most common cellular signals activating the SOS response are regions of single stranded DNA (ssDNA), arising from stalled replication forks or double strand breaks, which are processed by DNA helicase to separate the two DNA strands. Once the DNA damage is repaired or bypassed using polymerases or through recombination, the amount of single-stranded DNA in cells is decreased, lowering the amounts of RecA filaments decreases cleavage activity of LexA homodimer which subsequently binds to the SOS boxes near promoters and restores normal gene expression.
## Eukaryotic transcriptional responses to DNA damage
Eukaryotic cells exposed to DNA damaging agents also activate important defensive pathways by inducing multiple proteins involved in DNA repair, cell cycle checkpoint control, protein trafficking and degradation. Such genome wide transcriptional response is very complex and tightly regulated, thus allowing coordinated global response to damage. Exposure of yeast Saccharomyces cerevisiae to DNA damaging agents results in overlapping but distinct transcriptional profiles. Similarities to environmental shock response indicates that a general global stress response pathway exist at the level of transcriptional activation. In contrast, different human cell types respond to damage differently indicating an absence of a common global response. The probable explanation for this difference between yeast and human cells may be in the heterogeneity of mammalian cells. In an animal different types of cells are distributed amongst different organs which have evolved different sensitivities to DNA damage.
In general global response to DNA damage involves expression of multiple genes responsible for postreplication repair, homologous recombination, nucleotide excision repair, DNA damage checkpoint, global transcriptional activation, genes controlling mRNA decay and many others. The vast amount of damage to a cell leaves it with an important decision; undergo apoptosis and die, or survive at the cost of living with a modified genome. An increase in tolerance to damage can lead to an increased rate of survival which will allow a greater accumulation of mutations. Yeast Rev1 and human polymerase η are members of
# DNA repair and aging
## Pathological effects of poor DNA repair
Experimental animals with genetic deficiencies in DNA repair often show decreased lifespan and increased cancer incidence. For example, mice deficient in the dominant NHEJ pathway and in telomere maintenance mechanisms get lymphoma and infections more often, and consequently have shorter lifespans than wild-type mice. Similarly, mice deficient in a key repair and transcription protein that unwinds DNA helices have premature onset of aging-related diseases and consequent shortening of lifespan. However, not every DNA repair deficiency creates exactly the predicted effects; mice deficient in the NER pathway exhibited shortened lifespan without correspondingly higher rates of mutation.
If the rate of DNA damage exceeds the capacity of the cell to repair it, the accumulation of errors can overwhelm the cell and result in early senescence, apoptosis or cancer. Inherited diseases associated with faulty DNA repair functioning result in premature aging, increased sensitivity to carcinogens, and correspondingly increased cancer risk (see below). On the other hand, organisms with enhanced DNA repair systems, such as Deinococcus radiodurans, the most radiation-resistant known organism, exhibit remarkable resistance to the double strand break-inducing effects of radioactivity, likely due to enhanced efficiency of DNA repair and especially NHEJ. It is noteworthy that some works suggest that if a DNA damage event occurs during the self repair process then the combination of the two events will exert an effect greater than the sum of the individual events (if they occurred with a long time delay between them), this is the basis of the second event theory favoured by C. Busby (The Low Level Radiation Campaign).
## Longevity and caloric restriction
A number of individual genes have been identified as influencing variations in lifespan within a population of organisms. The effects of these genes is strongly dependent on the environment, particularly on the organism's diet. Caloric restriction reproducibly results in extended lifespan in a variety of organisms, likely via nutrient sensing pathways and decreased metabolic rate. The molecular mechanisms by which such restriction results in lengthened lifespan are as yet unclear (see for some discussion); however, the behavior of many genes known to be involved in DNA repair is altered under conditions of caloric restriction.
For example, increasing the gene dosage of the gene SIR-2, which regulates DNA packaging in the nematode worm Caenorhabditis elegans, can significantly extend lifespan. The mammalian homolog of SIR-2 is known to induce downstream DNA repair factors involved in NHEJ, an activity that is especially promoted under conditions of caloric restriction. Caloric restriction has been closely linked to the rate of base excision repair in the nuclear DNA of rodents, although similar effects have not been observed in mitochondrial DNA.
Interestingly, the C. elegans gene AGE-1, an upstream effector of DNA repair pathways, confers dramatically extended lifespan under free-feeding conditions but leads to a decrease in reproductive fitness under conditions of caloric restriction. This observation supports the pleiotropy theory of the biological origins of aging, which suggests that genes conferring a large survival advantage early in life will be selected for even if they carry a corresponding disadvantage late in life.
# Medicine and DNA repair modulation
## Hereditary DNA repair disorders
Defects in the NER mechanism are responsible for several genetic disorders, including:
- xeroderma pigmentosum: hypersensitivity to sunlight/UV, resulting in increased skin cancer incidence and premature aging
- Cockayne syndrome: hypersensitivity to UV and chemical agents
- trichothiodystrophy: sensitive skin, brittle hair and nails
Mental retardation often accompanies the latter two disorders, suggesting increased vulnerability of developmental neurons.
Other DNA repair disorders include:
- Werner's syndrome: premature aging and retarded growth
- Bloom's syndrome: sunlight hypersensitivity, high incidence of malignancies (especially leukemias).
- ataxia telangiectasia: sensitivity to ionizing radiation and some chemical agents
All of the above diseases are often called "segmental progerias" ("accelerated aging diseases") because their victims appear elderly and suffer from aging-related diseases at an abnormally young age.
Other diseases associated with reduced DNA repair function include Fanconi's anemia, hereditary breast cancer and hereditary colon cancer.
## DNA repair and cancer
Inherited mutations that affect DNA repair genes are strongly associated with high cancer risks in humans. Hereditary nonpolyposis colorectal cancer (HNPCC) is strongly associated with specific mutations in the DNA mismatch repair pathway. BRCA1 and BRCA2, two famous mutations conferring a hugely increased risk of breast cancer on carriers, are both associated with a large number of DNA repair pathways, especially NHEJ and homologous recombination.
Cancer therapy procedures such as chemotherapy and radiotherapy work by overwhelming the capacity of the cell to repair DNA damage, resulting in cell death. Cells that are most rapidly dividing - most typically cancer cells - are preferentially affected. The side effect is that other non-cancerous but rapidly dividing cells such as stem cells in the bone marrow are also affected. Modern cancer treatments attempt to localize the DNA damage to cells and tissues only associated with cancer, either by physical means (concentrating the therapeutic agent in the region of the tumor) or by biochemical means (exploiting a feature unique to cancer cells in the body).
# DNA repair and evolution
The basic processes of DNA repair are highly conserved among both prokaryotes and eukaryotes and even among bacteriophage (viruses that infect bacteria); however, more complex organisms with more complex genomes have correspondingly more complex repair mechanisms. The ability of a large number of protein structural motifs to catalyze relevant chemical reactions has played a significant role in the elaboration of repair mechanisms during evolution. For an extremely detailed review of hypotheses relating to the evolution of DNA repair, see.
The fossil record indicates that single celled life began to proliferate on the planet at some point during the Precambrian period, although exactly when recognizably modern life first emerged is unclear. Nucleic acids became the sole and universal means of encoding genetic information, requiring DNA repair mechanisms that in their basic form have been inherited by all extant life forms from their common ancestor. The emergence of Earth's oxygen-rich atmosphere (known as the "oxygen catastrophe") due to photosynthetic organisms, as well as the presence of potentially damaging free radicals in the cell due to oxidative phosphorylation, necessitated the evolution of DNA repair mechanisms that act specifically to counter the types of damage induced by oxidative stress.
## Rate of evolutionary change
On some occasions, DNA damage is not repaired, or is repaired by an error-prone mechanism which results in a change from the original sequence. When this occurs, mutations may propagate into the genomes of the cell's progeny. Should such an event occur in a germ line cell that will eventually produce a gamete, the mutation has the potential to be passed on to the organism's offspring. The rate of evolution in a particular species (or, more narrowly, in a particular gene) is a function of the rate of mutation. Consequently, the rate and accuracy of DNA repair mechanims have an influence over the process of evolutionary change. | DNA repair
DNA repair refers to a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as UV light can cause DNA damage, resulting in as many as 1 million individual molecular lesions per cell per day.[1] Many of these lesions cause structural damage to the DNA molecule and can alter or eliminate the cell's ability to transcribe the gene that the affected DNA encodes. Other lesions induce potentially harmful mutations in the cell's genome, which affect the survival of its daughter cells after it undergoes mitosis. Consequently, the DNA repair process must be constantly active so it can respond rapidly to any damage in the DNA structure.
The rate of DNA repair is dependent on many factors, including the cell type, the age of the cell, and the extracellular environment. A cell that has accumulated a large amount of DNA damage, or one that no longer effectively repairs damage incurred to its DNA, can enter one of three possible states:
- an irreversible state of dormancy, known as senescence
- cell suicide, also known as apoptosis or programmed cell death
- unregulated cell division, which can lead to the formation of a tumor that is cancerous
The DNA repair ability of a cell is vital to the integrity of its genome and thus to its normal functioning and that of the organism. Many genes that were initially shown to influence lifespan have turned out to be involved in DNA damage repair and protection.[2] Failure to correct molecular lesions in cells that form gametes can introduce mutations into the genomes of the offspring and thus influence the rate of evolution.
# DNA damage
DNA damage, due to environmental factors and normal metabolic processes inside the cell, occurs at a rate of 1,000 to 1,000,000 molecular lesions per cell per day.[1] While this constitutes only 0.000165% of the human genome's approximately 6 billion bases (3 billion base pairs), unrepaired lesions in critical genes (such as tumor suppressor genes) can impede a cell's ability to carry out its function and appreciably increase the likelihood of tumor formation.
The vast majority of DNA damage affects the primary structure of the double helix; that is, the bases themselves are chemically modified. These modifications can in turn disrupt the molecules' regular helical structure by introducing non-native chemical bonds or bulky adducts that do not fit in the standard double helix. Unlike proteins and RNA, DNA usually lacks tertiary structure and therefore damage or disturbance does not occur at that level. DNA is, however, supercoiled and wound around "packaging" proteins called histones (in eukaryotes), and both superstructures are vulnerable to the effects of DNA damage.
## Sources of damage
DNA damage can be subdivided into two main types:
- endogenous damage such as attack by reactive oxygen species produced from normal metabolic byproducts (spontaneous mutation), especially the process of oxidative deamination;
- exogenous damage caused by external agents such as
ultraviolet [UV 200-300nm] radiation from the sun
other radiation frequencies, including x-rays and gamma rays
hydrolysis or thermal disruption
certain plant toxins
human-made mutagenic chemicals, especially aromatic compounds that act as DNA intercalating agents
cancer chemotherapy and radiotherapy
- ultraviolet [UV 200-300nm] radiation from the sun
- other radiation frequencies, including x-rays and gamma rays
- hydrolysis or thermal disruption
- certain plant toxins
- human-made mutagenic chemicals, especially aromatic compounds that act as DNA intercalating agents
- cancer chemotherapy and radiotherapy
The replication of damaged DNA before cell division can lead to the incorporation of wrong bases opposite damaged ones. Daughter cells that inherit these wrong bases carry mutations from which the original DNA sequence is unrecoverable (except in the rare case of a back mutation, for example, through gene conversion).
## Types of damage
There are four main types of damage to DNA due to endogenous cellular processes:
- oxidation of bases [e.g. 8-oxo-7,8-dihydroguanine (8-oxoG)] and generation of DNA strand interruptions from reactive oxygen species,
- alkylation of bases (usually methylation), such as formation of 7-methylguanine, 1-methyladenine, O6 methylguanine
- hydrolysis of bases, such as deamination, depurination and depyrimidination.
- mismatch of bases, due to errors in DNA replication, in which the wrong DNA base is stitched into place in a newly forming DNA strand, or a DNA base is skipped over or mistakenly inserted.
Damage caused by exogenous agents comes in many forms. Some examples are:
- UV light causes crosslinking between adjacent cytosine and thymine bases creating pyrimidine dimers
- Ionizing radiation such as that created by radioactive decay or in cosmic rays causes breaks in DNA strands.
- Thermal disruption at elevated temperature increases the rate of depurination (loss of purine bases from the DNA backbone) and single strand breaks. For example, hydrolytic depurination is seen in the thermophilic bacteria, which grow in hot springs at 85–250°C.[3] The rate of depurination (300 purine residues per genome per generation) is too high in these species to be repaired by normal repair machinery, hence a possibility of an adaptive response cannot be ruled out.
- Industrial chemicals such as vinyl chloride and hydrogen peroxide, and environmental chemicals such as polycyclic hydrocarbons found in smoke, soot and tar create a huge diversity of DNA adducts- ethenobases, oxidized bases, alkylated phosphotriesters and Crosslinking of DNA just to name a few.
UV damage, alkylation/methylation, X-ray damage and oxidative damage are examples of induced damage. Spontaneous damage can include the loss of a base, deamination, sugar ring puckering and tautomeric shift.
## Nuclear versus mitochondrial DNA damage
In human cells, and eukaryotic cells in general, DNA is found in two cellular locations - inside the nucleus and inside the mitochondria. Nuclear DNA (nDNA) exists as chromatin during non-replicative stages of the cell cycle and is condensed into aggregate structures known as chromosomes during cell division. In either state the DNA is highly compacted and wound up around bead-like proteins called histones. Whenever a cell needs to express the genetic information encoded in its nDNA the required chromosomal region is unravelled, genes located therein are expressed, and then the region is condensed back to its resting conformation. Mitochondrial DNA (mtDNA) is located inside mitochondria organelles, exists in multiple copies, and is also tightly associated with a number of proteins to form a complex known as the nucleoid. Inside mitochondria, reactive oxygen species (ROS), or free radicals, byproducts of the constant production of adenosine triphosphate (ATP) via oxidative phosphorylation, create a highly oxidative environment that is known to damage mtDNA. A critical enzyme in counteracting the toxicity of these species is superoxide dismutase, which is present in both the mitochondria and cytoplasm of eukaryotic cells.
## Senescence and apoptosis
Senescence, an irreversible state in which the cell no longer divides (mitosis), is a protective response to the shortening of the chromosome ends (telomeres). The telomeres are long regions of repetitive noncoding DNA that cap chromosomes and undergo partial degradation each time a cell undergoes division (see Hayflick limit).[4] In contrast, quiescence is a reversible state of cellular dormancy that is unrelated to genome damage (see cell cycle). Senescence in cells may serve as a functional alternative to apoptosis in cases where the physical presence of a cell for spatial reasons is required by the organism,[5] which serves as a "last resort" mechanism to prevent a cell with damaged DNA from replicating inappropriately in the absence of pro-growth cellular signaling. Unregulated cell division can lead to the formation of a tumor (see cancer), which is potentially lethal to an organism. Therefore the induction of senescence and apoptosis is considered to be part of a strategy of protection against cancer.
# DNA repair mechanisms
Cells cannot function if DNA damage corrupts the integrity and accessibility of essential information in the genome (but cells remain superficially functional when so-called "non-essential" genes are missing or damaged). Depending on the type of damage inflicted on the DNA's double helical structure, a variety of repair strategies have evolved to restore lost information. If possible, cells use the unmodified complementary strand of the DNA or the sister chromatid as a template to losslessly recover the original information. Without access to a template, cells use an error-prone recovery mechanism known as translesion synthesis as a last resort.
Damage to DNA alters the spatial configuration of the helix and such alterations can be detected by the cell. Once damage is localized, specific DNA repair molecules are summoned to, and bind at or near the site of damage, inducing other molecules to bind and form a complex that enables the actual repair to take place. The types of molecules involved and the mechanism of repair that is mobilized depend on the type of damage that has occurred and the phase of the cell cycle that the cell is in.
## Direct reversal
Cells are known to eliminate three types of damage to their DNA by chemically reversing it. These mechanisms do not require a template, since the types of damage they counteract can only occur in one of the four bases. Such direct reversal mechanisms are specific to the type of damage incurred and do not involve breakage of the phosphodiester backbone. The formation of thymine dimers (a common type of cyclobutyl dimer) upon irradiation with UV light results in an abnormal covalent bond between adjacent thymidine bases. The photoreactivation process directly reverses this damage by the action of the enzyme photolyase, whose activation is obligately dependent on energy absorbed from blue/UV light (300–500nm wavelength) to promote catalysis.[6] Another type of damage, methylation of guanine bases, is directly reversed by the protein methyl guanine methyl transferase (MGMT), the bacterial equivalent of which is called as ogt. This is an expensive process because each MGMT molecule can only be used once; that is, the reaction is stoichiometric rather than catalytic.[7] A generalized response to methylating agents in bacteria is known as the adaptive response and confers a level of resistance to alkylating agents upon sustained exposure by upregulation of alkylation repair enzymes.[8] The third type of DNA damage reversed by cells is certain methylation of the bases cytosine and adenine.
## Single strand damage
When only one of the two strands of a double helix has a defect, the other strand can be used as a template to guide the correction of the damaged strand. In order to repair damage to one of the two paired molecules of DNA, there exist a number of excision repair mechanisms that remove the damaged nucleotide and replace it with an undamaged nucleotide complementary to that found in the undamaged DNA strand.[7]
- Base excision repair (BER), which repairs damage to a single nucleotide caused by oxidation, alkylation, hydrolysis, or deamination. The base is removed with glycosylase and ultimately replaced by repair synthesis with DNA ligase.
- Nucleotide excision repair (NER), which repairs damage affecting longer strands of 2–30 bases. This process recognizes bulky, helix-distorting changes such as thymine dimers as well as single-strand breaks (repaired with enzymes such UvrABC endonuclease). A specialized form of NER known as Transcription-Coupled Repair (TCR) deploys high-priority NER repair enzymes to genes that are being actively transcribed.
- Mismatch repair (MMR), which corrects errors of DNA replication and recombination that result in mispaired (but normal, that is non- damaged) nucleotides following DNA replication.
## Double-strand breaks
Double-strand breaks (DSBs), in which both strands in the double helix are severed, are particularly hazardous to the cell because they can lead to genome rearrangements. Two mechanisms exist to repair DSBs: non-homologous end joining (NHEJ) and recombinational repair (also known as template-assisted repair or homologous recombination repair).[7]
In NHEJ, DNA Ligase IV, a specialized DNA Ligase that forms a complex with the cofactor XRCC4, directly joins the two ends.[9] To guide accurate repair, NHEJ relies on short homologous sequences called microhomologies present on the single-stranded tails of the DNA ends to be joined. If these overhangs are compatible, repair is usually accurate.[10][11][12][13] NHEJ can also introduce mutations during repair. Loss of damaged nucleotides at the break site can lead to deletions, and joining of nonmatching termini forms translocations. NHEJ is especially important before the cell has replicated its DNA, since there is no template available for repair by homologous recombination. There are "backup" NHEJ pathways in higher eukaryotes.[14] Besides its role as a genome caretaker, NHEJ is required for joining hairpin-capped double-strand breaks induced during V(D)J recombination, the process that generates diversity in B-cell and T-cell receptors in the vertebrate immune system.[15]
Recombinational repair requires the presence of an identical or nearly identical sequence to be used as a template for repair of the break. The enzymatic machinery responsible for this repair process is nearly identical to the machinery responsible for chromosomal crossover during meiosis. This pathway allows a damaged chromosome to be repaired using a sister chromatid (available in G2 after DNA replication) or a homologous chromosome as a template. DSBs caused by the replication machinery attempting to synthesize across a single-strand break or unrepaired lesion cause collapse of the replication fork and are typically repaired by recombination.
Topoisomerases introduce both single- and double-strand breaks in the course of changing the DNA's state of supercoiling, which is especially common in regions near an open replication fork. Such breaks are not considered DNA damage because they are a natural intermediate in the topoisomerase biochemical mechanism and are immediately repaired by the enzymes that created them.
A team of French researchers bombarded Deinococcus radiodurans to study the mechanism of double-strand break DNA repair in that organism. At least two copies of the genome, with random DNA breaks, can form DNA fragments through annealing. Partially overlapping fragments are then used for synthesis of homologous regions through a moving D-loop that can continue extension until they find complementary partner strands. In the final step there is crossover by means of RecA-dependent homologous recombination.[16]
## Translesion synthesis
Translesion synthesis allows the DNA replication machinery to replicate past damaged DNA. This involves the use of specialized translesion DNA polymerases that can insert bases at the site of damage. Some mechanisms of translesion synthesis introduce mutations, but others do not. For example, Pol η mediates error-free bypass of lesions induced by UV irradiation, whereas Pol ζ introduces mutations at these sites. From the cell's perspective, the potential for introducing mutations during translesion synthesis is less dangerous than continuing the cell cycle with an incompletely replicated chromosome.
# Global response to DNA damage
Cells exposed to ionizing radiation, ultraviolet light or chemicals are prone to acquire multiple sites of bulky DNA lesions and double strand breaks. Moreover, DNA damaging agents can damage other biomolecules such as proteins, carbohydrates, lipids and RNA. The accumulation of damage, specifically double strand breaks or adducts stalling the replication forks, are among known stimulation signals for a global response to DNA damage.[17] The global response to damage is an act directed toward the cells' own preservation and triggers multiple pathways of macromolecular repair, lesion bypass, tolerance or apoptosis. The common features of global response are induction of multiple genes, cell cycle arrest, and inhibition of cell division.
## DNA damage checkpoints
After DNA damage, cell cycle checkpoints are activated. Checkpoint activation pauses the cell cycle and gives the cell time to repair the damage before continuing to divide. DNA damage checkpoints occur at the G1/S and G2/M boundaries. An intra-S checkpoint also exists. Checkpoint activation is controlled by two master kinases, ATM and ATR. ATM responds to DNA double-strand breaks and disruptions in chromatin structure,[18] whereas ATR primarily responds to stalled replication forks. These kinases phosphorylate downstream targets in a signal transduction cascade, eventually leading to cell cycle arrest. A class of checkpoint mediator proteins including BRCA1, MDC1, and 53BP1 has also been identified.[19] These proteins seem to be required for transmitting the checkpoint activation signal to downstream proteins.
p53 is an important downstream target of ATM and ATR, as it is required for inducing apoptosis following DNA damage.[20] At the G1/S checkpoint, p53 functions by deactivating the CDK2/cyclin E complex. Similarly, p21 mediates the G2/M checkpoint by deactivating the CDK1/cyclin B complex.
## The prokaryotic SOS response
The SOS response is the term used to describe changes in gene expression in Escherichia coli and other bacteria in response to DNA damage. The prokaryotic SOS system is regulated by two key proteins: LexA and RecA. The LexA homodimer is a transcriptional repressor that binds to operator sequences commonly referred to as SOS boxes. It is known that LexA regulates transcription of approximately 48 genes including the lexA and recA genes.[21]
The most common cellular signals activating the SOS response are regions of single stranded DNA (ssDNA), arising from stalled replication forks or double strand breaks, which are processed by DNA helicase to separate the two DNA strands. Once the DNA damage is repaired or bypassed using polymerases or through recombination, the amount of single-stranded DNA in cells is decreased, lowering the amounts of RecA filaments decreases cleavage activity of LexA homodimer which subsequently binds to the SOS boxes near promoters and restores normal gene expression.
## Eukaryotic transcriptional responses to DNA damage
Eukaryotic cells exposed to DNA damaging agents also activate important defensive pathways by inducing multiple proteins involved in DNA repair, cell cycle checkpoint control, protein trafficking and degradation. Such genome wide transcriptional response is very complex and tightly regulated, thus allowing coordinated global response to damage. Exposure of yeast Saccharomyces cerevisiae to DNA damaging agents results in overlapping but distinct transcriptional profiles. Similarities to environmental shock response indicates that a general global stress response pathway exist at the level of transcriptional activation. In contrast, different human cell types respond to damage differently indicating an absence of a common global response. The probable explanation for this difference between yeast and human cells may be in the heterogeneity of mammalian cells. In an animal different types of cells are distributed amongst different organs which have evolved different sensitivities to DNA damage.[22]
In general global response to DNA damage involves expression of multiple genes responsible for postreplication repair, homologous recombination, nucleotide excision repair, DNA damage checkpoint, global transcriptional activation, genes controlling mRNA decay and many others. The vast amount of damage to a cell leaves it with an important decision; undergo apoptosis and die, or survive at the cost of living with a modified genome. An increase in tolerance to damage can lead to an increased rate of survival which will allow a greater accumulation of mutations. Yeast Rev1 and human polymerase η are members of [Y family translesion DNA polymerases present during global response to DNA damage and are responsible for enhanced mutagenesis during a global response to DNA damage in eukaryotes.[17]
# DNA repair and aging
## Pathological effects of poor DNA repair
Experimental animals with genetic deficiencies in DNA repair often show decreased lifespan and increased cancer incidence. For example, mice deficient in the dominant NHEJ pathway and in telomere maintenance mechanisms get lymphoma and infections more often, and consequently have shorter lifespans than wild-type mice.[23] Similarly, mice deficient in a key repair and transcription protein that unwinds DNA helices have premature onset of aging-related diseases and consequent shortening of lifespan.[24] However, not every DNA repair deficiency creates exactly the predicted effects; mice deficient in the NER pathway exhibited shortened lifespan without correspondingly higher rates of mutation.[25]
If the rate of DNA damage exceeds the capacity of the cell to repair it, the accumulation of errors can overwhelm the cell and result in early senescence, apoptosis or cancer. Inherited diseases associated with faulty DNA repair functioning result in premature aging, increased sensitivity to carcinogens, and correspondingly increased cancer risk (see below). On the other hand, organisms with enhanced DNA repair systems, such as Deinococcus radiodurans, the most radiation-resistant known organism, exhibit remarkable resistance to the double strand break-inducing effects of radioactivity, likely due to enhanced efficiency of DNA repair and especially NHEJ.[26] It is noteworthy that some works suggest that if a DNA damage event occurs during the self repair process then the combination of the two events will exert an effect greater than the sum of the individual events (if they occurred with a long time delay between them), this is the basis of the second event theory favoured by C. Busby (The Low Level Radiation Campaign).
## Longevity and caloric restriction
A number of individual genes have been identified as influencing variations in lifespan within a population of organisms. The effects of these genes is strongly dependent on the environment, particularly on the organism's diet. Caloric restriction reproducibly results in extended lifespan in a variety of organisms, likely via nutrient sensing pathways and decreased metabolic rate. The molecular mechanisms by which such restriction results in lengthened lifespan are as yet unclear (see[27] for some discussion); however, the behavior of many genes known to be involved in DNA repair is altered under conditions of caloric restriction.
For example, increasing the gene dosage of the gene SIR-2, which regulates DNA packaging in the nematode worm Caenorhabditis elegans, can significantly extend lifespan.[28] The mammalian homolog of SIR-2 is known to induce downstream DNA repair factors involved in NHEJ, an activity that is especially promoted under conditions of caloric restriction.[29] Caloric restriction has been closely linked to the rate of base excision repair in the nuclear DNA of rodents,[30] although similar effects have not been observed in mitochondrial DNA.[31]
Interestingly, the C. elegans gene AGE-1, an upstream effector of DNA repair pathways, confers dramatically extended lifespan under free-feeding conditions but leads to a decrease in reproductive fitness under conditions of caloric restriction.[32] This observation supports the pleiotropy theory of the biological origins of aging, which suggests that genes conferring a large survival advantage early in life will be selected for even if they carry a corresponding disadvantage late in life.
# Medicine and DNA repair modulation
## Hereditary DNA repair disorders
Defects in the NER mechanism are responsible for several genetic disorders, including:
- xeroderma pigmentosum: hypersensitivity to sunlight/UV, resulting in increased skin cancer incidence and premature aging
- Cockayne syndrome: hypersensitivity to UV and chemical agents
- trichothiodystrophy: sensitive skin, brittle hair and nails
Mental retardation often accompanies the latter two disorders, suggesting increased vulnerability of developmental neurons.
Other DNA repair disorders include:
- Werner's syndrome: premature aging and retarded growth
- Bloom's syndrome: sunlight hypersensitivity, high incidence of malignancies (especially leukemias).
- ataxia telangiectasia: sensitivity to ionizing radiation and some chemical agents
All of the above diseases are often called "segmental progerias" ("accelerated aging diseases") because their victims appear elderly and suffer from aging-related diseases at an abnormally young age.
Other diseases associated with reduced DNA repair function include Fanconi's anemia, hereditary breast cancer and hereditary colon cancer.
## DNA repair and cancer
Inherited mutations that affect DNA repair genes are strongly associated with high cancer risks in humans. Hereditary nonpolyposis colorectal cancer (HNPCC) is strongly associated with specific mutations in the DNA mismatch repair pathway. BRCA1 and BRCA2, two famous mutations conferring a hugely increased risk of breast cancer on carriers, are both associated with a large number of DNA repair pathways, especially NHEJ and homologous recombination.
Cancer therapy procedures such as chemotherapy and radiotherapy work by overwhelming the capacity of the cell to repair DNA damage, resulting in cell death. Cells that are most rapidly dividing - most typically cancer cells - are preferentially affected. The side effect is that other non-cancerous but rapidly dividing cells such as stem cells in the bone marrow are also affected. Modern cancer treatments attempt to localize the DNA damage to cells and tissues only associated with cancer, either by physical means (concentrating the therapeutic agent in the region of the tumor) or by biochemical means (exploiting a feature unique to cancer cells in the body).
# DNA repair and evolution
The basic processes of DNA repair are highly conserved among both prokaryotes and eukaryotes and even among bacteriophage (viruses that infect bacteria); however, more complex organisms with more complex genomes have correspondingly more complex repair mechanisms.[33] The ability of a large number of protein structural motifs to catalyze relevant chemical reactions has played a significant role in the elaboration of repair mechanisms during evolution. For an extremely detailed review of hypotheses relating to the evolution of DNA repair, see.[34]
The fossil record indicates that single celled life began to proliferate on the planet at some point during the Precambrian period, although exactly when recognizably modern life first emerged is unclear. Nucleic acids became the sole and universal means of encoding genetic information, requiring DNA repair mechanisms that in their basic form have been inherited by all extant life forms from their common ancestor. The emergence of Earth's oxygen-rich atmosphere (known as the "oxygen catastrophe") due to photosynthetic organisms, as well as the presence of potentially damaging free radicals in the cell due to oxidative phosphorylation, necessitated the evolution of DNA repair mechanisms that act specifically to counter the types of damage induced by oxidative stress.
## Rate of evolutionary change
On some occasions, DNA damage is not repaired, or is repaired by an error-prone mechanism which results in a change from the original sequence. When this occurs, mutations may propagate into the genomes of the cell's progeny. Should such an event occur in a germ line cell that will eventually produce a gamete, the mutation has the potential to be passed on to the organism's offspring. The rate of evolution in a particular species (or, more narrowly, in a particular gene) is a function of the rate of mutation. Consequently, the rate and accuracy of DNA repair mechanims have an influence over the process of evolutionary change.[35] | https://www.wikidoc.org/index.php/DNA_damage | |
7ed36e6cba065375d8217a3b15777e1ca80469cd | wikidoc | DNA ladder | DNA ladder
A DNA ladder is a solution of DNA molecules of different lengths used in agarose gel electrophoresis. It is applied to an agarose gel as a reference to estimate the size of unknown DNA molecules. In addition it can be used to approximate the mass of a band by comparison to a special mass ladder.
Different DNA ladders are commercially available depending on expected DNA length. The 1kb ladder with fragment ranging from about 0.5 kbp to 10 or 12 kbp and the 100 bp ladder with fragments ranging from 100 bp to just above 1000 bp are the most frequent. DNA ladders are often produced by a suitable restriction digest of a plasmid. There are special DNA ladders for supercoiled DNA and RNA.
For example, a λ DNA-HindIII Digest: a common lamdba DNA ladder that has band sizes (in base pairs) of 23 130 , 9 416, 6 557, 4 361, 2 322, 2 027, 564 , 125 bp | DNA ladder
A DNA ladder is a solution of DNA molecules of different lengths used in agarose gel electrophoresis. It is applied to an agarose gel as a reference to estimate the size of unknown DNA molecules. In addition it can be used to approximate the mass of a band by comparison to a special mass ladder.
Different DNA ladders are commercially available depending on expected DNA length. The 1kb ladder with fragment ranging from about 0.5 kbp to 10 or 12 kbp and the 100 bp ladder with fragments ranging from 100 bp to just above 1000 bp are the most frequent. DNA ladders are often produced by a suitable restriction digest of a plasmid. There are special DNA ladders for supercoiled DNA and RNA.
For example, a λ DNA-HindIII Digest: a common lamdba DNA ladder that has band sizes (in base pairs) of 23 130 , 9 416, 6 557, 4 361, 2 322, 2 027, 564 , 125 bp
http://www.neb.com/nebecomm/products/productN3012.asp | https://www.wikidoc.org/index.php/DNA_ladder | |
6b8a812285c61bb7b59e3213ca365419647dcc6b | wikidoc | Transposon | Transposon
# Overview
Transposons are sequences of DNA that can move around to different positions within the genome of a single cell, a process called transposition. In the process, they can cause mutations and change the amount of DNA in the genome. Transposons were also once called "jumping genes", and are examples of mobile genetic elements. Discovered by Barbara McClintock early in her career, the discovery earned her a Nobel prize in 1983.
There are a variety of mobile genetic elements, and they can be grouped based on their mechanism of transposition. Class I mobile genetic elements, or retrotransposons, move in the genome by being transcribed to RNA and then back to DNA by reverse transcriptase, while class II mobile genetic elements move directly from one position to another within the genome using a transposase to "cut and paste" them within the genome.
Transposons are very useful to researchers as a means to alter DNA inside of a living organism. Transposons make up a large fraction of genome sizes which is evident through the C-values of eukaryotic species.
# Types of transposons
Transposons are classified into two classes based on their mechanism of transposition.
## Class I: Retrotransposons
Retrotransposons work by copying themselves and pasting copies back into the genome in multiple places. Initially retrotransposons copy themselves to RNA (transcription) but, in addition to being transcribed, the RNA is copied into DNA by a reverse transcriptase (often coded by the transposon itself) and inserted back into the genome.
Retrotransposons behave very similarly to retroviruses, such as HIV, giving a clue to the evolutionary origins of such viruses.
There are three main classes of Retrotransposons:
- Viral: encode reverse transcriptase (to reverse transcribe RNA into DNA), have long terminal repeats (LTRs), similar to retroviruses
- LINEs: encode reverse transcriptase, lack LTRs, transcribed by RNA polymerase II
- Nonviral superfamily: do not code for reverse transcriptase, transcribed by RNA polymerase III
RETROVIRUSES AS TRANSPOSABLE ELEMENTS:
Retroviruses were first identified 80 years ago as agents involved in the onset of cancer. More recently the AIDS epidemic has been shown to be due to the HIV retrovirus. In the early 1970s it was discovered that retroviruses had the ability to replicate their RNA genomes via conversion into DNA which became stably integrated in the DNA of the host cell. It is only comparatively recently that retroviruses have been recognized as particularly specialized forms of eukaryotic transposons. In effect they are transposons which move via RNA intermediates that usually can leave the host cells and infect other cells. The integrated DNA form (provirus) of the retrovirus bears a marked similarity to a transposon.
The transposition cycle of retroviruses has other similarities to prokaryotic transposons,which suggest a distant familial relationship between these two types of transposon. Crucial intermediates in retrovirus transposition are extrachromosomal DNA molecules. These are generated by copying the RNA of the virus paticle into DNA by a retrovirus-encoded polymerase called reverse transcriptase. The extra chromosomal linear DNA is the direct precursor of the integrated element and the insertion mechanism bears a strong similarity to "cut and paste" transposition.
## Class II: DNA transposons
The major difference of Class II transposons from retrotransposons is that their transposition mechanism does not involve an RNA intermediate. Class II transposons usually move by cut and paste, rather than copy and paste, using the transposase enzyme. Different types of transposase work in different ways. Some can bind to any part of the DNA molecule, and the target site can therefore be anywhere, while others bind to specific sequences. Transposase makes a staggered cut at the target site producing sticky ends, cuts out the transposon and ligates it into the target site. A DNA polymerase fills in the resulting gaps from the sticky ends and DNA ligase closes the sugar-phosphate backbone. This results in target site duplication and the insertion sites of DNA transposons may be identified by short direct repeats (a staggered cut in the target DNA filled by DNA polymerase) followed by inverted repeats (which are important for the transposon excision by transposase).
Not all DNA transposons transpose through cut and paste mechanism. In some cases a replicative transposition is observed in which transposon replicates itself to a new target site.
The transposons which only move by cut and paste may duplicate themselves if the transposition happens during S phase of the cell cycle when the "donor" site has already been replicated, but the "target" site has not.
Both classes of transposon may lose their ability to synthesise reverse transcriptase or transposase through mutation, yet continue to jump through the genome because other transposons are still producing the necessary enzyme.
# Examples
- The first transposons were discovered in maize (Zea mays), (corn species) by Barbara McClintock in 1948, for which she was awarded a Nobel Prize in 1983. She noticed insertions, deletions, and translocations, caused by these transposons. These changes in the genome could, for example, lead to a change in the color of corn kernels. About 50% of the total genome of maize consists of transposons. The Ac/Ds system McClintock described are class II transposons.
- One family of transposons in the fruit fly Drosophila melanogaster are called P elements. They seem to have first appeared in the species only in the middle of the twentieth century. Within 50 years, they have spread through every population of the species. Gerald Rubin and Allan Spradling pioneered technology to use artificial P elements to insert genes into Drosophila by injecting the embryo.
- Transposons in bacteria usually carry an additional gene for function other than transposition---often for antibiotic resistance. In bacteria, transposons can jump from chromosomal DNA to plasmid DNA and back, allowing for the transfer and permanent addition of genes such as those encoding antibiotic resistance (multi-antibiotic resistant bacterial strains can be generated in this way). Bacterial transposons of this type belong to the Tn family. When the transposable elements lack additional genes, they are known as insertion sequences.
- The most common form of transposon in humans is the Alu sequence. The Alu sequence is approximately 300 bases long and can be found between 300,000 and a million times in the human genome.
- Mu phage transposition is the best known example of replicative transposition. Its transposition mechanism is somewhat similar to a homologous recombination.
# Transposons causing diseases
Transposons are mutagens. They can damage the genome of their host cell in different ways:
- A transposon or a retroposon that inserts itself into a functional gene will most likely disable that gene.
- After a transposon leaves a gene, the resulting gap will probably not be repaired correctly.
- Multiple copies of the same sequence, such as Alu sequences can hinder precise chromosomal pairing during mitosis, resulting in unequal crossovers, one of the main reasons for chromosome duplication.
Diseases that are often caused by transposons include hemophilia A and B, severe combined immunodeficiency, porphyria, predisposition to cancer, and Duchenne muscular dystrophy.
Additionally, many transposons contain promoters which drive transcription of their own transposase. These promoters can cause aberrant expression of linked genes, causing disease or mutant phenotypes.
# Evolution of transposons
The evolution of transposons and their effect on genome evolution is currently a dynamic field of study.
Transposons are found in all major branches of life. They may or may not have originated in the last universal common ancestor, or arisen independently multiple times, or perhaps arisen once and then spread to other kingdoms by horizontal gene transfer. While transposons may confer some benefits on their hosts, they are generally considered to be selfish DNA parasites that live within the genome of cellular organisms. In this way, they are similar to viruses. Viruses and transposons also share features in their genome structure and biochemical abilities, leading to speculation that they share a common ancestor.
Since excessive transposon activity can destroy a genome, many organisms seem to have developed mechanisms to reduce transposition to a manageable level. Bacteria may undergo high rates of gene deletion as part of a mechanism to remove transposons and viruses from their genomes while eukaryotic organisms may have developed the RNA interference (RNAi) mechanism as a way of reducing transposon activity. In the nematode Caenorhabditis elegans, some genes required for RNAi also reduce transposon activity.
Transposons may have been co-opted by the vertebrate immune system as a means of producing antibody diversity. The V(D)J recombination system operates by a mechanism similar to that of transposons.
Evidence exists that transposable elements may act as mutators in bacteria.
# Applications
Transposons were first discovered in the plant maize (Zea mays, corn species), which is named dissociator (Ds). Likewise, the first transposon to be molecularly isolated was from a plant (Snapdragon).
Appropriately, transposons have been an especially useful tool in plant molecular biology. Researchers use transposons as a means of mutagenesis. In this context, a transposon jumps into a gene and produces a mutation. The presence of the transposon provides a straightforward means of identifying the mutant allele, relative to chemical mutagenesis methods.
Sometimes the insertion of a transposon into a gene can disrupt that gene's function in a reversible manner; transposase mediated excision of the transposon restores gene function. This produces plants in which neighboring cells have different genotypes. This feature allows researchers to distinguish between genes that must be present inside of a cell in order to function (cell-autonomous) and genes that produce observable effects in cells other than those where the gene is expressed.
Transposons are also a widely used tool for mutagenesis of all experimentally tractable organisms. | Transposon
# Overview
Transposons are sequences of DNA that can move around to different positions within the genome of a single cell, a process called transposition. In the process, they can cause mutations and change the amount of DNA in the genome. Transposons were also once called "jumping genes", and are examples of mobile genetic elements. Discovered by Barbara McClintock early in her career[1], the discovery earned her a Nobel prize in 1983.
There are a variety of mobile genetic elements, and they can be grouped based on their mechanism of transposition. Class I mobile genetic elements, or retrotransposons, move in the genome by being transcribed to RNA and then back to DNA by reverse transcriptase, while class II mobile genetic elements move directly from one position to another within the genome using a transposase to "cut and paste" them within the genome.
Transposons are very useful to researchers as a means to alter DNA inside of a living organism. Transposons make up a large fraction of genome sizes which is evident through the C-values of eukaryotic species.
# Types of transposons
Transposons are classified into two classes based on their mechanism of transposition.
## Class I: Retrotransposons
Retrotransposons work by copying themselves and pasting copies back into the genome in multiple places. Initially retrotransposons copy themselves to RNA (transcription) but, in addition to being transcribed, the RNA is copied into DNA by a reverse transcriptase (often coded by the transposon itself) and inserted back into the genome.
Retrotransposons behave very similarly to retroviruses, such as HIV, giving a clue to the evolutionary origins of such viruses.
There are three main classes of Retrotransposons:
- Viral: encode reverse transcriptase (to reverse transcribe RNA into DNA), have long terminal repeats (LTRs), similar to retroviruses
- LINEs: encode reverse transcriptase, lack LTRs, transcribed by RNA polymerase II
- Nonviral superfamily: do not code for reverse transcriptase, transcribed by RNA polymerase III
RETROVIRUSES AS TRANSPOSABLE ELEMENTS:
Retroviruses were first identified 80 years ago as agents involved in the onset of cancer. More recently the AIDS epidemic has been shown to be due to the HIV retrovirus. In the early 1970s it was discovered that retroviruses had the ability to replicate their RNA genomes via conversion into DNA which became stably integrated in the DNA of the host cell. It is only comparatively recently that retroviruses have been recognized as particularly specialized forms of eukaryotic transposons. In effect they are transposons which move via RNA intermediates that usually can leave the host cells and infect other cells. The integrated DNA form (provirus) of the retrovirus bears a marked similarity to a transposon.
The transposition cycle of retroviruses has other similarities to prokaryotic transposons,which suggest a distant familial relationship between these two types of transposon. Crucial intermediates in retrovirus transposition are extrachromosomal DNA molecules. These are generated by copying the RNA of the virus paticle into DNA by a retrovirus-encoded polymerase called reverse transcriptase. The extra chromosomal linear DNA is the direct precursor of the integrated element and the insertion mechanism bears a strong similarity to "cut and paste" transposition.
## Class II: DNA transposons
The major difference of Class II transposons from retrotransposons is that their transposition mechanism does not involve an RNA intermediate. Class II transposons usually move by cut and paste, rather than copy and paste, using the transposase enzyme. Different types of transposase work in different ways. Some can bind to any part of the DNA molecule, and the target site can therefore be anywhere, while others bind to specific sequences. Transposase makes a staggered cut at the target site producing sticky ends, cuts out the transposon and ligates it into the target site. A DNA polymerase fills in the resulting gaps from the sticky ends and DNA ligase closes the sugar-phosphate backbone. This results in target site duplication and the insertion sites of DNA transposons may be identified by short direct repeats (a staggered cut in the target DNA filled by DNA polymerase) followed by inverted repeats (which are important for the transposon excision by transposase).
Not all DNA transposons transpose through cut and paste mechanism. In some cases a replicative transposition is observed in which transposon replicates itself to a new target site.
The transposons which only move by cut and paste may duplicate themselves if the transposition happens during S phase of the cell cycle when the "donor" site has already been replicated, but the "target" site has not.
Both classes of transposon may lose their ability to synthesise reverse transcriptase or transposase through mutation, yet continue to jump through the genome because other transposons are still producing the necessary enzyme.
# Examples
- The first transposons were discovered in maize (Zea mays), (corn species) by Barbara McClintock in 1948, for which she was awarded a Nobel Prize in 1983. She noticed insertions, deletions, and translocations, caused by these transposons. These changes in the genome could, for example, lead to a change in the color of corn kernels. About 50% of the total genome of maize consists of transposons. The Ac/Ds system McClintock described are class II transposons.
- One family of transposons in the fruit fly Drosophila melanogaster are called P elements. They seem to have first appeared in the species only in the middle of the twentieth century. Within 50 years, they have spread through every population of the species. Gerald Rubin and Allan Spradling pioneered technology to use artificial P elements to insert genes into Drosophila by injecting the embryo.[2][3][4]
- Transposons in bacteria usually carry an additional gene for function other than transposition---often for antibiotic resistance. In bacteria, transposons can jump from chromosomal DNA to plasmid DNA and back, allowing for the transfer and permanent addition of genes such as those encoding antibiotic resistance (multi-antibiotic resistant bacterial strains can be generated in this way). Bacterial transposons of this type belong to the Tn family. When the transposable elements lack additional genes, they are known as insertion sequences.
- The most common form of transposon in humans is the Alu sequence. The Alu sequence is approximately 300 bases long and can be found between 300,000 and a million times in the human genome.
- Mu phage transposition is the best known example of replicative transposition. Its transposition mechanism is somewhat similar to a homologous recombination.
# Transposons causing diseases
Transposons are mutagens. They can damage the genome of their host cell in different ways:
- A transposon or a retroposon that inserts itself into a functional gene will most likely disable that gene.
- After a transposon leaves a gene, the resulting gap will probably not be repaired correctly.
- Multiple copies of the same sequence, such as Alu sequences can hinder precise chromosomal pairing during mitosis, resulting in unequal crossovers, one of the main reasons for chromosome duplication.
Diseases that are often caused by transposons include hemophilia A and B, severe combined immunodeficiency, porphyria, predisposition to cancer, and Duchenne muscular dystrophy.
Additionally, many transposons contain promoters which drive transcription of their own transposase. These promoters can cause aberrant expression of linked genes, causing disease or mutant phenotypes.
# Evolution of transposons
The evolution of transposons and their effect on genome evolution is currently a dynamic field of study.
Transposons are found in all major branches of life. They may or may not have originated in the last universal common ancestor, or arisen independently multiple times, or perhaps arisen once and then spread to other kingdoms by horizontal gene transfer. While transposons may confer some benefits on their hosts, they are generally considered to be selfish DNA parasites that live within the genome of cellular organisms. In this way, they are similar to viruses. Viruses and transposons also share features in their genome structure and biochemical abilities, leading to speculation that they share a common ancestor.
Since excessive transposon activity can destroy a genome, many organisms seem to have developed mechanisms to reduce transposition to a manageable level. Bacteria may undergo high rates of gene deletion as part of a mechanism to remove transposons and viruses from their genomes while eukaryotic organisms may have developed the RNA interference (RNAi) mechanism as a way of reducing transposon activity. In the nematode Caenorhabditis elegans, some genes required for RNAi also reduce transposon activity.
Transposons may have been co-opted by the vertebrate immune system as a means of producing antibody diversity. The V(D)J recombination system operates by a mechanism similar to that of transposons.
Evidence exists that transposable elements may act as mutators in bacteria.
# Applications
Transposons were first discovered in the plant maize (Zea mays, corn species), which is named dissociator (Ds). Likewise, the first transposon to be molecularly isolated was from a plant (Snapdragon).
Appropriately, transposons have been an especially useful tool in plant molecular biology. Researchers use transposons as a means of mutagenesis. In this context, a transposon jumps into a gene and produces a mutation. The presence of the transposon provides a straightforward means of identifying the mutant allele, relative to chemical mutagenesis methods.
Sometimes the insertion of a transposon into a gene can disrupt that gene's function in a reversible manner; transposase mediated excision of the transposon restores gene function. This produces plants in which neighboring cells have different genotypes. This feature allows researchers to distinguish between genes that must be present inside of a cell in order to function (cell-autonomous) and genes that produce observable effects in cells other than those where the gene is expressed.
Transposons are also a widely used tool for mutagenesis of all experimentally tractable organisms. | https://www.wikidoc.org/index.php/DNA_transposable_element | |
c7e544193b7e30c69bf9678f52cdc22884259aba | wikidoc | DUT (gene) | DUT (gene)
DUTP pyrophosphatase, also known as DUT, is an enzyme which in humans is encoded by the DUT gene on chromosome 15.
This gene encodes an essential enzyme of nucleotide metabolism. The encoded protein forms a ubiquitous, homotrimeric enzyme that hydrolyzes dUTP to dUMP and pyrophosphate. This reaction serves two cellular purposes: providing a precursor (dUMP) for the synthesis of thymine nucleotides needed for DNA replication, and limiting intracellular pools of dUTP. Elevated levels of dUTP lead to increased incorporation of uracil into DNA, which induces extensive excision repair mediated by uracil glycosylase. This repair process, resulting in the removal and reincorporation of dUTP, is self-defeating and leads to DNA fragmentation and cell death. Alternative splicing of this gene leads to different isoforms that localize to either the mitochondrion or nucleus. A related pseudogene is located on chromosome 19.
# Structure
In humans, this gene encodes a homotrimeric enzyme with two isoforms characterized by their distinct subcellular localizations: the nuclear isoform (DUT-N) and mitochondrial isoform (DUT-M).
## Gene
Northern blot analysis reveals distinct mRNA transcripts for DUT-N (1.1 kb) and DUT-M (1.4 kb). The isoforms are produced from alternative splicing at different 5' exons, with the first exon of DUT-N occurring 767 base pairs downstream of the first exon in DUT-M. Regulation at different promoters has been proposed to account for the differential expression of these isoforms.
## Protein
The mature forms of DUT-N (22 kDa) and DUT-M (23 kDa) are nearly identical except for a short N-terminal region present in DUT-M. The DUT-M precursor (31 kDa) contains an arginine-rich, 69-residue mitochondrial targeting sequence which undergoes post-translational cleavage to effect mitochondrial import. Meanwhile, the monopartite NLS sequence is critical for the function and nuclear localization of DUT-N, which would otherwise accumulate in the cytoplasm. Though both isoforms contain the NLS, the sequence in DUT-M is sequestered away from cognate karyopherins. The isoelectric points of DUT-N (6.0) and DUT-M (8.1) correspond to the pH of their respective subcellular compartments.
DUT is a homotrimer with three active sites formed by each of its three subunits. Typically, each subunit forms an eight-stranded barrel that swaps C-terminal β-strands with the other subunits to assemble into the trimer structure. In addition to the β-strand swapping, these subunits interact via extended bimolecular interfaces and three-fold central channel.
As a member of the dUTPase family, DUT requires the presence of a divalent metal ion such as Mg2+ for their enzymatic function. DUT-N also contains a consensus cyclin-dependent kinase phosphorylation site that is phosphorylated at the serine as part of its cell cycle regulation.
# Function
DUT is a member of the dUTPase family, which is known for catalyzing the pyrophosphoralysis of dUTP into dUMP and inorganic pyrophosphate. This function contributes to DNA replication and repair via de novo thymidylate biosynthesis, as the dUMP product is methylated by thymidylate synthase (TS) to form dTMP, which is then phosphorylated to dTTP. DUT is also crucial for maintaining genome integrity by reducing cellular dUTP levels, thereby preventing the repeated cycles of uracil misincorporation into DNA and DNA repair-mediated strand breaks that would lead to cell death.
In addition to their different localizations, the two DUT isoforms display different expression patterns: while DUT-M is constitutively expressed, DUT-N is under cell cycle control and notably upregulated during S phase. These expression patterns correspond with their roles in the DNA replication cycle of their respective genomes, and thus indicate different regulatory mechanisms affecting each isoform.
## Mechanism
The dUTP hydrolysis cycle can be outlined in the following four enzymatic steps: (i) fast substrate binding, (ii) isomerization of the enzyme-substrate complex into the catalytically competent conformation, (iii) hydrolysis of the substrate, and (iv) rapid, non-ordered release of the products.
# Clinical significance
Since many chemotherapeutic agents such as 5-fluorouracil treat neoplastic diseases, including head and neck cancer, breast cancer, and gastrointestinal cancer, by targeting TS in thymidylate metabolism, DUT may protect against the cytotoxic side effects by countering dUTP accumulation. At the same time, high levels of DUT-N have been associated with chemoresistance and faster tumor progression, and thus, could also serve as a prognostic marker for overall survival and response to chemotherapy. Similarly, DUT is significantly overexpressed in hepatocellular carcinoma and may serve as a prognostic marker for the cancer. Notably, DUT expression is regulated by the tumor suppressor gene p53 in order to promote apoptosis of tumor cells. Abnormal DUT expression and localization has been speculated to promote cancer transformation.
# Interactions
DUT interacts with dUTP to catalyze its hydrolysis into dUMP and pyrophosphate. E2F and Sp1 enhance DUT expression by binding its promoter, while p53 inhibits DUT transcription by binding its promoter. A putative NF-κB binding site was also identified in the DUT promoter. | DUT (gene)
DUTP pyrophosphatase, also known as DUT, is an enzyme which in humans is encoded by the DUT gene on chromosome 15.[1]
This gene encodes an essential enzyme of nucleotide metabolism. The encoded protein forms a ubiquitous, homotrimeric enzyme that hydrolyzes dUTP to dUMP and pyrophosphate. This reaction serves two cellular purposes: providing a precursor (dUMP) for the synthesis of thymine nucleotides needed for DNA replication, and limiting intracellular pools of dUTP. Elevated levels of dUTP lead to increased incorporation of uracil into DNA, which induces extensive excision repair mediated by uracil glycosylase. This repair process, resulting in the removal and reincorporation of dUTP, is self-defeating and leads to DNA fragmentation and cell death. Alternative splicing of this gene leads to different isoforms that localize to either the mitochondrion or nucleus. A related pseudogene is located on chromosome 19.[1]
# Structure
In humans, this gene encodes a homotrimeric enzyme with two isoforms characterized by their distinct subcellular localizations: the nuclear isoform (DUT-N) and mitochondrial isoform (DUT-M).[2][3][4]
## Gene
Northern blot analysis reveals distinct mRNA transcripts for DUT-N (1.1 kb) and DUT-M (1.4 kb).[3] The isoforms are produced from alternative splicing at different 5' exons, with the first exon of DUT-N occurring 767 base pairs downstream of the first exon in DUT-M.[3][4] Regulation at different promoters has been proposed to account for the differential expression of these isoforms.[3]
## Protein
The mature forms of DUT-N (22 kDa) and DUT-M (23 kDa) are nearly identical except for a short N-terminal region present in DUT-M. The DUT-M precursor (31 kDa) contains an arginine-rich, 69-residue mitochondrial targeting sequence which undergoes post-translational cleavage to effect mitochondrial import.[2][3][4] Meanwhile, the monopartite NLS sequence is critical for the function and nuclear localization of DUT-N, which would otherwise accumulate in the cytoplasm.[2][4] Though both isoforms contain the NLS, the sequence in DUT-M is sequestered away from cognate karyopherins.[2] The isoelectric points of DUT-N (6.0) and DUT-M (8.1) correspond to the pH of their respective subcellular compartments.[3]
DUT is a homotrimer with three active sites formed by each of its three subunits.[4] Typically, each subunit forms an eight-stranded barrel that swaps C-terminal β-strands with the other subunits to assemble into the trimer structure. In addition to the β-strand swapping, these subunits interact via extended bimolecular interfaces and three-fold central channel.[5]
As a member of the dUTPase family, DUT requires the presence of a divalent metal ion such as Mg2+ for their enzymatic function.[6] DUT-N also contains a consensus cyclin-dependent kinase phosphorylation site that is phosphorylated at the serine as part of its cell cycle regulation.[3]
# Function
DUT is a member of the dUTPase family, which is known for catalyzing the pyrophosphoralysis of dUTP into dUMP and inorganic pyrophosphate. This function contributes to DNA replication and repair via de novo thymidylate biosynthesis, as the dUMP product is methylated by thymidylate synthase (TS) to form dTMP, which is then phosphorylated to dTTP.[2][3][4][7] DUT is also crucial for maintaining genome integrity by reducing cellular dUTP levels, thereby preventing the repeated cycles of uracil misincorporation into DNA and DNA repair-mediated strand breaks that would lead to cell death.[2][3][4][6][7]
In addition to their different localizations, the two DUT isoforms display different expression patterns: while DUT-M is constitutively expressed, DUT-N is under cell cycle control and notably upregulated during S phase.[2][3] These expression patterns correspond with their roles in the DNA replication cycle of their respective genomes, and thus indicate different regulatory mechanisms affecting each isoform.[3]
## Mechanism
The dUTP hydrolysis cycle can be outlined in the following four enzymatic steps: (i) fast substrate binding, (ii) isomerization of the enzyme-substrate complex into the catalytically competent conformation, (iii) hydrolysis of the substrate, and (iv) rapid, non-ordered release of the products.[8]
# Clinical significance
Since many chemotherapeutic agents such as 5-fluorouracil treat neoplastic diseases, including head and neck cancer, breast cancer, and gastrointestinal cancer, by targeting TS in thymidylate metabolism, DUT may protect against the cytotoxic side effects by countering dUTP accumulation.[3][4][7][9][10] At the same time, high levels of DUT-N have been associated with chemoresistance and faster tumor progression, and thus, could also serve as a prognostic marker for overall survival and response to chemotherapy.[3][4][7][8][9] Similarly, DUT is significantly overexpressed in hepatocellular carcinoma and may serve as a prognostic marker for the cancer.[11] Notably, DUT expression is regulated by the tumor suppressor gene p53 in order to promote apoptosis of tumor cells.<pmid19015155/> Abnormal DUT expression and localization has been speculated to promote cancer transformation.[4]
# Interactions
DUT interacts with dUTP to catalyze its hydrolysis into dUMP and pyrophosphate.[1] E2F and Sp1 enhance DUT expression by binding its promoter, while p53 inhibits DUT transcription by binding its promoter. A putative NF-κB binding site was also identified in the DUT promoter.[10] | https://www.wikidoc.org/index.php/DUT_(gene) | |
5da24afb9941239e3ac64dc533f3a3edb390547c | wikidoc | Delta cell | Delta cell
# Overview
Delta cells (δ-cells or D cells) are somatostatin producing cells.
They can be found in the stomach, intestine and the Islets of Langerhans in the pancreas.
In rodents delta-cells are located in the periphery of the islets; in humans the islet architecture is generally less organized and delta-cells are frequently observed inside the islets as well.
In the electron microscope, delta-cells can be identified as cells with smaller and slightly more compact granules than beta cells.
# Clinical significance
A tumor of the delta cells is called a "somatostatinoma". | Delta cell
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Delta cells (δ-cells or D cells) are somatostatin producing cells.
They can be found in the stomach, intestine and the Islets of Langerhans in the pancreas.
In rodents delta-cells are located in the periphery of the islets; in humans the islet architecture is generally less organized and delta-cells are frequently observed inside the islets as well.
In the electron microscope, delta-cells can be identified as cells with smaller and slightly more compact granules than beta cells.
# Clinical significance
A tumor of the delta cells is called a "somatostatinoma".
# External links
- D+Cells at the US National Library of Medicine Medical Subject Headings (MeSH)
- Template:EMedicineDictionary
- Template:Dorlands
Template:Endocrine pancreas
no:Deltacelle
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/D_cell | |
01bf2a335ea0382d0380b6a7b5dac074f8d48fa7 | wikidoc | Dabigatran | Dabigatran
Synonyms / Brand Names: Pradaxa®
# Disclaimer
WikiDoc Drug Project is a constellation of drug information for healthcare providers and patients vigorously vetted on the basis of FDA package insert, MedlinePlus, Practice Guidelines, Scientific Statements, and scholarly medical literature. The information provided is not a medical advice or treatment. WikiDoc does not promote any medication or off-label use of drugs. Please read our full disclaimer here.
# Black Box Warning
# Overview
Dabigatran is a direct thrombin inhibitor that is FDA approved for the prophylaxis of stroke and systemic embolism in patients with non-valvular atrial fibrillation. There is a Black Box Warning for this drug as shown here. Common adverse reactions include esophagitis, gastritis, gastroesophageal reflux disease, gastrointestinal hemorrhage, gastrointestinal ulcer, indigestion,bleeding.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- Recommended dose for patients creatinine clearance (CrCl) >30 mL/min: 150 mg PO bid
- Recommended dose for patients (CrCl 15-30 mL/min): 75 mg PO bid
- Recommended dose for patients CrCl <15 mL/min or on dialysis: Not provided by FDA
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- Developed by: American College of Chest Physicians(ACCP)
- Class of Recommendation: ACCP guidelines classification scheme#Class II:Benefit ≥ Risk
- Level of Evidence:Level B
- Recommendation
- 220 mg or 150 mg PO qd
- Developed by: American College of Chest Physicians(ACCP)
- Class of Recommendation: ACCP guidelines classification scheme#Class II:Benefit ≥ Risk
- Level of Evidence:Level B
- Recommendation
- 150 mg PO bid
- Developed by: American College of Chest Physicians(ACCP)
- Class of Recommendation: ACCP guidelines classification scheme#Class II:Benefit ≥ Risk
- Level of Evidence:Level B
- Recommendation
- Developed by: American College of Chest Physicians(ACCP)
- Class of Recommendation: ACCP guidelines classification scheme#Class II:Benefit ≥ Risk
- Level of Evidence:Level B
# Pediatric Indications and Dosage
- Safety and effectiveness of PRADAXA in pediatric patients have not been established.
# Contraindications
- Active pathological bleeding.
- History of a serious hypersensitivity reaction to PRADAXA (e.g., anaphylactic reaction or anaphylactic shock) .
- Mechanical prosthetic heart valve.
# Warnings
- Discontinuing PRADAXA in absence of adequate alternative anticoagulation increases the risk of thrombotic events. If PRADAXA must be discontinued for a reason other than pathological bleeding, consider coverage with another anticoagulant.
- PRADAXA increases the risk of bleeding and can cause significant and, sometimes, fatal bleeding. Promptly evaluate any signs or symptoms of blood loss (e.g., a drop in hemoglobin and/or hematocrit or hypotension). Discontinue PRADAXA in patients with active pathological bleeding.
- Risk factors for bleeding include the concomitant use of other drugs that increase the risk of bleeding (e.g., anti-platelet agents, heparin, fibrinolytic therapy, and chronic use of NSAIDs). PRADAXA’s anticoagulant activity and half-life are increased in patients with renal impairment.
- A specific reversal agent for dabigatran is not available. Hemodialysis can remove dabigatran; however the clinical experience supporting the use of hemodialysis as a treatment for bleeding is limited. Activated prothrombin complex concentrates (aPCCs, e.g., FEIBA), or recombinant Factor VIIa, or concentrates of coagulation factors II, IX or X may be considered but their use has not been evaluated in clinical trials. Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of dabigatran. Consider administration of platelet concentrates in cases where thrombocytopenia is present or long-acting antiplatelet drugs have been used.
- The safety and efficacy of PRADAXA in patients with bileaflet mechanical prosthetic heart valves was evaluated in the RE-ALIGN trial, in which patients with bileaflet mechanical prosthetic heart valves (recently implanted or implanted more than three months prior to enrollment) were randomized to dose adjusted warfarin or 150, 220, or 300 mg of PRADAXA twice a day. RE-ALIGN was terminated early due to the occurrence of significantly more thromboembolic events (valve thrombosis, stroke, transient ischemic attack, and myocardial infarction) and an excess of major bleeding (predominantly post-operative pericardial effusions requiring intervention for hemodynamic compromise) in the PRADAXA treatment arm as compared to the warfarin treatment arm. These bleeding and thromboembolic events were seen both in patients who were initiated on PRADAXA post-operatively within three days of mechanical bileaflet valve implantation, as well as in patients whose valves had been implanted more than three months prior to enrollment. Therefore, the use of PRADAXA is contraindicated in patients with mechanical prosthetic valves.
- The use of PRADAXA for the prophylaxis of thromboembolic events in patients with atrial fibrillation in the setting of other forms of valvular heart disease, including the presence of a bioprosthetic heart valve, has not been studied and is not recommended.
- The concomitant use of PRADAXA with P-gp inducers (e.g. rifampin) reduces exposure to dabigatran and should generally be avoided.
- P-gp inhibition and impaired renal function are the major independent factors that result in increased exposure to dabigatran. Concomitant use of P-gp inhibitors in patients with renal impairment is expected to produce increased exposure of dabigatran compared to that seen with either factor alone.
- Consider reducing the dose of PRADAXA to 75 mg twice daily when dronedarone or systemic ketoconazole is coadministered with PRADAXA in patients with moderate renal impairment (CrCl 30-50 mL/min). Avoid use of PRADAXA and P-gp inhibitors in patients with severe renal impairment (CrCl 15-30 mL/min).
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reactions 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 RE-LY (Randomized Evaluation of Long-term Anticoagulant Therapy) study provided safety information on the use of two doses of PRADAXA and warfarin. The numbers of patients and their exposures are described in Table 1. Limited information is presented on the 110 mg dosing arm because this dose is not approved.
Drug Discontinuation in RE-LY
- The rates of adverse reactions leading to treatment discontinuation were 21% for PRADAXA 150 mg and 16% for warfarin. The most frequent adverse reactions leading to discontinuation of PRADAXA were bleeding and gastrointestinal events (i.e., dyspepsia, nausea, upper abdominal pain, gastrointestinal hemorrhage, and diarrhea).
Bleeding
- Table 2 shows the number of patients experiencing serious bleeding during the treatment period in the RE-LY study, with the bleeding rate per 800 patient-years (%). Major bleeds fulfilled one or more of the following criteria: bleeding associated with a reduction in hemoglobin of at least 2 grams per deciliter or leading to a transfusion of at least 2 units of blood, or symptomatic bleeding in a critical area or organ (intraocular, intracranial, intraspinal or intramuscular with compartment syndrome, retroperitoneal bleeding, intra-articular bleeding, or pericardial bleeding). A life-threatening bleed met one or more of the following criteria: fatal, symptomatic intracranial bleed, reduction in hemoglobin of at least 5 grams per deciliter, transfusion of at least 4 units of blood, associated with hypotension requiring the use of intravenous inotropic agents, or necessitating surgical intervention. Intracranial hemorrhage included intracerebral (hemorrhagic stroke), subarachnoid, and subdural bleeds.
- The risk of major bleeds was similar with PRADAXA 150 mg and warfarin across major subgroups defined by baseline characteristics, with the exception of age, where there was a trend towards a higher incidence of major bleeding on PRADAXA (hazard ratio 1.2, 95% CI: 1.0 to 1.4) for patients ≥75 years of age.
- There was a higher rate of major gastrointestinal bleeds in patients receiving PRADAXA 150 mg than in patients receiving warfarin (1.6% vs. 1.1%, respectively, with a hazard ratio vs. warfarin of 1.5, 95% CI, 1.2 to 1.9), and a higher rate of any gastrointestinal bleeds (6.1% vs. 4.0%, respectively).
Gastrointestinal Adverse Reactions
- Patients on PRADAXA 150 mg had an increased incidence of gastrointestinal adverse reactions (35% vs. 24% on warfarin). These were commonly dyspepsia (including abdominal pain upper, abdominal pain, abdominal discomfort, and epigastric discomfort) and gastritis-like symptoms (including GERD, esophagitis, erosive gastritis, gastric hemorrhage, hemorrhagic gastritis, hemorrhagic erosive gastritis, and gastrointestinal ulcer).
Hypersensitivity Reactions
- In the RE-LY study, drug hypersensitivity (including urticaria, rash, and pruritus), allergic edema, anaphylactic reaction, and anaphylactic shock were reported in <0.1% of patients receiving PRADAXA.
## Postmarketing
- The following adverse reactions have been identified during post approval use of PRADAXA. 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. The following adverse reactions have been identified during post approval use of PRADAXA: angioedema, thrombocytopenia, esophageal ulcer.
# Drug Interactions
- The concomitant use of PRADAXA with (e.g., rifampin) reduces exposure to dabigatran and should generally be avoided.
- P-gp inhibition and impaired renal function are the major independent factors that result in increased exposure to dabigatran. Concomitant use of P-gp inhibitors in patients with renal impairment is expected to produce increased exposure of dabigatran compared to that seen with either factor alone.
- In patients with moderate renal impairment (CrCl 30-50 mL/min), consider reducing the dose of PRADAXA to 75 mg twice daily when administered concomitantly with the P-gp inhibitor dronedarone or systemic ketoconazole. The use of P-gp inhibitors (verapamil, amiodarone, quinidine, and clarithromycin) does not require a dose adjustment of PRADAXA. These results should not be extrapolated to other P-gp inhibitors.
- The concomitant use of PRADAXA and P-gp inhibitors in patients with severe renal impairment (CrCl 15-30 mL/min) should be avoided.
- There are no adequate and well-controlled studies in pregnant women.
- Dabigatran has been shown to decrease the number of implantations when male and female rats were treated at a dosage of 70 mg/kg (about 2.6 to 3.0 times the human exposure at maximum recommended human dose of 300 mg/day based on area under the curve comparisons) prior to mating and up to implantation (gestation Day 6). Treatment of pregnant rats after implantation with dabigatran at the same dose increased the number of dead offspring and caused excess vaginal/uterine bleeding close to parturition. Although dabigatran increased the incidence of delayed or irregular ossification of fetal skull bones and vertebrae in the rat, it did not induce major malformations in rats or rabbits.
# Use in Specific Populations
### Pregnancy
### Labor and Delivery
- Safety and effectiveness of PRADAXA during labor and delivery have not been studied in clinical trials. Consider the risks of bleeding and of stroke in using PRADAXA in this setting.
- Death of offspring and mother rats during labor in association with uterine bleeding occurred during treatment of pregnant rats from implantation (gestation Day 7) to weaning (lactation Day 21) with dabigatran at a dose of 70 mg/kg (about 2.6 times the human exposure at MRHD of 300 mg/day based on AUC comparisons).
### Nursing Mothers
- It is not known whether dabigatran is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when PRADAXA is administered to a nursing woman.
### Pediatric Use
- Safety and effectiveness of PRADAXA in pediatric patients have not been established.
### Geriatric Use
- Of the total number of patients in the RE-LY study, 82% were 65 and over, while 40% were 75 and over. The risk of stroke and bleeding increases with age, but the risk-benefit profile is favorable in all age groups.
- Use In Renal Impair=No dose adjustment of PRADAXA is recommended in patients with mild or moderate renal impairment. Reduce the dose of PRADAXA in patients with severe renal impairment (CrCl 15-30 mL/min). Dosing recommendations for patients with CrCl <15 mL/min or on dialysis cannot be provided.
- Adjust dose appropriately in patients with renal impairment receiving concomitant P-gp inhibitors.
### Gender
- FDA Package Insert for Dabigatran contains no information regarding Gender.
### Race
- FDA Package Insert for Dabigatran contains no information regarding Race.
### Renal Impairment
- FDA Package Insert for Dabigatran contains no information regarding Renal Impairment.
### Hepatic Impairment
- FDA Package Insert for Dabigatran contains no information regarding Hepatic Impairment.
### Carcinogenesis, Mutagenesis, Impairment of Fertility
- Dabigatran was not carcinogenic when administered by oral gavage to mice and rats for up to 2 years. The highest doses tested (200 mg/kg/day) in mice and rats were approximately 3.6 and 6 times, respectively, the human exposure at MRHD of 300 mg/day based on AUC comparisons.
- Dabigatran was not mutagenic in in vitro tests, including bacterial reversion tests, mouse lymphoma assay and chromosomal aberration assay in human lymphocytes, and thein vivo micronucleus assay in rats.
- In the rat fertility study with oral gavage doses of 15, 70, and 200 mg/kg, males were treated for 29 days prior to mating, during mating up to scheduled termination, and females were treated 15 days prior to mating through gestation Day 6. No adverse effects on male or female fertility were observed at 200 mg/kg or 9 to 12 times the human exposure at MRHD of 300 mg/day based on AUC comparisons. However, the number of implantations decreased in females receiving 70 mg/kg, or 3 times the human exposure at MRHD based on AUC comparisons.
### Immunocompromised Patients
- FDA Package Insert for Dabigatran contains no information regarding Immunocompromised Patients.
### Miscellaneous
- FDA Package Insert for Dabigatran contains no information regarding Miscellaneous.
# Administration and Monitoring
### Administration
- Oral
## Instructions to Patients
- Instruct patients to swallow the capsules whole. PRADAXA should be taken with a full glass of water. Breaking, chewing, or emptying the contents of the capsule can result in increased exposure.
- If a dose of PRADAXA is not taken at the scheduled time, the dose should be taken as soon as possible on the same day; the missed dose should be skipped if it cannot be taken at least 6 hours before the next scheduled dose. The dose of PRADAXA should not be doubled to make up for a missed dose.
## Converting from or to Warfarin
- When converting patients from warfarin therapy to PRADAXA, discontinue warfarin and start PRADAXA when the INR is below 2.0.
- When converting from PRADAXA to warfarin, adjust the starting time of warfarin based on creatinine clearance as follows:
- For CrCl ≥50 mL/min, start warfarin 3 days before discontinuing PRADAXA.
- For CrCl 30-50 mL/min, start warfarin 2 days before discontinuing PRADAXA.
- For CrCl 15-30 mL/min, start warfarin 1 day before discontinuing PRADAXA.
- For CrCl <15 mL/min, no recommendations can be made.
- Because PRADAXA can increase INR, the INR will better reflect warfarin’s effect only after PRADAXA has been stopped for at least 2 days.
## Converting from or to Parenteral Anticoagulants
- For patients currently receiving a parenteral anticoagulant, start PRADAXA 0 to 2 hours before the time that the next dose of the parenteral drug was to have been administered or at the time of discontinuation of a continuously administered parenteral drug (e.g., intravenous unfractionated heparin).
- For patients currently taking PRADAXA, wait 12 hours (CrCl ≥30 mL/min) or 24 hours (CrCl <30 mL/min) after the last dose of PRADAXA before initiating treatment with a parenteral anticoagulant.
## Surgery and Interventions
- If possible, discontinue PRADAXA 1 to 2 days (CrCl ≥50 mL/min) or 3 to 5 days (CrCl <50 mL/min) before invasive or surgical procedures because of the increased risk of bleeding. Consider longer times for patients undergoing major surgery, spinal puncture, or placement of a spinal or epidural catheter or port, in whom complete hemostasis may be required.
- If surgery cannot be delayed, there is an increased risk of bleeding. This risk of bleeding should be weighed against the urgency of intervention.
- Monitoring=INR is relatively insensitive to the exposure to dabigatran and cannot be interpreted the same way as used for warfarin monitoring.
- IV Compat=FDA Package Insert for Metoprolol tartrate contains no information regarding Black Box Warning.
- Overdose=Accidental overdose may lead to hemorrhagic complications. There is no reversal agent for dabigatran. In the event of hemorrhagic complications, initiate appropriate clinical support, discontinue treatment with PRADAXA, and investigate the source of bleeding. Dabigatran is primarily eliminated by the kidneys with a low plasma protein binding of approximately 35%. Hemodialysis can remove dabigatran; however, data supporting this approach are limited. Using a high-flux dialyzer, blood flow rate of 200 mL/min, and dialysate flow rate of 700 mL/min, approximately 49% of total dabigatran can be cleared from plasma over 4 hours. At the same dialysate flow rate, approximately 57% can be cleared using a dialyzer blood flow rate of 300 mL/min, with no appreciable increase in clearance observed at higher blood flow rates. Upon cessation of hemodialysis, a redistribution effect of approximately 7% to 15% is seen. The effect of dialysis on dabigatran’s plasma concentration would be expected to vary based on patient specific characteristics. Measurement of aPTT or ECT may help guide therapy
# IV Compatibility
- FDA Package Insert for Dabigatran contains no information regarding IV Compatibility.
# Overdosage
- Accidental overdose may lead to hemorrhagic complications. There is no reversal agent for dabigatran. In the event of hemorrhagic complications, initiate appropriate clinical support, discontinue treatment with PRADAXA, and investigate the source of bleeding. Dabigatran is primarily eliminated by the kidneys with a low plasma protein binding of approximately 35%. Hemodialysis can remove dabigatran; however, data supporting this approach are limited. Using a high-flux dialyzer, blood flow rate of 200 mL/min, and dialysate flow rate of 700 mL/min, approximately 49% of total dabigatran can be cleared from plasma over 4 hours. At the same dialysate flow rate, approximately 57% can be cleared using a dialyzer blood flow rate of 300 mL/min, with no appreciable increase in clearance observed at higher blood flow rates. Upon cessation of hemodialysis, a redistribution effect of approximately 7% to 15% is seen. The effect of dialysis on dabigatran’s plasma concentration would be expected to vary based on patient specific characteristics. Measurement of aPTT or ECT may help guide therapy.
# Pharmacology
## Mechanism of Action
- Dabigatran and its acyl glucuronides are competitive, direct thrombin inhibitors. Because thrombin (serine protease) enables the conversion of fibrinogen into fibrin during the coagulation cascade, its inhibition prevents the development of a thrombus. Both free and clot-bound thrombin, and thrombin-induced platelet aggregation are inhibited by the active moieties.
## Structure
methyl-1H-benzimidazol-5-yl)carbonyl] (pyridin-2-yl-amino)propanoate
## Pharmacodynamics
- At recommended therapeutic doses, dabigatran etexilate prolongs the coagulation markers such as aPTT, ECT, and TT. INR is relatively insensitive to the exposure to dabigatran and cannot be interpreted the same way as used for warfarin monitoring.
- The aPTT test provides an approximation of PRADAXA’s anticoagulant effect. The average time course for effects on aPTT, following approved dosing regimens in patients with various degrees of renal impairment is shown in Figure 1. The curves represent mean levels without confidence intervals; variations should be expected when measuring aPTT. While advice cannot be provided on the level of recovery of aPTT needed in any particular clinical setting, the curves can be used to estimate the time to get to a particular level of recovery, even when the time since the last dose of PRADAXA is not precisely known. In the RE-LY trial, the median (10th to 90th percentile) trough aPTT in patients receiving the 150 mg dose was 52 (40 to 76) seconds.
- Simulations based on PK data from a study in subjects with renal impairment and PK/aPTT relationships derived from the RE-LY study; aPTT prolongation in RE-LY was measured centrally in citrate plasma using PTT Reagent Roche Diagnostics GmbH, Mannheim, Germany. There may be quantitative differences between various established methods for aPTT assessment.
- The degree of anticoagulant activity can also be assessed by the ecarin clotting time (ECT). This test is a more specific measure of the effect of dabigatran than activated partial thromboplastin time (aPTT). In the RE-LY trial, the median (10th to 90th percentile) trough ECT in patients receiving the 150 mg dose was 63 (44 to 103) seconds.
### Cardiac Electrophysiology
- No prolongation of the QTc interval was observed with dabigatran etexilate at doses up to 600 mg.
## Pharmacokinetics
- Dabigatran etexilate mesylate is absorbed as the dabigatran etexilate ester. The ester is then hydrolyzed, forming dabigatran, the active moiety. Dabigatran is metabolized to four different acyl glucuronides and both the glucuronides and dabigatran have similar pharmacological activity. Pharmacokinetics described here refer to the sum of dabigatran and its glucuronides. Dabigatran displays dose-proportional pharmacokinetics in healthy subjects and patients in the range of doses from 10 to 400 mg.
### Distribution
- Dabigatran is approximately 35% bound to human plasma proteins. The red blood cell to plasma partitioning of dabigatran measured as total radioactivity is less than 0.3. The volume of distribution of dabigatran is 50 to 70 L. Dabigatran pharmacokinetics are dose proportional after single doses of 10 to 400 mg. Given twice daily, dabigatran’s accumulation factor is approximately two.
### Elimination
- Dabigatran is eliminated primarily in the urine. Renal clearance of dabigatran is 80% of total clearance after intravenous administration. After oral administration of radiolabeled dabigatran, 7% of radioactivity is recovered in urine and 86% in feces. The half-life of dabigatran in healthy subjects is 12 to 17 hours.
### Metabolism
- After oral administration, dabigatran etexilate is converted to dabigatran. The cleavage of the dabigatran etexilate by esterase-catalyzed hydrolysis to the active principal dabigatran is the predominant metabolic reaction. Dabigatran is not a substrate, inhibitor, or inducer of CYP450 enzymes. Dabigatran is subject to conjugation forming pharmacologically active acyl glucuronides. Four positional isomers, 1-O, 2-O, 3-O, and 4-O-acylglucuronide exist, and each accounts for less than 10% of total dabigatran in plasma.
### Renal Impairment
- An open, parallel-group single-center study compared dabigatran pharmacokinetics in healthy subjects and patients with mild to moderate renal impairment receiving a single dose of PRADAXA 150 mg. Exposure to dabigatran increases with severity of renal function impairment (Table 3). Similar findings were observed in the RE-LY trial.
### Hepatic Impairment
- Administration of PRADAXA in patients with moderate hepatic impairment (Child-Pugh B) showed a large inter-subject variability, but no evidence of a consistent change in exposure or pharmacodynamics.
### Drug Interactions
- Impact of Other Drugs on Dabigatran
### P-gp Inducers
- Rifampin: Rifampin 600 mg once daily for 7 days followed by a single dose of dabigatran decreased its AUC and Cmax by 66% and 67%, respectively. By Day 7 after cessation of rifampin treatment, dabigatran exposure was close to normal.
### P-gp Inhibitors
- In studies with the P-gp inhibitors ketoconazole, amiodarone, verapamil, and quinidine, the time to peak, terminal half-life, and mean residence time of dabigatran were not affected. Any observed changes in Cmax and AUC are described below.
Dronedarone: Simultaneous administration of dabigatran etexilate and dronedarone (administered once or twice daily) increases exposure to dabigatran by 70 to 140% compared to dabigatran alone. The increase in exposure is only 30 to 60% higher compared to dabigatran alone when dronedarone is administered 2 hours after dabigatran etexilate.
Ketoconazole: Systemic ketoconazole increased dabigatran AUC and Cmax values by 138% and 135%, respectively, after a single dose of 400 mg, and 153%, and 149%, respectively, after multiple daily doses of 400 mg.
Verapamil: When dabigatran etexilate was coadministered with oral verapamil, the Cmax and AUC of dabigatran were increased. The extent of increase depends on the formulation of verapamil and timing of administration. If verapamil is present in the gut when dabigatran is taken, it will increase exposure to dabigatran with the greatest increase observed when a single dose of immediate-release verapamil is given one hour prior to dabigatran (AUC increased by a factor of 2.4). If verapamil is given 2 hours after dabigatran, the increase in AUC is negligible. In the population pharmacokinetics study from RE-LY, no important changes in dabigatran trough levels were observed in patients who received verapamil.
Amiodarone: When dabigatran etexilate was coadministered with a single 600 mg oral dose of amiodarone, the dabigatran AUC and Cmax increased by 58% and 50%, respectively. The increase in exposure was mitigated by a 65% increase in the renal clearance of dabigatran in the presence of amiodarone. The increase in renal clearance may persist after amiodarone is discontinued because of amiodarone’s long half-life. In the population pharmacokinetics study from RE-LY, no important changes in dabigatran trough levels were observed in patients who received amiodarone.
Quinidine: Quinidine was given as 200 mg dose every 2 hours up to a total dose of 1000 mg. Dabigatran etexilate was given over 3 consecutive days, the last evening dose on Day 3 with or without quinidine pre-dosing. Concomitant quinidine administration increased dabigatran’s AUC and Cmax by 53% and 56%, respectively.
Clarithromycin: Coadministered clarithromycin had no impact on the exposure to dabigatran.
### Other Drugs
Clopidogrel: When dabigatran etexilate was given concomitantly with a loading dose of 300 mg or 600 mg clopidogrel, the dabigatran AUC and Cmax increased by approximately 30% and 40%, respectively. The concomitant administration of dabigatran etexilate and clopidogrel resulted in no further prolongation of capillary bleeding times compared to clopidogrel monotherapy. When comparing combined treatment and the respective mono-treatments, the coagulation measures for dabigatran’s effect (aPTT, ECT, and TT) remained unchanged, and inhibition of platelet aggregation (IPA), a measurement of clopidogrel’s effect, remained unchanged.
Enoxaparin: Enoxaparin 40 mg given subcutaneously for 3 days with the last dose given 24 hours before a single dose of PRADAXA had no impact on the exposure to dabigatran or the coagulation measures aPTT, ECT, or TT.
Diclofenac, Ranitidine, and Digoxin:None of these drugs alters exposure to dabigatran.
In RE-LY, dabigatran plasma samples were also collected. The concomitant use of proton pump inhibitors, H2 antagonists, and digoxin did not appreciably change the trough concentration of dabigatran.
Impact of Dabigatran on Other Drugs
- In clinical studies exploring CYP3A4, CYP2C9, P-gp and other pathways, dabigatran did not meaningfully alter the pharmacokinetics of amiodarone, atorvastatin, clarithromycin, diclofenac, clopidogrel, digoxin, pantoprazole, or ranitidine.
## Nonclinical Toxicology
- FDA Package Insert for Dabigatran contains no information regarding Nonclinical Toxicology.
# Clinical Studies
- The clinical evidence for the efficacy of PRADAXA was derived from RE-LY (Randomized Evaluation of Long-term Anticoagulant Therapy), a multi-center, multi-national, randomized parallel group trial comparing two blinded doses of PRADAXA (110 mg twice daily and 150 mg twice daily) with open-label warfarin (dosed to target INR of 2 to 3) in patients with non-valvular, persistent, paroxysmal, or permanent atrial fibrillation and one or more of the following additional risk factors:
- Previous stroke, transient ischemic attack (TIA), or systemic embolism
- Left ventricular ejection fraction <40%
- Symptomatic heart failure, ≥ New York Heart Association Class 2
- Age ≥75 years
- Age ≥65 years and one of the following: diabetes mellitus, coronary artery disease (CAD), or hypertension
- The primary objective of this study was to determine if PRADAXA was non-inferior to warfarin in reducing the occurrence of the composite endpoint, stroke (ischemic and hemorrhagic) and systemic embolism. The study was designed to ensure that PRADAXA preserved more than 50% of warfarin’s effect as established by previous randomized, placebo-controlled trials of warfarin in atrial fibrillation. Statistical superiority was also analyzed.
- A total of 18,113 patients were randomized and followed for a median of 2 years. The patient’s mean age was 71.5 years and the mean CHADS2 score was 2.1. The patient population was 64% male, 70% Caucasian, 16% Asian, and 1% black. Twenty percent of patients had a history of a stroke or TIA and 50% were Vitamin K antagonist (VKA) naïve, defined as less than 2 months total lifetime exposure to a VKA. Thirty-two percent of the population had never been exposed to a VKA. Concomitant diseases of patients in this trial included hypertension 79%, diabetes 23%, and CAD 28%. At baseline, 40% of patients were on aspirin and 6% were on clopidogrel. For patients randomized to warfarin, the mean percentage of time in therapeutic range (INR 2 to 3) was 64%.
- Relative to warfarin and to PRADAXA 110 mg twice daily, PRADAXA 150 mg twice daily significantly reduced the primary composite endpoint of stroke and systemic embolism (see Table 4 and Figure 2).
- The contributions of the components of the composite endpoint, including stroke by subtype, are shown in Table 5. The treatment effect was primarily a reduction in stroke. PRADAXA 150 mg twice daily was superior in reducing ischemic and hemorrhagic strokes relative to warfarin.
- In the RE-LY trial, the rate of all-cause mortality was lower on dabigatran 150 mg than on warfarin (3.6% per year versus 4.1% per year). The rate of vascular death was lower on dabigatran 150 mg compared to warfarin (2.3% per year versus 2.7% per year). Non-vascular death rates were similar in the treatment arms.
- The efficacy of PRADAXA 150 mg twice daily was generally consistent across major subgroups (see Figure 3).
- In RE-LY, a higher rate of clinical myocardial infarction was reported in patients who received PRADAXA (0.7 per 100 patient-years for 150 mg dose) than in those who received warfarin (0.6).
# How supplied
- PRADAXA 75 mg capsules have a cream-colored opaque cap imprinted with the Boehringer Ingelheim company symbol and a cream-colored opaque body imprinted with "R75". The color of the imprinting is black. The capsules are supplied in the packages listed:
- NDC 0597-0149-54 Unit of use bottle of 60 capsules
- NDC 0597-0149-60 Blister package containing 60 capsules (10 x 6 capsule blister cards)
- PRADAXA 150 mg capsules have a light blue opaque cap imprinted with the Boehringer Ingelheim company symbol and a cream-colored opaque body imprinted with "R150". The color of the imprinting is black. The capsules are supplied in the packages listed:
- NDC 0597-0135-54 Unit of use bottle of 60 capsules
- NDC 0597-0135-60 Blister package containing 60 capsules (10 x 6 capsule blister cards)
## Bottles
- Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). Once opened, the product must be used within 4 months. Keep the bottle tightly closed. Store in the original package to protect from moisture.
## Blisters
- Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). Store in the original package to protect from moisture.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Information
## Patient Information from FDA
- Advise the patient to read the FDA-approved patient labeling (Medication Guide).
## Instructions for Patients
- Tell patients to take PRADAXA exactly as prescribed.
- Remind patients not to discontinue PRADAXA without talking to the health care provider who prescribed it.
- Keep PRADAXA in the original bottle to protect from moisture. Do not put PRADAXA in pill boxes or pill organizers.
- When more than one bottle is dispensed to the patient, instruct them to open only one bottle at a time.
- Instruct patient to remove only one capsule from the opened bottle at the time of use. The bottle should be immediately and tightly closed.
- Advise patients not to chew or break the capsules before swallowing them and not to open the capsules and take the pellets alone.
- Advise patients that the capsule should be taken with a full glass of water.
## Bleeding
- Inform patients that they may bleed more easily, may bleed longer, and should call their health care provider for any signs or symptoms of bleeding.
- Instruct patients to seek emergency care right away if they have any of the following, which may be a sign or symptom of serious bleeding:
- Unusual bruising (bruises that appear without known cause or that get bigger)
- Pink or brown urine
- Red or black, tarry stools
- Coughing up blood
- Vomiting blood, or vomit that looks like coffee grounds
- Instruct patients to call their health care provider or to get prompt medical attention if they experience any signs or symptoms of bleeding:
- Pain, swelling or discomfort in a joint
- Headaches, dizziness, or weakness
- Reoccurring nose bleeds
- Unusual bleeding from gums
- Bleeding from a cut that takes a long time to stop
- Menstrual bleeding or vaginal bleeding that is heavier than normal
## Gastrointestinal Adverse Reactions
- Instruct patients to call their health care provider if they experience any signs or symptoms of dyspepsia or gastritis:
- Dyspepsia (upset stomach), burning, or nausea
- Abdominal pain or discomfort
- Epigastric discomfort, GERD (gastric indigestion)
## Invasive or Surgical Procedures
- Instruct patients to inform their health care provider that they are taking PRADAXA before any invasive procedure (including dental procedures) is scheduled.
## Concomitant Medications
- Ask patients to list all prescription medications, over-the-counter medications, or dietary supplements they are taking or plan to take so their health care provider knows about other treatments that may affect bleeding risk (e.g., aspirin or NSAIDs) or dabigatran exposure (e.g., dronedarone or systemic ketoconazole).
## Prosthetic Heart Valves
- Instruct patients to inform their health care provider if they will have or have had surgery to place a prosthetic heart valve.
## Patient Information from NLM
- For patient information about dabigatran from NLM, click here.
# Precautions with Alcohol
- Alcohol-Dabigatran interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Pradaxa®
# Look-Alike Drug Names
# Drug Shortage Status
# Price | Dabigatran
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2]
Synonyms / Brand Names: Pradaxa®
# Disclaimer
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# Black Box Warning
# Overview
Dabigatran is a direct thrombin inhibitor that is FDA approved for the prophylaxis of stroke and systemic embolism in patients with non-valvular atrial fibrillation. There is a Black Box Warning for this drug as shown here. Common adverse reactions include esophagitis, gastritis, gastroesophageal reflux disease, gastrointestinal hemorrhage, gastrointestinal ulcer, indigestion,bleeding.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- Recommended dose for patients creatinine clearance (CrCl) >30 mL/min: 150 mg PO bid
- Recommended dose for patients (CrCl 15-30 mL/min): 75 mg PO bid
- Recommended dose for patients CrCl <15 mL/min or on dialysis: Not provided by FDA
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- Developed by: American College of Chest Physicians(ACCP)
- Class of Recommendation: ACCP guidelines classification scheme#Class II:Benefit ≥ Risk
- Level of Evidence:Level B
- Recommendation
- 220 mg or 150 mg PO qd
- Developed by: American College of Chest Physicians(ACCP)
- Class of Recommendation: ACCP guidelines classification scheme#Class II:Benefit ≥ Risk
- Level of Evidence:Level B
- Recommendation
- 150 mg PO bid [1]
- Developed by: American College of Chest Physicians(ACCP)
- Class of Recommendation: ACCP guidelines classification scheme#Class II:Benefit ≥ Risk
- Level of Evidence:Level B
- Recommendation
- Developed by: American College of Chest Physicians(ACCP)
- Class of Recommendation: ACCP guidelines classification scheme#Class II:Benefit ≥ Risk
- Level of Evidence:Level B
# Pediatric Indications and Dosage
- Safety and effectiveness of PRADAXA in pediatric patients have not been established.
# Contraindications
- Active pathological bleeding.
- History of a serious hypersensitivity reaction to PRADAXA (e.g., anaphylactic reaction or anaphylactic shock) .
- Mechanical prosthetic heart valve.
# Warnings
- Discontinuing PRADAXA in absence of adequate alternative anticoagulation increases the risk of thrombotic events. If PRADAXA must be discontinued for a reason other than pathological bleeding, consider coverage with another anticoagulant.
- PRADAXA increases the risk of bleeding and can cause significant and, sometimes, fatal bleeding. Promptly evaluate any signs or symptoms of blood loss (e.g., a drop in hemoglobin and/or hematocrit or hypotension). Discontinue PRADAXA in patients with active pathological bleeding.
- Risk factors for bleeding include the concomitant use of other drugs that increase the risk of bleeding (e.g., anti-platelet agents, heparin, fibrinolytic therapy, and chronic use of NSAIDs). PRADAXA’s anticoagulant activity and half-life are increased in patients with renal impairment.
- A specific reversal agent for dabigatran is not available. Hemodialysis can remove dabigatran; however the clinical experience supporting the use of hemodialysis as a treatment for bleeding is limited. Activated prothrombin complex concentrates (aPCCs, e.g., FEIBA), or recombinant Factor VIIa, or concentrates of coagulation factors II, IX or X may be considered but their use has not been evaluated in clinical trials. Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of dabigatran. Consider administration of platelet concentrates in cases where thrombocytopenia is present or long-acting antiplatelet drugs have been used.
- The safety and efficacy of PRADAXA in patients with bileaflet mechanical prosthetic heart valves was evaluated in the RE-ALIGN trial, in which patients with bileaflet mechanical prosthetic heart valves (recently implanted or implanted more than three months prior to enrollment) were randomized to dose adjusted warfarin or 150, 220, or 300 mg of PRADAXA twice a day. RE-ALIGN was terminated early due to the occurrence of significantly more thromboembolic events (valve thrombosis, stroke, transient ischemic attack, and myocardial infarction) and an excess of major bleeding (predominantly post-operative pericardial effusions requiring intervention for hemodynamic compromise) in the PRADAXA treatment arm as compared to the warfarin treatment arm. These bleeding and thromboembolic events were seen both in patients who were initiated on PRADAXA post-operatively within three days of mechanical bileaflet valve implantation, as well as in patients whose valves had been implanted more than three months prior to enrollment. Therefore, the use of PRADAXA is contraindicated in patients with mechanical prosthetic valves.
- The use of PRADAXA for the prophylaxis of thromboembolic events in patients with atrial fibrillation in the setting of other forms of valvular heart disease, including the presence of a bioprosthetic heart valve, has not been studied and is not recommended.
- The concomitant use of PRADAXA with P-gp inducers (e.g. rifampin) reduces exposure to dabigatran and should generally be avoided.
- P-gp inhibition and impaired renal function are the major independent factors that result in increased exposure to dabigatran. Concomitant use of P-gp inhibitors in patients with renal impairment is expected to produce increased exposure of dabigatran compared to that seen with either factor alone.
- Consider reducing the dose of PRADAXA to 75 mg twice daily when dronedarone or systemic ketoconazole is coadministered with PRADAXA in patients with moderate renal impairment (CrCl 30-50 mL/min). Avoid use of PRADAXA and P-gp inhibitors in patients with severe renal impairment (CrCl 15-30 mL/min).
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reactions 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 RE-LY (Randomized Evaluation of Long-term Anticoagulant Therapy) study provided safety information on the use of two doses of PRADAXA and warfarin. The numbers of patients and their exposures are described in Table 1. Limited information is presented on the 110 mg dosing arm because this dose is not approved.
Drug Discontinuation in RE-LY
- The rates of adverse reactions leading to treatment discontinuation were 21% for PRADAXA 150 mg and 16% for warfarin. The most frequent adverse reactions leading to discontinuation of PRADAXA were bleeding and gastrointestinal events (i.e., dyspepsia, nausea, upper abdominal pain, gastrointestinal hemorrhage, and diarrhea).
Bleeding
- Table 2 shows the number of patients experiencing serious bleeding during the treatment period in the RE-LY study, with the bleeding rate per 800 patient-years (%). Major bleeds fulfilled one or more of the following criteria: bleeding associated with a reduction in hemoglobin of at least 2 grams per deciliter or leading to a transfusion of at least 2 units of blood, or symptomatic bleeding in a critical area or organ (intraocular, intracranial, intraspinal or intramuscular with compartment syndrome, retroperitoneal bleeding, intra-articular bleeding, or pericardial bleeding). A life-threatening bleed met one or more of the following criteria: fatal, symptomatic intracranial bleed, reduction in hemoglobin of at least 5 grams per deciliter, transfusion of at least 4 units of blood, associated with hypotension requiring the use of intravenous inotropic agents, or necessitating surgical intervention. Intracranial hemorrhage included intracerebral (hemorrhagic stroke), subarachnoid, and subdural bleeds.
- The risk of major bleeds was similar with PRADAXA 150 mg and warfarin across major subgroups defined by baseline characteristics, with the exception of age, where there was a trend towards a higher incidence of major bleeding on PRADAXA (hazard ratio 1.2, 95% CI: 1.0 to 1.4) for patients ≥75 years of age.
- There was a higher rate of major gastrointestinal bleeds in patients receiving PRADAXA 150 mg than in patients receiving warfarin (1.6% vs. 1.1%, respectively, with a hazard ratio vs. warfarin of 1.5, 95% CI, 1.2 to 1.9), and a higher rate of any gastrointestinal bleeds (6.1% vs. 4.0%, respectively).
Gastrointestinal Adverse Reactions
- Patients on PRADAXA 150 mg had an increased incidence of gastrointestinal adverse reactions (35% vs. 24% on warfarin). These were commonly dyspepsia (including abdominal pain upper, abdominal pain, abdominal discomfort, and epigastric discomfort) and gastritis-like symptoms (including GERD, esophagitis, erosive gastritis, gastric hemorrhage, hemorrhagic gastritis, hemorrhagic erosive gastritis, and gastrointestinal ulcer).
Hypersensitivity Reactions
- In the RE-LY study, drug hypersensitivity (including urticaria, rash, and pruritus), allergic edema, anaphylactic reaction, and anaphylactic shock were reported in <0.1% of patients receiving PRADAXA.
## Postmarketing
- The following adverse reactions have been identified during post approval use of PRADAXA. 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. The following adverse reactions have been identified during post approval use of PRADAXA: angioedema, thrombocytopenia, esophageal ulcer.
# Drug Interactions
- The concomitant use of PRADAXA with [P-gp inducers] (e.g., rifampin) reduces exposure to dabigatran and should generally be avoided.
- P-gp inhibition and impaired renal function are the major independent factors that result in increased exposure to dabigatran. Concomitant use of P-gp inhibitors in patients with renal impairment is expected to produce increased exposure of dabigatran compared to that seen with either factor alone.
- In patients with moderate renal impairment (CrCl 30-50 mL/min), consider reducing the dose of PRADAXA to 75 mg twice daily when administered concomitantly with the P-gp inhibitor dronedarone or systemic ketoconazole. The use of P-gp inhibitors (verapamil, amiodarone, quinidine, and clarithromycin) does not require a dose adjustment of PRADAXA. These results should not be extrapolated to other P-gp inhibitors.
- The concomitant use of PRADAXA and P-gp inhibitors in patients with severe renal impairment (CrCl 15-30 mL/min) should be avoided.
- There are no adequate and well-controlled studies in pregnant women.
- Dabigatran has been shown to decrease the number of implantations when male and female rats were treated at a dosage of 70 mg/kg (about 2.6 to 3.0 times the human exposure at maximum recommended human dose [MRHD] of 300 mg/day based on area under the curve [AUC] comparisons) prior to mating and up to implantation (gestation Day 6). Treatment of pregnant rats after implantation with dabigatran at the same dose increased the number of dead offspring and caused excess vaginal/uterine bleeding close to parturition. Although dabigatran increased the incidence of delayed or irregular ossification of fetal skull bones and vertebrae in the rat, it did not induce major malformations in rats or rabbits.
# Use in Specific Populations
### Pregnancy
### Labor and Delivery
- Safety and effectiveness of PRADAXA during labor and delivery have not been studied in clinical trials. Consider the risks of bleeding and of stroke in using PRADAXA in this setting.
- Death of offspring and mother rats during labor in association with uterine bleeding occurred during treatment of pregnant rats from implantation (gestation Day 7) to weaning (lactation Day 21) with dabigatran at a dose of 70 mg/kg (about 2.6 times the human exposure at MRHD of 300 mg/day based on AUC comparisons).
### Nursing Mothers
- It is not known whether dabigatran is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when PRADAXA is administered to a nursing woman.
### Pediatric Use
- Safety and effectiveness of PRADAXA in pediatric patients have not been established.
### Geriatric Use
- Of the total number of patients in the RE-LY study, 82% were 65 and over, while 40% were 75 and over. The risk of stroke and bleeding increases with age, but the risk-benefit profile is favorable in all age groups.
- Use In Renal Impair=No dose adjustment of PRADAXA is recommended in patients with mild or moderate renal impairment. Reduce the dose of PRADAXA in patients with severe renal impairment (CrCl 15-30 mL/min). Dosing recommendations for patients with CrCl <15 mL/min or on dialysis cannot be provided.
- Adjust dose appropriately in patients with renal impairment receiving concomitant P-gp inhibitors.
### Gender
- FDA Package Insert for Dabigatran contains no information regarding Gender.
### Race
- FDA Package Insert for Dabigatran contains no information regarding Race.
### Renal Impairment
- FDA Package Insert for Dabigatran contains no information regarding Renal Impairment.
### Hepatic Impairment
- FDA Package Insert for Dabigatran contains no information regarding Hepatic Impairment.
### Carcinogenesis, Mutagenesis, Impairment of Fertility
- Dabigatran was not carcinogenic when administered by oral gavage to mice and rats for up to 2 years. The highest doses tested (200 mg/kg/day) in mice and rats were approximately 3.6 and 6 times, respectively, the human exposure at MRHD of 300 mg/day based on AUC comparisons.
- Dabigatran was not mutagenic in in vitro tests, including bacterial reversion tests, mouse lymphoma assay and chromosomal aberration assay in human lymphocytes, and thein vivo micronucleus assay in rats.
- In the rat fertility study with oral gavage doses of 15, 70, and 200 mg/kg, males were treated for 29 days prior to mating, during mating up to scheduled termination, and females were treated 15 days prior to mating through gestation Day 6. No adverse effects on male or female fertility were observed at 200 mg/kg or 9 to 12 times the human exposure at MRHD of 300 mg/day based on AUC comparisons. However, the number of implantations decreased in females receiving 70 mg/kg, or 3 times the human exposure at MRHD based on AUC comparisons.
### Immunocompromised Patients
- FDA Package Insert for Dabigatran contains no information regarding Immunocompromised Patients.
### Miscellaneous
- FDA Package Insert for Dabigatran contains no information regarding Miscellaneous.
# Administration and Monitoring
### Administration
- Oral
## Instructions to Patients
- Instruct patients to swallow the capsules whole. PRADAXA should be taken with a full glass of water. Breaking, chewing, or emptying the contents of the capsule can result in increased exposure.
- If a dose of PRADAXA is not taken at the scheduled time, the dose should be taken as soon as possible on the same day; the missed dose should be skipped if it cannot be taken at least 6 hours before the next scheduled dose. The dose of PRADAXA should not be doubled to make up for a missed dose.
## Converting from or to Warfarin
- When converting patients from warfarin therapy to PRADAXA, discontinue warfarin and start PRADAXA when the INR is below 2.0.
- When converting from PRADAXA to warfarin, adjust the starting time of warfarin based on creatinine clearance as follows:
- For CrCl ≥50 mL/min, start warfarin 3 days before discontinuing PRADAXA.
- For CrCl 30-50 mL/min, start warfarin 2 days before discontinuing PRADAXA.
- For CrCl 15-30 mL/min, start warfarin 1 day before discontinuing PRADAXA.
- For CrCl <15 mL/min, no recommendations can be made.
- Because PRADAXA can increase INR, the INR will better reflect warfarin’s effect only after PRADAXA has been stopped for at least 2 days.
## Converting from or to Parenteral Anticoagulants
- For patients currently receiving a parenteral anticoagulant, start PRADAXA 0 to 2 hours before the time that the next dose of the parenteral drug was to have been administered or at the time of discontinuation of a continuously administered parenteral drug (e.g., intravenous unfractionated heparin).
- For patients currently taking PRADAXA, wait 12 hours (CrCl ≥30 mL/min) or 24 hours (CrCl <30 mL/min) after the last dose of PRADAXA before initiating treatment with a parenteral anticoagulant.
## Surgery and Interventions
- If possible, discontinue PRADAXA 1 to 2 days (CrCl ≥50 mL/min) or 3 to 5 days (CrCl <50 mL/min) before invasive or surgical procedures because of the increased risk of bleeding. Consider longer times for patients undergoing major surgery, spinal puncture, or placement of a spinal or epidural catheter or port, in whom complete hemostasis may be required.
- If surgery cannot be delayed, there is an increased risk of bleeding. This risk of bleeding should be weighed against the urgency of intervention.
- Monitoring=INR is relatively insensitive to the exposure to dabigatran and cannot be interpreted the same way as used for warfarin monitoring.
- IV Compat=FDA Package Insert for Metoprolol tartrate contains no information regarding Black Box Warning.
- Overdose=Accidental overdose may lead to hemorrhagic complications. There is no reversal agent for dabigatran. In the event of hemorrhagic complications, initiate appropriate clinical support, discontinue treatment with PRADAXA, and investigate the source of bleeding. Dabigatran is primarily eliminated by the kidneys with a low plasma protein binding of approximately 35%. Hemodialysis can remove dabigatran; however, data supporting this approach are limited. Using a high-flux dialyzer, blood flow rate of 200 mL/min, and dialysate flow rate of 700 mL/min, approximately 49% of total dabigatran can be cleared from plasma over 4 hours. At the same dialysate flow rate, approximately 57% can be cleared using a dialyzer blood flow rate of 300 mL/min, with no appreciable increase in clearance observed at higher blood flow rates. Upon cessation of hemodialysis, a redistribution effect of approximately 7% to 15% is seen. The effect of dialysis on dabigatran’s plasma concentration would be expected to vary based on patient specific characteristics. Measurement of aPTT or ECT may help guide therapy
# IV Compatibility
- FDA Package Insert for Dabigatran contains no information regarding IV Compatibility.
# Overdosage
- Accidental overdose may lead to hemorrhagic complications. There is no reversal agent for dabigatran. In the event of hemorrhagic complications, initiate appropriate clinical support, discontinue treatment with PRADAXA, and investigate the source of bleeding. Dabigatran is primarily eliminated by the kidneys with a low plasma protein binding of approximately 35%. Hemodialysis can remove dabigatran; however, data supporting this approach are limited. Using a high-flux dialyzer, blood flow rate of 200 mL/min, and dialysate flow rate of 700 mL/min, approximately 49% of total dabigatran can be cleared from plasma over 4 hours. At the same dialysate flow rate, approximately 57% can be cleared using a dialyzer blood flow rate of 300 mL/min, with no appreciable increase in clearance observed at higher blood flow rates. Upon cessation of hemodialysis, a redistribution effect of approximately 7% to 15% is seen. The effect of dialysis on dabigatran’s plasma concentration would be expected to vary based on patient specific characteristics. Measurement of aPTT or ECT may help guide therapy.
# Pharmacology
## Mechanism of Action
- Dabigatran and its acyl glucuronides are competitive, direct thrombin inhibitors. Because thrombin (serine protease) enables the conversion of fibrinogen into fibrin during the coagulation cascade, its inhibition prevents the development of a thrombus. Both free and clot-bound thrombin, and thrombin-induced platelet aggregation are inhibited by the active moieties.
## Structure
methyl-1H-benzimidazol-5-yl)carbonyl] (pyridin-2-yl-amino)propanoate
## Pharmacodynamics
- At recommended therapeutic doses, dabigatran etexilate prolongs the coagulation markers such as aPTT, ECT, and TT. INR is relatively insensitive to the exposure to dabigatran and cannot be interpreted the same way as used for warfarin monitoring.
- The aPTT test provides an approximation of PRADAXA’s anticoagulant effect. The average time course for effects on aPTT, following approved dosing regimens in patients with various degrees of renal impairment is shown in Figure 1. The curves represent mean levels without confidence intervals; variations should be expected when measuring aPTT. While advice cannot be provided on the level of recovery of aPTT needed in any particular clinical setting, the curves can be used to estimate the time to get to a particular level of recovery, even when the time since the last dose of PRADAXA is not precisely known. In the RE-LY trial, the median (10th to 90th percentile) trough aPTT in patients receiving the 150 mg dose was 52 (40 to 76) seconds.
- Simulations based on PK data from a study in subjects with renal impairment and PK/aPTT relationships derived from the RE-LY study; aPTT prolongation in RE-LY was measured centrally in citrate plasma using PTT Reagent Roche Diagnostics GmbH, Mannheim, Germany. There may be quantitative differences between various established methods for aPTT assessment.
- The degree of anticoagulant activity can also be assessed by the ecarin clotting time (ECT). This test is a more specific measure of the effect of dabigatran than activated partial thromboplastin time (aPTT). In the RE-LY trial, the median (10th to 90th percentile) trough ECT in patients receiving the 150 mg dose was 63 (44 to 103) seconds.
### Cardiac Electrophysiology
- No prolongation of the QTc interval was observed with dabigatran etexilate at doses up to 600 mg.
## Pharmacokinetics
- Dabigatran etexilate mesylate is absorbed as the dabigatran etexilate ester. The ester is then hydrolyzed, forming dabigatran, the active moiety. Dabigatran is metabolized to four different acyl glucuronides and both the glucuronides and dabigatran have similar pharmacological activity. Pharmacokinetics described here refer to the sum of dabigatran and its glucuronides. Dabigatran displays dose-proportional pharmacokinetics in healthy subjects and patients in the range of doses from 10 to 400 mg.
### Distribution
- Dabigatran is approximately 35% bound to human plasma proteins. The red blood cell to plasma partitioning of dabigatran measured as total radioactivity is less than 0.3. The volume of distribution of dabigatran is 50 to 70 L. Dabigatran pharmacokinetics are dose proportional after single doses of 10 to 400 mg. Given twice daily, dabigatran’s accumulation factor is approximately two.
### Elimination
- Dabigatran is eliminated primarily in the urine. Renal clearance of dabigatran is 80% of total clearance after intravenous administration. After oral administration of radiolabeled dabigatran, 7% of radioactivity is recovered in urine and 86% in feces. The half-life of dabigatran in healthy subjects is 12 to 17 hours.
### Metabolism
- After oral administration, dabigatran etexilate is converted to dabigatran. The cleavage of the dabigatran etexilate by esterase-catalyzed hydrolysis to the active principal dabigatran is the predominant metabolic reaction. Dabigatran is not a substrate, inhibitor, or inducer of CYP450 enzymes. Dabigatran is subject to conjugation forming pharmacologically active acyl glucuronides. Four positional isomers, 1-O, 2-O, 3-O, and 4-O-acylglucuronide exist, and each accounts for less than 10% of total dabigatran in plasma.
### Renal Impairment
- An open, parallel-group single-center study compared dabigatran pharmacokinetics in healthy subjects and patients with mild to moderate renal impairment receiving a single dose of PRADAXA 150 mg. Exposure to dabigatran increases with severity of renal function impairment (Table 3). Similar findings were observed in the RE-LY trial.
### Hepatic Impairment
- Administration of PRADAXA in patients with moderate hepatic impairment (Child-Pugh B) showed a large inter-subject variability, but no evidence of a consistent change in exposure or pharmacodynamics.
### Drug Interactions
- Impact of Other Drugs on Dabigatran
### P-gp Inducers
- Rifampin: Rifampin 600 mg once daily for 7 days followed by a single dose of dabigatran decreased its AUC and Cmax by 66% and 67%, respectively. By Day 7 after cessation of rifampin treatment, dabigatran exposure was close to normal.
### P-gp Inhibitors
- In studies with the P-gp inhibitors ketoconazole, amiodarone, verapamil, and quinidine, the time to peak, terminal half-life, and mean residence time of dabigatran were not affected. Any observed changes in Cmax and AUC are described below.
Dronedarone: Simultaneous administration of dabigatran etexilate and dronedarone (administered once or twice daily) increases exposure to dabigatran by 70 to 140% compared to dabigatran alone. The increase in exposure is only 30 to 60% higher compared to dabigatran alone when dronedarone is administered 2 hours after dabigatran etexilate.
Ketoconazole: Systemic ketoconazole increased dabigatran AUC and Cmax values by 138% and 135%, respectively, after a single dose of 400 mg, and 153%, and 149%, respectively, after multiple daily doses of 400 mg.
Verapamil: When dabigatran etexilate was coadministered with oral verapamil, the Cmax and AUC of dabigatran were increased. The extent of increase depends on the formulation of verapamil and timing of administration. If verapamil is present in the gut when dabigatran is taken, it will increase exposure to dabigatran with the greatest increase observed when a single dose of immediate-release verapamil is given one hour prior to dabigatran (AUC increased by a factor of 2.4). If verapamil is given 2 hours after dabigatran, the increase in AUC is negligible. In the population pharmacokinetics study from RE-LY, no important changes in dabigatran trough levels were observed in patients who received verapamil.
Amiodarone: When dabigatran etexilate was coadministered with a single 600 mg oral dose of amiodarone, the dabigatran AUC and Cmax increased by 58% and 50%, respectively. The increase in exposure was mitigated by a 65% increase in the renal clearance of dabigatran in the presence of amiodarone. The increase in renal clearance may persist after amiodarone is discontinued because of amiodarone’s long half-life. In the population pharmacokinetics study from RE-LY, no important changes in dabigatran trough levels were observed in patients who received amiodarone.
Quinidine: Quinidine was given as 200 mg dose every 2 hours up to a total dose of 1000 mg. Dabigatran etexilate was given over 3 consecutive days, the last evening dose on Day 3 with or without quinidine pre-dosing. Concomitant quinidine administration increased dabigatran’s AUC and Cmax by 53% and 56%, respectively.
Clarithromycin: Coadministered clarithromycin had no impact on the exposure to dabigatran.
### Other Drugs
Clopidogrel: When dabigatran etexilate was given concomitantly with a loading dose of 300 mg or 600 mg clopidogrel, the dabigatran AUC and Cmax increased by approximately 30% and 40%, respectively. The concomitant administration of dabigatran etexilate and clopidogrel resulted in no further prolongation of capillary bleeding times compared to clopidogrel monotherapy. When comparing combined treatment and the respective mono-treatments, the coagulation measures for dabigatran’s effect (aPTT, ECT, and TT) remained unchanged, and inhibition of platelet aggregation (IPA), a measurement of clopidogrel’s effect, remained unchanged.
Enoxaparin: Enoxaparin 40 mg given subcutaneously for 3 days with the last dose given 24 hours before a single dose of PRADAXA had no impact on the exposure to dabigatran or the coagulation measures aPTT, ECT, or TT.
Diclofenac, Ranitidine, and Digoxin:None of these drugs alters exposure to dabigatran.
In RE-LY, dabigatran plasma samples were also collected. The concomitant use of proton pump inhibitors, H2 antagonists, and digoxin did not appreciably change the trough concentration of dabigatran.
Impact of Dabigatran on Other Drugs
- In clinical studies exploring CYP3A4, CYP2C9, P-gp and other pathways, dabigatran did not meaningfully alter the pharmacokinetics of amiodarone, atorvastatin, clarithromycin, diclofenac, clopidogrel, digoxin, pantoprazole, or ranitidine.
## Nonclinical Toxicology
- FDA Package Insert for Dabigatran contains no information regarding Nonclinical Toxicology.
# Clinical Studies
- The clinical evidence for the efficacy of PRADAXA was derived from RE-LY (Randomized Evaluation of Long-term Anticoagulant Therapy), a multi-center, multi-national, randomized parallel group trial comparing two blinded doses of PRADAXA (110 mg twice daily and 150 mg twice daily) with open-label warfarin (dosed to target INR of 2 to 3) in patients with non-valvular, persistent, paroxysmal, or permanent atrial fibrillation and one or more of the following additional risk factors:
- Previous stroke, transient ischemic attack (TIA), or systemic embolism
- Left ventricular ejection fraction <40%
- Symptomatic heart failure, ≥ New York Heart Association Class 2
- Age ≥75 years
- Age ≥65 years and one of the following: diabetes mellitus, coronary artery disease (CAD), or hypertension
- The primary objective of this study was to determine if PRADAXA was non-inferior to warfarin in reducing the occurrence of the composite endpoint, stroke (ischemic and hemorrhagic) and systemic embolism. The study was designed to ensure that PRADAXA preserved more than 50% of warfarin’s effect as established by previous randomized, placebo-controlled trials of warfarin in atrial fibrillation. Statistical superiority was also analyzed.
- A total of 18,113 patients were randomized and followed for a median of 2 years. The patient’s mean age was 71.5 years and the mean CHADS2 score was 2.1. The patient population was 64% male, 70% Caucasian, 16% Asian, and 1% black. Twenty percent of patients had a history of a stroke or TIA and 50% were Vitamin K antagonist (VKA) naïve, defined as less than 2 months total lifetime exposure to a VKA. Thirty-two percent of the population had never been exposed to a VKA. Concomitant diseases of patients in this trial included hypertension 79%, diabetes 23%, and CAD 28%. At baseline, 40% of patients were on aspirin and 6% were on clopidogrel. For patients randomized to warfarin, the mean percentage of time in therapeutic range (INR 2 to 3) was 64%.
- Relative to warfarin and to PRADAXA 110 mg twice daily, PRADAXA 150 mg twice daily significantly reduced the primary composite endpoint of stroke and systemic embolism (see Table 4 and Figure 2).
- The contributions of the components of the composite endpoint, including stroke by subtype, are shown in Table 5. The treatment effect was primarily a reduction in stroke. PRADAXA 150 mg twice daily was superior in reducing ischemic and hemorrhagic strokes relative to warfarin.
- In the RE-LY trial, the rate of all-cause mortality was lower on dabigatran 150 mg than on warfarin (3.6% per year versus 4.1% per year). The rate of vascular death was lower on dabigatran 150 mg compared to warfarin (2.3% per year versus 2.7% per year). Non-vascular death rates were similar in the treatment arms.
- The efficacy of PRADAXA 150 mg twice daily was generally consistent across major subgroups (see Figure 3).
- In RE-LY, a higher rate of clinical myocardial infarction was reported in patients who received PRADAXA (0.7 per 100 patient-years for 150 mg dose) than in those who received warfarin (0.6).
# How supplied
- PRADAXA 75 mg capsules have a cream-colored opaque cap imprinted with the Boehringer Ingelheim company symbol and a cream-colored opaque body imprinted with "R75". The color of the imprinting is black. The capsules are supplied in the packages listed:
- NDC 0597-0149-54 Unit of use bottle of 60 capsules
- NDC 0597-0149-60 Blister package containing 60 capsules (10 x 6 capsule blister cards)
- PRADAXA 150 mg capsules have a light blue opaque cap imprinted with the Boehringer Ingelheim company symbol and a cream-colored opaque body imprinted with "R150". The color of the imprinting is black. The capsules are supplied in the packages listed:
- NDC 0597-0135-54 Unit of use bottle of 60 capsules
- NDC 0597-0135-60 Blister package containing 60 capsules (10 x 6 capsule blister cards)
## Bottles
- Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). Once opened, the product must be used within 4 months. Keep the bottle tightly closed. Store in the original package to protect from moisture.
## Blisters
- Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). Store in the original package to protect from moisture.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Information
## Patient Information from FDA
- Advise the patient to read the FDA-approved patient labeling (Medication Guide).
## Instructions for Patients
- Tell patients to take PRADAXA exactly as prescribed.
- Remind patients not to discontinue PRADAXA without talking to the health care provider who prescribed it.
- Keep PRADAXA in the original bottle to protect from moisture. Do not put PRADAXA in pill boxes or pill organizers.
- When more than one bottle is dispensed to the patient, instruct them to open only one bottle at a time.
- Instruct patient to remove only one capsule from the opened bottle at the time of use. The bottle should be immediately and tightly closed.
- Advise patients not to chew or break the capsules before swallowing them and not to open the capsules and take the pellets alone.
- Advise patients that the capsule should be taken with a full glass of water.
## Bleeding
- Inform patients that they may bleed more easily, may bleed longer, and should call their health care provider for any signs or symptoms of bleeding.
- Instruct patients to seek emergency care right away if they have any of the following, which may be a sign or symptom of serious bleeding:
- Unusual bruising (bruises that appear without known cause or that get bigger)
- Pink or brown urine
- Red or black, tarry stools
- Coughing up blood
- Vomiting blood, or vomit that looks like coffee grounds
- Instruct patients to call their health care provider or to get prompt medical attention if they experience any signs or symptoms of bleeding:
- Pain, swelling or discomfort in a joint
- Headaches, dizziness, or weakness
- Reoccurring nose bleeds
- Unusual bleeding from gums
- Bleeding from a cut that takes a long time to stop
- Menstrual bleeding or vaginal bleeding that is heavier than normal
## Gastrointestinal Adverse Reactions
- Instruct patients to call their health care provider if they experience any signs or symptoms of dyspepsia or gastritis:
- Dyspepsia (upset stomach), burning, or nausea
- Abdominal pain or discomfort
- Epigastric discomfort, GERD (gastric indigestion)
## Invasive or Surgical Procedures
- Instruct patients to inform their health care provider that they are taking PRADAXA before any invasive procedure (including dental procedures) is scheduled.
## Concomitant Medications
- Ask patients to list all prescription medications, over-the-counter medications, or dietary supplements they are taking or plan to take so their health care provider knows about other treatments that may affect bleeding risk (e.g., aspirin or NSAIDs) or dabigatran exposure (e.g., dronedarone or systemic ketoconazole).
## Prosthetic Heart Valves
- Instruct patients to inform their health care provider if they will have or have had surgery to place a prosthetic heart valve.
## Patient Information from NLM
- For patient information about dabigatran from NLM, click here.
# Precautions with Alcohol
- Alcohol-Dabigatran interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Pradaxa®
# Look-Alike Drug Names
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Dabi | |
126b4c2711727d16c204028171af8bd5a45da71c | wikidoc | Daclizumab | Daclizumab
Daclizumab (Zenapax) is a humanized monoclonal antibody to the IL-2Rα receptor of T cells. It is used to prevent rejection in organ transplantation, especially in kidney transplants.
It is given in multiple doses, the first 1 hour before the transplant operation and 5 further doses given at two week intervals after the transplant. These saturate the receptors and prevent T cell activation and thus prevent formation of antibodies against the transplant.
Like the similar drug basiliximab, daclizumab reduces the incidence and severity of acute rejection in kidney transplantation without increasing the incidence of opportunistic infections.
Daclizumab can also be used in place of a calcineurin-inhibitor (ciclosporin or tacrolimus) in the early phase after kidney transplantation when the kidney is recovering and vulnerable to calcineurin-inhibitor toxicity. This has been shown to be beneficial in non-heart beating donor kidney transplantation.
In the United Kingdom, the National Institute for Health and Clinical Excellence has recommended its use be considered for all kidney transplant recipients.
Daclizumab is now being tested as a possible Multiple Sclerosis treatment in a phase 2 clinical trial across the United States and Europe, which started 2006 and will end in 2007. It has also been used to arrest the progression of autoimmune diseases, especially birdshot retinochoroidopathy. | Daclizumab
Template:Drugbox-mab
Daclizumab (Zenapax) is a humanized monoclonal antibody to the IL-2Rα receptor of T cells. It is used to prevent rejection in organ transplantation, especially in kidney transplants.
It is given in multiple doses, the first 1 hour before the transplant operation and 5 further doses given at two week intervals after the transplant. These saturate the receptors and prevent T cell activation and thus prevent formation of antibodies against the transplant.
Like the similar drug basiliximab, daclizumab reduces the incidence and severity of acute rejection in kidney transplantation without increasing the incidence of opportunistic infections.
Daclizumab can also be used in place of a calcineurin-inhibitor (ciclosporin or tacrolimus) in the early phase after kidney transplantation when the kidney is recovering and vulnerable to calcineurin-inhibitor toxicity. This has been shown to be beneficial in non-heart beating donor kidney transplantation.
In the United Kingdom, the National Institute for Health and Clinical Excellence has recommended its use be considered for all kidney transplant recipients.
Daclizumab is now being tested as a possible Multiple Sclerosis treatment in a phase 2 clinical trial across the United States and Europe, which started 2006 and will end in 2007. It has also been used to arrest the progression of autoimmune diseases, especially birdshot retinochoroidopathy.
# External links
- Official website
Template:Immunosuppressants
Template:Humanizedmonoclonals
de:Daclizumab
Template:Jb1
Template:WH
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Dacliximab | |
1acb62de3d0cb4344bbff225fc688f931c6372dd | wikidoc | Decitabine | Decitabine
# 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
Decitabine is an antineoplastic agent that is FDA approved for the treatment of myelodysplastic syndromes (MDS). Common adverse reactions include neutropenia, thrombocytopenia, anemia and pyrexia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Decitabine is indicated for treatment of patients with myelodysplastic syndromes (MDS) including previously treated and untreated, de novo and secondary MDS of all French-American-British subtypes and intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups.
- Treatment Regimen – Option 1:
- Dose of 15 mg/m2 by continuous intravenous infusion over 3 hours repeated every 8 hours for 3 days
- This cycle should be repeated every 6 weeks
- Patients may be premedicated with standard anti-emetic therapy.
- Treatment Regimen – Option 2
- Dose of 20 mg/m2 by continuous intravenous infusion over 1 hour repeated daily for 5 days
- This cycle should be repeated every 4 weeks
- Patients may be premedicated with standard anti-emetic therapy
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Decitabine in adult patients.
### Non–Guideline-Supported Use
- Acute myeloid leukemia
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Safety and efficacy not established in pediatric patients
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Decitabine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Decitabine in pediatric patients.
# Contraindications
None
# Warnings
Treatment with decitabine is associated with neutropenia and thrombocytopenia. Complete blood and platelet counts should be performed as needed to monitor response and toxicity, but at a minimum, prior to each dosing cycle. After administration of the recommended dosage for the first cycle, treatment for subsequent cycles should be adjusted. Clinicians should consider the need for early institution of growth factors and/or antimicrobial agents for the prevention or treatment of infections in patients with MDS. Myelosuppression and worsening neutropenia may occur more frequently in the first or second treatment cycles, and may not necessarily indicate progression of underlying MDS.
# 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.
Most Commonly Occurring Adverse Reactions: neutropenia, thrombocytopenia, anemia, fatigue, pyrexia, nausea, cough, petechiae, constipation, diarrhea, and hyperglycemia.
Adverse Reactions Most Frequently (≥ 1%) Resulting in Clinical Intervention in the Phase 3 Trials in the decitabine Arm:
- Discontinuation: thrombocytopenia, neutropenia, pneumonia, Mycobacterium avium complex infection, cardiorespiratory arrest, increased blood bilirubin, intracranial hemorrhage, abnormal liver function tests.
- Dose Delayed: neutropenia, pulmonary edema, atrial fibrillation, central line infection, febrile neutropenia.
- Dose Reduced: neutropenia, thrombocytopenia, anemia, lethargy, edema, tachycardia, depression, pharyngitis.
Decitabine was studied in 3 single-arm studies (N = 66, N = 98, N = 99) and 1 controlled supportive care study (N = 83 decitabine, N = 81 supportive care ). The data described below reflect exposure to decitabine in 83 patients in the MDS trial. In the trial, patients received 15 mg/m2 intravenously every 8 hours for 3 days every 6 weeks. The median number of decitabine cycles was 3 (range 0 to 9).
Table 1 presents all adverse events regardless of causality occurring in at least 5% of patients in the decitabine group and at a rate greater than supportive care.
In the controlled trial using decitabine dosed at 15 mg/m2, administered by continuous intravenous infusion over 3 hours repeated every 8 hours for 3 days, the highest incidence of Grade 3 or Grade 4 adverse events in the decitabine arm were neutropenia (87%), thrombocytopenia (85%), febrile neutropenia (23%) and leukopenia (22%). Bone marrow suppression was the most frequent cause of dose reduction, delay and discontinuation. Six patients had fatal events associated with their underlying disease and myelosuppression (anemia, neutropenia, and thrombocytopenia) that were considered at least possibly related to drug treatment . Of the 83 decitabine-treated patients, 8 permanently discontinued therapy for adverse events; compared to 1 of 81 patients in the supportive care arm.
In a single-arm MDS study (N=99) decitabine was dosed at 20 mg/m2 intravenous, infused over one hour daily for 5 consecutive days of a 4 week cycle. Table 2 presents all adverse events regardless of causality occurring in at least 5% of patients.
In the single-arm study (N=99) when decitabine was dosed at 20 mg/m2 intravenous, infused over one hour daily for 5 consecutive days, the highest incidence of Grade 3 or Grade 4 adverse events were neutropenia (37%), thrombocytopenia (24%) and anemia (22%). Seventy-eight percent of patients had dose delays, the median duration of this delay was 7 days and the largest percentage of delays were due to hematologic toxicities. Hematologic toxicities and infections were the most frequent causes of dose delays and discontinuation. Eight patients had fatal events due to infection and/or bleeding (seven of which occurred in the clinical setting of myelosuppression) that were considered at least possibly related to drug treatment. Nineteen of 99 patients permanently discontinued therapy for adverse events.
No overall difference in safety was detected between patients > 65 years of age and younger patients in these myelodysplasia trials. No significant gender differences in safety or efficacy were detected. Patients with renal or hepatic dysfunction were not studied. Insufficient numbers of non-white patients were available to draw conclusions in these clinical trials.
Serious Adverse Events that occurred in patients receiving decitabine regardless of causality, not previously reported in Tables 1 and 2 include:
- Blood and Lymphatic System Disorders: myelosuppression, splenomegaly.
- Cardiac Disorders: myocardial infarction, cardiorespiratory arrest, cardiomyopathy, atrial fibrillation, supraventricular tachycardia.
- Gastrointestinal Disorders: gingival pain, upper gastrointestinal hemorrhage.
- General Disorders and Administrative Site Conditions: chest pain, catheter site hemorrhage.
- Hepatobiliary Disorders: cholecystitis.
- Infections and Infestations: fungal infection, sepsis, bronchopulmonary aspergillosis, peridiverticular abscess, respiratory tract infection, pseudomonal lung infection, Mycobacterium avium complex infection.
- Injury, Poisoning and Procedural Complications: post procedural pain, post procedural hemorrhage.
- Nervous System Disorders: intracranial hemorrhage.
- Psychiatric Disorders: mental status changes.
- Renal and Urinary Disorders: renal failure, urethral hemorrhage.
- Respiratory, Thoracic and Mediastinal Disorders: hemoptysis, lung infiltration, pulmonary embolism, respiratory arrest, pulmonary mass.
- Allergic Reaction: Hypersensitivity (anaphylactic reaction) to decitabine has been reported in a Phase 2 trial.
## Postmarketing Experience
The following adverse reactions have been identified during post-approval use of decitabine. 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.
Cases of Sweet’s Syndrome (acute febrile neutrophilic dermatosis) have been reported.
# Drug Interactions
Drug interaction studies with decitabine have not been conducted. In vitro studies in human liver microsomes suggest that decitabine is unlikely to inhibit or induce cytochrome P450 enzymes. In vitro metabolism studies have suggested that decitabine is not a substrate for human liver cytochrome P450 enzymes. As plasma protein binding of decitabine is negligible (<1%), interactions due to displacement of more highly protein bound drugs from plasma proteins are not expected.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
Decitabine can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of decitabine in pregnant women.
The developmental toxicity of decitabine was examined in mice exposed to single IP (intraperitoneal) injections (0, 0.9 and 3.0 mg/m2, approximately 2% and 7% of the recommended daily clinical dose, respectively) over gestation days 8, 9, 10 or 11. No maternal toxicity was observed but reduced fetal survival was observed after treatment at 3 mg/m2 and decreased fetal weight was observed at both dose levels. The 3 mg/m2 dose elicited characteristic fetal defects for each treatment day, including supernumerary ribs (both dose levels), fused vertebrae and ribs, cleft palate, vertebral defects, hind-limb defects and digital defects of fore- and hind-limbs. In rats given a single IP injection of 2.4, 3.6 or 6 mg/m2 (approximately 5, 8, or 13% the daily recommended clinical dose, respectively) on gestation days 9-12, no maternal toxicity was observed. No live fetuses were seen at any dose when decitabine was injected on gestation day 9. A significant decrease in fetal survival and reduced fetal weight at doses greater than 3.6 mg/m2 was seen when decitabine was given on gestation day 10. Increased incidences of vertebral and rib anomalies were seen at all dose levels, and induction of exophthalmia, exencephaly, and cleft palate were observed at 6.0 mg/m2. Increased incidence of foredigit defects was seen in fetuses at doses greater than 3.6 mg/m2. Reduced size and ossification of long bones of the fore-limb and hind-limb were noted at 6.0 mg/m2. 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. Women of child bearing potential should be advised to avoid becoming pregnant while taking decitabine.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Decitabine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Decitabine during labor and delivery.
### Nursing Mothers
It is not known whether decitabine or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions from decitabine in nursing infants, 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 safety and effectiveness of decitabine in pediatric patients have not been established.
### Geriatic Use
Of the total number of patients exposed to decitabine in the controlled clinical trial, 61 of 83 patients were age 65 and over, while 21 of 83 patients were age 75 and over. 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, but greater sensitivity of some older individuals cannot be ruled out.
### Gender
There is no FDA guidance on the use of Decitabine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Decitabine with respect to specific racial populations.
### Renal Impairment
There are no data on the use of decitabine in patients with renal dysfunction; therefore, decitabine should be used with caution in these patients.
### Hepatic Impairment
There are no data on the use of decitabine in patients with hepatic dysfunction; therefore, decitabine should be used with caution in these patients.
### Females of Reproductive Potential and Males
The effect of decitabine on postnatal development and reproductive capacity was evaluated in mice administered a single 3 mg/m2 IP injection (approximately 7% the recommended daily clinical dose) on day 10 of gestation. Body weights of males and females exposed in utero to decitabine were significantly reduced relative to controls at all postnatal time points. No consistent effect on fertility was seen when female mice exposed in utero were mated to untreated males. Untreated females mated to males exposed in utero showed decreased fertility at 3 and 5 months of age (36% and 0% pregnancy rate, respectively). In male mice given IP injections of 0.15, 0.3 or 0.45 mg/m2 decitabine (approximately 0.3% to 1% the recommended clinical dose) 3 times a week for 7 weeks, decitabine did not affect survival, body weight gain or hematological measures (hemoglobin and WBC counts). Testes weights were reduced, abnormal histology was observed and significant decreases in sperm number were found at doses ≥ 0.3 mg/m2. In females mated to males dosed with ≥ 0.3 mg/m2 decitabine, pregnancy rate was reduced and preimplantation loss was significantly increased.
### Immunocompromised Patients
There is no FDA guidance one the use of Decitabine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Intravenous
### Monitoring
There is limited information regarding Decitabine Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Decitabine and IV administrations.
# Overdosage
There is no known antidote for overdosage with decitabine. Higher doses are associated with increased myelosuppression including prolonged neutropenia and thrombocytopenia. Standard supportive measures should be taken in the event of an overdose.
# Pharmacology
## Mechanism of Action
Decitabine is believed to exert its antineoplastic effects after phosphorylation and direct incorporation into DNA and inhibition of DNA methyltransferase, causing hypomethylation of DNA and cellular differentiation or apoptosis. Decitabine inhibits DNA methylation in vitro, which is achieved at concentrations that do not cause major suppression of DNA synthesis. Decitabine-induced hypomethylation in neoplastic cells may restore normal function to genes that are critical forthe control of cellulardifferentiation and proliferation. In rapidly dividing cells, the cytotoxicity of decitabine may also be attributed to the formation of covalent adducts between DNA methyltransferase and decitabine incorporated into DNA. Non-proliferating cells are relatively insensitive to decitabine.
## Structure
Decitabine has the following structural formula:
## Pharmacodynamics
Decitabine has been shown to induce hypomethylation both in vitro and in vivo. However, there have been no studies of decitabine-induced hypomethylation and pharmacokinetic parameters.
## Pharmacokinetics
Pharmacokinetic parameters were evaluated in patients. Eleven patients received 20 mg/m2 infused over 1 hour intravenously (treatment Option 2), Fourteen patients received 15 mg/m2 infused over 3 hours (treatment Option 1). PK parameters are shown in Table 3. Plasma concentration-time profiles after discontinuation of infusion showed a biexponential decline. The CL of decitabine was higher following treatment Option 2. Upon repeat doses there was no systemic accumulation of decitabine or any changes in PK parameters. Population PK analysis (N=35) showed that the cumulative AUC per cycle for treatment Option 2 was 2.3-fold lower than the cumulative AUC per cycle following treatment Option 1.
The exact route of elimination and metabolic fate of decitabine is not known in humans. One of the pathways of elimination of decitabine appears to be deamination by cytidine deaminase found principally in the liver but also in granulocytes, intestinal epithelium and whole blood.
## Nonclinical Toxicology
- Carcinogenicity studies with decitabine have not been conducted.
- The mutagenic potential of decitabine was tested in several in vitro and in vivo systems. Decitabine increased mutation frequency in L5178Y mouse lymphoma cells, and mutations were produced in an Escherichiacoli lac-I transgene in colonic DNA of decitabine-treated mice. Decitabine caused chromosomal rearrangements in larvae of fruit flies.
# Clinical Studies
A randomized open-label, multicenter, controlled trial evaluated 170 adult patients with myelodysplastic syndromes (MDS) meeting French-American-British (FAB) classification criteria and International Prognostic Scoring System (IPSS) High-Risk, Intermediate-2 and Intermediate-1 prognostic scores. Eighty-nine patients were randomized to decitabine therapy plus supportive care (only 83 received decitabine), and 81 to Supportive Care (SC) alone. Patients with Acute Myeloid Leukemia (AML) were not intended to be included. Of the 170 patients included in the study, independent review (adjudicated diagnosis) found that 12 patients (9 in the decitabine arm and 3 in the SC arm) had the diagnosis of AML at baseline. Baseline demographics and other patient characteristics in the Intent-to-Treat (ITT) population were similar between the 2 groups, as shown in Table 4.
Patients randomized to the decitabine arm received decitabine intravenously infused at a dose of 15 mg/m2 over a 3-hour period, every 8 hours, for 3 consecutive days. This cycle was repeated every 6 weeks, depending on the patient’s clinical response and toxicity. Supportive care consisted of blood and blood product transfusions, prophylactic antibiotics, and hematopoietic growth factors. The study endpoints were overall response rate (complete response + partial response) and time to AML or death. Responses were classified using the MDS International Working Group (IWG) criteria; patients were required to be RBC and platelet transfusion independent during the time of response. Response criteria are given in Table 5:
All patients with a CR or PR were RBC and platelet transfusion independent in the absence of growth factors.
Responses occurred in patients with an adjudicated baseline diagnosis of AML.
Three open-label, single-arm, multicenter studies were conducted to evaluate the safety and efficacy of decitabine in MDS patients with any of the FAB subtypes. In one study conducted in North America, 99 patients with IPSS Intermediate-1, Intermediate-2, or high risk prognostic scores received decitabine by intravenous infusion at a dose of 20 mg/m2 IV over 1-hour daily, on days 1-5 of week 1 every 4 weeks (1 cycle). The results were consistent with the results of the controlled trial and summarized in Table 8.
# How Supplied
Decitabine 50 mg single-dose vial
- NDC 62856-600-01
## Storage
Store at 25°C (77°F)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with decitabine and for I month afterwards, and to use effective contraception during this time.
- Men should be advised not to father a child while receiving treatment with decitabine, and for 2 months afterwards. During these times, men with female partners of childbearing potential should use effective contraception.
- Patients should be advised to monitor and report any symptoms of neutropenia, thrombocytopenia, or fever to their physician as soon as possible.
# Precautions with Alcohol
Alcohol-Decitabine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Dacogen
# Look-Alike Drug Names
There is limited information regarding Decitabine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Decitabine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gloria Picoy [2]; Sree Teja Yelamanchili, MBBS [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
Decitabine is an antineoplastic agent that is FDA approved for the treatment of myelodysplastic syndromes (MDS). Common adverse reactions include neutropenia, thrombocytopenia, anemia and pyrexia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Decitabine is indicated for treatment of patients with myelodysplastic syndromes (MDS) including previously treated and untreated, de novo and secondary MDS of all French-American-British subtypes and intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups.
- Treatment Regimen – Option 1:
- Dose of 15 mg/m2 by continuous intravenous infusion over 3 hours repeated every 8 hours for 3 days
- This cycle should be repeated every 6 weeks
- Patients may be premedicated with standard anti-emetic therapy.
- Treatment Regimen – Option 2
- Dose of 20 mg/m2 by continuous intravenous infusion over 1 hour repeated daily for 5 days
- This cycle should be repeated every 4 weeks
- Patients may be premedicated with standard anti-emetic therapy
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Decitabine in adult patients.
### Non–Guideline-Supported Use
- Acute myeloid leukemia
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Safety and efficacy not established in pediatric patients
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Decitabine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Decitabine in pediatric patients.
# Contraindications
None
# Warnings
Treatment with decitabine is associated with neutropenia and thrombocytopenia. Complete blood and platelet counts should be performed as needed to monitor response and toxicity, but at a minimum, prior to each dosing cycle. After administration of the recommended dosage for the first cycle, treatment for subsequent cycles should be adjusted. Clinicians should consider the need for early institution of growth factors and/or antimicrobial agents for the prevention or treatment of infections in patients with MDS. Myelosuppression and worsening neutropenia may occur more frequently in the first or second treatment cycles, and may not necessarily indicate progression of underlying MDS.
# 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.
Most Commonly Occurring Adverse Reactions: neutropenia, thrombocytopenia, anemia, fatigue, pyrexia, nausea, cough, petechiae, constipation, diarrhea, and hyperglycemia.
Adverse Reactions Most Frequently (≥ 1%) Resulting in Clinical Intervention in the Phase 3 Trials in the decitabine Arm:
- Discontinuation: thrombocytopenia, neutropenia, pneumonia, Mycobacterium avium complex infection, cardiorespiratory arrest, increased blood bilirubin, intracranial hemorrhage, abnormal liver function tests.
- Dose Delayed: neutropenia, pulmonary edema, atrial fibrillation, central line infection, febrile neutropenia.
- Dose Reduced: neutropenia, thrombocytopenia, anemia, lethargy, edema, tachycardia, depression, pharyngitis.
Decitabine was studied in 3 single-arm studies (N = 66, N = 98, N = 99) and 1 controlled supportive care study (N = 83 decitabine, N = 81 supportive care ). The data described below reflect exposure to decitabine in 83 patients in the MDS trial. In the trial, patients received 15 mg/m2 intravenously every 8 hours for 3 days every 6 weeks. The median number of decitabine cycles was 3 (range 0 to 9).
Table 1 presents all adverse events regardless of causality occurring in at least 5% of patients in the decitabine group and at a rate greater than supportive care.
In the controlled trial using decitabine dosed at 15 mg/m2, administered by continuous intravenous infusion over 3 hours repeated every 8 hours for 3 days, the highest incidence of Grade 3 or Grade 4 adverse events in the decitabine arm were neutropenia (87%), thrombocytopenia (85%), febrile neutropenia (23%) and leukopenia (22%). Bone marrow suppression was the most frequent cause of dose reduction, delay and discontinuation. Six patients had fatal events associated with their underlying disease and myelosuppression (anemia, neutropenia, and thrombocytopenia) that were considered at least possibly related to drug treatment [See Warnings and Precautions (5.1)]. Of the 83 decitabine-treated patients, 8 permanently discontinued therapy for adverse events; compared to 1 of 81 patients in the supportive care arm.
In a single-arm MDS study (N=99) decitabine was dosed at 20 mg/m2 intravenous, infused over one hour daily for 5 consecutive days of a 4 week cycle. Table 2 presents all adverse events regardless of causality occurring in at least 5% of patients.
In the single-arm study (N=99) when decitabine was dosed at 20 mg/m2 intravenous, infused over one hour daily for 5 consecutive days, the highest incidence of Grade 3 or Grade 4 adverse events were neutropenia (37%), thrombocytopenia (24%) and anemia (22%). Seventy-eight percent of patients had dose delays, the median duration of this delay was 7 days and the largest percentage of delays were due to hematologic toxicities. Hematologic toxicities and infections were the most frequent causes of dose delays and discontinuation. Eight patients had fatal events due to infection and/or bleeding (seven of which occurred in the clinical setting of myelosuppression) that were considered at least possibly related to drug treatment. Nineteen of 99 patients permanently discontinued therapy for adverse events.
No overall difference in safety was detected between patients > 65 years of age and younger patients in these myelodysplasia trials. No significant gender differences in safety or efficacy were detected. Patients with renal or hepatic dysfunction were not studied. Insufficient numbers of non-white patients were available to draw conclusions in these clinical trials.
Serious Adverse Events that occurred in patients receiving decitabine regardless of causality, not previously reported in Tables 1 and 2 include:
- Blood and Lymphatic System Disorders: myelosuppression, splenomegaly.
- Cardiac Disorders: myocardial infarction, cardiorespiratory arrest, cardiomyopathy, atrial fibrillation, supraventricular tachycardia.
- Gastrointestinal Disorders: gingival pain, upper gastrointestinal hemorrhage.
- General Disorders and Administrative Site Conditions: chest pain, catheter site hemorrhage.
- Hepatobiliary Disorders: cholecystitis.
- Infections and Infestations: fungal infection, sepsis, bronchopulmonary aspergillosis, peridiverticular abscess, respiratory tract infection, pseudomonal lung infection, Mycobacterium avium complex infection.
- Injury, Poisoning and Procedural Complications: post procedural pain, post procedural hemorrhage.
- Nervous System Disorders: intracranial hemorrhage.
- Psychiatric Disorders: mental status changes.
- Renal and Urinary Disorders: renal failure, urethral hemorrhage.
- Respiratory, Thoracic and Mediastinal Disorders: hemoptysis, lung infiltration, pulmonary embolism, respiratory arrest, pulmonary mass.
- Allergic Reaction: Hypersensitivity (anaphylactic reaction) to decitabine has been reported in a Phase 2 trial.
## Postmarketing Experience
The following adverse reactions have been identified during post-approval use of decitabine. 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.
Cases of Sweet’s Syndrome (acute febrile neutrophilic dermatosis) have been reported.
# Drug Interactions
Drug interaction studies with decitabine have not been conducted. In vitro studies in human liver microsomes suggest that decitabine is unlikely to inhibit or induce cytochrome P450 enzymes. In vitro metabolism studies have suggested that decitabine is not a substrate for human liver cytochrome P450 enzymes. As plasma protein binding of decitabine is negligible (<1%), interactions due to displacement of more highly protein bound drugs from plasma proteins are not expected.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
Decitabine can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of decitabine in pregnant women.
The developmental toxicity of decitabine was examined in mice exposed to single IP (intraperitoneal) injections (0, 0.9 and 3.0 mg/m2, approximately 2% and 7% of the recommended daily clinical dose, respectively) over gestation days 8, 9, 10 or 11. No maternal toxicity was observed but reduced fetal survival was observed after treatment at 3 mg/m2 and decreased fetal weight was observed at both dose levels. The 3 mg/m2 dose elicited characteristic fetal defects for each treatment day, including supernumerary ribs (both dose levels), fused vertebrae and ribs, cleft palate, vertebral defects, hind-limb defects and digital defects of fore- and hind-limbs. In rats given a single IP injection of 2.4, 3.6 or 6 mg/m2 (approximately 5, 8, or 13% the daily recommended clinical dose, respectively) on gestation days 9-12, no maternal toxicity was observed. No live fetuses were seen at any dose when decitabine was injected on gestation day 9. A significant decrease in fetal survival and reduced fetal weight at doses greater than 3.6 mg/m2 was seen when decitabine was given on gestation day 10. Increased incidences of vertebral and rib anomalies were seen at all dose levels, and induction of exophthalmia, exencephaly, and cleft palate were observed at 6.0 mg/m2. Increased incidence of foredigit defects was seen in fetuses at doses greater than 3.6 mg/m2. Reduced size and ossification of long bones of the fore-limb and hind-limb were noted at 6.0 mg/m2. 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. Women of child bearing potential should be advised to avoid becoming pregnant while taking decitabine.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Decitabine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Decitabine during labor and delivery.
### Nursing Mothers
It is not known whether decitabine or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions from decitabine in nursing infants, 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 safety and effectiveness of decitabine in pediatric patients have not been established.
### Geriatic Use
Of the total number of patients exposed to decitabine in the controlled clinical trial, 61 of 83 patients were age 65 and over, while 21 of 83 patients were age 75 and over. 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, but greater sensitivity of some older individuals cannot be ruled out.
### Gender
There is no FDA guidance on the use of Decitabine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Decitabine with respect to specific racial populations.
### Renal Impairment
There are no data on the use of decitabine in patients with renal dysfunction; therefore, decitabine should be used with caution in these patients.
### Hepatic Impairment
There are no data on the use of decitabine in patients with hepatic dysfunction; therefore, decitabine should be used with caution in these patients.
### Females of Reproductive Potential and Males
The effect of decitabine on postnatal development and reproductive capacity was evaluated in mice administered a single 3 mg/m2 IP injection (approximately 7% the recommended daily clinical dose) on day 10 of gestation. Body weights of males and females exposed in utero to decitabine were significantly reduced relative to controls at all postnatal time points. No consistent effect on fertility was seen when female mice exposed in utero were mated to untreated males. Untreated females mated to males exposed in utero showed decreased fertility at 3 and 5 months of age (36% and 0% pregnancy rate, respectively). In male mice given IP injections of 0.15, 0.3 or 0.45 mg/m2 decitabine (approximately 0.3% to 1% the recommended clinical dose) 3 times a week for 7 weeks, decitabine did not affect survival, body weight gain or hematological measures (hemoglobin and WBC counts). Testes weights were reduced, abnormal histology was observed and significant decreases in sperm number were found at doses ≥ 0.3 mg/m2. In females mated to males dosed with ≥ 0.3 mg/m2 decitabine, pregnancy rate was reduced and preimplantation loss was significantly increased.
### Immunocompromised Patients
There is no FDA guidance one the use of Decitabine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Intravenous
### Monitoring
There is limited information regarding Decitabine Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Decitabine and IV administrations.
# Overdosage
There is no known antidote for overdosage with decitabine. Higher doses are associated with increased myelosuppression including prolonged neutropenia and thrombocytopenia. Standard supportive measures should be taken in the event of an overdose.
# Pharmacology
## Mechanism of Action
Decitabine is believed to exert its antineoplastic effects after phosphorylation and direct incorporation into DNA and inhibition of DNA methyltransferase, causing hypomethylation of DNA and cellular differentiation or apoptosis. Decitabine inhibits DNA methylation in vitro, which is achieved at concentrations that do not cause major suppression of DNA synthesis. Decitabine-induced hypomethylation in neoplastic cells may restore normal function to genes that are critical forthe control of cellulardifferentiation and proliferation. In rapidly dividing cells, the cytotoxicity of decitabine may also be attributed to the formation of covalent adducts between DNA methyltransferase and decitabine incorporated into DNA. Non-proliferating cells are relatively insensitive to decitabine.
## Structure
Decitabine has the following structural formula:
## Pharmacodynamics
Decitabine has been shown to induce hypomethylation both in vitro and in vivo. However, there have been no studies of decitabine-induced hypomethylation and pharmacokinetic parameters.
## Pharmacokinetics
Pharmacokinetic parameters were evaluated in patients. Eleven patients received 20 mg/m2 infused over 1 hour intravenously (treatment Option 2), Fourteen patients received 15 mg/m2 infused over 3 hours (treatment Option 1). PK parameters are shown in Table 3. Plasma concentration-time profiles after discontinuation of infusion showed a biexponential decline. The CL of decitabine was higher following treatment Option 2. Upon repeat doses there was no systemic accumulation of decitabine or any changes in PK parameters. Population PK analysis (N=35) showed that the cumulative AUC per cycle for treatment Option 2 was 2.3-fold lower than the cumulative AUC per cycle following treatment Option 1.
The exact route of elimination and metabolic fate of decitabine is not known in humans. One of the pathways of elimination of decitabine appears to be deamination by cytidine deaminase found principally in the liver but also in granulocytes, intestinal epithelium and whole blood.
## Nonclinical Toxicology
- Carcinogenicity studies with decitabine have not been conducted.
- The mutagenic potential of decitabine was tested in several in vitro and in vivo systems. Decitabine increased mutation frequency in L5178Y mouse lymphoma cells, and mutations were produced in an Escherichiacoli lac-I transgene in colonic DNA of decitabine-treated mice. Decitabine caused chromosomal rearrangements in larvae of fruit flies.
# Clinical Studies
A randomized open-label, multicenter, controlled trial evaluated 170 adult patients with myelodysplastic syndromes (MDS) meeting French-American-British (FAB) classification criteria and International Prognostic Scoring System (IPSS) High-Risk, Intermediate-2 and Intermediate-1 prognostic scores. Eighty-nine patients were randomized to decitabine therapy plus supportive care (only 83 received decitabine), and 81 to Supportive Care (SC) alone. Patients with Acute Myeloid Leukemia (AML) were not intended to be included. Of the 170 patients included in the study, independent review (adjudicated diagnosis) found that 12 patients (9 in the decitabine arm and 3 in the SC arm) had the diagnosis of AML at baseline. Baseline demographics and other patient characteristics in the Intent-to-Treat (ITT) population were similar between the 2 groups, as shown in Table 4.
Patients randomized to the decitabine arm received decitabine intravenously infused at a dose of 15 mg/m2 over a 3-hour period, every 8 hours, for 3 consecutive days. This cycle was repeated every 6 weeks, depending on the patient’s clinical response and toxicity. Supportive care consisted of blood and blood product transfusions, prophylactic antibiotics, and hematopoietic growth factors. The study endpoints were overall response rate (complete response + partial response) and time to AML or death. Responses were classified using the MDS International Working Group (IWG) criteria; patients were required to be RBC and platelet transfusion independent during the time of response. Response criteria are given in Table 5:
All patients with a CR or PR were RBC and platelet transfusion independent in the absence of growth factors.
Responses occurred in patients with an adjudicated baseline diagnosis of AML.
Three open-label, single-arm, multicenter studies were conducted to evaluate the safety and efficacy of decitabine in MDS patients with any of the FAB subtypes. In one study conducted in North America, 99 patients with IPSS Intermediate-1, Intermediate-2, or high risk prognostic scores received decitabine by intravenous infusion at a dose of 20 mg/m2 IV over 1-hour daily, on days 1-5 of week 1 every 4 weeks (1 cycle). The results were consistent with the results of the controlled trial and summarized in Table 8.
# How Supplied
Decitabine 50 mg single-dose vial
- NDC 62856-600-01
## Storage
Store at 25°C (77°F)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with decitabine and for I month afterwards, and to use effective contraception during this time.
- Men should be advised not to father a child while receiving treatment with decitabine, and for 2 months afterwards. During these times, men with female partners of childbearing potential should use effective contraception.
- Patients should be advised to monitor and report any symptoms of neutropenia, thrombocytopenia, or fever to their physician as soon as possible.
# Precautions with Alcohol
Alcohol-Decitabine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Dacogen [1]
# Look-Alike Drug Names
There is limited information regarding Decitabine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Dacogen | |
24e2ca0dbf8944d6362b57eb75cc5b56272327d7 | wikidoc | Daflon 500 | Daflon 500
DAFLON 500 is also distributed as:
Detralex, Arvenum 500, Alvenor, Ardium, Capiven, Elatec and Venitol
- Official web site
DAFLON 500 abridged prescribing information
# Presentation and Composition:
Micronized Purified Flavonoid Fraction 500mg: diosmin 450 mg, flavonoids expressed as hesperidin 50 mg.
# Therapeutic properties:
Vascular protector and venotonic.
DAFLON 500 mg acts on the return vascular system: it reduces venous distensibility and venous stasis; in the microcirculation, it normalizes capillary permeability and reinforces capillary resistance.
# Pharmacokinetics:
Micronization of Daflon 500 mg increases its gastrointestinal absorption compared with nonmicronized diosmin (urinary excretion 57.9% vs 32.7%).
# Therapeutic indications:
Treatment of organic and idiopathic chronic venous disease of the lower limbs with the following symptoms: heavy legs, pain, nocturnal cramps, edema.
Treatment of hemorrhoids and acute hemorrhoidal attacks.
# Side effects:
Some cases of minor gastrointestinal and autonomic disorders have been reported, but these never required cessation of treatment.
# Drug interactions:
None
# Precautions:
Pregnancy: experimental studies in animal have not demonstrated any teratogenic effects and no harmful effects have been reported in man to date.
Lactation: in the absence of data concerning the diffusion into breast milk, breast-feeding is not recommended during treatment.
# Contraindications:
None
# Dosage and administration:
In chronic venous disease: 2 tablets daily.
In hemorrhoidal disease:
- Acute crisis: 6 tablets daily for 4 days, then 4 tablets daily for 3 days.
- Chronic treatment: 2 tablets daily. | Daflon 500
Template:Wikify
DAFLON 500 is also distributed as:
Detralex, Arvenum 500, Alvenor, Ardium, Capiven, Elatec and Venitol
- Official web site
DAFLON 500 abridged prescribing information
# Presentation and Composition:
Micronized Purified Flavonoid Fraction 500mg: diosmin 450 mg, flavonoids expressed as hesperidin 50 mg.
# Therapeutic properties:
Vascular protector and venotonic.
DAFLON 500 mg acts on the return vascular system: it reduces venous distensibility and venous stasis; in the microcirculation, it normalizes capillary permeability and reinforces capillary resistance.
# Pharmacokinetics:
Micronization of Daflon 500 mg increases its gastrointestinal absorption compared with nonmicronized diosmin (urinary excretion 57.9% vs 32.7%).
# Therapeutic indications:
Treatment of organic and idiopathic chronic venous disease of the lower limbs with the following symptoms: heavy legs, pain, nocturnal cramps, edema.
Treatment of hemorrhoids and acute hemorrhoidal attacks.
# Side effects:
Some cases of minor gastrointestinal and autonomic disorders have been reported, but these never required cessation of treatment.
# Drug interactions:
None
# Precautions:
Pregnancy: experimental studies in animal have not demonstrated any teratogenic effects and no harmful effects have been reported in man to date.
Lactation: in the absence of data concerning the diffusion into breast milk, breast-feeding is not recommended during treatment.
# Contraindications:
None
# Dosage and administration:
In chronic venous disease: 2 tablets daily.
In hemorrhoidal disease:
- Acute crisis: 6 tablets daily for 4 days, then 4 tablets daily for 3 days.
- Chronic treatment: 2 tablets daily.
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Daflon_500 | |
d675ade54104d7829afbbbd895fcec61007ee0ad | wikidoc | Dalteparin | Dalteparin
# 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
Dalteparin is a low molecular weight heparin that is FDA approved for the prophylaxis of ischemic complications in unstable angina and non-q-wave myocardial infarction, deep vein thrombosis, extended treatment of symptomatic venous thromboembolism in patients with cancer. Common adverse reactions include hematoma and irritation symptom.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Prophylaxis of Ischemic Complications in Unstable Angina and Non-Q-Wave Myocardial Infarction
- Dosing information
- Recommended dosage: 120 IU/kg IV SC q12h, but not more than 10,000 IU,
- Concurrent with: aspirin 75 to 165 mg PO qd‘’‘. Treatment should be continued until the patient is clinically stabilized.
- Concurrent aspirin therapy is recommended except when contraindicated.
- The usual duration: 5 to 8 days.
- Table 1 lists the volume of Dalteparin, based on the 9.5 mL multiple-dose vial (10,000 IU/mL), to be administered for a range of patient weights.
### Prophylaxis of Venous Thromboembolism Following Hip Replacement Surgery
- Dosing information
- Usual duration: 5 to 10 days after surgery; up to 14 days of treatment with Dalteparin have been well tolerated in clinical trials.
- Table 2 presents the dosing options for patients undergoing hip replacement surgery.
### Abdominal Surgery
- Dosing information
- In patients undergoing abdominal surgery with a risk of thromboembolic complications
- Recommended dose: 2500 IU IV SC qd, starting 1 to 2 hours prior to surgery and repeated once daily postoperatively.
- Usual duration: 5 to 10 days.
- In patients undergoing abdominal surgery associated with a high risk of thromboembolic complications
- Recommended dose: 5000 IU IV SC’‘’ the evening before surgery, then once daily postoperatively.
- Usual duration: 5 to 10 days.
- Alternatively, in patients with malignancy, 2500 IU IV SC 1 to 2 hours before surgery followed by 2500 IU IV SC 12 hours later, and then ’‘’5000 IU IV SC qd‘’‘ postoperatively.
- Usual duration: 5 to 10 days.
### Medical Patients During Acute Illness
- Dosing information
- Recommended dosage: 5000 IU IV SC qd‘’‘.
- Usual duration: 12 to 14 days.
### Extended Treatment of Symptomatic Venous Thromboembolism in Patients with Cancer
- Dosing information
- Recommended dosage:
- For the first 30 days: ‘’‘200 IU/kg total body weight IV SC qd’‘’.
- The total daily dose should not exceed ’‘’18,000 IU‘’‘.
- Table 3 lists the dose of Dalteparin to be administered once daily during the first month for a range of patient weights.
Month 1
Months 2 to 6
- Administer Dalteparin at a dose of approximately ’‘’150 IU/kg‘’‘, subcutaneously once daily during Months 2 through 6. The total daily dose should not exceed ’‘’18,000 IU‘’‘. Table 4 lists the dose of Dalteparin to be administered once daily for a range of patient weights during months 2-6.
- Safety and efficacy beyond six months have not been evaluated in patients with cancer and acute symptomatic VTE.
### Dose Reductions for Thrombocytopenia in Patients with Cancer and Acute Symptomatic VTE
- Dosing information
- In patients receiving Dalteparin who experience platelet counts between 50,000 and 100,000/mm3, reduce the daily dose of Dalteparin by 2,500 IU until the platelet count recovers to ≥ 100,000/mm3. In patients receiving Dalteparin who experience platelet counts < 50,000/mm3, discontinue Dalteparin until the platelet count recovers above 50,000/mm3.
### Dose Reductions for Renal Insufficiency in Extended Treatment of Acute Symptomatic Venous Thromboembolism in Patients with Cancer
- Dosing information
- In patients with severely impaired renal function (CrCl < 30 mL/min), monitor anti-Xa levels to determine the appropriate Dalteparin dose.
- Target anti-Xa range is 0.5-1.5 IU/mL. When monitoring anti-Xa in these patients, perform sampling 4-6 hrs after Dalteparin dosing and only after the patient has received 3-4 doses.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Dalteparin in pediatric patients.
### Non–Guideline-Supported Use
### Disseminated intravascular coagulation
- Dosing information
- 150 anti-Xa units/kilogram/day
### Adjunct treatment of Percutaneous coronary intervention
- Dosing information
- 60 IU/kg IV
### Static Ulcer
- Dosing information
- Not applicable
### Prophylaxis of Arterial thromboembolism
- Dosing information
- 100 IU/kg IV SC bid
# 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
There is limited information regarding Off-Label Guideline-Supported Use of Dalteparin in pediatric patients.
### Non–Guideline-Supported Use
### Prophylaxis of Arterial thromboembolism
- Dosing information
- Not applicable 10650853
# Contraindications
- Active major bleeding
- History of heparin induced thrombocytopenia or heparin induced thrombocytopenia with thrombosis.
- Hypersensitivity to dalteparin sodium (e.g., pruritis, rash, anaphylactic reactions)
- In patients undergoing Epidural/Neuraxial anesthesia, do not administer Dalteparin;
- As a treatment for unstable angina and non_q wave MI
- For prolonged VTE prophylaxis.
- Hypersensitivity to heparin or pork products
# Warnings
### Increased Risk of hemorrhage
- Spinal or epidural hemorrhage and subsequent hematomas can occur with the associated use of low molecular weight heparins or heparinoids and neuraxial (spinal/epidural) anesthesia or spinal puncture. The risk of these events is higher with the use of post-operative indwelling epidural catheters, with the concomitant use of additional drugs affecting hemostasis such as NSAIDs, with traumatic or repeated epidural or spinal puncture, or in patients with a history of spinal surgery or spinal deformity.
- To reduce the potential risk of bleeding associated with the concurrent use of dalteparin sodium and epidural or spinal anesthesia/analgesia or spinal puncture, consider the pharmacokinetic profile of dalteparin.
- Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of dalteparin is low; however, the exact timing to reach a sufficiently low anticoagulant effect in each patient is not known. No additional hemostasis-altering medications should be administered due to the additive effects.
- Patients on preoperative Dalteparin thromboprophylaxis can be assumed to have altered coagulation. The first postoperative Dalteparin thrombophylaxis dose (2500 IU) should be administered 6 to 8 hrs postoperatively. The second postoperative dose (2500 or 5000 IU) should occur no sooner than 24 hrs after the first dose. Placement or removal of a catheter should be delayed for at least 12 hours after administration of lower doses (2500 IU or 5000 IU once daily) of Dalteparin, and at least 24 hours after the administration of higher doses (200 IU/kg once daily, 120 IU/kg twice daily) of Dalteparin. Anti-Xa levels are still detectable at these time points, and these delays are not a guarantee that neuraxial hematoma will be avoided.
- Although a specific recommendation for timing of a subsequent Dalteparin dose after catheter removal cannot be made, consider delaying this next dose for at least four hours, based on a benefit-risk assessment considering both the risk for thrombosis and the risk for bleeding in the context of the procedure and patient risk factors. For patients with creatinine clearance <30mL/minute, additional considerations are necessary because elimination of Dalteparin may be more prolonged; consider doubling the timing of removal of a catheter, at least 24 hours for the lower prescribed dose of Dalteparin (2500 IU or 5000 IU once daily) and at least 48 hours for the higher dose (200 IU/kg once daily, 120 IU/kg twice daily).
- Should the physician decide to administer anticoagulation in the context of epidural or spinal anesthesia/analgesia or lumbar puncture, frequent monitoring must be exercised to detect any signs and symptoms of neurological impairment such as midline back pain, sensory and motor deficits (numbness or weakness in lower limbs), bowel and/or bladder dysfunction. *Instruct patients to report immediately if they experience any of the above signs or symptoms. If signs or symptoms of spinal hematoma are suspected, initiate urgent diagnosis and treatment including consideration for spinal cord decompression even though such treatment may not prevent or reverse neurological sequelae.
- Use Dalteparin with extreme caution in patients who have an increased risk of hemorrhage, such as those with severe uncontrolled hypertension, bacterial endocarditis, congenital or acquired bleeding disorders, active ulceration and angiodysplastic gastrointestinal disease, hemorrhagic stroke, or shortly after brain, spinal or ophthalmological surgery. Dalteparin may enhance the risk of bleeding in patients with thrombocytopenia or platelet defects; severe liver or renal insufficiency, hypertensive or diabetic retinopathy, and recent gastrointestinal bleeding. Bleeding can occur at any site during therapy with Dalteparin.
### Thrombocytopenia
- Heparin-induced thrombocytopenia can occur with the administration of Dalteparin. The incidence of this complication is unknown at present. In clinical practice, cases of thrombocytopenia with thrombosis, amputation and death have been observed. Closely monitor thrombocytopenia of any degree.
- In Dalteparin clinical trials supporting non-cancer indications, platelet counts of < 50,000/mm3 occurred in < 1% of patients.
- In the clinical trial of patients with cancer and acute symptomatic venous thromboembolism treated for up to 6 months in the Dalteparin treatment arm, platelet counts of < 100,000/mm3 occurred in 13.6% of patients, including 6.5% who also had platelet counts less than 50,000/mm3. In the same clinical trial, thrombocytopenia was reported as an adverse event in 10.9% of patients in the Dalteparin arm and 8.1% of patients in the OAC arm. Dalteparin dose was decreased or interrupted in patients whose platelet counts fell below 100,000/mm3.
### Benzyl Alcohol
- Each multiple-dose vial of Dalteparin contains benzyl alcohol as a preservative. Benzyl alcohol has been reported to be associated with a fatal "Gasping Syndrome" in premature infants. Because benzyl alcohol may cross the placenta, use caution when administering Dalteparin preserved with benzyl alcohol to pregnant women. If anticoagulation with Dalteparin is needed during pregnancy, use preservative-free formulations, where possible.
### Laboratory Tests
- Periodic routine complete blood counts, including platelet count, blood chemistry, and stool occult blood tests are recommended during the course of treatment with Dalteparin. When administered at recommended prophylaxis doses, routine coagulation tests such as Prothrombin Time (PT) and Activated Partial Thromboplastin Time (APTT) are relatively insensitive measures of Dalteparin activity and, therefore, unsuitable for monitoring the anticoagulant effect of Dalteparin. Anti-Factor Xa may be used to monitor the anticoagulant effect of Dalteparin, such as in patients with severe renal impairment or if abnormal coagulation parameters or bleeding occurs during Dalteparin therapy.
# 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 accurately reflect the rates observed in practice.
### Hemorrhage
- The incidence of hemorrhagic complications during treatment with Dalteparin Injection has been low. The most commonly reported side effect is hematoma at the injection site. The risk for bleeding varies with the indication and may increase with higher doses.
### Unstable Angina and Non-Q-Wave Myocardial Infarction
- Table 5 summarizes major bleeding reactions that occurred with Dalteparin, heparin, and placebo in clinical trials of unstable angina and non-Q-wave myocardial infarction.
### Hip Replacement Surgery
- Table 6 summarizes: 1) all major bleeding reactions and, 2) other bleeding reactions possibly or probably related to treatment with Dalteparin (preoperative dosing regimen), warfarin sodium, or heparin in two hip replacement surgery clinical trials.
- Six of the patients treated with Dalteparin experienced seven major bleeding reactions. Two of the reactions were wound hematoma (one requiring reoperation), three were bleeding from the operative site, one was intraoperative bleeding due to vessel damage, and one was gastrointestinal bleeding. None of the patients experienced retroperitoneal or intracranial hemorrhage or died of bleeding complications.
- In the third hip replacement surgery clinical trial, the incidence of major bleeding reactions was similar in all three treatment groups: 3.6% (18/496) for patients who started Dalteparin before surgery; 2.5% (12/487) for patients who started Dalteparin after surgery; and 3.1% (15/489) for patients treated with warfarin sodium.
### Abdominal Surgery
- Table 7 summarizes bleeding reactions that occurred in clinical trials which studied Dalteparin 2500 and 5000 IU administered once daily to abdominal surgery patients.
- In a trial comparing Dalteparin 5000 IU once daily to Dalteparin 2500 IU once daily in patients undergoing surgery for malignancy, the incidence of bleeding reactions was 4.6% and 3.6%, respectively (n.s.). In a trial comparing Dalteparin 5000 IU once daily to heparin 5000 U twice daily, in the malignancy subgroup the incidence of bleeding reactions was 3.2% and 2.7%, respectively for Dalteparin and Heparin (n.s.).
### Medical Patients with Severely Restricted Mobility During Acute Illness
- Table 8 summarizes major bleeding reactions that occurred in a clinical trial of medical patients with severely restricted mobility during acute illness.
- Three of the major bleeding reactions that occurred by Day 21 were fatal, all due to gastrointestinal hemorrhage (two patients in the group treated with Dalteparin and one in the group receiving placebo).
### Patients with Cancer and Acute Symptomatic Venous Thromboembolism
- Table 9 summarizes the number of patients with bleeding reactions that occurred in the clinical trial of patients with cancer and acute symptomatic venous thromboembolism. A bleeding event was considered major if it: 1) was accompanied by a decrease in hemoglobin of ≥ 2 g/dL in connection with clinical symptoms; 2) occurred at a critical site (intraocular, spinal/epidural, intracranial, retroperitoneal, or pericardial bleeding); 3) required transfusion of ≥ 2 units of blood products; or 4) led to death. Minor bleeding was classified as clinically overt bleeding that did not meet criteria for major bleeding.
- At the end of the six-month study, a total of 46 (13.6%) patients in the Dalteparin arm and 62 (18.5%) patients in the OAC arm experienced any bleeding event. One bleeding event (hemoptysis in a patient in the Dalteparin arm at Day 71) was fatal.
### Elevations of Serum Transaminases
- In Dalteparin clinical trials supporting non-cancer indications, where hepatic transaminases were measured, asymptomatic increases in transaminase levels (SGOT/AST and SGPT/ALT) greater than three times the upper limit of normal of the laboratory reference range were seen in 4.7% and 4.2%, respectively, of patients during treatment with Dalteparin.
- In the Dalteparin clinical trial of patients with cancer and acute symptomatic venous thromboembolism treated with Dalteparin for up to 6 months, asymptomatic increases in transaminase levels, AST and ALT, greater than three times the upper limit of normal of the laboratory reference range were reported in 8.9% and 9.5% of patients, respectively. The frequencies of Grades 3 and 4 increases in AST and ALT, as classified by the National Cancer Institute, Common Toxicity Criteria (NCI-CTC) Scoring System, were 3% and 3.8%, respectively. Grades 2, 3 & 4 combined have been reported in 12% and 14% of patients, respectively.
### Other
- Allergic Reactions: Allergic reactions (i.e., pruritus, rash, fever, injection site reaction, bullous eruption) have occurred. Cases of anaphylactoid reactions have been reported.
- Local Reactions: Pain at the injection site, the only non-bleeding event determined to be possibly or probably related to treatment with Dalteparin and reported at a rate of at least 2% in the group treated with Dalteparin, was reported in 4.5% of patients treated with Dalteparin 5000 IU once daily vs 11.8% of patients treated with heparin 5000 U twice daily in the abdominal surgery trials. In the hip replacement trials, pain at injection site was reported in 12% of patients treated with Dalteparin 5000 IU once daily vs 13% of patients treated with heparin 5000 U three times a day.
## Postmarketing Experience
- The following adverse reactions have been identified during postapproval use of Dalteparin. 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.
- Since first international market introduction in 1985, there have been more than 15 reports of epidural or spinal hematoma formation with concurrent use of dalteparin sodium and spinal/epidural anesthesia or spinal puncture. The majority of patients had postoperative indwelling epidural catheters placed for analgesia or received additional drugs affecting hemostasis. In some cases the hematoma resulted in long-term or permanent paralysis (partial or complete).
- Skin necrosis has occurred. There have been cases of alopecia reported that improved on drug discontinuation.
# Drug Interactions
- Use Dalteparin with care in patients receiving oral anticoagulants, platelet inhibitors, and thrombolytic agents because of increased risk of bleeding.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
- There are no adequate and well-controlled studies of Dalteparin use in pregnant women. In reproductive and developmental toxicity studies, pregnant rats and rabbits received dalteparin sodium at intravenous doses up to 2400 IU/kg (14,160 IU/m2) (rats) and 4800 IU/kg (40,800 IU/m2) (rabbits). These exposures were 2 to 4 times (rats) and 4 times (rabbits) the human dose of 100 IU/kg dalteparin based on the body surface area. No evidence of impaired fertility or harm to the fetuses occurred in these studies. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
- Cases of "Gasping Syndrome" have occurred in premature infants when large amounts of benzyl alcohol have been administered (99-404 mg/kg/day). The 9.5 mL and the 3.8 mL multiple-dose vials of Dalteparin contain 14 mg/mL of benzyl alcohol.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Dalteparin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Dalteparin during labor and delivery.
### Nursing Mothers
- Based on limited published data dalteparin is minimally excreted in human milk. One study of 15 lactating women receiving prophylactic doses of dalteparin, in the immediate postpartum period, detected small amounts of anti-Xa activity (range < 0.005 to 0.037 IU/ml) in breast milk that were equivalent to a milk/plasma ratio of < 0.025-0.224. Oral absorption of LMWH is extremely low, but the clinical implications, if any, of this small amount of anticoagulant activity on a nursing infant are unknown. Caution should be exercised when Dalteparin is administered to a nursing woman.
### Pediatric Use
- Safety and effectiveness in pediatric patients have not been established.
### Geriatic Use
- Of the total number of patients in clinical studies of Dalteparin, 5516 patients were 65 years of age or older and 2237 were 75 or older. No overall differences in effectiveness were observed between these subjects and younger subjects. Some studies suggest that the risk of bleeding increases with age. Postmarketing surveillance and literature reports have not revealed additional differences in the safety of Dalteparin between elderly and younger patients. Give careful attention to dosing intervals and concomitant medications (especially antiplatelet medications) in geriatric patients, particularly in those with low body weight (< 45 kg) and those predisposed to decreased renal function.
### Gender
There is no FDA guidance on the use of Dalteparin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Dalteparin with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Dalteparin in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Dalteparin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Dalteparin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Dalteparin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Subcutaneous injection technique: Patients should be sitting or lying down and Dalteparin administered by deep subcutaneous injection. Dalteparin may be injected in a U-shape area around the navel, the upper outer side of the thigh or the upper outer quadrangle of the buttock. The injection site should be varied daily. When the area around the navel or the thigh is used, using the thumb and forefinger, you must lift up a fold of skin while giving the injection. The entire length of the needle should be inserted at a 45 to 90 degree angle.
- Inspect Dalteparin prefilled syringes and vials visually for particulate matter and discoloration prior to administration
- After first penetration of the rubber stopper, store the multiple-dose vials at room temperature for up to 2 weeks. Discard any unused solution after 2 weeks.
- Fixed dose syringes: To ensure delivery of the full dose, do not expel the air bubble from the prefilled syringe before injection. Hold the syringe assembly by the open sides of the device. Remove the needle shield. Insert the needle into the injection area as instructed above. Depress the plunger of the syringe while holding the finger flange until the entire dose has been given. The needle guard will not be activated unless the entire dose has been given. Remove needle from the patient. Let go of the plunger and allow syringe to move up inside the device until the entire needle is guarded. Discard the syringe assembly in approved containers.
- Graduated syringes: Hold the syringe assembly by the open sides of the device. Remove the needle shield. With the needle pointing up, prepare the syringe by expelling the air bubble and then continuing to push the plunger to the desired dose or volume, discarding the extra solution in an appropriate manner. Insert the needle into the injection area as instructed above. Depress the plunger of the syringe while holding the finger flange until the entire dose remaining in the syringe has been given. The needle guard will not be activated unless the entire dose has been given. Remove needle from the patient. Let go of the plunger and allow syringe to move up inside the device until the entire needle is guarded. Discard the syringe assembly in approved containers.
### Monitoring
FDA Package Insert for Dalteparin contains no information regarding drug monitoring.
# IV Compatibility
There is limited information about the IV Compatibility.
# Overdosage
- An excessive dosage of Dalteparin Injection may lead to hemorrhagic complications. These may generally be stopped by slow intravenous injection of protamine sulfate (1% solution), at a dose of 1 mg protamine for every 100 anti-Xa IU of Dalteparin given. If the APTT measured 2 to 4 hours after the first infusion remains prolonged, a second infusion of 0.5 mg protamine sulfate per 100 anti-Xa IU of Dalteparin may be administered. Even with these additional doses of protamine, the APTT may remain more prolonged than would usually be found following administration of unfractionated heparin. In all cases, the anti-Factor Xa activity is never completely neutralized (maximum about 60 to 75%).
- Take particular care to avoid overdosage with protamine sulfate. Administration of protamine sulfate can cause severe hypotensive and anaphylactoid reactions. Because fatal reactions, often resembling anaphylaxis, have been reported with protamine sulfate, give protamine sulfate only when resuscitation techniques and treatment for anaphylactic shock are readily available. For additional information, consult the labeling of Protamine Sulfate Injection, USP, products.
# Pharmacology
## Mechanism of Action
- Dalteparin is a low molecular weight heparin with antithrombotic properties. It acts by enhancing the inhibition of Factor Xa and thrombin by antithrombin. In humans, dalteparin potentiates preferentially the inhibition of coagulation Factor Xa, while only slightly affecting the activated partial thromboplastin time (APTT).
## Structure
- Dalteparin Injection (dalteparin sodium injection) is a sterile, low molecular weight heparin. It is available in single-dose, prefilled syringes preassembled with a needle guard device, and multiple-dose vials. With reference to the W.H.O. First International Low Molecular Weight Heparin Reference Standard, each syringe contains either 2500, 5000, 7500, 10,000, 12,500, 15,000 or 18,000 anti-Factor Xa international units (IU), equivalent to 16, 32, 48, 64, 80, 96 or 115.2 mg dalteparin sodium, respectively. Each multiple-dose vial contains either 10,000 or 25,000 anti-Factor Xa IU per 1 mL (equivalent to 64 or 160 mg dalteparin sodium, respectively), for a total of 95,000 anti-Factor Xa IU per vial.
- Each prefilled syringe also contains Water for Injection and sodium chloride, when required, to maintain physiologic ionic strength. The prefilled syringes are preservative-free. Each multiple-dose vial also contains Water for Injection and 14 mg of benzyl alcohol per mL as a preservative. The pH of both formulations is 5.0 to 7.5.
- Dalteparin sodium is produced through controlled nitrous acid depolymerization of sodium heparin from porcine intestinal mucosa followed by a chromatographic purification process. It is composed of strongly acidic sulfated polysaccharide chains (oligosaccharide, containing 2,5-anhydro-D-mannitol residues as end groups) with an average molecular weight of 5000 and about 90% of the material within the range 2000-9000. The molecular weight distribution is:
- < 3000 daltons 3.0-15%
- 3000 to 8000 daltons 65.0-78.0%
- > 8000 daltons 14.0-26.0%
## Pharmacodynamics
- Doses of Dalteparin Injection of up to 10,000 anti-Factor Xa IU administered subcutaneously as a single dose or two 5000 IU doses 12 hours apart to healthy subjects did not produce a significant change in platelet aggregation, fibrinolysis, or global clotting tests such as prothrombin time (PT), thrombin time (TT) or APTT. Subcutaneous administration of doses of 5000 IU twice daily of Dalteparin for seven consecutive days to patients undergoing abdominal surgery did not markedly affect APTT, Platelet Factor 4 (PF4), or lipoprotein lipase.
## Pharmacokinetics
- Mean peak levels of plasma anti-Factor Xa activity following single subcutaneous doses of 2500, 5000 and 10,000 IU were 0.19 ± 0.04, 0.41 ± 0.07 and 0.82 ± 0.10 IU/mL, respectively, and were attained in about 4 hours in most subjects. Absolute bioavailability in healthy volunteers, measured as the anti-Factor Xa activity, was 87 ± 6%. Increasing the dose from 2500 to 10,000 IU resulted in an overall increase in anti-Factor Xa AUC that was greater than proportional by about one-third.
- Peak anti-Factor Xa activity increased more or less linearly with dose over the same dose range. There appeared to be no appreciable accumulation of anti-Factor Xa activity with twice-daily dosing of 100 IU/kg subcutaneously for up to 7 days.
- The volume of distribution for dalteparin anti-Factor Xa activity was 40 to 60 mL/kg. The mean plasma clearances of dalteparin anti-Factor Xa activity in normal volunteers following single intravenous bolus doses of 30 and 120 anti-Factor Xa IU/kg were 24.6 ± 5.4 and 15.6 ± 2.4 mL/hr/kg, respectively. The corresponding mean disposition half-lives were 1.47 ± 0.3 and 2.5 ± 0.3 hours.
- Following intravenous doses of 40 and 60 IU/kg, mean terminal half-lives were 2.1 ± 0.3 and 2.3 ± 0.4 hours, respectively. Longer apparent terminal half-lives (3 to 5 hours) are observed following subcutaneous dosing, possibly due to delayed absorption. In patients with chronic renal insufficiency requiring hemodialysis, the mean terminal half-life of anti-Factor Xa activity following a single intravenous dose of 5000 IU Dalteparin was 5.7 ± 2.0 hours, i.e. considerably longer than values observed in healthy volunteers, therefore, greater accumulation can be expected in these patients.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
- Dalteparin sodium has not been tested for its carcinogenic potential in long-term animal studies. It was not mutagenic in the in vitro Ames Test, mouse lymphoma cell forward mutation test and human lymphocyte chromosomal aberration test and in the in vivo mouse micronucleus test. Dalteparin sodium at subcutaneous doses up to 1200 IU/kg (7080 IU/m2) did not affect the fertility or reproductive performance of male and female rats.
# Clinical Studies
### Prophylaxis of Ischemic Complications in Unstable Angina and Non-Q-Wave Myocardial Infarction
- In a double-blind, randomized, placebo-controlled clinical trial, patients who recently experienced unstable angina with EKG changes or non-Q-wave myocardial infarction (MI) were randomized to Dalteparin Injection 120 IU/kg or placebo every 12 hours subcutaneously. In this trial, unstable angina was defined to include only angina with EKG changes. All patients, except when contraindicated, were treated concurrently with aspirin (75 mg once daily) and beta blockers. Treatment was initiated within 72 hours of the event (the majority of patients received treatment within 24 hours) and continued for 5 to 8 days. A total of 1506 patients were enrolled and treated; 746 received Dalteparin and 760 received placebo. The mean age of the study population was 68 years (range 40 to 90 years) and the majority of patients were white (99.7%) and male (63.9%). The combined incidence of the endpoint of death or myocardial infarction was lower for Dalteparin compared with placebo at 6 days after initiation of therapy. These results were observed in an analysis of all-randomized and all-treated patients. The combined incidence of death, MI, need for intravenous heparin or intravenous nitroglycerin, and revascularization was also lower for Dalteparin than for placebo (see Table 10).
- In a second randomized, controlled trial designed to evaluate long-term treatment with Dalteparin (days 6 to 45), data were also collected comparing 1-week (5 to 8 days) treatment of Dalteparin 120 IU/kg every 12 hours subcutaneously with heparin at an APTT-adjusted dosage. All patients, except when contraindicated, were treated concurrently with aspirin (100 to 165 mg per day). Of the 1499 patients enrolled, 1482 patients were treated; 751 received Dalteparin and 731 received heparin. The mean age of the study population was 64 years (range 25 to 92 years) and the majority of patients were white (96.0%) and male (64.2%). The incidence of the combined endpoint of death, myocardial infarction, or recurrent angina during this 1-week treatment period (5 to 8 days) was 9.3% for Dalteparin and 7.6% for heparin (p=0.323).
### Prophylaxis of Deep Vein Thrombosis in Patients Following Hip Replacement Surgery
- In an open-label randomized study, Dalteparin 5000 IU administered once daily subcutaneously was compared with warfarin sodium, administered orally, in patients undergoing hip replacement surgery. Treatment with Dalteparin was initiated with a 2500 IU dose subcutaneously within 2 hours before surgery, followed by a 2500 IU dose subcutaneously the evening of the day of surgery. Then, a dosing regimen of Dalteparin 5000 IU subcutaneously once daily was initiated on the first postoperative day. The first dose of warfarin sodium was given the evening before surgery, then continued daily at a dose adjusted for INR 2 to 3. Treatment in both groups was then continued for 5 to 9 days postoperatively. Of the 580 patients enrolled, 553 were treated and 550 underwent surgery. Of those who underwent surgery, 271 received Dalteparin and 279 received warfarin sodium. The mean age of the study population was 63 years (range 20 to 92 years) and the majority of patients were white (91.1%) and female (52.9%). The incidence of deep vein thrombosis (DVT), as determined by evaluable venography, was significantly lower for the group treated with Dalteparin compared with patients treated with warfarin sodium (see Table 11).
# How Supplied
- After first penetration of the rubber stopper, store the multiple-dose vials at room temperature for up to 2 weeks.
## Storage
- Store at controlled room temperature 20° to 25°C (68° to 77°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- If patients have had neuraxial anesthesia or spinal puncture, and particularly, if they are taking concomitant NSAIDs, platelet inhibitors, or other anticoagulants, inform the patients to watch for signs and symptoms of spinal or epidural hematoma, such as tingling, numbness (especially in the lower limbs) and muscular weakness. If any of these symptoms occur the patient should contact his or her physician immediately.
- Additionally, the use of aspirin and other NSAIDs may enhance the risk of hemorrhage. Discontinue their use prior to dalteparin therapy whenever possible; if co-administration is essential, the patient's clinical and laboratory status should be closely monitored.
- Inform patients:
- of the instructions for injecting Dalteparin if their therapy is to continue after discharge from the hospitals.
- it may take them longer than usual to stop bleeding.
- they may bruise and/or bleed more easily when they are treated with Dalteparin.
- they should report any unusual bleeding, bruising, or signs of thrombocytopenia (such as a rash of dark red spots under the skin) to their physician.
- to tell their physicians and dentists they are taking Dalteparin and/or any other product known to affect bleeding before any surgery is scheduled and before any new drug is take.
- to tell their physicians and dentists of all medications they are taking, including those obtained without a prescription, such as aspirin or other NSAIDs.
- Dalteparin is a registered trademark of Pfizer Health AB and is licensed to Eisai Inc.
# Precautions with Alcohol
Alcohol-Dalteparin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
Fragmin
# Look-Alike Drug Names
There is limited information regarding Dalteparin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Dalteparin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2]
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# Overview
Dalteparin is a low molecular weight heparin that is FDA approved for the prophylaxis of ischemic complications in unstable angina and non-q-wave myocardial infarction, deep vein thrombosis, extended treatment of symptomatic venous thromboembolism in patients with cancer. Common adverse reactions include hematoma and irritation symptom.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Prophylaxis of Ischemic Complications in Unstable Angina and Non-Q-Wave Myocardial Infarction
- Dosing information
- Recommended dosage: 120 IU/kg IV SC q12h, but not more than 10,000 IU,
- Concurrent with: aspirin 75 to 165 mg PO qd‘’‘. Treatment should be continued until the patient is clinically stabilized.
- Concurrent aspirin therapy is recommended except when contraindicated.
- The usual duration: 5 to 8 days.
- Table 1 lists the volume of Dalteparin, based on the 9.5 mL multiple-dose vial (10,000 IU/mL), to be administered for a range of patient weights.
### Prophylaxis of Venous Thromboembolism Following Hip Replacement Surgery
- Dosing information
- Usual duration: 5 to 10 days after surgery; up to 14 days of treatment with Dalteparin have been well tolerated in clinical trials.
- Table 2 presents the dosing options for patients undergoing hip replacement surgery.
### Abdominal Surgery
- Dosing information
- In patients undergoing abdominal surgery with a risk of thromboembolic complications
- Recommended dose: 2500 IU IV SC qd, starting 1 to 2 hours prior to surgery and repeated once daily postoperatively.
- Usual duration: 5 to 10 days.
- In patients undergoing abdominal surgery associated with a high risk of thromboembolic complications
- Recommended dose: 5000 IU IV SC’‘’ the evening before surgery, then once daily postoperatively.
- Usual duration: 5 to 10 days.
- Alternatively, in patients with malignancy, 2500 IU IV SC 1 to 2 hours before surgery followed by 2500 IU IV SC 12 hours later, and then ’‘’5000 IU IV SC qd‘’‘ postoperatively.
- Usual duration: 5 to 10 days.
### Medical Patients During Acute Illness
- Dosing information
- Recommended dosage: 5000 IU IV SC qd‘’‘.
- Usual duration: 12 to 14 days.
### Extended Treatment of Symptomatic Venous Thromboembolism in Patients with Cancer
- Dosing information
- Recommended dosage:
- For the first 30 days: ‘’‘200 IU/kg total body weight IV SC qd’‘’.
- The total daily dose should not exceed ’‘’18,000 IU‘’‘.
- Table 3 lists the dose of Dalteparin to be administered once daily during the first month for a range of patient weights.
Month 1
Months 2 to 6
- Administer Dalteparin at a dose of approximately ’‘’150 IU/kg‘’‘, subcutaneously once daily during Months 2 through 6. The total daily dose should not exceed ’‘’18,000 IU‘’‘. Table 4 lists the dose of Dalteparin to be administered once daily for a range of patient weights during months 2-6.
- Safety and efficacy beyond six months have not been evaluated in patients with cancer and acute symptomatic VTE.
### Dose Reductions for Thrombocytopenia in Patients with Cancer and Acute Symptomatic VTE
- Dosing information
- In patients receiving Dalteparin who experience platelet counts between 50,000 and 100,000/mm3, reduce the daily dose of Dalteparin by 2,500 IU until the platelet count recovers to ≥ 100,000/mm3. In patients receiving Dalteparin who experience platelet counts < 50,000/mm3, discontinue Dalteparin until the platelet count recovers above 50,000/mm3.
### Dose Reductions for Renal Insufficiency in Extended Treatment of Acute Symptomatic Venous Thromboembolism in Patients with Cancer
- Dosing information
- In patients with severely impaired renal function (CrCl < 30 mL/min), monitor anti-Xa levels to determine the appropriate Dalteparin dose.
- Target anti-Xa range is 0.5-1.5 IU/mL. When monitoring anti-Xa in these patients, perform sampling 4-6 hrs after Dalteparin dosing and only after the patient has received 3-4 doses.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Dalteparin in pediatric patients.
### Non–Guideline-Supported Use
### Disseminated intravascular coagulation
- Dosing information
- 150 anti-Xa units/kilogram/day[1]
### Adjunct treatment of Percutaneous coronary intervention
- Dosing information
- 60 IU/kg IV[2]
### Static Ulcer
- Dosing information
- Not applicable [3]
### Prophylaxis of Arterial thromboembolism
- Dosing information
- 100 IU/kg IV SC bid [4]
# 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
There is limited information regarding Off-Label Guideline-Supported Use of Dalteparin in pediatric patients.
### Non–Guideline-Supported Use
### Prophylaxis of Arterial thromboembolism
- Dosing information
- Not applicable 10650853
# Contraindications
- Active major bleeding
- History of heparin induced thrombocytopenia or heparin induced thrombocytopenia with thrombosis.
- Hypersensitivity to dalteparin sodium (e.g., pruritis, rash, anaphylactic reactions)
- In patients undergoing Epidural/Neuraxial anesthesia, do not administer Dalteparin;
- As a treatment for unstable angina and non_q wave MI
- For prolonged VTE prophylaxis.
- Hypersensitivity to heparin or pork products
# Warnings
### Increased Risk of hemorrhage
- Spinal or epidural hemorrhage and subsequent hematomas can occur with the associated use of low molecular weight heparins or heparinoids and neuraxial (spinal/epidural) anesthesia or spinal puncture. The risk of these events is higher with the use of post-operative indwelling epidural catheters, with the concomitant use of additional drugs affecting hemostasis such as NSAIDs, with traumatic or repeated epidural or spinal puncture, or in patients with a history of spinal surgery or spinal deformity.
- To reduce the potential risk of bleeding associated with the concurrent use of dalteparin sodium and epidural or spinal anesthesia/analgesia or spinal puncture, consider the pharmacokinetic profile of dalteparin.
- Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of dalteparin is low; however, the exact timing to reach a sufficiently low anticoagulant effect in each patient is not known. No additional hemostasis-altering medications should be administered due to the additive effects.
- Patients on preoperative Dalteparin thromboprophylaxis can be assumed to have altered coagulation. The first postoperative Dalteparin thrombophylaxis dose (2500 IU) should be administered 6 to 8 hrs postoperatively. The second postoperative dose (2500 or 5000 IU) should occur no sooner than 24 hrs after the first dose. Placement or removal of a catheter should be delayed for at least 12 hours after administration of lower doses (2500 IU or 5000 IU once daily) of Dalteparin, and at least 24 hours after the administration of higher doses (200 IU/kg once daily, 120 IU/kg twice daily) of Dalteparin. Anti-Xa levels are still detectable at these time points, and these delays are not a guarantee that neuraxial hematoma will be avoided.
- Although a specific recommendation for timing of a subsequent Dalteparin dose after catheter removal cannot be made, consider delaying this next dose for at least four hours, based on a benefit-risk assessment considering both the risk for thrombosis and the risk for bleeding in the context of the procedure and patient risk factors. For patients with creatinine clearance <30mL/minute, additional considerations are necessary because elimination of Dalteparin may be more prolonged; consider doubling the timing of removal of a catheter, at least 24 hours for the lower prescribed dose of Dalteparin (2500 IU or 5000 IU once daily) and at least 48 hours for the higher dose (200 IU/kg once daily, 120 IU/kg twice daily).
- Should the physician decide to administer anticoagulation in the context of epidural or spinal anesthesia/analgesia or lumbar puncture, frequent monitoring must be exercised to detect any signs and symptoms of neurological impairment such as midline back pain, sensory and motor deficits (numbness or weakness in lower limbs), bowel and/or bladder dysfunction. *Instruct patients to report immediately if they experience any of the above signs or symptoms. If signs or symptoms of spinal hematoma are suspected, initiate urgent diagnosis and treatment including consideration for spinal cord decompression even though such treatment may not prevent or reverse neurological sequelae.
- Use Dalteparin with extreme caution in patients who have an increased risk of hemorrhage, such as those with severe uncontrolled hypertension, bacterial endocarditis, congenital or acquired bleeding disorders, active ulceration and angiodysplastic gastrointestinal disease, hemorrhagic stroke, or shortly after brain, spinal or ophthalmological surgery. Dalteparin may enhance the risk of bleeding in patients with thrombocytopenia or platelet defects; severe liver or renal insufficiency, hypertensive or diabetic retinopathy, and recent gastrointestinal bleeding. Bleeding can occur at any site during therapy with Dalteparin.
### Thrombocytopenia
- Heparin-induced thrombocytopenia can occur with the administration of Dalteparin. The incidence of this complication is unknown at present. In clinical practice, cases of thrombocytopenia with thrombosis, amputation and death have been observed. Closely monitor thrombocytopenia of any degree.
- In Dalteparin clinical trials supporting non-cancer indications, platelet counts of < 50,000/mm3 occurred in < 1% of patients.
- In the clinical trial of patients with cancer and acute symptomatic venous thromboembolism treated for up to 6 months in the Dalteparin treatment arm, platelet counts of < 100,000/mm3 occurred in 13.6% of patients, including 6.5% who also had platelet counts less than 50,000/mm3. In the same clinical trial, thrombocytopenia was reported as an adverse event in 10.9% of patients in the Dalteparin arm and 8.1% of patients in the OAC arm. Dalteparin dose was decreased or interrupted in patients whose platelet counts fell below 100,000/mm3.
### Benzyl Alcohol
- Each multiple-dose vial of Dalteparin contains benzyl alcohol as a preservative. Benzyl alcohol has been reported to be associated with a fatal "Gasping Syndrome" in premature infants. Because benzyl alcohol may cross the placenta, use caution when administering Dalteparin preserved with benzyl alcohol to pregnant women. If anticoagulation with Dalteparin is needed during pregnancy, use preservative-free formulations, where possible.
### Laboratory Tests
- Periodic routine complete blood counts, including platelet count, blood chemistry, and stool occult blood tests are recommended during the course of treatment with Dalteparin. When administered at recommended prophylaxis doses, routine coagulation tests such as Prothrombin Time (PT) and Activated Partial Thromboplastin Time (APTT) are relatively insensitive measures of Dalteparin activity and, therefore, unsuitable for monitoring the anticoagulant effect of Dalteparin. Anti-Factor Xa may be used to monitor the anticoagulant effect of Dalteparin, such as in patients with severe renal impairment or if abnormal coagulation parameters or bleeding occurs during Dalteparin therapy.
# 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 accurately reflect the rates observed in practice.
### Hemorrhage
- The incidence of hemorrhagic complications during treatment with Dalteparin Injection has been low. The most commonly reported side effect is hematoma at the injection site. The risk for bleeding varies with the indication and may increase with higher doses.
### Unstable Angina and Non-Q-Wave Myocardial Infarction
- Table 5 summarizes major bleeding reactions that occurred with Dalteparin, heparin, and placebo in clinical trials of unstable angina and non-Q-wave myocardial infarction.
### Hip Replacement Surgery
- Table 6 summarizes: 1) all major bleeding reactions and, 2) other bleeding reactions possibly or probably related to treatment with Dalteparin (preoperative dosing regimen), warfarin sodium, or heparin in two hip replacement surgery clinical trials.
- Six of the patients treated with Dalteparin experienced seven major bleeding reactions. Two of the reactions were wound hematoma (one requiring reoperation), three were bleeding from the operative site, one was intraoperative bleeding due to vessel damage, and one was gastrointestinal bleeding. None of the patients experienced retroperitoneal or intracranial hemorrhage or died of bleeding complications.
- In the third hip replacement surgery clinical trial, the incidence of major bleeding reactions was similar in all three treatment groups: 3.6% (18/496) for patients who started Dalteparin before surgery; 2.5% (12/487) for patients who started Dalteparin after surgery; and 3.1% (15/489) for patients treated with warfarin sodium.
### Abdominal Surgery
- Table 7 summarizes bleeding reactions that occurred in clinical trials which studied Dalteparin 2500 and 5000 IU administered once daily to abdominal surgery patients.
- In a trial comparing Dalteparin 5000 IU once daily to Dalteparin 2500 IU once daily in patients undergoing surgery for malignancy, the incidence of bleeding reactions was 4.6% and 3.6%, respectively (n.s.). In a trial comparing Dalteparin 5000 IU once daily to heparin 5000 U twice daily, in the malignancy subgroup the incidence of bleeding reactions was 3.2% and 2.7%, respectively for Dalteparin and Heparin (n.s.).
### Medical Patients with Severely Restricted Mobility During Acute Illness
- Table 8 summarizes major bleeding reactions that occurred in a clinical trial of medical patients with severely restricted mobility during acute illness.
- Three of the major bleeding reactions that occurred by Day 21 were fatal, all due to gastrointestinal hemorrhage (two patients in the group treated with Dalteparin and one in the group receiving placebo).
### Patients with Cancer and Acute Symptomatic Venous Thromboembolism
- Table 9 summarizes the number of patients with bleeding reactions that occurred in the clinical trial of patients with cancer and acute symptomatic venous thromboembolism. A bleeding event was considered major if it: 1) was accompanied by a decrease in hemoglobin of ≥ 2 g/dL in connection with clinical symptoms; 2) occurred at a critical site (intraocular, spinal/epidural, intracranial, retroperitoneal, or pericardial bleeding); 3) required transfusion of ≥ 2 units of blood products; or 4) led to death. Minor bleeding was classified as clinically overt bleeding that did not meet criteria for major bleeding.
- At the end of the six-month study, a total of 46 (13.6%) patients in the Dalteparin arm and 62 (18.5%) patients in the OAC arm experienced any bleeding event. One bleeding event (hemoptysis in a patient in the Dalteparin arm at Day 71) was fatal.
### Elevations of Serum Transaminases
- In Dalteparin clinical trials supporting non-cancer indications, where hepatic transaminases were measured, asymptomatic increases in transaminase levels (SGOT/AST and SGPT/ALT) greater than three times the upper limit of normal of the laboratory reference range were seen in 4.7% and 4.2%, respectively, of patients during treatment with Dalteparin.
- In the Dalteparin clinical trial of patients with cancer and acute symptomatic venous thromboembolism treated with Dalteparin for up to 6 months, asymptomatic increases in transaminase levels, AST and ALT, greater than three times the upper limit of normal of the laboratory reference range were reported in 8.9% and 9.5% of patients, respectively. The frequencies of Grades 3 and 4 increases in AST and ALT, as classified by the National Cancer Institute, Common Toxicity Criteria (NCI-CTC) Scoring System, were 3% and 3.8%, respectively. Grades 2, 3 & 4 combined have been reported in 12% and 14% of patients, respectively.
### Other
- Allergic Reactions: Allergic reactions (i.e., pruritus, rash, fever, injection site reaction, bullous eruption) have occurred. Cases of anaphylactoid reactions have been reported.
- Local Reactions: Pain at the injection site, the only non-bleeding event determined to be possibly or probably related to treatment with Dalteparin and reported at a rate of at least 2% in the group treated with Dalteparin, was reported in 4.5% of patients treated with Dalteparin 5000 IU once daily vs 11.8% of patients treated with heparin 5000 U twice daily in the abdominal surgery trials. In the hip replacement trials, pain at injection site was reported in 12% of patients treated with Dalteparin 5000 IU once daily vs 13% of patients treated with heparin 5000 U three times a day.
## Postmarketing Experience
- The following adverse reactions have been identified during postapproval use of Dalteparin. 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.
- Since first international market introduction in 1985, there have been more than 15 reports of epidural or spinal hematoma formation with concurrent use of dalteparin sodium and spinal/epidural anesthesia or spinal puncture. The majority of patients had postoperative indwelling epidural catheters placed for analgesia or received additional drugs affecting hemostasis. In some cases the hematoma resulted in long-term or permanent paralysis (partial or complete).
- Skin necrosis has occurred. There have been cases of alopecia reported that improved on drug discontinuation.
# Drug Interactions
- Use Dalteparin with care in patients receiving oral anticoagulants, platelet inhibitors, and thrombolytic agents because of increased risk of bleeding.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
- There are no adequate and well-controlled studies of Dalteparin use in pregnant women. In reproductive and developmental toxicity studies, pregnant rats and rabbits received dalteparin sodium at intravenous doses up to 2400 IU/kg (14,160 IU/m2) (rats) and 4800 IU/kg (40,800 IU/m2) (rabbits). These exposures were 2 to 4 times (rats) and 4 times (rabbits) the human dose of 100 IU/kg dalteparin based on the body surface area. No evidence of impaired fertility or harm to the fetuses occurred in these studies. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
- Cases of "Gasping Syndrome" have occurred in premature infants when large amounts of benzyl alcohol have been administered (99-404 mg/kg/day). The 9.5 mL and the 3.8 mL multiple-dose vials of Dalteparin contain 14 mg/mL of benzyl alcohol.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Dalteparin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Dalteparin during labor and delivery.
### Nursing Mothers
- Based on limited published data dalteparin is minimally excreted in human milk. One study of 15 lactating women receiving prophylactic doses of dalteparin, in the immediate postpartum period, detected small amounts of anti-Xa activity (range < 0.005 to 0.037 IU/ml) in breast milk that were equivalent to a milk/plasma ratio of < 0.025-0.224. Oral absorption of LMWH is extremely low, but the clinical implications, if any, of this small amount of anticoagulant activity on a nursing infant are unknown. Caution should be exercised when Dalteparin is administered to a nursing woman.
### Pediatric Use
- Safety and effectiveness in pediatric patients have not been established.
### Geriatic Use
- Of the total number of patients in clinical studies of Dalteparin, 5516 patients were 65 years of age or older and 2237 were 75 or older. No overall differences in effectiveness were observed between these subjects and younger subjects. Some studies suggest that the risk of bleeding increases with age. Postmarketing surveillance and literature reports have not revealed additional differences in the safety of Dalteparin between elderly and younger patients. Give careful attention to dosing intervals and concomitant medications (especially antiplatelet medications) in geriatric patients, particularly in those with low body weight (< 45 kg) and those predisposed to decreased renal function.
### Gender
There is no FDA guidance on the use of Dalteparin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Dalteparin with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Dalteparin in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Dalteparin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Dalteparin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Dalteparin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Subcutaneous injection technique: Patients should be sitting or lying down and Dalteparin administered by deep subcutaneous injection. Dalteparin may be injected in a U-shape area around the navel, the upper outer side of the thigh or the upper outer quadrangle of the buttock. The injection site should be varied daily. When the area around the navel or the thigh is used, using the thumb and forefinger, you must lift up a fold of skin while giving the injection. The entire length of the needle should be inserted at a 45 to 90 degree angle.
- Inspect Dalteparin prefilled syringes and vials visually for particulate matter and discoloration prior to administration
- After first penetration of the rubber stopper, store the multiple-dose vials at room temperature for up to 2 weeks. Discard any unused solution after 2 weeks.
- Fixed dose syringes: To ensure delivery of the full dose, do not expel the air bubble from the prefilled syringe before injection. Hold the syringe assembly by the open sides of the device. Remove the needle shield. Insert the needle into the injection area as instructed above. Depress the plunger of the syringe while holding the finger flange until the entire dose has been given. The needle guard will not be activated unless the entire dose has been given. Remove needle from the patient. Let go of the plunger and allow syringe to move up inside the device until the entire needle is guarded. Discard the syringe assembly in approved containers.
- Graduated syringes: Hold the syringe assembly by the open sides of the device. Remove the needle shield. With the needle pointing up, prepare the syringe by expelling the air bubble and then continuing to push the plunger to the desired dose or volume, discarding the extra solution in an appropriate manner. Insert the needle into the injection area as instructed above. Depress the plunger of the syringe while holding the finger flange until the entire dose remaining in the syringe has been given. The needle guard will not be activated unless the entire dose has been given. Remove needle from the patient. Let go of the plunger and allow syringe to move up inside the device until the entire needle is guarded. Discard the syringe assembly in approved containers.
### Monitoring
FDA Package Insert for Dalteparin contains no information regarding drug monitoring.
# IV Compatibility
There is limited information about the IV Compatibility.
# Overdosage
- An excessive dosage of Dalteparin Injection may lead to hemorrhagic complications. These may generally be stopped by slow intravenous injection of protamine sulfate (1% solution), at a dose of 1 mg protamine for every 100 anti-Xa IU of Dalteparin given. If the APTT measured 2 to 4 hours after the first infusion remains prolonged, a second infusion of 0.5 mg protamine sulfate per 100 anti-Xa IU of Dalteparin may be administered. Even with these additional doses of protamine, the APTT may remain more prolonged than would usually be found following administration of unfractionated heparin. In all cases, the anti-Factor Xa activity is never completely neutralized (maximum about 60 to 75%).
- Take particular care to avoid overdosage with protamine sulfate. Administration of protamine sulfate can cause severe hypotensive and anaphylactoid reactions. Because fatal reactions, often resembling anaphylaxis, have been reported with protamine sulfate, give protamine sulfate only when resuscitation techniques and treatment for anaphylactic shock are readily available. For additional information, consult the labeling of Protamine Sulfate Injection, USP, products.
# Pharmacology
## Mechanism of Action
- Dalteparin is a low molecular weight heparin with antithrombotic properties. It acts by enhancing the inhibition of Factor Xa and thrombin by antithrombin. In humans, dalteparin potentiates preferentially the inhibition of coagulation Factor Xa, while only slightly affecting the activated partial thromboplastin time (APTT).
## Structure
- Dalteparin Injection (dalteparin sodium injection) is a sterile, low molecular weight heparin. It is available in single-dose, prefilled syringes preassembled with a needle guard device, and multiple-dose vials. With reference to the W.H.O. First International Low Molecular Weight Heparin Reference Standard, each syringe contains either 2500, 5000, 7500, 10,000, 12,500, 15,000 or 18,000 anti-Factor Xa international units (IU), equivalent to 16, 32, 48, 64, 80, 96 or 115.2 mg dalteparin sodium, respectively. Each multiple-dose vial contains either 10,000 or 25,000 anti-Factor Xa IU per 1 mL (equivalent to 64 or 160 mg dalteparin sodium, respectively), for a total of 95,000 anti-Factor Xa IU per vial.
- Each prefilled syringe also contains Water for Injection and sodium chloride, when required, to maintain physiologic ionic strength. The prefilled syringes are preservative-free. Each multiple-dose vial also contains Water for Injection and 14 mg of benzyl alcohol per mL as a preservative. The pH of both formulations is 5.0 to 7.5.
- Dalteparin sodium is produced through controlled nitrous acid depolymerization of sodium heparin from porcine intestinal mucosa followed by a chromatographic purification process. It is composed of strongly acidic sulfated polysaccharide chains (oligosaccharide, containing 2,5-anhydro-D-mannitol residues as end groups) with an average molecular weight of 5000 and about 90% of the material within the range 2000-9000. The molecular weight distribution is:
- < 3000 daltons 3.0-15%
- 3000 to 8000 daltons 65.0-78.0%
- > 8000 daltons 14.0-26.0%
## Pharmacodynamics
- Doses of Dalteparin Injection of up to 10,000 anti-Factor Xa IU administered subcutaneously as a single dose or two 5000 IU doses 12 hours apart to healthy subjects did not produce a significant change in platelet aggregation, fibrinolysis, or global clotting tests such as prothrombin time (PT), thrombin time (TT) or APTT. Subcutaneous administration of doses of 5000 IU twice daily of Dalteparin for seven consecutive days to patients undergoing abdominal surgery did not markedly affect APTT, Platelet Factor 4 (PF4), or lipoprotein lipase.
## Pharmacokinetics
- Mean peak levels of plasma anti-Factor Xa activity following single subcutaneous doses of 2500, 5000 and 10,000 IU were 0.19 ± 0.04, 0.41 ± 0.07 and 0.82 ± 0.10 IU/mL, respectively, and were attained in about 4 hours in most subjects. Absolute bioavailability in healthy volunteers, measured as the anti-Factor Xa activity, was 87 ± 6%. Increasing the dose from 2500 to 10,000 IU resulted in an overall increase in anti-Factor Xa AUC that was greater than proportional by about one-third.
- Peak anti-Factor Xa activity increased more or less linearly with dose over the same dose range. There appeared to be no appreciable accumulation of anti-Factor Xa activity with twice-daily dosing of 100 IU/kg subcutaneously for up to 7 days.
- The volume of distribution for dalteparin anti-Factor Xa activity was 40 to 60 mL/kg. The mean plasma clearances of dalteparin anti-Factor Xa activity in normal volunteers following single intravenous bolus doses of 30 and 120 anti-Factor Xa IU/kg were 24.6 ± 5.4 and 15.6 ± 2.4 mL/hr/kg, respectively. The corresponding mean disposition half-lives were 1.47 ± 0.3 and 2.5 ± 0.3 hours.
- Following intravenous doses of 40 and 60 IU/kg, mean terminal half-lives were 2.1 ± 0.3 and 2.3 ± 0.4 hours, respectively. Longer apparent terminal half-lives (3 to 5 hours) are observed following subcutaneous dosing, possibly due to delayed absorption. In patients with chronic renal insufficiency requiring hemodialysis, the mean terminal half-life of anti-Factor Xa activity following a single intravenous dose of 5000 IU Dalteparin was 5.7 ± 2.0 hours, i.e. considerably longer than values observed in healthy volunteers, therefore, greater accumulation can be expected in these patients.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
- Dalteparin sodium has not been tested for its carcinogenic potential in long-term animal studies. It was not mutagenic in the in vitro Ames Test, mouse lymphoma cell forward mutation test and human lymphocyte chromosomal aberration test and in the in vivo mouse micronucleus test. Dalteparin sodium at subcutaneous doses up to 1200 IU/kg (7080 IU/m2) did not affect the fertility or reproductive performance of male and female rats.
# Clinical Studies
### Prophylaxis of Ischemic Complications in Unstable Angina and Non-Q-Wave Myocardial Infarction
- In a double-blind, randomized, placebo-controlled clinical trial, patients who recently experienced unstable angina with EKG changes or non-Q-wave myocardial infarction (MI) were randomized to Dalteparin Injection 120 IU/kg or placebo every 12 hours subcutaneously. In this trial, unstable angina was defined to include only angina with EKG changes. All patients, except when contraindicated, were treated concurrently with aspirin (75 mg once daily) and beta blockers. Treatment was initiated within 72 hours of the event (the majority of patients received treatment within 24 hours) and continued for 5 to 8 days. A total of 1506 patients were enrolled and treated; 746 received Dalteparin and 760 received placebo. The mean age of the study population was 68 years (range 40 to 90 years) and the majority of patients were white (99.7%) and male (63.9%). The combined incidence of the endpoint of death or myocardial infarction was lower for Dalteparin compared with placebo at 6 days after initiation of therapy. These results were observed in an analysis of all-randomized and all-treated patients. The combined incidence of death, MI, need for intravenous heparin or intravenous nitroglycerin, and revascularization was also lower for Dalteparin than for placebo (see Table 10).
- In a second randomized, controlled trial designed to evaluate long-term treatment with Dalteparin (days 6 to 45), data were also collected comparing 1-week (5 to 8 days) treatment of Dalteparin 120 IU/kg every 12 hours subcutaneously with heparin at an APTT-adjusted dosage. All patients, except when contraindicated, were treated concurrently with aspirin (100 to 165 mg per day). Of the 1499 patients enrolled, 1482 patients were treated; 751 received Dalteparin and 731 received heparin. The mean age of the study population was 64 years (range 25 to 92 years) and the majority of patients were white (96.0%) and male (64.2%). The incidence of the combined endpoint of death, myocardial infarction, or recurrent angina during this 1-week treatment period (5 to 8 days) was 9.3% for Dalteparin and 7.6% for heparin (p=0.323).
### Prophylaxis of Deep Vein Thrombosis in Patients Following Hip Replacement Surgery
- In an open-label randomized study, Dalteparin 5000 IU administered once daily subcutaneously was compared with warfarin sodium, administered orally, in patients undergoing hip replacement surgery. Treatment with Dalteparin was initiated with a 2500 IU dose subcutaneously within 2 hours before surgery, followed by a 2500 IU dose subcutaneously the evening of the day of surgery. Then, a dosing regimen of Dalteparin 5000 IU subcutaneously once daily was initiated on the first postoperative day. The first dose of warfarin sodium was given the evening before surgery, then continued daily at a dose adjusted for INR 2 to 3. Treatment in both groups was then continued for 5 to 9 days postoperatively. Of the 580 patients enrolled, 553 were treated and 550 underwent surgery. Of those who underwent surgery, 271 received Dalteparin and 279 received warfarin sodium. The mean age of the study population was 63 years (range 20 to 92 years) and the majority of patients were white (91.1%) and female (52.9%). The incidence of deep vein thrombosis (DVT), as determined by evaluable venography, was significantly lower for the group treated with Dalteparin compared with patients treated with warfarin sodium (see Table 11).
# How Supplied
- After first penetration of the rubber stopper, store the multiple-dose vials at room temperature for up to 2 weeks.
## Storage
- Store at controlled room temperature 20° to 25°C (68° to 77°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- If patients have had neuraxial anesthesia or spinal puncture, and particularly, if they are taking concomitant NSAIDs, platelet inhibitors, or other anticoagulants, inform the patients to watch for signs and symptoms of spinal or epidural hematoma, such as tingling, numbness (especially in the lower limbs) and muscular weakness. If any of these symptoms occur the patient should contact his or her physician immediately.
- Additionally, the use of aspirin and other NSAIDs may enhance the risk of hemorrhage. Discontinue their use prior to dalteparin therapy whenever possible; if co-administration is essential, the patient's clinical and laboratory status should be closely monitored.
- Inform patients:
- of the instructions for injecting Dalteparin if their therapy is to continue after discharge from the hospitals.
- it may take them longer than usual to stop bleeding.
- they may bruise and/or bleed more easily when they are treated with Dalteparin.
- they should report any unusual bleeding, bruising, or signs of thrombocytopenia (such as a rash of dark red spots under the skin) to their physician.
- to tell their physicians and dentists they are taking Dalteparin and/or any other product known to affect bleeding before any surgery is scheduled and before any new drug is take.
- to tell their physicians and dentists of all medications they are taking, including those obtained without a prescription, such as aspirin or other NSAIDs.
- Dalteparin is a registered trademark of Pfizer Health AB and is licensed to Eisai Inc.
# Precautions with Alcohol
Alcohol-Dalteparin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
Fragmin
# Look-Alike Drug Names
There is limited information regarding Dalteparin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Dalteparin | |
58f2cc35d1b35fce34e1ae3f6f0afa7bdd6ae888 | wikidoc | Danaparoid | Danaparoid
# Overview
Danaparoid sodium (Orgaran®) is an anticoagulant that works by inhibiting activated factor X (factor Xa).
Danaparoid is considered a "low molecular weight heparin" by some sources, but is chemically distinct from heparin and thus has little cross-reactivity in heparin-intolerant patients.
# Uses
It is used to prevent deep venous clots, particularly in situations with a high risk of clot formation, such as after hip surgery.
It is also used as a heparinoid substitute in heparin-induced thrombocytopenia which may otherwise cause paradoxical thrombosis.
# Discontinuation
On August 14, 2002, this drug was withdrawn by Organon International.
# Administration
- IV
- SC
# Side Effects
- Bleeding problems
- Low platelets, due to a low level of structural similarity between danaparoid and heparin
- Asthma exacerbations, due to allergies to sulphites contained within the medicine | Danaparoid
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Danaparoid sodium (Orgaran®) is an anticoagulant that works by inhibiting activated factor X (factor Xa).
Danaparoid is considered a "low molecular weight heparin" by some sources, but is chemically distinct from heparin and thus has little cross-reactivity in heparin-intolerant patients.
# Uses
It is used to prevent deep venous clots, particularly in situations with a high risk of clot formation, such as after hip surgery.
It is also used as a heparinoid substitute in heparin-induced thrombocytopenia which may otherwise cause paradoxical thrombosis.
# Discontinuation
On August 14, 2002, this drug was withdrawn by Organon International.[1]
# Administration
- IV
- SC
# Side Effects
- Bleeding problems
- Low platelets, due to a low level of structural similarity between danaparoid and heparin
- Asthma exacerbations, due to allergies to sulphites contained within the medicine
# External Links
- danaparoid at the US National Library of Medicine Medical Subject Headings (MeSH) | https://www.wikidoc.org/index.php/Danaparoid | |
773e7ffa4c2032af3ed0f62f3059f3c37c057d6f | wikidoc | Dantrolene | Dantrolene
- Dantrium (dantrolene sodium) has a potential for hepatotoxicity, and should not be used in conditions other than those recommended. Symptomatic hepatitis (fatal and non-fatal) has been reported at various dose levels of the drug. The incidence reported in patients taking up to 400 mg/day is much lower than in those taking doses of 800 mg or more per day. Even sporadic short courses of these higher dose levels within a treatment regimen markedly increased the risk of serious hepatic injury. Liver dysfunction as evidenced by blood chemical abnormalities alone (liver enzyme elevations) has been observed in patients exposed to Dantrium for varying periods of time. Overt hepatitis has occurred at varying intervals after initiation of therapy, but has been most frequently observed between the third and twelfth month of therapy. The risk of hepatic injury appears to be greater in females, in patients over 35 years of age, and in patients taking other medication(s) in addition to Dantrium (dantrolene sodium). Spontaneous reports suggest a higher proportion of hepatic events with fatal outcome in elderly patients receiving Dantrium. However, the majority of these cases were complicated with confounding factors such as intercurrent illnesses and/or concomitant potentially hepatotoxic medications. Dantrium should be used only in conjunction with appropriate monitoring of hepatic function including frequent determination of SGOT or SGPT. If no observable benefit is derived from the administration of Dantrium after a total of 45 days, therapy should be discontinued. The lowest possible effective dose for the individual patient should be prescribed.
- In Chronic Spasticity
- Dantrium is indicated in controlling the manifestations of clinical spasticity resulting from upper motor neuron disorders like :
- spinal cord injury
- stroke
- cerebral palsy
- multiple sclerosis
- It is of particular benefit to the patient whose functional rehabilitation has been retarded by the sequelae of spasticity. Such patients must have presumably reversible spasticity where relief of spasticity will aid in restoring residual function. Dantrium is not indicated in the treatment of skeletal muscle spasm resulting from rheumatic disorders.
- If improvement occurs, it will ordinarily occur within the dosage titration, and will be manifested by a decrease in the severity of spasticity and the ability to resume a daily function not quite attainable without Dantrium.
- Occasionally, subtle but meaningful improvement in spasticity may occur with Dantrium therapy. In such instances, information regarding improvement should be solicited from the patient and those who are in constant daily contact and attendance with him. Brief withdrawal of Dantrium for a period of 2 to 4 days will frequently demonstrate exacerbation of the manifestations of spasticity and may serve to confirm a clinical impression.
- A decision to continue the administration of Dantrium on a long-term basis is justified if introduction of the drug into the patient's regimen:
- produces a significant reduction in painful and/or disabling spasticity such as clonus, or
- permits a significant reduction in the intensity and/or degree of nursing care required, or
- rids the patient of any annoying manifestation of spasticity considered important by the patient himself.
- In Malignant Hyperthermia
- Oral Dantrium is also indicated preoperatively to prevent or attenuate the development of signs of malignant hyperthermia in known, or strongly suspect, malignant hyperthermia susceptible patients who require anesthesia and/or surgery. Currently accepted clinical practices in the management of such patients must still be adhered to (careful monitoring for early signs of malignant hyperthermia, minimizing exposure to triggering mechanisms and prompt use of intravenous dantrolene sodium and indicated supportive measures should signs of malignant hyperthermia appear)
- Oral Dantrium should be administered following a malignant hyperthermic crisis to prevent recurrence of the signs of malignant hyperthermia.
- Dantrium Intravenous is indicated, along with appropriate supportive measures, for the management of the fulminant hypermetabolism of skeletal muscle characteristic of malignant hyperthermia crises in patients of all ages. Dantrium Intravenous should be administered by continuous rapid intravenous push as soon as the malignant hyperthermia reaction is recognized (i.e., tachycardia, tachypnea, central venous desaturation, hypercarbia, metabolic acidosis, skeletal muscle rigidity, increased utilization of anesthesia circuit carbon dioxide absorber, cyanosis and mottling of the skin, and, in many cases, fever).
- Dantrium Intravenous is also indicated preoperatively, and sometimes postoperatively, to prevent or attenuate the development of clinical and laboratory signs of malignant hyperthermia in individuals judged to be malignant hyperthermia susceptible.
# Dosage
- Prior to the administration of Dantrium, consideration should be given to the potential response to treatment. A decrease in spasticity sufficient to allow a daily function not otherwise attainable should be the therapeutic goal of treatment with Dantrium.
- It is important to establish a therapeutic goal (regain and maintain a specific function such as therapeutic exercise program, utilization of braces, transfer maneuvers, etc.) before beginning Dantrium therapy. Dosage should be increased until the maximum performance compatible with the dysfunction due to underlying disease is achieved. No further increase in dosage is then indicated.
- It is important that the dosage be titrated and individualized for maximum effect. The lowest dose compatible with optimal response is recommended.
- In view of the potential for liver damage in long-term Dantrium use, therapy should be stopped if benefits are not evident within 45 days.
- The following gradual titration schedule is suggested. Some patients will not respond until higher daily dosage is achieved. Each dosage level should be maintained for seven days to determine the patient's response. If no further benefit is observed at the next higher dose, dosage should be decreased to the previous lower dose.
- 25 mg once daily for seven days, then
- 25 mg t.i.d. for seven days
- 50 mg t.i.d. for seven days
- 100 mg t.i.d.
- Therapy with a dose four times daily may be necessary for some individuals. Doses higher than 100 mg four times daily should not be used.
- Administer 4 to 8 mg/kg/day of oral Dantrium in 3 or 4 divided doses for one or two days prior to surgery, with the last dose being given approximately 3 to 4 hours before scheduled surgery with a minimum of water.
- This dosage will usually be associated with skeletal muscle weakness and sedation (sleepiness or drowsiness); adjustment can usually be made within the recommended dosage range to avoid incapacitation or excessive gastrointestinal irritation (including nausea and/or vomiting).
- Oral Dantrium should also be administered following a malignant hyperthermia crisis, in doses of 4 to 8 mg/kg per day in four divided doses, for a one to three day period to prevent recurrence of the manifestations of malignant hyperthermia.
- As soon as the malignant hyperthermia reaction is recognized, all anesthetic agents should be discontinued; the administration of 100% oxygen is recommended. Dantrium Intravenous should be administered by continuous rapid intravenous push beginning at a minimum dose of 1 mg/kg, and continuing until symptoms subside or the maximum cumulative dose of 10 mg/kg has been reached
- If the physiologic and metabolic abnormalities reappear, the regimen may be repeated. It is important to note that administration of Dantrium Intravenous should be continuous until symptoms subside. The effective dose to reverse the crisis is directly dependent upon the individual's degree of susceptibility to malignant hyperthermia, the amount and time of exposure to the triggering agent, and the time elapsed between onset of the crisis and initiation of treatment.
- Dantrium Intravenous and/or Dantrium Capsules may be administered preoperatively to patients judged malignant hyperthermia susceptible as part of the overall patient management to prevent or attenuate the development of clinical and laboratory signs of malignant hyperthermia.
- The recommended prophylactic dose of Dantrium Intravenous is 2.5 mg/kg, starting approximately 1-1/4 hours before anticipated anesthesia and infused over approximately 1 hour. This dose should prevent or attenuate the development of clinical and laboratory signs of malignant hyperthermia provided that the usual precautions, such as avoidance of established malignant hyperthermia triggering agents, are followed.
- Additional Dantrium Intravenous may be indicated during anesthesia and surgery because of the appearance of early clinical and/or blood gas signs of malignant hyperthermia or because of prolonged surgery.Additional doses must be individualized.
- Intravenous Dantrium may be used postoperatively to prevent or attenuate the recurrence of signs of malignant hyperthermia when oral Dantrium administration is not practical. The i.v. dose of Dantrium in the postoperative period must be individualized, starting with 1 mg/kg or more as the clinical situation dictates.
- Tetanus
- The following gradual titration schedule is suggested. Some patients will not respond until higher daily dosage is achieved. Each dosage level should be maintained for seven days to determine the patient's response. If no further benefit is observed at the next higher dose, dosage should be decreased to the previous lower dose.
- 0.5 mg/kg once daily for seven days, then
- 0.5 mg/kg t.i.d. for seven days
- 1 mg/kg t.i.d. for seven days
- 2 mg/kg t.i.d.
- Therapy with a dose four times daily may be necessary for some individuals. Doses higher than 100 mg four times daily should not be used.
- Experience to date indicates that the dose of Dantrium Intravenous for pediatric patients is the same as for adults.
- hepatitis
- cirrhosis
- Dantrium is contraindicated where spasticity is utilized to sustain upright posture and balance in locomotion or whenever spasticity is utilized to obtain or maintain increased function.
- At the start of Dantrium therapy, it is desirable to do liver function studies (SGOT, SGPT, alkaline phosphatase, total bilirubin) for a baseline or to establish whether there is pre-existing liver disease. If baseline liver abnormalities exist and are confirmed, there is a clear possibility that the potential for Dantrium hepatotoxicity could be enhanced, although such a possibility has not yet been established.
- Liver function studies (e.g., SGOT or SGPT) should be performed at appropriate intervals during Dantrium therapy. If such studies reveal abnormal values, therapy should generally be discontinued. Only where benefits of the drug have been of major importance to the patient, should reinitiation or continuation of therapy be considered. Some patients have revealed a return to normal laboratory values in the face of continued therapy while others have not.
- If symptoms compatible with hepatitis, accompanied by abnormalities in liver function tests or jaundice appear, Dantrium should be discontinued. If caused by Dantrium and detected early, the abnormalities in liver function characteristically have reverted to normal when the drug was discontinued.
- Dantrium therapy has been reinstituted in a few patients who have developed clinical and/or laboratory evidence of hepatocellular injury. If such reinstitution of therapy is done, it should be attempted only in patients who clearly need Dantrium and only after previous symptoms and laboratory abnormalities have cleared. The patient should be hospitalized and the drug should be restarted in very small and gradually increasing doses. Laboratory monitoring should be frequent and the drug should be withdrawn immediately if there is any indication of recurrent liver involvement. Some patients have reacted with unmistakable signs of liver abnormality upon administration of a challenge dose, while others have not.
- Dantrium should be used with particular caution in females and in patients over 35 years of age in view of apparent greater likelihood of drug-induced, potentially fatal, hepatocellular disease in these groups. Spontaneous reports suggest a higher proportion of hepatic events with fatal outcome in elderly patients receiving Dantrium. However, the majority of these cases were complicated with confounding factors such as intercurrent illnesses and/or concomitant potentially hepatotoxic medications
- The use of Dantrium Intravenous in the management of malignant hyperthermia crisis is not a substitute for previously known supportive measures. These measures must be individualized, but it will usually be necessary to discontinue the suspect triggering agents, attend to increased oxygen requirements, manage the metabolic acidosis, institute cooling when necessary, monitor urinary output, and monitor for electrolyte imbalance.
- Since the effect of disease state and other drugs on Dantrium related skeletal muscle weakness, including possible respiratory depression, cannot be predicted, patients who receive i.v. Dantrium preoperatively should have vital signs monitored.
- If patients judged malignant hyperthermia susceptible are administered intravenous or oral Dantrium preoperatively, anesthetic preparation must still follow a standard malignant hyperthermia susceptible regimen, including the avoidance of known triggering agents. Monitoring for early clinical and metabolic signs of malignant hyperthermia is indicated because attenuation of malignant hyperthermia, rather than prevention, is possible. These signs usually call for the administration of additional i.v. dantrolene.
# Precautions
- Dantrium should be used with caution in patients with impaired pulmonary function, particularly those with obstructive pulmonary disease, and in patients with severely impaired cardiac function due to myocardial disease. Dantrium is associated with pleural effusion with associated eosinophilia. It should be used with caution in patients with a history of previous liver disease or dysfunction
- Dantrium might possibly evoke a photosensitivity reaction; patients should be cautioned about exposure to sunlight while taking it.
- Care must be taken to prevent extravasation of Dantrium solution into the surrounding tissues due to the high pH of the intravenous formulation and potential for tissue necrosis.
- When mannitol is used for prevention or treatment of late renal complications of malignant hyperthermia, the 3 g of mannitol needed to dissolve each 20 mg vial of i.v. Dantrium should be taken into consideration.
- Dantrium (dantrolene sodium) has a potential for hepatotoxicity, and should not be used in conditions other than those recommended. Symptomatic hepatitis (fatal and non-fatal) has been reported at various dose levels of the drug. The incidence reported in patients taking up to 400 mg/day is much lower than in those taking doses of 800 mg or more per day. Even sporadic short courses of these higher dose levels within a treatment regimen markedly increased the risk of serious hepatic injury. Liver dysfunction as evidenced by blood chemical abnormalities alone (liver enzyme elevations) has been observed in patients exposed to Dantrium for varying periods of time. Overt hepatitis has occurred at varying intervals after initiation of therapy, but has been most frequently observed between the third and twelfth month of therapy. The risk of hepatic injury appears to be greater in females, in patients over 35 years of age, and in patients taking other medication(s) in addition to Dantrium (dantrolene sodium). Dantrium should be used only in conjunction with appropriate monitoring of hepatic function including frequent determination of SGOT or SGPT.
- Fatal and non-fatal liver disorders of an idiosyncratic or hypersensitivity type may occur with Dantrium therapy.
- drowsiness
- dizziness
- weakness
- general malaise
- fatigue
- diarrhea
- These are generally transient, occurring early in treatment, and can often be obviated by beginning with a low dose and increasing dosage gradually until an optimal regimen is established. Diarrhea may be severe and may necessitate temporary withdrawal of Dantrium therapy. If diarrhea recurs upon readministration of Dantrium, therapy should probably be withdrawn permanently.
- Other less frequent side effects, listed according to system, are:
- Tachycardia
- erratic blood pressure
- phlebitis
- heart failure
- Constipation, rarely progressing to signs of intestinal obstruction
- GI bleeding
- anorexia
- swallowing difficulty
- gastric irritation
- abdominal cramps
- nausea
- vomiting
- Hepatitis
- Aplastic anemia
- anemia
- leukopenia
- lymphocytic lymphoma
- thrombocytopenia
- Myalgia
- backache
- Speech disturbance
- seizure
- headache
- light-headedness
- visual disturbance
- diplopia
- alteration of taste
- insomnia
- drooling
- Mental depression
- mental confusion
- increased nervousness
- Feeling of suffocation
- respiratory depression
- Abnormal hair growth
- acne-like rash
- pruritus
- urticaria
- eczematoid eruption
- sweating
- Pleural effusion with pericarditis
- Pleural effusion with associated eosinophilia
- anaphylaxis
- Excessive tearing
- Increased urinary frequency
- crystalluria
- hematuria
- difficult erection
- urinary incontinence
- nocturia
- difficult urination
- urinary retention
- Chills
- fever
- There have been occasional reports of death following malignant hyperthermia crisis even when treated with intravenous dantrolene; incidence figures are not available (the pre-dantrolene mortality of malignant hyperthermia crisis was approximately 50%). Most of these deaths can be accounted for by late recognition, delayed treatment, inadequate dosage, lack of supportive therapy, intercurrent disease and/or the development of delayed complications such as renal failure or disseminated intravascular coagulopathy. In some cases there are insufficient data to completely rule out therapeutic failure of dantrolene.
- There are reports of fatality in malignant hyperthermia crisis, despite initial satisfactory response to i.v. dantrolene, which involve patients who could not be weaned from dantrolene after initial treatment.
- The administration of intravenous Dantrium to human volunteers is associated with loss of grip strength and weakness in the legs, as well as drowsiness and dizziness.
- The following adverse reactions are in approximate order of severity:
- There are rare reports of pulmonary edema developing during the treatment of malignant hyperthermia crisis in which the diluent volume and mannitol needed to deliver i.v. dantrolene possibly contributed.
- There have been reports of thrombophlebitis following administration of intravenous dantrolene; actual incidence figures are not available. Tissue necrosis secondary to extravasation has been reported.
- There have been rare reports of urticaria and erythema possibly associated with the administration of i.v. Dantrium. There has been one case of anaphylaxis.
- Injection site reactions (pain, erythema, swelling), commonly due to extravasation, have been reported.
- None of the serious reactions occasionally reported with long-term oral Dantrium use, such as hepatitis, seizures, and pleural effusion with pericarditis, have been reasonably associated with short-term Dantrium Intravenous therapy.
- Drowsiness may occur with Dantrium therapy, and the concomitant administration of CNS depressants such as sedatives and tranquilizing agents may result in further drowsiness.
- Estrogen
- While a definite drug interaction with estrogen therapy has not yet been established, caution should be observed if the two drugs are to be given concomitantly. Hepatotoxicity has occurred more often in women over 35 years of age receiving concomitant estrogen therapy.
- Verapamil
- Cardiovascular collapse in patients treated simultaneously with verapamil and dantrolene sodium is rare. The combination of therapeutic doses of intravenous dantrolene sodium and verapamil in halothane/α-chloralose anesthetized swine has resulted in ventricular fibrillation and cardiovascular collapse in association with marked hyperkalemia. Until the relevance of these findings to humans is established, the combination of dantrolene sodium and calcium channel blockers is not recommended during the management of malignant hyperthermia.
- Vecuronium
- Administration of Dantrium may potentiate vecuronium-induced neuromuscular block.
- Dantrium is metabolized by the liver, and it is theoretically possible that its metabolism may be enhanced by drugs known to induce hepatic microsomal enzymes. However, neither phenobarbital nor diazepam appears to affect Dantrium metabolism. Binding to plasma protein is not significantly altered by diazepam, diphenylhydantoin, or phenylbutazone. Binding to plasma proteins is reduced by warfarin and clofibrate and increased by tolbutamide.
- Intravenous
- Each vial of Dantrium Intravenous should be reconstituted by adding 60 mL of sterile water for injection USP (without a bacteriostatic agent), and the vial shaken until the solution is clear. 5% Dextrose Injection USP, 0.9% Sodium Chloride Injection USP, and other acidic solutions are not compatible with Dantrium Intravenous and should not be used. The contents of the vial must be protected from direct light and used within 6 hours after reconstitution. Store reconstituted solutions between 15° to 30°C (59° to 86°F).
- Reconstituted Dantrium Intravenous should not be transferred to large glass bottles for prophylactic infusion due to precipitate formation observed with the use of some glass bottles as reservoirs.
- For prophylactic infusion, the required number of individual vials of Dantrium Intravenous should be reconstituted as outlined above. The contents of individual vials are then transferred to a larger volume sterile intravenous plastic bag. Stability data on file at JHP Pharmaceuticals indicate commercially available sterile plastic bags are acceptable drug delivery devices. However, it is recommended that the prepared infusion be inspected carefully for cloudiness and/or precipitation prior to dispensing and administration. Such solutions should not be used. While stable for 6 hours, it is recommended that the infusion be prepared immediately prior to the anticipated dosage administration time.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.
- Intravenous fluids should be administered in fairly large quantities to avert the possibility of crystalluria. An adequate airway should be maintained and artificial resuscitation equipment should be at hand. Electrocardiographic monitoring should be instituted, and the patient carefully observed. To date, no experience has been reported with dialysis and its value in Dantrium overdose is not known.
- In the anesthetic-induced malignant hyperthermia syndrome, evidence points to an intrinsic abnormality of skeletal muscle tissue. In affected humans, it has been postulated that "triggering agents" (e.g., general anesthetics and depolarizing neuromuscular blocking agents) produce a change within the cell which results in an elevated myoplasmic calcium. This elevated myoplasmic calcium activates acute cellular catabolic processes that cascade to the malignant hyperthermia crisis.
- It is hypothesized that addition of Dantrium to the "triggered" malignant hyperthermic muscle cell reestablishes a normal level of ionized calcium in the myoplasm. Inhibition of calcium release from the sarcoplasmic reticulum by Dantrium reestablishes the myoplasmic calcium equilibrium, increasing the percentage of bound calcium. In this way, physiologic, metabolic, and biochemical changes associated with the malignant hyperthermia crisis may be reversed or attenuated. Experimental results in malignant hyperthermia susceptible swine show that prophylactic administration of intravenous or oral dantrolene prevents or attenuates the development of vital sign and blood gas changes characteristic of malignant hyperthermia in a dose related manner. The efficacy of intravenous dantrolene in the treatment of human and porcine malignant hyperthermia crisis, when considered along with prophylactic experiments in malignant hyperthermia susceptible swine, lends support to prophylactic use of oral or intravenous dantrolene in malignant hyperthermia susceptible humans. When prophylactic intravenous dantrolene is administered as directed, whole blood concentrations remain at a near steady state level for 3 or more hours after the infusion is completed. Clinical experience has shown that early vital sign and/or blood gas changes characteristic of malignant hyperthermia may appear during or after anesthesia and surgery despite the prophylactic use of dantrolene and adherence to currently accepted patient management practices. These signs are compatible with attenuated malignant hyperthermia and respond to the administration of additional i.v. dantrolene. The administration of the recommended prophylactic dose of intravenous dantrolene to healthy volunteers was not associated with clinically significant cardiorespiratory changes.
- Specific metabolic pathways for the degradation and elimination of Dantrium in humans have been established. Dantrolene is found in measurable amounts in blood and urine. Its major metabolites in body fluids are 5-hydroxy dantrolene and an acetylamino metabolite of dantrolene. Another metabolite with an unknown structure appears related to the latter. Dantrium may also undergo hydrolysis and subsequent oxidation forming nitrophenylfuroic acid.
- The mean biologic half-life of Dantrium after intravenous administration is variable, between 4 to 8 hours under most experimental conditions. Based on assays of whole blood and plasma, slightly greater amounts of dantrolene are associated with red blood cells than with the plasma fraction of blood. Significant amounts of dantrolene are bound to plasma proteins, mostly albumin, and this binding is readily reversible.
- Cardiopulmonary depression has not been observed in malignant hyperthermia susceptible swine following the administration of up to 7.5 mg/kg i.v. dantrolene. This is twice the amount needed to maximally diminish twitch response to single supramaximal peripheral nerve stimulation (95% inhibition). A transient, inconsistent, depressant effect on gastrointestinal smooth muscles has been observed at high doses.
- Long-term safety of Dantrium in humans has not been established. Chronic studies in rats, dogs, and monkeys at dosages greater than 30 mg/kg/day showed growth or weight depression and signs of hepatopathy and possible occlusion nephropathy, all of which were reversible upon cessation of treatment. Sprague-Dawley female rats fed dantrolene sodium for 18 months at dosage levels of 15, 30, and 60 mg/kg/day showed an increased incidence of benign and malignant mammary tumors compared with concurrent controls. At the highest dose level, there was an increase in the incidence of benign lymphatic neoplasms. In a 30-month study at the same dose levels also in Sprague-Dawley rats, dantrolene sodium produced a decrease in the time of onset of mammary neoplasms. Female rats at the highest dose level showed an increased incidence of hepatic lymphangiomas and hepatic angiosarcomas.
- The only drug-related effect seen in a 30-month study in Fischer-344 rats was a dose-related reduction in the time of onset of mammary and testicular tumors. A 24-month study in HaM/ICR mice revealed no evidence of carcinogenic activity. Carcinogenicity in humans cannot be fully excluded, so that this possible risk of chronic administration must be weighed against the benefits of the drug (i.e., after a brief trial) for the individual patient.
- Dantrolene sodium has produced positive results in the Ames S. Typhimurium bacterial mutagenesis assay in the presence and absence of a liver activating system.
- Dantrium Intravenous (NDC 42023-123-06) is available in vials containing a sterile lyophilized mixture of 20 mg dantrolene sodium, 3000 mg mannitol, and sufficient sodium hydroxide to yield a pH of approximately 9.5 when reconstituted with 60 mL sterile water for injection USP (without a bacteriostatic agent).
- Dantrium might possibly evoke a photosensitivity reaction; patients should be cautioned about exposure to sunlight while taking it.
- Dantrium intravenous®
- ↑ Tsutsumi Y, Yamamoto K, Matsuura S, Hata S, Sakai M, Shirakura K (1998). "The treatment of neuroleptic malignant syndrome using dantrolene sodium". Psychiatry Clin Neurosci. 52 (4): 433–8. doi:10.1046/j.1440-1819.1998.00416.x. PMID 9766694.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}
- ↑ Tsujimoto S, Maeda K, Sugiyama T, Yokochi A, Chikusa H, Maruyama K (1998). "Efficacy of prolonged large-dose dantrolene for severe neuroleptic malignant syndrome". Anesth Analg. 86 (5): 1143–4. PMID 9585314.CS1 maint: Multiple names: authors list (link)
- ↑ Kaplan RF, Feinglass NG, Webster W, Mudra S (1986). "Phenelzine overdose treated with dantrolene sodium". JAMA. 255 (5): 642–4. PMID 3944965.CS1 maint: Multiple names: authors list (link)
- ↑ Farquhar I, Hutchinson A, Curran J (1988). "Dantrolene in severe tetanus". Intensive Care Med. 14 (3): 249–50. PMID 3379189.CS1 maint: Multiple names: authors list (link)
- ↑ Tidyman M, Prichard JG, Deamer RL, Mac N (1985). "Adjunctive use of dantrolene in severe tetanus". Anesth Analg. 64 (5): 538–40. PMID 3922250.CS1 maint: Multiple names: authors list (link)
- ↑ "Dantrolene".
- ↑ "Dantrolene". | Dantrolene
- Dantrium (dantrolene sodium) has a potential for hepatotoxicity, and should not be used in conditions other than those recommended. Symptomatic hepatitis (fatal and non-fatal) has been reported at various dose levels of the drug. The incidence reported in patients taking up to 400 mg/day is much lower than in those taking doses of 800 mg or more per day. Even sporadic short courses of these higher dose levels within a treatment regimen markedly increased the risk of serious hepatic injury. Liver dysfunction as evidenced by blood chemical abnormalities alone (liver enzyme elevations) has been observed in patients exposed to Dantrium for varying periods of time. Overt hepatitis has occurred at varying intervals after initiation of therapy, but has been most frequently observed between the third and twelfth month of therapy. The risk of hepatic injury appears to be greater in females, in patients over 35 years of age, and in patients taking other medication(s) in addition to Dantrium (dantrolene sodium). Spontaneous reports suggest a higher proportion of hepatic events with fatal outcome in elderly patients receiving Dantrium. However, the majority of these cases were complicated with confounding factors such as intercurrent illnesses and/or concomitant potentially hepatotoxic medications. Dantrium should be used only in conjunction with appropriate monitoring of hepatic function including frequent determination of SGOT or SGPT. If no observable benefit is derived from the administration of Dantrium after a total of 45 days, therapy should be discontinued. The lowest possible effective dose for the individual patient should be prescribed.
- In Chronic Spasticity
- Dantrium is indicated in controlling the manifestations of clinical spasticity resulting from upper motor neuron disorders like :
- spinal cord injury
- stroke
- cerebral palsy
- multiple sclerosis
- It is of particular benefit to the patient whose functional rehabilitation has been retarded by the sequelae of spasticity. Such patients must have presumably reversible spasticity where relief of spasticity will aid in restoring residual function. Dantrium is not indicated in the treatment of skeletal muscle spasm resulting from rheumatic disorders.
- If improvement occurs, it will ordinarily occur within the dosage titration, and will be manifested by a decrease in the severity of spasticity and the ability to resume a daily function not quite attainable without Dantrium.
- Occasionally, subtle but meaningful improvement in spasticity may occur with Dantrium therapy. In such instances, information regarding improvement should be solicited from the patient and those who are in constant daily contact and attendance with him. Brief withdrawal of Dantrium for a period of 2 to 4 days will frequently demonstrate exacerbation of the manifestations of spasticity and may serve to confirm a clinical impression.
- A decision to continue the administration of Dantrium on a long-term basis is justified if introduction of the drug into the patient's regimen:
- produces a significant reduction in painful and/or disabling spasticity such as clonus, or
- permits a significant reduction in the intensity and/or degree of nursing care required, or
- rids the patient of any annoying manifestation of spasticity considered important by the patient himself.
- In Malignant Hyperthermia
- Oral Dantrium is also indicated preoperatively to prevent or attenuate the development of signs of malignant hyperthermia in known, or strongly suspect, malignant hyperthermia susceptible patients who require anesthesia and/or surgery. Currently accepted clinical practices in the management of such patients must still be adhered to (careful monitoring for early signs of malignant hyperthermia, minimizing exposure to triggering mechanisms and prompt use of intravenous dantrolene sodium and indicated supportive measures should signs of malignant hyperthermia appear)
- Oral Dantrium should be administered following a malignant hyperthermic crisis to prevent recurrence of the signs of malignant hyperthermia.
- [[malignant hyperthermia crises]]
- Dantrium Intravenous is indicated, along with appropriate supportive measures, for the management of the fulminant hypermetabolism of skeletal muscle characteristic of malignant hyperthermia crises in patients of all ages. Dantrium Intravenous should be administered by continuous rapid intravenous push as soon as the malignant hyperthermia reaction is recognized (i.e., tachycardia, tachypnea, central venous desaturation, hypercarbia, metabolic acidosis, skeletal muscle rigidity, increased utilization of anesthesia circuit carbon dioxide absorber, cyanosis and mottling of the skin, and, in many cases, fever).
- Dantrium Intravenous is also indicated preoperatively, and sometimes postoperatively, to prevent or attenuate the development of clinical and laboratory signs of malignant hyperthermia in individuals judged to be malignant hyperthermia susceptible.
### Dosage
- Prior to the administration of Dantrium, consideration should be given to the potential response to treatment. A decrease in spasticity sufficient to allow a daily function not otherwise attainable should be the therapeutic goal of treatment with Dantrium.
- It is important to establish a therapeutic goal (regain and maintain a specific function such as therapeutic exercise program, utilization of braces, transfer maneuvers, etc.) before beginning Dantrium therapy. Dosage should be increased until the maximum performance compatible with the dysfunction due to underlying disease is achieved. No further increase in dosage is then indicated.
- It is important that the dosage be titrated and individualized for maximum effect. The lowest dose compatible with optimal response is recommended.
- In view of the potential for liver damage in long-term Dantrium use, therapy should be stopped if benefits are not evident within 45 days.
- The following gradual titration schedule is suggested. Some patients will not respond until higher daily dosage is achieved. Each dosage level should be maintained for seven days to determine the patient's response. If no further benefit is observed at the next higher dose, dosage should be decreased to the previous lower dose.
- 25 mg once daily for seven days, then
- 25 mg t.i.d. for seven days
- 50 mg t.i.d. for seven days
- 100 mg t.i.d.
- Therapy with a dose four times daily may be necessary for some individuals. Doses higher than 100 mg four times daily should not be used.
- Administer 4 to 8 mg/kg/day of oral Dantrium in 3 or 4 divided doses for one or two days prior to surgery, with the last dose being given approximately 3 to 4 hours before scheduled surgery with a minimum of water.
- This dosage will usually be associated with skeletal muscle weakness and sedation (sleepiness or drowsiness); adjustment can usually be made within the recommended dosage range to avoid incapacitation or excessive gastrointestinal irritation (including nausea and/or vomiting).
- Oral Dantrium should also be administered following a malignant hyperthermia crisis, in doses of 4 to 8 mg/kg per day in four divided doses, for a one to three day period to prevent recurrence of the manifestations of malignant hyperthermia.
- As soon as the malignant hyperthermia reaction is recognized, all anesthetic agents should be discontinued; the administration of 100% oxygen is recommended. Dantrium Intravenous should be administered by continuous rapid intravenous push beginning at a minimum dose of 1 mg/kg, and continuing until symptoms subside or the maximum cumulative dose of 10 mg/kg has been reached
- If the physiologic and metabolic abnormalities reappear, the regimen may be repeated. It is important to note that administration of Dantrium Intravenous should be continuous until symptoms subside. The effective dose to reverse the crisis is directly dependent upon the individual's degree of susceptibility to malignant hyperthermia, the amount and time of exposure to the triggering agent, and the time elapsed between onset of the crisis and initiation of treatment.
- Dantrium Intravenous and/or Dantrium Capsules may be administered preoperatively to patients judged malignant hyperthermia susceptible as part of the overall patient management to prevent or attenuate the development of clinical and laboratory signs of malignant hyperthermia.
- The recommended prophylactic dose of Dantrium Intravenous is 2.5 mg/kg, starting approximately 1-1/4 hours before anticipated anesthesia and infused over approximately 1 hour. This dose should prevent or attenuate the development of clinical and laboratory signs of malignant hyperthermia provided that the usual precautions, such as avoidance of established malignant hyperthermia triggering agents, are followed.
- Additional Dantrium Intravenous may be indicated during anesthesia and surgery because of the appearance of early clinical and/or blood gas signs of malignant hyperthermia or because of prolonged surgery.Additional doses must be individualized.
- Intravenous Dantrium may be used postoperatively to prevent or attenuate the recurrence of signs of malignant hyperthermia when oral Dantrium administration is not practical. The i.v. dose of Dantrium in the postoperative period must be individualized, starting with 1 mg/kg or more as the clinical situation dictates.
- Tetanus[4][5]
- The following gradual titration schedule is suggested. Some patients will not respond until higher daily dosage is achieved. Each dosage level should be maintained for seven days to determine the patient's response. If no further benefit is observed at the next higher dose, dosage should be decreased to the previous lower dose.
- 0.5 mg/kg once daily for seven days, then
- 0.5 mg/kg t.i.d. for seven days
- 1 mg/kg t.i.d. for seven days
- 2 mg/kg t.i.d.
- Therapy with a dose four times daily may be necessary for some individuals. Doses higher than 100 mg four times daily should not be used.
- Experience to date indicates that the dose of Dantrium Intravenous for pediatric patients is the same as for adults.
- hepatitis
- cirrhosis
- Dantrium is contraindicated where spasticity is utilized to sustain upright posture and balance in locomotion or whenever spasticity is utilized to obtain or maintain increased function.
- At the start of Dantrium therapy, it is desirable to do liver function studies (SGOT, SGPT, alkaline phosphatase, total bilirubin) for a baseline or to establish whether there is pre-existing liver disease. If baseline liver abnormalities exist and are confirmed, there is a clear possibility that the potential for Dantrium hepatotoxicity could be enhanced, although such a possibility has not yet been established.
- Liver function studies (e.g., SGOT or SGPT) should be performed at appropriate intervals during Dantrium therapy. If such studies reveal abnormal values, therapy should generally be discontinued. Only where benefits of the drug have been of major importance to the patient, should reinitiation or continuation of therapy be considered. Some patients have revealed a return to normal laboratory values in the face of continued therapy while others have not.
- If symptoms compatible with hepatitis, accompanied by abnormalities in liver function tests or jaundice appear, Dantrium should be discontinued. If caused by Dantrium and detected early, the abnormalities in liver function characteristically have reverted to normal when the drug was discontinued.
- Dantrium therapy has been reinstituted in a few patients who have developed clinical and/or laboratory evidence of hepatocellular injury. If such reinstitution of therapy is done, it should be attempted only in patients who clearly need Dantrium and only after previous symptoms and laboratory abnormalities have cleared. The patient should be hospitalized and the drug should be restarted in very small and gradually increasing doses. Laboratory monitoring should be frequent and the drug should be withdrawn immediately if there is any indication of recurrent liver involvement. Some patients have reacted with unmistakable signs of liver abnormality upon administration of a challenge dose, while others have not.
- Dantrium should be used with particular caution in females and in patients over 35 years of age in view of apparent greater likelihood of drug-induced, potentially fatal, hepatocellular disease in these groups. Spontaneous reports suggest a higher proportion of hepatic events with fatal outcome in elderly patients receiving Dantrium. However, the majority of these cases were complicated with confounding factors such as intercurrent illnesses and/or concomitant potentially hepatotoxic medications
- The use of Dantrium Intravenous in the management of malignant hyperthermia crisis is not a substitute for previously known supportive measures. These measures must be individualized, but it will usually be necessary to discontinue the suspect triggering agents, attend to increased oxygen requirements, manage the metabolic acidosis, institute cooling when necessary, monitor urinary output, and monitor for electrolyte imbalance.
- Since the effect of disease state and other drugs on Dantrium related skeletal muscle weakness, including possible respiratory depression, cannot be predicted, patients who receive i.v. Dantrium preoperatively should have vital signs monitored.
- If patients judged malignant hyperthermia susceptible are administered intravenous or oral Dantrium preoperatively, anesthetic preparation must still follow a standard malignant hyperthermia susceptible regimen, including the avoidance of known triggering agents. Monitoring for early clinical and metabolic signs of malignant hyperthermia is indicated because attenuation of malignant hyperthermia, rather than prevention, is possible. These signs usually call for the administration of additional i.v. dantrolene.
### Precautions
- Dantrium should be used with caution in patients with impaired pulmonary function, particularly those with obstructive pulmonary disease, and in patients with severely impaired cardiac function due to myocardial disease. Dantrium is associated with pleural effusion with associated eosinophilia. It should be used with caution in patients with a history of previous liver disease or dysfunction
- Dantrium might possibly evoke a photosensitivity reaction; patients should be cautioned about exposure to sunlight while taking it.
- Care must be taken to prevent extravasation of Dantrium solution into the surrounding tissues due to the high pH of the intravenous formulation and potential for tissue necrosis.
- When mannitol is used for prevention or treatment of late renal complications of malignant hyperthermia, the 3 g of mannitol needed to dissolve each 20 mg vial of i.v. Dantrium should be taken into consideration.
- Dantrium (dantrolene sodium) has a potential for hepatotoxicity, and should not be used in conditions other than those recommended. Symptomatic hepatitis (fatal and non-fatal) has been reported at various dose levels of the drug. The incidence reported in patients taking up to 400 mg/day is much lower than in those taking doses of 800 mg or more per day. Even sporadic short courses of these higher dose levels within a treatment regimen markedly increased the risk of serious hepatic injury. Liver dysfunction as evidenced by blood chemical abnormalities alone (liver enzyme elevations) has been observed in patients exposed to Dantrium for varying periods of time. Overt hepatitis has occurred at varying intervals after initiation of therapy, but has been most frequently observed between the third and twelfth month of therapy. The risk of hepatic injury appears to be greater in females, in patients over 35 years of age, and in patients taking other medication(s) in addition to Dantrium (dantrolene sodium). Dantrium should be used only in conjunction with appropriate monitoring of hepatic function including frequent determination of SGOT or SGPT.
- Fatal and non-fatal liver disorders of an idiosyncratic or hypersensitivity type may occur with Dantrium therapy.
- drowsiness
- dizziness
- weakness
- general malaise
- fatigue
- diarrhea
- These are generally transient, occurring early in treatment, and can often be obviated by beginning with a low dose and increasing dosage gradually until an optimal regimen is established. Diarrhea may be severe and may necessitate temporary withdrawal of Dantrium therapy. If diarrhea recurs upon readministration of Dantrium, therapy should probably be withdrawn permanently.
- Other less frequent side effects, listed according to system, are:
- Tachycardia
- erratic blood pressure
- phlebitis
- heart failure
- Constipation, rarely progressing to signs of intestinal obstruction
- GI bleeding
- anorexia
- swallowing difficulty
- gastric irritation
- abdominal cramps
- nausea
- vomiting
- Hepatitis
- Aplastic anemia
- anemia
- leukopenia
- lymphocytic lymphoma
- thrombocytopenia
- Myalgia
- backache
- Speech disturbance
- seizure
- headache
- light-headedness
- visual disturbance
- diplopia
- alteration of taste
- insomnia
- drooling
- Mental depression
- mental confusion
- increased nervousness
- Feeling of suffocation
- respiratory depression
- Abnormal hair growth
- acne-like rash
- pruritus
- urticaria
- eczematoid eruption
- sweating
- Pleural effusion with pericarditis
- Pleural effusion with associated eosinophilia
- anaphylaxis
- Excessive tearing
- Increased urinary frequency
- crystalluria
- hematuria
- difficult erection
- urinary incontinence
- nocturia
- difficult urination
- urinary retention
- Chills
- fever
- There have been occasional reports of death following malignant hyperthermia crisis even when treated with intravenous dantrolene; incidence figures are not available (the pre-dantrolene mortality of malignant hyperthermia crisis was approximately 50%). Most of these deaths can be accounted for by late recognition, delayed treatment, inadequate dosage, lack of supportive therapy, intercurrent disease and/or the development of delayed complications such as renal failure or disseminated intravascular coagulopathy. In some cases there are insufficient data to completely rule out therapeutic failure of dantrolene.
- There are reports of fatality in malignant hyperthermia crisis, despite initial satisfactory response to i.v. dantrolene, which involve patients who could not be weaned from dantrolene after initial treatment.
- The administration of intravenous Dantrium to human volunteers is associated with loss of grip strength and weakness in the legs, as well as drowsiness and dizziness.
- The following adverse reactions are in approximate order of severity:
- There are rare reports of pulmonary edema developing during the treatment of malignant hyperthermia crisis in which the diluent volume and mannitol needed to deliver i.v. dantrolene possibly contributed.
- There have been reports of thrombophlebitis following administration of intravenous dantrolene; actual incidence figures are not available. Tissue necrosis secondary to extravasation has been reported.
- There have been rare reports of urticaria and erythema possibly associated with the administration of i.v. Dantrium. There has been one case of anaphylaxis.
- Injection site reactions (pain, erythema, swelling), commonly due to extravasation, have been reported.
- None of the serious reactions occasionally reported with long-term oral Dantrium use, such as hepatitis, seizures, and pleural effusion with pericarditis, have been reasonably associated with short-term Dantrium Intravenous therapy.
- Drowsiness may occur with Dantrium therapy, and the concomitant administration of CNS depressants such as sedatives and tranquilizing agents may result in further drowsiness.
- Estrogen
- While a definite drug interaction with estrogen therapy has not yet been established, caution should be observed if the two drugs are to be given concomitantly. Hepatotoxicity has occurred more often in women over 35 years of age receiving concomitant estrogen therapy.
- Verapamil
- Cardiovascular collapse in patients treated simultaneously with verapamil and dantrolene sodium is rare. The combination of therapeutic doses of intravenous dantrolene sodium and verapamil in halothane/α-chloralose anesthetized swine has resulted in ventricular fibrillation and cardiovascular collapse in association with marked hyperkalemia. Until the relevance of these findings to humans is established, the combination of dantrolene sodium and calcium channel blockers is not recommended during the management of malignant hyperthermia.
- Vecuronium
- Administration of Dantrium may potentiate vecuronium-induced neuromuscular block.
- Dantrium is metabolized by the liver, and it is theoretically possible that its metabolism may be enhanced by drugs known to induce hepatic microsomal enzymes. However, neither phenobarbital nor diazepam appears to affect Dantrium metabolism. Binding to plasma protein is not significantly altered by diazepam, diphenylhydantoin, or phenylbutazone. Binding to plasma proteins is reduced by warfarin and clofibrate and increased by tolbutamide.
- Intravenous
- Each vial of Dantrium Intravenous should be reconstituted by adding 60 mL of sterile water for injection USP (without a bacteriostatic agent), and the vial shaken until the solution is clear. 5% Dextrose Injection USP, 0.9% Sodium Chloride Injection USP, and other acidic solutions are not compatible with Dantrium Intravenous and should not be used. The contents of the vial must be protected from direct light and used within 6 hours after reconstitution. Store reconstituted solutions between 15° to 30°C (59° to 86°F).
- Reconstituted Dantrium Intravenous should not be transferred to large glass bottles for prophylactic infusion due to precipitate formation observed with the use of some glass bottles as reservoirs.
- For prophylactic infusion, the required number of individual vials of Dantrium Intravenous should be reconstituted as outlined above. The contents of individual vials are then transferred to a larger volume sterile intravenous plastic bag. Stability data on file at JHP Pharmaceuticals indicate commercially available sterile plastic bags are acceptable drug delivery devices. However, it is recommended that the prepared infusion be inspected carefully for cloudiness and/or precipitation prior to dispensing and administration. Such solutions should not be used. While stable for 6 hours, it is recommended that the infusion be prepared immediately prior to the anticipated dosage administration time.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.
- Intravenous fluids should be administered in fairly large quantities to avert the possibility of crystalluria. An adequate airway should be maintained and artificial resuscitation equipment should be at hand. Electrocardiographic monitoring should be instituted, and the patient carefully observed. To date, no experience has been reported with dialysis and its value in Dantrium overdose is not known.
- In the anesthetic-induced malignant hyperthermia syndrome, evidence points to an intrinsic abnormality of skeletal muscle tissue. In affected humans, it has been postulated that "triggering agents" (e.g., general anesthetics and depolarizing neuromuscular blocking agents) produce a change within the cell which results in an elevated myoplasmic calcium. This elevated myoplasmic calcium activates acute cellular catabolic processes that cascade to the malignant hyperthermia crisis.
- It is hypothesized that addition of Dantrium to the "triggered" malignant hyperthermic muscle cell reestablishes a normal level of ionized calcium in the myoplasm. Inhibition of calcium release from the sarcoplasmic reticulum by Dantrium reestablishes the myoplasmic calcium equilibrium, increasing the percentage of bound calcium. In this way, physiologic, metabolic, and biochemical changes associated with the malignant hyperthermia crisis may be reversed or attenuated. Experimental results in malignant hyperthermia susceptible swine show that prophylactic administration of intravenous or oral dantrolene prevents or attenuates the development of vital sign and blood gas changes characteristic of malignant hyperthermia in a dose related manner. The efficacy of intravenous dantrolene in the treatment of human and porcine malignant hyperthermia crisis, when considered along with prophylactic experiments in malignant hyperthermia susceptible swine, lends support to prophylactic use of oral or intravenous dantrolene in malignant hyperthermia susceptible humans. When prophylactic intravenous dantrolene is administered as directed, whole blood concentrations remain at a near steady state level for 3 or more hours after the infusion is completed. Clinical experience has shown that early vital sign and/or blood gas changes characteristic of malignant hyperthermia may appear during or after anesthesia and surgery despite the prophylactic use of dantrolene and adherence to currently accepted patient management practices. These signs are compatible with attenuated malignant hyperthermia and respond to the administration of additional i.v. dantrolene. The administration of the recommended prophylactic dose of intravenous dantrolene to healthy volunteers was not associated with clinically significant cardiorespiratory changes.
- Specific metabolic pathways for the degradation and elimination of Dantrium in humans have been established. Dantrolene is found in measurable amounts in blood and urine. Its major metabolites in body fluids are 5-hydroxy dantrolene and an acetylamino metabolite of dantrolene. Another metabolite with an unknown structure appears related to the latter. Dantrium may also undergo hydrolysis and subsequent oxidation forming nitrophenylfuroic acid.
- The mean biologic half-life of Dantrium after intravenous administration is variable, between 4 to 8 hours under most experimental conditions. Based on assays of whole blood and plasma, slightly greater amounts of dantrolene are associated with red blood cells than with the plasma fraction of blood. Significant amounts of dantrolene are bound to plasma proteins, mostly albumin, and this binding is readily reversible.
- Cardiopulmonary depression has not been observed in malignant hyperthermia susceptible swine following the administration of up to 7.5 mg/kg i.v. dantrolene. This is twice the amount needed to maximally diminish twitch response to single supramaximal peripheral nerve stimulation (95% inhibition). A transient, inconsistent, depressant effect on gastrointestinal smooth muscles has been observed at high doses.
- Long-term safety of Dantrium in humans has not been established. Chronic studies in rats, dogs, and monkeys at dosages greater than 30 mg/kg/day showed growth or weight depression and signs of hepatopathy and possible occlusion nephropathy, all of which were reversible upon cessation of treatment. Sprague-Dawley female rats fed dantrolene sodium for 18 months at dosage levels of 15, 30, and 60 mg/kg/day showed an increased incidence of benign and malignant mammary tumors compared with concurrent controls. At the highest dose level, there was an increase in the incidence of benign lymphatic neoplasms. In a 30-month study at the same dose levels also in Sprague-Dawley rats, dantrolene sodium produced a decrease in the time of onset of mammary neoplasms. Female rats at the highest dose level showed an increased incidence of hepatic lymphangiomas and hepatic angiosarcomas.
- The only drug-related effect seen in a 30-month study in Fischer-344 rats was a dose-related reduction in the time of onset of mammary and testicular tumors. A 24-month study in HaM/ICR mice revealed no evidence of carcinogenic activity. Carcinogenicity in humans cannot be fully excluded, so that this possible risk of chronic administration must be weighed against the benefits of the drug (i.e., after a brief trial) for the individual patient.
- Dantrolene sodium has produced positive results in the Ames S. Typhimurium bacterial mutagenesis assay in the presence and absence of a liver activating system.
- Dantrium Intravenous (NDC 42023-123-06) is available in vials containing a sterile lyophilized mixture of 20 mg dantrolene sodium, 3000 mg mannitol, and sufficient sodium hydroxide to yield a pH of approximately 9.5 when reconstituted with 60 mL sterile water for injection USP (without a bacteriostatic agent).
- Dantrium might possibly evoke a photosensitivity reaction; patients should be cautioned about exposure to sunlight while taking it.
- Dantrium intravenous®[7]
- ↑ Tsutsumi Y, Yamamoto K, Matsuura S, Hata S, Sakai M, Shirakura K (1998). "The treatment of neuroleptic malignant syndrome using dantrolene sodium". Psychiatry Clin Neurosci. 52 (4): 433–8. doi:10.1046/j.1440-1819.1998.00416.x. PMID 9766694.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}
- ↑ Tsujimoto S, Maeda K, Sugiyama T, Yokochi A, Chikusa H, Maruyama K (1998). "Efficacy of prolonged large-dose dantrolene for severe neuroleptic malignant syndrome". Anesth Analg. 86 (5): 1143–4. PMID 9585314.CS1 maint: Multiple names: authors list (link)
- ↑ Kaplan RF, Feinglass NG, Webster W, Mudra S (1986). "Phenelzine overdose treated with dantrolene sodium". JAMA. 255 (5): 642–4. PMID 3944965.CS1 maint: Multiple names: authors list (link)
- ↑ Farquhar I, Hutchinson A, Curran J (1988). "Dantrolene in severe tetanus". Intensive Care Med. 14 (3): 249–50. PMID 3379189.CS1 maint: Multiple names: authors list (link)
- ↑ Tidyman M, Prichard JG, Deamer RL, Mac N (1985). "Adjunctive use of dantrolene in severe tetanus". Anesth Analg. 64 (5): 538–40. PMID 3922250.CS1 maint: Multiple names: authors list (link)
- ↑ "Dantrolene".
- ↑ "Dantrolene". | https://www.wikidoc.org/index.php/Dantrium | |
c1ba65d1a22a995215a20408e37e07b448406327 | wikidoc | Dapoxetine | Dapoxetine
Steven C. Campbell, M.D., Ph.D.
# Overview
Dapoxetine is the International Nonproprietary Name of a short-acting SSRI drug currently being considered for approval by the Food and Drug Administration (FDA) for the treatment of premature ejaculation in men, which would make it the first drug approved for such treatment. It is currently in Phase III of the approval process.
# Function
If approved, this would make Dapoxetine join the ranks of erectile dysfunction drugs such as sildenafil (Viagra®), tadalafil (Cialis®), and vardenafil (Levitra®), and some dopamine agonists such as cabergoline (Dostinex®) and pramipexole, as drugs which can be used to improve male sexual health. Misuse of these drugs as aphrodisiacs or sexual enhancers in individuals who do not suffer from sexual health problems is also a possibility and there have been some concerns about doctors being pressured to prescribe such drugs off-label to people who do not actually have a medical need for the drug.
Some research has shown Dapoxetine to have a benefit in the treatment of premature ejaculation.
# Approval process
Dapoxetine was created by Eli Lilly and Company and is credited to biochemist David T. Wong. Originally known as LY 210448, it was being developed by Lilly as an antidepressant. Eli Lilly sold the patent to Johnson & Johnson for $65 million dollars and future royalties in December 2003.
Dapoxetine was submitted to the FDA in the form of dapoxetine hydrochloride by the ALZA Corporation and its parent company, Johnson & Johnson for the treatment of premature ejaculation with a New Drug Application (NDA) to the Food and Drug Administration (FDA) on December 28, 2004.
In October of 2005, the FDA issued a "not approvable" letter for dapoxetine.
Despite two clinical trials finished in 2006, experts doubt it will be approved by the FDA soon because SSRIs come with undesirable side-effects after long-term use, such as psychiatric problems, dermatological reactions, increase in body weight, lower sex-drive, nausea, headache, upset stomach and weakness, thus not significantly outweighing the benefit of premature ejaculation medication versus the risks. | Dapoxetine
Template:Search infobox
Steven C. Campbell, M.D., Ph.D.
# Overview
Dapoxetine is the International Nonproprietary Name of a short-acting SSRI drug currently being considered for approval by the Food and Drug Administration (FDA) for the treatment of premature ejaculation in men, which would make it the first drug approved for such treatment. It is currently in Phase III of the approval process.
# Function
If approved, this would make Dapoxetine join the ranks of erectile dysfunction drugs such as sildenafil (Viagra®), tadalafil (Cialis®), and vardenafil (Levitra®), and some dopamine agonists such as cabergoline (Dostinex®) and pramipexole, as drugs which can be used to improve male sexual health. Misuse of these drugs as aphrodisiacs or sexual enhancers in individuals who do not suffer from sexual health problems is also a possibility and there have been some concerns about doctors being pressured to prescribe such drugs off-label to people who do not actually have a medical need for the drug.
Some research has shown Dapoxetine to have a benefit in the treatment of premature ejaculation.[1]
# Approval process
Dapoxetine was created by Eli Lilly and Company and is credited to biochemist David T. Wong. Originally known as LY 210448, it was being developed by Lilly as an antidepressant. Eli Lilly sold the patent to Johnson & Johnson for $65 million dollars and future royalties in December 2003.
Dapoxetine was submitted to the FDA in the form of dapoxetine hydrochloride by the ALZA Corporation and its parent company, Johnson & Johnson for the treatment of premature ejaculation with a New Drug Application (NDA) to the Food and Drug Administration (FDA) on December 28, 2004.
In October of 2005, the FDA issued a "not approvable" letter for dapoxetine.[2]
Despite two clinical trials finished in 2006, experts doubt it will be approved by the FDA soon because SSRIs come with undesirable side-effects after long-term use, such as psychiatric problems, dermatological reactions, increase in body weight, lower sex-drive, nausea, headache, upset stomach and weakness, thus not significantly outweighing the benefit of premature ejaculation medication versus the risks. | https://www.wikidoc.org/index.php/Dapoxetine | |
12b728da47228ca17ce6d4467af5ef89a8ad3f6f | wikidoc | Dysarthria | Dysarthria
Synonyms and keywords: Motor Speech Disorder
# Overview
Dysarthria is a motor speech disorder caused by a neurological deficit resulting in weakening or paralysis of the muscles responsible for speech formation. The term dysarthria is derived from New Latin. Dysarthria may be classified according to presentation of symptoms into 7 subgroups. Neurological deficit in CNS and/or PNS causes weakness and/or paralysis of muscles responsible for speech. Dysarthria must be differentiated from other motor speech disorders like apraxia and developmental verbal dyspraxia. Incidence and prevalence is not fully established. Dysarthria affects men and women equally. There are no established risk factors for dysarthria. There is insufficient evidence to recommend routine screening for dysarthria. Common complications of dysarthria include social distancing, irritability, and depression. Detailed history and examination are important to identify the cause and to classify dysarthria. There are no CT scan findings associated with dysarthria. However, it provides a detailed image of CNS to help identify the underlying cause of the speech problems. Treatment includes exercises and techniques to adjust speech rate, strengthen muscles of articulation, increase breath support, improve articulation, safe chewing and swallowing, avoiding conversations when feeling tired, repeat words and syllables, and techniques to deal with the frustration while speaking.
# Historical Perspective
- The term dysarthria is derived from New Latin.
- 'Dys' means dysfunctional/impaired and 'arthr' means joint/vocal articulation.
- Tradiationally, dysarthria has been defined as disorders of oral speech resulting from lesions within the nervous system.
- Recently, dysarthria includes speech disorders resulting from problems in muscular control of speech formation.
# Classification
- Dysarthria may be classified according to presentation of symptoms into the following:
# Pathophysiology
- Dysarthria is a motor speech disorder, marked by poor articulation caused by neuromuscular impairment.
- Neurological deficit in CNS and/or PNS causes weakness and/or paralysis of muscles responsible for speech.
- Following subsystems contribute to speech formation, impairment of these subsystems results into poor perceptual speech:
Respiration
Phonation
Resonance
Prosody
Articulation
- Respiration
- Phonation
- Resonance
- Prosody
- Articulation
# Causes
Common causes of dysarthria include:
# Differentiating Dysarthria from other Diseases
- Dysarthria must be differentiated from other motor speech disorders like apraxia and developmental verbal dyspraxia.
- Apraxia is a neurological disorder where there are abilities and motivations to form speech but the patient cannot due to neurological deficit.
- Development verbal dyspraxia lacks muscle weakness and is characterized by the developmental inability to motor plan volitional movement for the production of speech. Links to the FOXP2 gene have been identified.
# Epidemiology and Demographics
- Incidence and prevalence is not fully established.
- Disease based prevalence of dysarthria is as following:
Stroke: Approximately 8%–60% of individuals with stroke present with dysarthria.
Parkinson's disease: Approximately 70%–100% of individuals develop dysarthria.
Multiple sclerosis: 25% and 50% of individuals with multiple sclerosis present with dysarthria at some point.
Amyotrophic lateral sclerosis: Approximately 30%-100% depending on the stage of the disease.
Traumatic brain injury: Approximately 10%–65% of individuals with traumatic brain injury develop dysarthria.
- Stroke: Approximately 8%–60% of individuals with stroke present with dysarthria.
- Parkinson's disease: Approximately 70%–100% of individuals develop dysarthria.
- Multiple sclerosis: 25% and 50% of individuals with multiple sclerosis present with dysarthria at some point.
- Amyotrophic lateral sclerosis: Approximately 30%-100% depending on the stage of the disease.
- Traumatic brain injury: Approximately 10%–65% of individuals with traumatic brain injury develop dysarthria.
- There is no racial predilection to dysarthria.
- Dysarthria affects men and women equally.
# Risk Factors
- There are no established risk factors for dysarthria.
# Screening
- There is insufficient evidence to recommend routine screening for dysarthria.
# Natural History, Complications, and Prognosis
- Common complications of dysarthria include social distancing, irritability, and depression.
- Prognosis varies depending on the severity of underlying disease and response to speech therapy.
# Diagnosis
## Diagnostic Study of Choice
- There are no established criteria for the diagnosis of dysarthria.
- Detailed history and examination are important to identify the cause and to classify dysarthria.
- Speech assessment should be conducted by a speech-language pathologist to identify perceptual speech and subsystem involvement.
## History and Symptoms
- Signs and symptoms of dysarthria vary, depending on the underlying cause and the type of dysarthria.
- Patient may present with slow or rapid speech, nasal speech, uneven or monotone, slurred speech and/or abnormal speech volume or rhythm.
## Physical Examination
- Physical examination varies depending on the underlying cause of dysarthria.
## Laboratory Findings
- There are no diagnostic laboratory findings associated with dysarthria. Laboratory findings defer on the basis of the underlying cause.
## Electrocardiogram
- There are no ECG findings associated with dysarthria.
## X-ray
- There are no x-ray findings associated with dysarthria.
## Echocardiography or Ultrasound
- There are no echocardiography/ultrasound findings associated with dysarthria.
## CT Scan
- There are no CT scan findings associated with dysarthria. However, it provides a detailed image of CNS to help identify the underlying cause of the speech problems.
## MRI
- There are no MRI findings associated with dysarthria. However, it provides a detailed image of CNS to help identify the underlying cause of the speech problems.
## Other Imaging Findings
- There are no other imaging findings associated with dysarthria.
## Other Diagnostic Studies
- There are no other diagnostic studies associated with dysarthria.
# Treatment
## Medical Therapy
- Treatment is focused on achieving independent daily living for the patients.
- A speech language pathologist assist in improving respiration, phonation, resonance, prosody and/or articulation using various techniques.
- These treatment includes exercises and techniques to adjust speech rate, strengthen muscles of articulation, increase breath support, improve articulation, safe chewing and swallowing, avoiding conversations when feeling tired, repeat words and syllables, and techniques to deal with the frustration while speaking.
- If dysarthria is severe, another possible technique includes using a computer or flip cards to communicate more effectively.
- Augmentative and alternative communication (AAC) is used by speech language pathologist to supplement or replace natural speech.
- Lee Silverman voice treatment(LSVT) focuses on increasing vocal loudness and is found to be effective in patients with Parkinson's disease.
- Pitch Limiting Voice Treatment (PLVT) increases loudness without increasing pitch.
- Treat the underlying cause and slowing progression of the disease-causing motor speech dysfunction.
## Surgery
- Surgical intervention is not recommended for the management of dysarthria.
## Primary Prevention
- There are no established measures for the primary prevention of dysarthria.
## Secondary Prevention
- There are no established measures for the secondary prevention of dysarthria. | Dysarthria
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Zehra Malik, M.B.B.S[2]
Synonyms and keywords: Motor Speech Disorder
# Overview
Dysarthria is a motor speech disorder caused by a neurological deficit resulting in weakening or paralysis of the muscles responsible for speech formation. The term dysarthria is derived from New Latin. Dysarthria may be classified according to presentation of symptoms into 7 subgroups. Neurological deficit in CNS and/or PNS causes weakness and/or paralysis of muscles responsible for speech. Dysarthria must be differentiated from other motor speech disorders like apraxia and developmental verbal dyspraxia. Incidence and prevalence is not fully established. Dysarthria affects men and women equally. There are no established risk factors for dysarthria. There is insufficient evidence to recommend routine screening for dysarthria. Common complications of dysarthria include social distancing, irritability, and depression. Detailed history and examination are important to identify the cause and to classify dysarthria. There are no CT scan findings associated with dysarthria. However, it provides a detailed image of CNS to help identify the underlying cause of the speech problems. Treatment includes exercises and techniques to adjust speech rate, strengthen muscles of articulation, increase breath support, improve articulation, safe chewing and swallowing, avoiding conversations when feeling tired, repeat words and syllables, and techniques to deal with the frustration while speaking.
# Historical Perspective
- The term dysarthria is derived from New Latin.
- 'Dys' means dysfunctional/impaired and 'arthr' means joint/vocal articulation.[1]
- Tradiationally, dysarthria has been defined as disorders of oral speech resulting from lesions within the nervous system.[2]
- Recently, dysarthria includes speech disorders resulting from problems in muscular control of speech formation.[3]
# Classification
- Dysarthria may be classified according to presentation of symptoms into the following:[4] [5]
# Pathophysiology
- Dysarthria is a motor speech disorder, marked by poor articulation caused by neuromuscular impairment.[6]
- Neurological deficit in CNS and/or PNS causes weakness and/or paralysis of muscles responsible for speech.
- Following subsystems contribute to speech formation, impairment of these subsystems results into poor perceptual speech:[7]
Respiration
Phonation
Resonance
Prosody
Articulation
- Respiration
- Phonation
- Resonance
- Prosody
- Articulation
# Causes
Common causes of dysarthria include:
# Differentiating Dysarthria from other Diseases
- Dysarthria must be differentiated from other motor speech disorders like apraxia and developmental verbal dyspraxia.
- Apraxia is a neurological disorder where there are abilities and motivations to form speech but the patient cannot due to neurological deficit.
- Development verbal dyspraxia lacks muscle weakness and is characterized by the developmental inability to motor plan volitional movement for the production of speech. Links to the FOXP2 gene have been identified.[8]
# Epidemiology and Demographics
- Incidence and prevalence is not fully established.
- Disease based prevalence of dysarthria is as following:
Stroke: Approximately 8%–60% of individuals with stroke present with dysarthria.[9]
Parkinson's disease: Approximately 70%–100% of individuals develop dysarthria.[10]
Multiple sclerosis: 25% and 50% of individuals with multiple sclerosis present with dysarthria at some point.[11]
Amyotrophic lateral sclerosis: Approximately 30%-100% depending on the stage of the disease.[12]
Traumatic brain injury: Approximately 10%–65% of individuals with traumatic brain injury develop dysarthria.[13]
- Stroke: Approximately 8%–60% of individuals with stroke present with dysarthria.[9]
- Parkinson's disease: Approximately 70%–100% of individuals develop dysarthria.[10]
- Multiple sclerosis: 25% and 50% of individuals with multiple sclerosis present with dysarthria at some point.[11]
- Amyotrophic lateral sclerosis: Approximately 30%-100% depending on the stage of the disease.[12]
- Traumatic brain injury: Approximately 10%–65% of individuals with traumatic brain injury develop dysarthria.[13]
- There is no racial predilection to dysarthria.
- Dysarthria affects men and women equally.
# Risk Factors
- There are no established risk factors for dysarthria.
# Screening
- There is insufficient evidence to recommend routine screening for dysarthria.
# Natural History, Complications, and Prognosis
- Common complications of dysarthria include social distancing, irritability, and depression.
- Prognosis varies depending on the severity of underlying disease and response to speech therapy.
# Diagnosis
## Diagnostic Study of Choice
- There are no established criteria for the diagnosis of dysarthria.
- Detailed history and examination are important to identify the cause and to classify dysarthria.
- Speech assessment should be conducted by a speech-language pathologist to identify perceptual speech and subsystem involvement.
## History and Symptoms
- Signs and symptoms of dysarthria vary, depending on the underlying cause and the type of dysarthria.[14]
- Patient may present with slow or rapid speech, nasal speech, uneven or monotone, slurred speech and/or abnormal speech volume or rhythm.[15]
## Physical Examination
- Physical examination varies depending on the underlying cause of dysarthria.
## Laboratory Findings
- There are no diagnostic laboratory findings associated with dysarthria. Laboratory findings defer on the basis of the underlying cause.
## Electrocardiogram
- There are no ECG findings associated with dysarthria.
## X-ray
- There are no x-ray findings associated with dysarthria.
## Echocardiography or Ultrasound
- There are no echocardiography/ultrasound findings associated with dysarthria.
## CT Scan
- There are no CT scan findings associated with dysarthria. However, it provides a detailed image of CNS to help identify the underlying cause of the speech problems.
## MRI
- There are no MRI findings associated with dysarthria. However, it provides a detailed image of CNS to help identify the underlying cause of the speech problems.
## Other Imaging Findings
- There are no other imaging findings associated with dysarthria.
## Other Diagnostic Studies
- There are no other diagnostic studies associated with dysarthria.
# Treatment
## Medical Therapy
- Treatment is focused on achieving independent daily living for the patients.
- A speech language pathologist assist in improving respiration, phonation, resonance, prosody and/or articulation using various techniques.
- These treatment includes exercises and techniques to adjust speech rate, strengthen muscles of articulation, increase breath support, improve articulation, safe chewing and swallowing, avoiding conversations when feeling tired, repeat words and syllables, and techniques to deal with the frustration while speaking.
- If dysarthria is severe, another possible technique includes using a computer or flip cards to communicate more effectively.[16]
- Augmentative and alternative communication (AAC) is used by speech language pathologist to supplement or replace natural speech.
- Lee Silverman voice treatment(LSVT) focuses on increasing vocal loudness and is found to be effective in patients with Parkinson's disease.[17]
- Pitch Limiting Voice Treatment (PLVT) increases loudness without increasing pitch.[18]
- Treat the underlying cause and slowing progression of the disease-causing motor speech dysfunction.
## Surgery
- Surgical intervention is not recommended for the management of dysarthria.
## Primary Prevention
- There are no established measures for the primary prevention of dysarthria.
## Secondary Prevention
- There are no established measures for the secondary prevention of dysarthria. | https://www.wikidoc.org/index.php/Ddx:Dysarthria | |
32418c0d6a05ed2c1e23506a5bcca808df224d7f | wikidoc | Fibrinogen | Fibrinogen
Fibrinogen (factor I) is a glycoprotein that circulates in the blood of vertebrates. During tissue and vascular injury it is converted enzymatically by thrombin to fibrin and subsequently to a fibrin-based blood clot. Fibrinogen functions primarily to occlude blood vessels and thereby stop excessive bleeding. However, fibrinogen's product, fibrin, binds and reduces the activity of thrombin. This activity, sometimes referred to as antithrombin I, serves to limit blood clotting. Loss or reduction in this antithrombin 1 activity due to mutations in fibrinogen genes or hypo-fibrinogen conditions can lead to excessive blood clotting and thrombosis. Fibrin also mediates blood platelet and endothelial cell spreading, tissue fibroblast proliferation, capillary tube formation, and angiogenesis and thereby functions to promote tissue revascularization, wound healing, and tissue repair.
Reduced and/or dysfunctional fibrinogens occur in various congenital and acquired human fibrinogen-related disorders. These disorders represent a clinically important group of rare conditions in which individuals may present with severe episodes of pathological bleeding and thrombosis; these conditions are treated by supplementing blood fibrinogen levels and inhibiting blood clotting, respectively. Certain of these disorders may also be the cause of liver and kidney diseases.
Fibrinogen is a "positive" acute-phase protein, i.e. its blood levels rise in response to systemic inflammation, tissue injury, and certain other events. It is also elevated in various cancers. Elevated levels of fibrinogen in inflammation as well as cancer and other conditions have been suggested to be the cause of thrombosis and vascular injury that accompanies these conditions.
# Genes
Fibrinogen is made and secreted into the blood primarily by liver hepatocyte cells. Endothelium cells are also reported to make what appears to be small amounts of fibrinogen but this fibrinogen has not been fully characterized; blood platelets and their precursors, bone marrow megakaryocytes, while once thought to make fibrinogen, are now known to take up and store but not make the glycoprotein. The final secreted, hepatocyte-derived glycoprotein is composed of two trimers with each trimer composed of three different polypeptide chains, the fibrinogen alpha chain (also termed the Aα or α chain) encoded by the FGA gene, the fibrinogen beta chain (also termed the Bβ or β chain) encoded by the FGB gene, and the fibrinogen gamma chain (also termed the γ chain) encoded by the FGG gene. All three genes are located on the long or "p" arm of human chromosome 4 (at positions 4q31.3, 4q31.3, and 4q32.1, respectively). Alternate splicing of the FGA gene produces a minor expanded isoform of Aα termed AαE which replaces Aα in 1–3% of circulating fibrinogen; alternate splicing of FGG produces a minor isoform of γ termed γ' which replaces γ in 8–10% of circulating fibrinogen; FGA is not alternatively spliced. Hence, the final fibrinogen product is composed principally of Aα, Bβ, and γ chains with a small percentage of it containing AαE and/or γ' chains in place of Aα and/or γ chains, respectively. The three genes are transcribed and translated in co-ordination by a mechanism(s) which remains incompletely understood. The coordinated transcription of these three fibrinogen genes is rapidly and greatly increased by systemic conditions such as inflammation and tissue injury. Cytokines produced during these systemic conditions, such as interleukin 6 and interleukin 1β, appear responsible for up-regulating this transcription.
# Structure
The Aα, Bβ, and γ chains are transcribed and translated coordinately on the endoplasmic reticulum (ER) with their peptide chains being passed into the ER while their signal peptide portions are removed. Inside the ER, the three chains are assembled initially into Aαγ and Bβγ dimers, then to AαBβγ trimers, and finally to (AαBβγ)2 heximers, i.e. two AαBβγ trimers joined together by numerous disulfide bonds. The heximer is transferred to the Golgi where it is glycosylated, hydroxylated, sulfated, and phosphorylated to form the mature fibrinogen glycoprotein that is secreted into the blood. Mature fibrinogen is arranged as a long flexible protein array of three nodules held together by a very thin thread which is estimated to have a diameter between 8 and 15 Angstrom (Å). The two end nodules (termed D regions or domains) are alike in consisting of Bβ and γ chains while the center slightly smaller nodule (termed the E region or domain) consists of two intertwined Aα alpha chains. Measurements of shadow lengths indicate that nodule diameters are in the range 50 to 70 Å. The length of the dried molecule is 475 ± 25 Å.
The fibrinogen molecule circulates as a soluble plasma glycoprotein with a typical molecular weight (depending on its content of Aα verses AαE and γ versus γ' chains) of ~340 kDa. It has a rod-like shape with dimensions of 9 × 47.5 × 6 nm and has a negative net charge at physiological pH ( its isoelectric point is pH 5.8). The normal concentration of fibrinogen in blood plasma is 150–400 mg/dL with levels appreciably below or above this range associated with pathological bleeding and/or thrombosis. Fibrinogen has a circulating half-life of ~4 days.
# Blood clot formation
During blood clotting, thrombin attacks the N-terminus of the Aα and Bβ chains in fibrinogen to form individual fibrin strands plus two small polypeptides, fibrinopeptides a and b derived from these respective chains. The individual fibrin strands then polymerize and are cross-linked with other fibrin stands by blood factor XIIIa to form an extensive interconnected fibrin network that is the basis for the formation of a mature fibrin clot. In addition to forming fibrin, fibrinogen also promotes blood clotting by forming bridges between, and activating, blood platelets through binding to their GpIIb/IIIa surface membrane fibrinogen receptor.
Fibrin participates in limiting blood clot formation and lysing formed blood clots by at least two important mechanisms. First, it possesses three low affinity binding sites (two in fibrin's E domain; one in its D domain) for thrombin; this binding sequesters thrombin from attacking fibrinogen. Second, fibrin's Aα chain accelerates by at least 100-fold the mount of plasmin activated by tissue plasminogen activator; plasmin breaks-down blood clots. Plasmin's attack on fibrin releases D-dimers (also termed DD dimers). The detection of these dimers in blood is used as a clinical test for fibrinolysis.
# Fibrinogen disorders
Several disorders in the quantity and/or quality of fibrinogen cause pathological bleeding, pathological blood clotting, and/or the deposition of fibrinogen in the liver, kidneys, and other tissues. The following list of these disorders briefly describes and compares them and gives linkages to main article Wikipedia pages that offer more complete descriptions.
## Congenital afibrinogenemia
Congenital afibrinogenemia is a rare and generally autosomal recessive inherited disorder in which blood does not clot due to a lack of fibrinogen (plasma fibrinogen levels typically 0 but sometimes detected at extremely low levels, e.g. <10 mg/dL. This severe disorder is usually caused by mutations in both the maternal and paternal copies of either the FGA, FGB, or FBG gene. The mutations have virtually complete genetic penetrance with essentially all homozygous bearers experiencing frequent and sometimes life-threatening episodes of bleeding and/or thrombosis. Pathological bleeding occurs early in life, for example often being seen at birth with excessive hemorrhage from the umbilicus.
## Congenital hypofibrinogenemia
Congenital hypofibrinogenemia is a rare inherited disorder in which blood may not clot normally due to reduced levels of fibrinogen (plasma fibrinogen typically 50 mg/dL). The disorder reflects a disruptive mutation in only one of the two parental FGA, FGB, or FBG genes and has a low degree of genetic penetrance, i.e. only some family members with the defective gene ever exhibit symptoms. Symptoms of the disorder, which more often occurs in individuals with lower plasma fibrinogen levels include episodic bleeding and thrombosis that typically begin in late childhood or adulthood.
## Fibrinogen storage disease
Fibringogen storage disease is a extremely rare disorder. It is a form of congenital hypofibrinogenemia in which certain specific hereditary mutations in one copy of the FGG gene causes its fibrinogen product to accumulate in, and damage, liver cells. The disorder has not reported with FGA or FGB mutations. Symptoms of these FGG mutations have a low level of penetrance. The plasma fibrinogen levels (generally 50 mg/dL) detected in this disorder reflect the fibrinogen made by the normal gene. Fibrinogen storage disease may lead to abnormal bleeding and thrombosis but is distinguished by also sometimes leading to liver cirrhosis.
## Congenital dysfibrinogenemia
Congenital dysfibrinogenemia is a rare autosomal dominant inherited disorder in which plasma fibrinogen is composed of a dysfunctional fibrinogen made by a mutated FGA, FGB, or FBG gene inherited from one parent plus a normal fibrinogen made by a normal gene inherited from the other parent. As a reflection of this duality, plasma fibrinogen levels measured by immunological methods are normal (>150 mg/dL) but are c. 50% lower when measured by clot formation methods. The disorder exhibits reduced penetrance with only some individuals with the abnormal gene showing symptoms of abnormal bleeding and thrombosis.
## Hereditary fibrinogen Aα-Chain amyloidosis
Hereditary fibrinogen Aα-Chain amyloidosis is an autosomal dominant extremely rare inherited disorder caused by a mutation in one of the two copies of the FGA gene. It is a form of congenital dysfibrinogenemia in which certain mutations lead to the production of an abnormal fibrinogen that circulates in the blood while gradually accumulating in the kidney. This accumulation leads over time to one form of familial renal amyloidosis. Plasma fibrinogen levels are similar to that seen in other forms of congenital dysfibrinogenemia. Fibrinogen Aα-Chain amyloidosis has not associated with abnormal bleeding or thrombosis.
## Acquired dysfibrinogenemia
Acquired dysfibrinogenemia is a rare disorder in which circulating fibrinogen is composed at least in part of a dysfunctional fibrinogen due to various acquired diseases. One well-studied cause of the disorder is severe liver disease including hepatoma, chronic active hepatitis, cirrhosis, and jaundice due to biliary tract obstruction. The diseased liver synthesizes a fibrinogen which has a normally functional amino acid sequence but is incorrectly glycosylated (i.e. has a wrong amount of sugar residues) added to it during its passage through the Golgi. The incorrectly glycosalated fibrinogen is dysfunctional and may cause pathological episodes of bleeding and/or blood clotting. Other, less well understood, causes are plasma cell dyscrasias and autoimmune disorders in which a circulating abnormal immunoglobulin or other protein interferes with fibrinogen function, and rare cases of cancer and medication (isotretinoin, glucocorticoids, and antileukemic drugs) toxicities.
## Congenital hypodysfibrinogenemia
Congenital hypodysfibrinogenemia is a rare inherited disorder in which low levels (i.e. <150 mg/d) of immunologically detected plasma fibrinogen are and composed at least in part of a dysfunctional fibrinogen. The disorder reflects mutations typically in both inherited fibrinogen genes one of which produces a dysfunctional fibrinogen while the other produces low amounts of fibrinogen. The disorder, while having reduced penetrance is usually more severe that congenital dysfibrinogenemia but like the latter disorder causes pathological episodes of bleeding and/or blood clotting.
## Cryofibrinogenemia
Cryofibrinogenemia is an acquired disorder in which fibrinogen precipitates at cold temperatures and may lead to the intravascular precipitation of fibrinogen, fibrin, and other circulating proteins thereby causing the infarction of various tissues and bodily extremities. Cryoglobulonemia may occur without evidence of an underlying associated disorders, i.e. primary cryoglobulinemia (also termed essential cryoglobulinemia) or, far more commonly, with evidence of an underlying disease, i.e. secondary cryoglobulonemia. Secondary cryofibrinoenemia can develop in individuals suffering infection (c. 12% of cases), malignant or premalignant disorders (21%), vasculitis (25%), and autoimmune diseases (42%). In these cases, cryofibinogenema may or may not cause tissue injury and/or other symptoms and the actual cause-effect relationship between these diseases and the development of cryofibrinogenmia is unclear. Cryofibrinogenemia can also occur in association with the intake of certain drugs.
## Acquired hypofibrinogenemia
Acquired hypofibrinogenemia is a deficiency in circulating fibrinogen due to excessive consumption that may occur as a result of trauma, certain phases of disseminated intravascular coagulation, and sepsis. It may also occur as a result of hemodilution as a result of blood losses and/or transfusions with packed red blood cells or other fibrinogen-poor whole blood replacements.
# Laboratory Tests
Clinical analyses of the fibrinogen disorders typically measure blood clotting using the following successive steps: Higher levels are, amongst others, associated with cardiovascular disease (>3.43 g/L). It may be elevated in any form of inflammation, as it is an acute-phase protein; for example, it is especially apparent in human gingival tissue during the initial phase of periodontal disease.
- Blood clotting is measured using standard tests, e.g. prothrombin time, partial thromboplastin time, thrombin time, and/or reptilase time; low fibrinogen levels and dysfunctional fibrinogens usually prolong these times whereas the lack of fibrinogen (i.e. afibrinogenemia) renders these times infinitely prolonged.
- Antigenic levels of fibrinogen levels are measured in the plasma isolated from venous blood by immunoassays with normal levels being about 1.5-3 gram/liter, depending on the method used. These levels are normal in dysfibrinogenmia (i.e. 1.5-3 gram/liter), decreased in hypofibrinogenemia and hypdysfibrinogenemia (i.e. <1.5 gram/liter), and absent (i.e. <0.02 gram/liter) in afibrinogenima.
- Functional levels of fibrinogen are measured on plasma induced to clot. The levels of clotted fibrinogen in this test should be decreased in hypofibrinogenemia, hypodysfibrinogenemia, and dysfibrinogenemia and undetectable in afibrinogenemia.
- Functional fibrinogen/antigenic fibrinogen levels are <0.7 in hypofibrinogenemia, hypodsyfibrinogenemia, and dysfibringognemia and not applicable in afibringenemia.
- Fibrinogen analysis can also be tested on whole-blood samples by thromboelastometry. This analysis investigates the interaction of coagulation factors, their inhibitors, anticoagulant drugs, blood cells, specifically platelets, during clotting and subsequent fibrinolysis as it occurs in whole blood. The test provides information on hemostatic efficacy and maximum clod firmness to give additional information on fibrin-platelet interactions and the rate of fibrinolysis (see Thromboelastometry).
- Scanning electron microscopy and confocal laser scanning microscopy of in vitro-formed clots can give information on fibrin clot density and architecture.
- The fibrinogen uptake test or fibrinogen scan was formerly used to detect deep vein thrombosis. In this method, radioactively labeled fibrinogen, typically with radioiodine, is given to individuals, incorporated into a thrombus, and detected by scintigraphy.
# Hyperfibrinogenemia
Levels of functionally normal fibrinogen increase in pregnancy to an average of 4.5 gram/liter compared to an average of 3 g/l in non-pregnant people. They may also increase in various forms of cancer, particularly gastric, lung, prostate, and ovarian cancers. In these cases, the hyperfibrinogenemia may contribute to the development of pathological thrombosis. A particular pattern of migratory superficial vein thrombosis, termed trousseau's syndrome, occurs in, and may precede all other signs and symptoms of, these cancers. Hyperfibrinogenemia has also been linked as a cause of persistent pulmonary hypertension of the newborn and post-operative thrombosis. High fibrinogen levels had been proposed as a predictor of hemorrhagic complications during catheter-directed trombolysis for acute or subacute peripheral native artery and arterial bypass occlusions. However, a systematic review of the available literature until January 2016 found that the predictive value of plasma fibrinogen level for predicting hemorrhagic complications after catheter-directed thrombolysis is unproven. | Fibrinogen
Fibrinogen (factor I) is a glycoprotein that circulates in the blood of vertebrates. During tissue and vascular injury it is converted enzymatically by thrombin to fibrin and subsequently to a fibrin-based blood clot. Fibrinogen functions primarily to occlude blood vessels and thereby stop excessive bleeding. However, fibrinogen's product, fibrin, binds and reduces the activity of thrombin. This activity, sometimes referred to as antithrombin I, serves to limit blood clotting. Loss or reduction in this antithrombin 1 activity due to mutations in fibrinogen genes or hypo-fibrinogen conditions can lead to excessive blood clotting and thrombosis.[2] Fibrin also mediates blood platelet and endothelial cell spreading, tissue fibroblast proliferation, capillary tube formation, and angiogenesis and thereby functions to promote tissue revascularization, wound healing, and tissue repair.[3]
Reduced and/or dysfunctional fibrinogens occur in various congenital and acquired human fibrinogen-related disorders. These disorders represent a clinically important group of rare conditions in which individuals may present with severe episodes of pathological bleeding and thrombosis; these conditions are treated by supplementing blood fibrinogen levels and inhibiting blood clotting, respectively.[4][5] Certain of these disorders may also be the cause of liver and kidney diseases.[2]
Fibrinogen is a "positive" acute-phase protein, i.e. its blood levels rise in response to systemic inflammation, tissue injury, and certain other events. It is also elevated in various cancers. Elevated levels of fibrinogen in inflammation as well as cancer and other conditions have been suggested to be the cause of thrombosis and vascular injury that accompanies these conditions.[6][7]
# Genes
Fibrinogen is made and secreted into the blood primarily by liver hepatocyte cells. Endothelium cells are also reported to make what appears to be small amounts of fibrinogen but this fibrinogen has not been fully characterized; blood platelets and their precursors, bone marrow megakaryocytes, while once thought to make fibrinogen, are now known to take up and store but not make the glycoprotein.[4][7] The final secreted, hepatocyte-derived glycoprotein is composed of two trimers with each trimer composed of three different polypeptide chains, the fibrinogen alpha chain (also termed the Aα or α chain) encoded by the FGA gene, the fibrinogen beta chain (also termed the Bβ or β chain) encoded by the FGB gene, and the fibrinogen gamma chain (also termed the γ chain) encoded by the FGG gene. All three genes are located on the long or "p" arm of human chromosome 4 (at positions 4q31.3, 4q31.3, and 4q32.1, respectively).[2] Alternate splicing of the FGA gene produces a minor expanded isoform of Aα termed AαE which replaces Aα in 1–3% of circulating fibrinogen; alternate splicing of FGG produces a minor isoform of γ termed γ' which replaces γ in 8–10% of circulating fibrinogen; FGA is not alternatively spliced. Hence, the final fibrinogen product is composed principally of Aα, Bβ, and γ chains with a small percentage of it containing AαE and/or γ' chains in place of Aα and/or γ chains, respectively. The three genes are transcribed and translated in co-ordination by a mechanism(s) which remains incompletely understood.[8][9][10][11][12] The coordinated transcription of these three fibrinogen genes is rapidly and greatly increased by systemic conditions such as inflammation and tissue injury. Cytokines produced during these systemic conditions, such as interleukin 6 and interleukin 1β, appear responsible for up-regulating this transcription.[11]
# Structure
The Aα, Bβ, and γ chains are transcribed and translated coordinately on the endoplasmic reticulum (ER) with their peptide chains being passed into the ER while their signal peptide portions are removed. Inside the ER, the three chains are assembled initially into Aαγ and Bβγ dimers, then to AαBβγ trimers, and finally to (AαBβγ)2 heximers, i.e. two AαBβγ trimers joined together by numerous disulfide bonds. The heximer is transferred to the Golgi where it is glycosylated, hydroxylated, sulfated, and phosphorylated to form the mature fibrinogen glycoprotein that is secreted into the blood.[10][12] Mature fibrinogen is arranged as a long flexible protein array of three nodules held together by a very thin thread which is estimated to have a diameter between 8 and 15 Angstrom (Å). The two end nodules (termed D regions or domains) are alike in consisting of Bβ and γ chains while the center slightly smaller nodule (termed the E region or domain) consists of two intertwined Aα alpha chains. Measurements of shadow lengths indicate that nodule diameters are in the range 50 to 70 Å. The length of the dried molecule is 475 ± 25 Å.[13]
The fibrinogen molecule circulates as a soluble plasma glycoprotein with a typical molecular weight (depending on its content of Aα verses AαE and γ versus γ' chains) of ~340 kDa. It has a rod-like shape with dimensions of 9 × 47.5 × 6 nm and has a negative net charge at physiological pH ( its isoelectric point is pH 5.8).[14][15] The normal concentration of fibrinogen in blood plasma is 150–400 mg/dL with levels appreciably below or above this range associated with pathological bleeding and/or thrombosis. Fibrinogen has a circulating half-life of ~4 days.[12]
# Blood clot formation
During blood clotting, thrombin attacks the N-terminus of the Aα and Bβ chains in fibrinogen to form individual fibrin strands plus two small polypeptides, fibrinopeptides a and b derived from these respective chains. The individual fibrin strands then polymerize and are cross-linked with other fibrin stands by blood factor XIIIa to form an extensive interconnected fibrin network that is the basis for the formation of a mature fibrin clot.[3][7][16] In addition to forming fibrin, fibrinogen also promotes blood clotting by forming bridges between, and activating, blood platelets through binding to their GpIIb/IIIa surface membrane fibrinogen receptor.[16]
Fibrin participates in limiting blood clot formation and lysing formed blood clots by at least two important mechanisms. First, it possesses three low affinity binding sites (two in fibrin's E domain; one in its D domain) for thrombin; this binding sequesters thrombin from attacking fibrinogen.[16] Second, fibrin's Aα chain accelerates by at least 100-fold the mount of plasmin activated by tissue plasminogen activator; plasmin breaks-down blood clots.[5][16][3][7] Plasmin's attack on fibrin releases D-dimers (also termed DD dimers). The detection of these dimers in blood is used as a clinical test for fibrinolysis.[5]
# Fibrinogen disorders
Several disorders in the quantity and/or quality of fibrinogen cause pathological bleeding, pathological blood clotting, and/or the deposition of fibrinogen in the liver, kidneys, and other tissues. The following list of these disorders briefly describes and compares them and gives linkages to main article Wikipedia pages that offer more complete descriptions.
## Congenital afibrinogenemia
Congenital afibrinogenemia is a rare and generally autosomal recessive inherited disorder in which blood does not clot due to a lack of fibrinogen (plasma fibrinogen levels typically 0 but sometimes detected at extremely low levels, e.g. <10 mg/dL. This severe disorder is usually caused by mutations in both the maternal and paternal copies of either the FGA, FGB, or FBG gene. The mutations have virtually complete genetic penetrance with essentially all homozygous bearers experiencing frequent and sometimes life-threatening episodes of bleeding and/or thrombosis. Pathological bleeding occurs early in life, for example often being seen at birth with excessive hemorrhage from the umbilicus.[4]
## Congenital hypofibrinogenemia
Congenital hypofibrinogenemia is a rare inherited disorder in which blood may not clot normally due to reduced levels of fibrinogen (plasma fibrinogen typically <150 but >50 mg/dL). The disorder reflects a disruptive mutation in only one of the two parental FGA, FGB, or FBG genes and has a low degree of genetic penetrance, i.e. only some family members with the defective gene ever exhibit symptoms. Symptoms of the disorder, which more often occurs in individuals with lower plasma fibrinogen levels include episodic bleeding and thrombosis that typically begin in late childhood or adulthood.[4]
## Fibrinogen storage disease
Fibringogen storage disease is a extremely rare disorder. It is a form of congenital hypofibrinogenemia in which certain specific hereditary mutations in one copy of the FGG gene causes its fibrinogen product to accumulate in, and damage, liver cells. The disorder has not reported with FGA or FGB mutations. Symptoms of these FGG mutations have a low level of penetrance. The plasma fibrinogen levels (generally <150 but >50 mg/dL) detected in this disorder reflect the fibrinogen made by the normal gene. Fibrinogen storage disease may lead to abnormal bleeding and thrombosis but is distinguished by also sometimes leading to liver cirrhosis.[17]
## Congenital dysfibrinogenemia
Congenital dysfibrinogenemia is a rare autosomal dominant inherited disorder in which plasma fibrinogen is composed of a dysfunctional fibrinogen made by a mutated FGA, FGB, or FBG gene inherited from one parent plus a normal fibrinogen made by a normal gene inherited from the other parent. As a reflection of this duality, plasma fibrinogen levels measured by immunological methods are normal (>150 mg/dL) but are c. 50% lower when measured by clot formation methods. The disorder exhibits reduced penetrance with only some individuals with the abnormal gene showing symptoms of abnormal bleeding and thrombosis.[18]
## Hereditary fibrinogen Aα-Chain amyloidosis
Hereditary fibrinogen Aα-Chain amyloidosis is an autosomal dominant extremely rare inherited disorder caused by a mutation in one of the two copies of the FGA gene. It is a form of congenital dysfibrinogenemia in which certain mutations lead to the production of an abnormal fibrinogen that circulates in the blood while gradually accumulating in the kidney. This accumulation leads over time to one form of familial renal amyloidosis. Plasma fibrinogen levels are similar to that seen in other forms of congenital dysfibrinogenemia. Fibrinogen Aα-Chain amyloidosis has not associated with abnormal bleeding or thrombosis.[19]
## Acquired dysfibrinogenemia
Acquired dysfibrinogenemia is a rare disorder in which circulating fibrinogen is composed at least in part of a dysfunctional fibrinogen due to various acquired diseases. One well-studied cause of the disorder is severe liver disease including hepatoma, chronic active hepatitis, cirrhosis, and jaundice due to biliary tract obstruction. The diseased liver synthesizes a fibrinogen which has a normally functional amino acid sequence but is incorrectly glycosylated (i.e. has a wrong amount of sugar residues) added to it during its passage through the Golgi. The incorrectly glycosalated fibrinogen is dysfunctional and may cause pathological episodes of bleeding and/or blood clotting. Other, less well understood, causes are plasma cell dyscrasias and autoimmune disorders in which a circulating abnormal immunoglobulin or other protein interferes with fibrinogen function, and rare cases of cancer and medication (isotretinoin, glucocorticoids, and antileukemic drugs) toxicities.[16]
## Congenital hypodysfibrinogenemia
Congenital hypodysfibrinogenemia is a rare inherited disorder in which low levels (i.e. <150 mg/d) of immunologically detected plasma fibrinogen are and composed at least in part of a dysfunctional fibrinogen. The disorder reflects mutations typically in both inherited fibrinogen genes one of which produces a dysfunctional fibrinogen while the other produces low amounts of fibrinogen. The disorder, while having reduced penetrance is usually more severe that congenital dysfibrinogenemia but like the latter disorder causes pathological episodes of bleeding and/or blood clotting.[20]
## Cryofibrinogenemia
Cryofibrinogenemia is an acquired disorder in which fibrinogen precipitates at cold temperatures and may lead to the intravascular precipitation of fibrinogen, fibrin, and other circulating proteins thereby causing the infarction of various tissues and bodily extremities. Cryoglobulonemia may occur without evidence of an underlying associated disorders, i.e. primary cryoglobulinemia (also termed essential cryoglobulinemia) or, far more commonly, with evidence of an underlying disease, i.e. secondary cryoglobulonemia. Secondary cryofibrinoenemia can develop in individuals suffering infection (c. 12% of cases), malignant or premalignant disorders (21%), vasculitis (25%), and autoimmune diseases (42%). In these cases, cryofibinogenema may or may not cause tissue injury and/or other symptoms and the actual cause-effect relationship between these diseases and the development of cryofibrinogenmia is unclear. Cryofibrinogenemia can also occur in association with the intake of certain drugs.[21][22][23][24]
## Acquired hypofibrinogenemia
Acquired hypofibrinogenemia is a deficiency in circulating fibrinogen due to excessive consumption that may occur as a result of trauma, certain phases of disseminated intravascular coagulation, and sepsis. It may also occur as a result of hemodilution as a result of blood losses and/or transfusions with packed red blood cells or other fibrinogen-poor whole blood replacements.[25]
# Laboratory Tests
Clinical analyses of the fibrinogen disorders typically measure blood clotting using the following successive steps:[26] Higher levels are, amongst others, associated with cardiovascular disease (>3.43 g/L). It may be elevated in any form of inflammation, as it is an acute-phase protein; for example, it is especially apparent in human gingival tissue during the initial phase of periodontal disease.[27][28]
- Blood clotting is measured using standard tests, e.g. prothrombin time, partial thromboplastin time, thrombin time, and/or reptilase time; low fibrinogen levels and dysfunctional fibrinogens usually prolong these times whereas the lack of fibrinogen (i.e. afibrinogenemia) renders these times infinitely prolonged.
- Antigenic levels of fibrinogen levels are measured in the plasma isolated from venous blood by immunoassays with normal levels being about 1.5-3 gram/liter, depending on the method used. These levels are normal in dysfibrinogenmia (i.e. 1.5-3 gram/liter), decreased in hypofibrinogenemia and hypdysfibrinogenemia (i.e. <1.5 gram/liter), and absent (i.e. <0.02 gram/liter) in afibrinogenima.
- Functional levels of fibrinogen are measured on plasma induced to clot. The levels of clotted fibrinogen in this test should be decreased in hypofibrinogenemia, hypodysfibrinogenemia, and dysfibrinogenemia and undetectable in afibrinogenemia.
- Functional fibrinogen/antigenic fibrinogen levels are <0.7 in hypofibrinogenemia, hypodsyfibrinogenemia, and dysfibringognemia and not applicable in afibringenemia.
- Fibrinogen analysis can also be tested on whole-blood samples by thromboelastometry. This analysis investigates the interaction of coagulation factors, their inhibitors, anticoagulant drugs, blood cells, specifically platelets, during clotting and subsequent fibrinolysis as it occurs in whole blood. The test provides information on hemostatic efficacy and maximum clod firmness to give additional information on fibrin-platelet interactions and the rate of fibrinolysis (see Thromboelastometry).
- Scanning electron microscopy and confocal laser scanning microscopy of in vitro-formed clots can give information on fibrin clot density and architecture.
- The fibrinogen uptake test or fibrinogen scan was formerly used to detect deep vein thrombosis. In this method, radioactively labeled fibrinogen, typically with radioiodine, is given to individuals, incorporated into a thrombus, and detected by scintigraphy.
# Hyperfibrinogenemia
Levels of functionally normal fibrinogen increase in pregnancy to an average of 4.5 gram/liter compared to an average of 3 g/l in non-pregnant people. They may also increase in various forms of cancer, particularly gastric, lung, prostate, and ovarian cancers. In these cases, the hyperfibrinogenemia may contribute to the development of pathological thrombosis. A particular pattern of migratory superficial vein thrombosis, termed trousseau's syndrome, occurs in, and may precede all other signs and symptoms of, these cancers.[7][29] Hyperfibrinogenemia has also been linked as a cause of persistent pulmonary hypertension of the newborn[30] and post-operative thrombosis.[31] High fibrinogen levels had been proposed as a predictor of hemorrhagic complications during catheter-directed trombolysis for acute or subacute peripheral native artery and arterial bypass occlusions.[32] However, a systematic review of the available literature until January 2016 found that the predictive value of plasma fibrinogen level for predicting hemorrhagic complications after catheter-directed thrombolysis is unproven.[33] | https://www.wikidoc.org/index.php/Ddx:Fibrinogen | |
85772e1be1c01cbdc0faaf999eaa3154165e8e74 | wikidoc | Hematocrit | Hematocrit
# Overview
The hematocrit (Ht or HCT) and packed cell volume (PCV) are measures of the proportion of blood volume that is occupied by red blood cells. It is normally 45 ± 7 (38-52%) for males and 42 ± 5 (37-47%) for females.
The packed cell volume can be determined by centrifuging. Heparinized blood in a capillary tube (also known as a microhematocrit tube) is typically centrifuged at 10,000 RPM for five minutes. This separates the blood into layers. The volume of packed red blood cells, divided by the total volume of the blood sample gives the PCV. Because a tube is used this can be calculated by measuring the lengths of the layers.
With modern lab equipment the hematocrit is calculated by an automated analyzer and not directly measured. It is determined by multiplying the red cell count by the mean cell volume. The hematocrit is slightly more accurate as the PCV includes small amounts of blood plasma trapped between the red cells. An estimated hematocrit as a percentage may be derived by multiplying the hemoglobin concentration in g/dL times three and dropping the units. . The hemoglobin level is the measure used by blood banks.
The hematocrit is considered an integral part of a person's complete blood count or CBC results along with the hemoglobin concentration, white blood cell count, and platelet count.
There have been cases where the blood for testing was inadvertently drawn from the same arm with the intravenous line running in a transfusion of packed red cells. In this sample, the hemoglobin measurement will be high because it is measuring the fluid being transfused (that is, mostly red cells) rather than the diluted serum. In this case, the hematocrit measurement will be artificially very high.
Conversely, if blood for hematology testing is drawn from a site proximal to that of an intravenous line infusing fluids into a patient, the blood sample will be diluted by those fluids and the hematocrit will be artificially low.
If a patient is dehydrated, the hematocrit may be elevated. Repeat testing after adequate hydration therapy will usually result in a more reliable result.
In mammals, hematocrit is independent of body size.
# Elevated hematocrit
In cases of dengue fever, where the full blood count is done daily, a high hematocrit is a danger sign of an increased risk of dengue shock syndrome.
Polycythemia vera (PV) is associated with elevated hematocrit. PV is a myeloproliferative disorder in which the bone marrow produces excessive numbers of red cells, and reflects excessive numbers of RBC precursors in the bone marrow, as well as some abnormal forms. This condition is called erythroid hyperplasia. Excessive production of both RBCs and WBCs is called bilineage hyperplasia, and if there are excessive numbers of platelets also, trilineage hyperplasia. If PV is present, it is not uncommon to see the serum uric acid level elevated, reflecting an increase in the rate of cell turnover, reflecting increased pyridine metabolism.
Another myeloproliferative disorder is called essential thrombocythemia, in which primarily the platelets are elevated in number.
Chronic obstructive pulmonary disease (COPD) and other pulmonary conditions associated with hypoxia may elicit an increased production of red blood cells. This increase is mediated by the increased levels of erythropoietin by the kidneys in response to hypoxia.
# Lowered hematocrit
Lowered hematocrit can imply significant hemorrhage (for example, in an ectopic pregnancy.)
The mean corpuscular volume (MCV) and the red cell distribution width (RDW) can be quite helpful in evaluating a lower-than-normal hematocrit, because it can help the clinician determine whether blood loss is chronic or acute. The MCV is the size of the red cells and the RDW is a relative measure of the variation in size of the red cell population. A low hematocrit with a low MCV with a high RDW suggests a chronic iron-deficient erythropoiesis, but a normal RDW suggests a blood loss that is more acute, such as a hemorrhage. | Hematocrit
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
The hematocrit (Ht or HCT) and packed cell volume (PCV) are measures of the proportion of blood volume that is occupied by red blood cells. It is normally 45 ± 7 (38-52%) for males and 42 ± 5 (37-47%) for females.
The packed cell volume can be determined by centrifuging. Heparinized blood in a capillary tube (also known as a microhematocrit tube) is typically centrifuged at 10,000 RPM for five minutes. [2] This separates the blood into layers. The volume of packed red blood cells, divided by the total volume of the blood sample gives the PCV. Because a tube is used this can be calculated by measuring the lengths of the layers.
With modern lab equipment the hematocrit is calculated by an automated analyzer and not directly measured. It is determined by multiplying the red cell count by the mean cell volume. The hematocrit is slightly more accurate as the PCV includes small amounts of blood plasma trapped between the red cells. An estimated hematocrit as a percentage may be derived by multiplying the hemoglobin concentration in g/dL times three and dropping the units. [3]. The hemoglobin level is the measure used by blood banks.
The hematocrit is considered an integral part of a person's complete blood count or CBC results along with the hemoglobin concentration, white blood cell count, and platelet count.
There have been cases where the blood for testing was inadvertently drawn from the same arm with the intravenous line running in a transfusion of packed red cells. In this sample, the hemoglobin measurement will be high because it is measuring the fluid being transfused (that is, mostly red cells) rather than the diluted serum. In this case, the hematocrit measurement will be artificially very high.
Conversely, if blood for hematology testing is drawn from a site proximal to that of an intravenous line infusing fluids into a patient, the blood sample will be diluted by those fluids and the hematocrit will be artificially low.
If a patient is dehydrated, the hematocrit may be elevated. Repeat testing after adequate hydration therapy will usually result in a more reliable result.
In mammals, hematocrit is independent of body size.
# Elevated hematocrit
In cases of dengue fever, where the full blood count is done daily, a high hematocrit is a danger sign of an increased risk of dengue shock syndrome.
Polycythemia vera (PV) is associated with elevated hematocrit. PV is a myeloproliferative disorder in which the bone marrow produces excessive numbers of red cells, and reflects excessive numbers of RBC precursors in the bone marrow, as well as some abnormal forms. This condition is called erythroid hyperplasia. Excessive production of both RBCs and WBCs is called bilineage hyperplasia, and if there are excessive numbers of platelets also, trilineage hyperplasia. If PV is present, it is not uncommon to see the serum uric acid level elevated, reflecting an increase in the rate of cell turnover, reflecting increased pyridine metabolism.
Another myeloproliferative disorder is called essential thrombocythemia, in which primarily the platelets are elevated in number.
Chronic obstructive pulmonary disease (COPD) and other pulmonary conditions associated with hypoxia may elicit an increased production of red blood cells. This increase is mediated by the increased levels of erythropoietin by the kidneys in response to hypoxia.
# Lowered hematocrit
Lowered hematocrit can imply significant hemorrhage (for example, in an ectopic pregnancy.)
The mean corpuscular volume (MCV) and the red cell distribution width (RDW) can be quite helpful in evaluating a lower-than-normal hematocrit, because it can help the clinician determine whether blood loss is chronic or acute. The MCV is the size of the red cells and the RDW is a relative measure of the variation in size of the red cell population. A low hematocrit with a low MCV with a high RDW suggests a chronic iron-deficient erythropoiesis, but a normal RDW suggests a blood loss that is more acute, such as a hemorrhage. | https://www.wikidoc.org/index.php/Ddx:Hematocrit | |
429f1e41c7a9dc3b87a16dc5e5709bb38f974b55 | wikidoc | Nyctalopia | Nyctalopia
Synonyms and related keywords: nocturnal amblyopia, night blindness.
Nyctalopia (Greek for "night blindness") is a condition making it difficult or impossible to see in relatively low light. It is a symptom of several eye diseases. Night blindness may exist from birth, or be caused by injury or malnutrition (for example, a lack of vitamin A).
The most common cause of nyctalopia is retinitis pigmentosa, a disorder in which the rod cells in the retina gradually lose their ability to respond to the light. Patients suffering from this genetic condition have progressive nyctalopia and eventually their daytime vision may also be affected. In X-linked congenital stationary night blindness, from birth the rods either do not work at all, or work very little, but the condition doesn't get worse.
Another cause of night blindness is a deficiency of retinol, or vitamin A, found in fish oils, liver and dairy products. In the Second World War misinformation was spread by the British to cover up the reason for their pilots' successful night time missions. Their success was, in the misinformation, attributed to improved night vision and pilots flying night missions were encouraged to eat plenty of carrots, which contain carotenoids and can be converted into retinol. The actual reason for their success was their use of advanced radar technologies.
The opposite problem, known as hemeralopia, is much rarer.
The outer area of the retina is made up of more rods than cones. The rod cells are the cells that enable us to see in poor illumination. This is the reason why loss of side vision often results in night blindness. Individuals suffering from night blindness not only see poorly at night, but also require some time for their eyes to adjust from brightly lit areas to dim ones. Contrast vision may also be greatly reduced.
## Historical usage
Aulus Cornelius Celsus, writing ca. 30 AD, described night blindness and recommended an effective dietary supplement: "There is besides a weakness of the eyes, owing to which people see well enough indeed in the daytime but not at all at night; in women whose menstruation is regular this does not happen. But success sufferers should anoint their eyeballs with the stuff dripping from a liver whilst roasting, preferably of a he-goat, or failing that of a she-goat; and as well they should eat some of the liver itself."
Historically, nyctalopia, also known as moonblink, was a temporary night blindness believed to be caused by sleeping in moonlight in the tropics.
# Differential Diagnosis of Causes of Nyctalopia
Causes
- Albinism
- Cataracts
- Cirrhosis
- Glaucoma
- Gyrate atrophy
- Hereditary
- Hypoxia
- Laurence-Moon-Biedl Syndrome
- Oguchi's Disease
- Optic atrophy
- Peripheral Chorioretinitis
- Retinitis Pigmentosa
- Siderosis retinae
- Uncorrected myopia
- Vitamin A deficiency
- Zinc deficiency | Nyctalopia
Template:DiseaseDisorder infobox
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Synonyms and related keywords: nocturnal amblyopia, night blindness.
Nyctalopia (Greek for "night blindness") is a condition making it difficult or impossible to see in relatively low light. It is a symptom of several eye diseases. Night blindness may exist from birth, or be caused by injury or malnutrition (for example, a lack of vitamin A).
The most common cause of nyctalopia is retinitis pigmentosa, a disorder in which the rod cells in the retina gradually lose their ability to respond to the light. Patients suffering from this genetic condition have progressive nyctalopia and eventually their daytime vision may also be affected. In X-linked congenital stationary night blindness, from birth the rods either do not work at all, or work very little, but the condition doesn't get worse.
Another cause of night blindness is a deficiency of retinol, or vitamin A, found in fish oils, liver and dairy products. In the Second World War misinformation was spread by the British to cover up the reason for their pilots' successful night time missions. Their success was, in the misinformation, attributed to improved night vision and pilots flying night missions were encouraged to eat plenty of carrots, which contain carotenoids and can be converted into retinol. The actual reason for their success was their use of advanced radar technologies.
The opposite problem, known as hemeralopia, is much rarer.
The outer area of the retina is made up of more rods than cones. The rod cells are the cells that enable us to see in poor illumination. This is the reason why loss of side vision often results in night blindness. Individuals suffering from night blindness not only see poorly at night, but also require some time for their eyes to adjust from brightly lit areas to dim ones. Contrast vision may also be greatly reduced.
## Historical usage
Aulus Cornelius Celsus, writing ca. 30 AD, described night blindness and recommended an effective dietary supplement: "There is besides a weakness of the eyes, owing to which people see well enough indeed in the daytime but not at all at night; in women whose menstruation is regular this does not happen. But success sufferers should anoint their eyeballs with the stuff dripping from a liver whilst roasting, preferably of a he-goat, or failing that of a she-goat; and as well they should eat some of the liver itself."
Historically, nyctalopia, also known as moonblink, was a temporary night blindness believed to be caused by sleeping in moonlight in the tropics.[1]
# Differential Diagnosis of Causes of Nyctalopia
Causes
- Albinism
- Cataracts
- Cirrhosis
- Glaucoma
- Gyrate atrophy
- Hereditary
- Hypoxia
- Laurence-Moon-Biedl Syndrome
- Oguchi's Disease
- Optic atrophy
- Peripheral Chorioretinitis
- Retinitis Pigmentosa
- Siderosis retinae
- Uncorrected myopia
- Vitamin A deficiency
- Zinc deficiency [2] [3] | https://www.wikidoc.org/index.php/Ddx:Night_Blindness | |
cd86d05427cd8cf23a9dd36d76fbf25b999fd001 | wikidoc | Overeating | Overeating
# Overview
Overeating is a behavior that, while generally not a medical problem, in some cases is a symptom of binge eating disorder or bulimia. In more general terms it refers to the persistent consumption of excess food in relation to the energy that the person expends, leading to weight gain and often to obesity. This may be a brief or short term process (many people overindulge generally during festivities or while on holiday) or a longer term process.
# Causes
Overeating has been linked to the use of medications known as dopamine agonists, such as pramipexole.
# Treatment
One organization that helps over eaters is Overeaters Anonymous, which operates a 12-step program.
# Related Chapters
- Binge eating
- Addiction | Overeating
Template:Search infobox
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Overeating is a behavior that, while generally not a medical problem, in some cases is a symptom of binge eating disorder or bulimia. In more general terms it refers to the persistent consumption of excess food in relation to the energy that the person expends, leading to weight gain and often to obesity. This may be a brief or short term process (many people overindulge generally during festivities or while on holiday) or a longer term process.
# Causes
Overeating has been linked to the use of medications known as dopamine agonists, such as pramipexole.
# Treatment
One organization that helps over eaters is Overeaters Anonymous, which operates a 12-step program.
# Related Chapters
- Binge eating
- Addiction | https://www.wikidoc.org/index.php/Ddx:Overeating | |
f7efe2d91b1605f3ce55e115eee80398fd1b349b | wikidoc | Paraplegia | Paraplegia
# Overview
Paraplegia is an impairment in motor and/or sensory function of the lower extremities. It is usually the result of spinal cord injury or a congenital condition such as spina bifida which affects the neural elements of the spinal canal. The area of the spinal canal which is affected in paraplegia is either the thoracic, lumbar, or sacral regions. If the arms are also affected by paralysis, quadriplegia is the proper terminology.
# Causes
The causes range from trauma (acute spinal cord injury: transsection or compression of the cord, usually by bone fragments from vertebral fractures) to tumors (chronic compression of the cord), myelitis transversa and multiple sclerosis.
## Central Nervous System (CNS)
Any disease process affecting the corticospinal or pyrimidal tracts of the spinal cord from the thoracic spine downward may lead to paraplegia. These tracts are responsible for movement or the "instructions" for movement from the brain to the anterior horncells respectively. The most common cause of paraplegis (and all spinal cord injuries) is motor vehicle accidents. Other causes include violence, sports, cancer (tumors) involving the epidural or dural space, vertebral fractures) and transverse myelitis. Gunshot wounds to the spine, although decreasing, are one of the major causes of paraplegic spinal cord injuries (for instance, Ron Kovic, author of Born on the Fourth of July, is a paraplegic as a result of a gunshot wound suffered in the Vietnam War). Sometimes, paralysis of both legs can result from injury to the brain (bilateral injury of the motor cortex controlling the legs, e.g. due to a stroke or a brain tumor).
## Peripheral nervous system
Rarer is the type which is caused by damage to the nerves supplying the legs. This form of damage is not usually symmetrical and would not cause paraplegia, but polyneuropathy may cause paraplegia if motor fibres are affected. While in theory the arms should also be affected, the fibres that supply the legs are longer and hence more vulnerable to damage.
## Drug Causes
- Cladribine
- Epidural injection of Dexamethasone
- Cytarabine
# Disability
While some people with paraplegia can walk to a degree, many are dependent on wheelchairs or other supportive measures. Impotence and various degrees of urinary and fecal incontinence are very common in those affected. Many use catheters and/or a bowel management program (often involving suppositories, enemas, or digital stimulation of the bowels) to address these problems. With successful bladder and bowel management, paraplegics can virtually prevent all accidental urinary or bowel discharges; it is however another option for the patient to wear undergarments such as diapers to further protect from bladder or fecal incontinence. Some prefer diapers for the comfort level they provide.
# Complications
Due to decreased movement and loss of the ability to run, paraplegia may cause numerous medical complications, many of which can be prevented with vigilant self care. These include pressure sores (decubitus), thrombosis and pneumonia. Physiotherapy and various assistive technology, such as a standing frame, may aid in preventing these complications.
# Treatment
## Paraplegia physical therapy
# Support organizations
- Back-Up Trust
- Spinal Cord Injury Peer Support
- Spinal Cord Injury Support
- Canadian Paraplegic Association | Paraplegia
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Paraplegia is an impairment in motor and/or sensory function of the lower extremities. It is usually the result of spinal cord injury or a congenital condition such as spina bifida which affects the neural elements of the spinal canal. The area of the spinal canal which is affected in paraplegia is either the thoracic, lumbar, or sacral regions. If the arms are also affected by paralysis, quadriplegia is the proper terminology.
# Causes
The causes range from trauma (acute spinal cord injury: transsection or compression of the cord, usually by bone fragments from vertebral fractures) to tumors (chronic compression of the cord), myelitis transversa and multiple sclerosis.
## Central Nervous System (CNS)
Any disease process affecting the corticospinal or pyrimidal tracts of the spinal cord from the thoracic spine downward may lead to paraplegia. These tracts are responsible for movement or the "instructions" for movement from the brain to the anterior horncells respectively. The most common cause of paraplegis (and all spinal cord injuries) is motor vehicle accidents. Other causes include violence, sports, cancer (tumors) involving the epidural or dural space, vertebral fractures) and transverse myelitis. Gunshot wounds to the spine, although decreasing, are one of the major causes of paraplegic spinal cord injuries (for instance, Ron Kovic, author of Born on the Fourth of July, is a paraplegic as a result of a gunshot wound suffered in the Vietnam War). Sometimes, paralysis of both legs can result from injury to the brain (bilateral injury of the motor cortex controlling the legs, e.g. due to a stroke or a brain tumor).
## Peripheral nervous system
Rarer is the type which is caused by damage to the nerves supplying the legs. This form of damage is not usually symmetrical and would not cause paraplegia, but polyneuropathy may cause paraplegia if motor fibres are affected. While in theory the arms should also be affected, the fibres that supply the legs are longer and hence more vulnerable to damage.
## Drug Causes
- Cladribine
- Epidural injection of Dexamethasone
- Cytarabine
# Disability
While some people with paraplegia can walk to a degree, many are dependent on wheelchairs or other supportive measures. Impotence and various degrees of urinary and fecal incontinence are very common in those affected. Many use catheters and/or a bowel management program (often involving suppositories, enemas, or digital stimulation of the bowels) to address these problems. With successful bladder and bowel management, paraplegics can virtually prevent all accidental urinary or bowel discharges; it is however another option for the patient to wear undergarments such as diapers to further protect from bladder or fecal incontinence. Some prefer diapers for the comfort level they provide.
# Complications
Due to decreased movement and loss of the ability to run, paraplegia may cause numerous medical complications, many of which can be prevented with vigilant self care. These include pressure sores (decubitus), thrombosis and pneumonia. Physiotherapy and various assistive technology, such as a standing frame, may aid in preventing these complications.
# Treatment
## Paraplegia physical therapy
# Support organizations
- Back-Up Trust
- Spinal Cord Injury Peer Support
- Spinal Cord Injury Support
- Canadian Paraplegic Association | https://www.wikidoc.org/index.php/Ddx:Paraplegia | |
a3c973ab62a911c18a9ad529bcb6364054fac50c | wikidoc | Percussion | Percussion
# Overview
Percussion is a method used by a healthcare provider to find out about the changes in the thorax or abdomen. It is done by tapping on a surface to determine the underlying structure. It is one of the four methods of clinical examination: inspection (medicine), palpation, percussion and auscultation. It is done with the middle finger of right hand tapping on the middle finger of the left hand, which is positioned with the whole palm on the body.
There are two types of percussion: direct percussion, which uses only 1 or two fingers, and indirect percussion, utilizing the middle/flexor finger. The method was initially used to distinguish between empty and filled barrels of liquor.
There are four different percussion sounds:
- Sonorous
- Hypersonorous
- Relatively dull sound
- Completely dull sound
The presence of a solid mass underneath the surface will produce a dull sound. Hollow, air-containing structures will lead to a more sonore sound.
# Percussion of the thorax
It is used to diagnose pneumothorax, emphysema and other diseases. It can be used to access the respiratory mobility of the thorax.
## Differential Diagnosis of Abnormalities in Percussion of the Lung
In alphabetical order:
### Dullness
- Foreign body
- Lobar pneumonia
- Lung abscess
- Lung tumor
- Pleural Effusion
- Pleural tumor
- Pulmonary edema
- Pulmonary infarction
- Tuberculosis infiltrate
- Tumor
### Flatness
- Large Pleural Effusion
### Resonance
- Chronic Bronchitis
### Hyperresonance
- Emphysema
- Pneumothorax
- Status asthmaticus
### Tympany
- Intestinal loop
- Large pneumothorax
- Lung caverns
- Lung cyst
# Percussion of the abdomen
It is used to find whether any organ is enlarged and similar. It is based on the principle of setting tissue and spaces in between at vibration. The sound thus generated is used to determine if the tissue is healthy or pathological. | Percussion
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Percussion is a method used by a healthcare provider to find out about the changes in the thorax or abdomen. It is done by tapping on a surface to determine the underlying structure. It is one of the four methods of clinical examination: inspection (medicine), palpation, percussion and auscultation. It is done with the middle finger of right hand tapping on the middle finger of the left hand, which is positioned with the whole palm on the body.
There are two types of percussion: direct percussion, which uses only 1 or two fingers, and indirect percussion, utilizing the middle/flexor finger. The method was initially used to distinguish between empty and filled barrels of liquor.
There are four different percussion sounds:
- Sonorous
- Hypersonorous
- Relatively dull sound
- Completely dull sound
The presence of a solid mass underneath the surface will produce a dull sound. Hollow, air-containing structures will lead to a more sonore sound.
# Percussion of the thorax
It is used to diagnose pneumothorax, emphysema and other diseases. It can be used to access the respiratory mobility of the thorax.
## Differential Diagnosis of Abnormalities in Percussion of the Lung
In alphabetical order: [1] [2]
### Dullness
- Foreign body
- Lobar pneumonia
- Lung abscess
- Lung tumor
- Pleural Effusion
- Pleural tumor
- Pulmonary edema
- Pulmonary infarction
- Tuberculosis infiltrate
- Tumor
### Flatness
- Large Pleural Effusion
### Resonance
- Chronic Bronchitis
### Hyperresonance
- Emphysema
- Pneumothorax
- Status asthmaticus
### Tympany
- Intestinal loop
- Large pneumothorax
- Lung caverns
- Lung cyst
# Percussion of the abdomen
It is used to find whether any organ is enlarged and similar. It is based on the principle of setting tissue and spaces in between at vibration. The sound thus generated is used to determine if the tissue is healthy or pathological. | https://www.wikidoc.org/index.php/Ddx:Percussion_of_the_Lungs | |
3a0f3f07a6bda06577361d366ae025a632418871 | wikidoc | Scalp rash | Scalp rash
# Overview
Though diagnosis of scalp dermatitis / infection is easy, treatment can be more difficult. Topical therapy alone, or topical therapy in coordination with systemic therapy for long periods may be essential to maintain complete control of these problems.
# Differentiating a Scalp Rash from other Diseases
In alphabetical order.
- Contact dermatitis
- Dissecting cellulitis of the scalp
- Discoid lupus
- Kerion
- Psoriasis
- Scalp folliculitis
- Seborrheic dermatitis
- Tinea capitis
# Diagnosis
## History and Symptoms
### Seborrheic dermatitis
- Diffuse
- White
- Non-adherent
### Bacterial folliculitis
- Use intact scalp pustule to determine diagnosis.
## Laboratory Findings
- KOH prep can be done in the office to check for spores within the hair shaft.
- Fungal cultures can be taken at the site of a kerion or scalp scale to rule out tinea capitis.
- Ensure root is intact.
- A shave biopsy should not be done liberally, and it can aid in the determination of seborrheic dermatitis.
# Treatment
## Medical Therapy
### Acute Pharmacotherapies
- Ketoconazole
- Tar
- Salicylic acid shampoos
- Zinc pyrithione
- Antifungal therapy
- Anti-fungal therapy
- Steroids
- 1st generation cephalosporin or tetracycline derivative for 2-4 weeks
### Injections
- Intralesional injection of steroids
- Intralesional steroids
- Systemic retinoids
- Antibiotic therapy | Scalp rash
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Though diagnosis of scalp dermatitis / infection is easy, treatment can be more difficult. Topical therapy alone, or topical therapy in coordination with systemic therapy for long periods may be essential to maintain complete control of these problems.
# Differentiating a Scalp Rash from other Diseases
In alphabetical order. [1][2]
- Contact dermatitis
- Dissecting cellulitis of the scalp
- Discoid lupus
- Kerion
- Psoriasis
- Scalp folliculitis
- Seborrheic dermatitis
- Tinea capitis
# Diagnosis
## History and Symptoms
### Seborrheic dermatitis
- Diffuse
- White
- Non-adherent
### Bacterial folliculitis
- Use intact scalp pustule to determine diagnosis.
## Laboratory Findings
- KOH prep can be done in the office to check for spores within the hair shaft.
- Fungal cultures can be taken at the site of a kerion or scalp scale to rule out tinea capitis.
- Ensure root is intact.
- A shave biopsy should not be done liberally, and it can aid in the determination of seborrheic dermatitis.
# Treatment
## Medical Therapy
### Acute Pharmacotherapies
- Ketoconazole
- Tar
- Salicylic acid shampoos
- Zinc pyrithione
- Antifungal therapy
- Anti-fungal therapy
- Steroids
- 1st generation cephalosporin or tetracycline derivative for 2-4 weeks
### Injections
- Intralesional injection of steroids
- Intralesional steroids
- Systemic retinoids
- Antibiotic therapy | https://www.wikidoc.org/index.php/Ddx:Scalp_Rash | |
d3da35789b168e3811898f660c6804aec29c4dec | wikidoc | Tooth loss | Tooth loss
Tooth loss is defined as the premature loss of teeth. Tooth loss is normal for deciduous teeth (baby teeth), when they are replaced by a person's adult teeth. Otherwise, losing teeth is undesirable and is the result of injury or disease, such as mouth trauma, tooth injury, tooth decay, and gum disease.
The condition of being toothless or missing one or more teeth, is called edentulism.
# Differential Diagnosis of Causes of Tooth Loss
In alphabetical order.
- Accident
- Acromegaly
- Actalasia
- Chediak-Higashi Syndrome
- Chronic neutropenia
- Cholera
- Cyclic neutropenia
- Dentin dysplasia
- Diabetes Mellitus
- Down's Syndrome
- Drugs
- Hand-Schuller-Christian Syndrome
- Histiocytosis X
- Hypophosphotasia
- Hypophosphtemic vitamin D resistant rickets
- Hypopituitarism
- Hypothyroidism
- Leptospirosis
- Lesch-Nyhan Syndrome
- Leukemia
- Local tumor
- Lymphoma
- Odontodysplasia
- Osteomyelitis
- Papillon-Lefevre Syndrome
- Periodontitis
- Primary Hypothyroidism
- Psychosis
- Radiation
- Reticulosis
- Syphillis
- Tuberculosis
- Vitamin C deficiency
# Prevention of tooth loss
Tooth loss due to tooth decay and gum disease may be prevented by practicing good oral hygiene, and regular check-ups (twice per year) at the dentist's office.
In contact sports, risk of mouth trauma and tooth injury is reduced by wearing mouthguards and helmets with a facemask (e.g., football helmet, and goalie mask).
# Missing tooth replacement
There are three basic ways to replace a missing tooth or teeth, including a fixed dental bridge, dentures, and dental implants. | Tooth loss
Template:Search infobox
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Tooth loss is defined as the premature loss of teeth. Tooth loss is normal for deciduous teeth (baby teeth), when they are replaced by a person's adult teeth. Otherwise, losing teeth is undesirable and is the result of injury or disease, such as mouth trauma, tooth injury, tooth decay, and gum disease.
The condition of being toothless or missing one or more teeth, is called edentulism.
# Differential Diagnosis of Causes of Tooth Loss
In alphabetical order. [1] [2]
- Accident
- Acromegaly
- Actalasia
- Chediak-Higashi Syndrome
- Chronic neutropenia
- Cholera
- Cyclic neutropenia
- Dentin dysplasia
- Diabetes Mellitus
- Down's Syndrome
- Drugs
- Hand-Schuller-Christian Syndrome
- Histiocytosis X
- Hypophosphotasia
- Hypophosphtemic vitamin D resistant rickets
- Hypopituitarism
- Hypothyroidism
- Leptospirosis
- Lesch-Nyhan Syndrome
- Leukemia
- Local tumor
- Lymphoma
- Odontodysplasia
- Osteomyelitis
- Papillon-Lefevre Syndrome
- Periodontitis
- Primary Hypothyroidism
- Psychosis
- Radiation
- Reticulosis
- Syphillis
- Tuberculosis
- Vitamin C deficiency
# Prevention of tooth loss
Tooth loss due to tooth decay and gum disease may be prevented by practicing good oral hygiene, and regular check-ups (twice per year) at the dentist's office.
In contact sports, risk of mouth trauma and tooth injury is reduced by wearing mouthguards and helmets with a facemask (e.g., football helmet, and goalie mask).
# Missing tooth replacement
There are three basic ways to replace a missing tooth or teeth, including a fixed dental bridge, dentures, and dental implants. | https://www.wikidoc.org/index.php/Ddx:Tooth_Loss | |
4aba64ac2371ec771d51d835a1fb0f9d7ef3e0e1 | wikidoc | Xerostomia | Xerostomia
# Overview
Xerostomia is the medical term for a dry mouth due to a lack of saliva. Xerostomia is sometimes colloquially called pasties or cottonmouth.
Xerostomia can cause difficulty in speech and eating. It also leads to halitosis and a dramatic rise in the number of cavities, as the protective effect of saliva is no longer present, and can make the mucosa of the mouth more vulnerable to infection. Notably, a symptom of methamphetamine abuse usually called "meth mouth" is largely caused by xerostomia.
# Causes
It may be a sign of an underlying disease, such as Sjögren's syndrome, poorly controlled diabetes, dehydration , or a side effects of medication.
Other causes of insufficient saliva include anxiety, alcohol, trauma to the salivary glands or their ducts or nerves, excessive mouth breathing, previous radiation therapy, and also a natural result of aging. The vast majority of elderly individuals will suffer xerostomia to some degree. Playing or exercising a long time outside on a hot day will often cause your saliva glands to simply dry up as your bodily fluids are concentrated elsewhere. Drugs have also been known to cause this problem, such as cannabis, and DXM.It can also be associated with rare condition like Eaton-Lambert syndrome.
## Causes by organ system
# Causes in alphabetical order
- 3-Quinuclidinyl benzilate
- Abciximab
- Acamprosate calcium
- Acitretin
- Actiq
- Adderall
- Ajulemic acid
- Albuterol
- Alfentanil Hydrochloride Injection
- Anticholinergic
- Anxiety
- Arsenic Poisoning
- Azelastine
- Benzatropine
- Benztropine Mesylate Oral
- Benzydamine
- Benzylpiperazine
- Bepridil
- Bevacizumab Injection
- Biperiden
- Botulism
- Brompheniramine
- Budesonide
- Buprenorphine
- Bupropion
- Buspirone
- Butorphanol
- Butorphanol Injection
- Calcitriol
- Calcium carbonate
- Carbamazepine
- Cetuximab Injection
- Cevimeline
- Chlordiazepoxide
- Chloropyramine
- Chlorpheniramine
- Chlorpromazine
- Chlorprothixene
- Clomipramine
- Clonazepam
- Clonidine
- Clozapine
- Codeine
- Cyclobenzaprine
- Cyproheptadine
- Dehydration
- Desloratadine
- Dextroamphetamine
- Diabetes
- Diazepam
- Dicyclomine
- Diethylpropion
- Diltiazem
- Dimenhydrinate
- Diphenhydramine
- Diphenoxylate and Atropine
- Dosulepin hydrochloride
- Doxylamine
- Duloxetine
- Eaton-Lambert syndrome
- Eribulin
- Erlotinib)
- Esomeprazole
- Estazola
- Excessive mouth breathing
- Exenatide Injection
- Fencamfamine
- Fexofenadine
- Flavoxate
- Fluacizine
- Flucytosine
- Fluphenazine
- Fosamprenavir
- Frovatriptan
- Gabapentin
- Galantamine
- Ganciclovir
- Gatifloxacin
- Glimepiride
- Glipizide
- Glyburide
- Glycopyrrolate
- Guanabenz
- Guanethidine
- Guanfacine
- Haloperidol Oral
- Hexamethonium
- Hydroxyzine
- Hyoscyamine
- Hyperglycemia
- Hyperosmolar syndrome
- Imipramine
- Insulin Aspart (rDNA Origin) Injection
- Interferon beta-1a Subcutaneous Injection
- Ipratropium Oral Inhalation
- Isocarboxazid
- Isoetharine Oral Inhalation
- Isoproterenol Oral Inhalation
- Isosorbide
- Ketorolac
- Ketotifen
- Levalbuterol Oral Inhalation
- Levodopa and Carbidopa
- Levomepromazine
- Lithium
- Lofepramine
- Loperamide
- Loratadine (patient information)
- Lorazepam (patient information)
- Loxapine Oral (patient information)
- Meperidine (patient information)
- Meropenem Injection (patient information)
- Mesalamine (patient information)
- Mesoridazine Oral (patient information)
- Metaproterenol (patient information)
- Metformin (patient information)
- Methylphenidate Transdermal (patient information)
- Metoprolol (patient information)
- Metronidazole Oral (patient information)
- Miglitol (patient information)
- Milnacipran hydrochloride
- Moclobemide
- Modafinil (patient information)
- Moxonidine
- Multiple chemical sensitivity
- Nabilone (patient information)
- Nabumetone (patient information)
- Nalbuphine injection (patient information)
- Nateglinide oral (patient information)
- Nefazodone (patient information)
- Nialamide
- Nicardipine (patient information)
- Nitroglycerin ointment (patient information)
- Nortriptyline (patient information)
- Olanzapine (patient information)
- Omeprazole (patient information)
- Orphenadrine (patient information)
- Oxaliplatin injection (patient information)
- Oxazepam (patient information)
- Oxcarbazepine (patient information)
- Peginterferon alfa-2a (patient information)
- Peginterferon alfa-2b (patient information)
- Penbutolol (patient information)
- Pergolide (patient information)
- Perphenazine oral (patient information)
- Phentermine (patient information)
- Pimozide (patient information)
- Pindolol (patient information)
- Pioglitazone (patient information)
- Pirbuterol acetate oral inhalation (patient information)
- Pizotifen
- Pramipexole (patient information)
- Prazepam (patient information)
- Pregabalin (patient information)
- Procarbazine (patient information)
- Procyclidine (patient information)
- Propafenone (patient information)
- Propantheline (patient information)
- Protriptyline (patient information)
- Quetiapine (patient information)
- Quinethazone
- Rabeprazole (patient information)
- Radiation therapy
- Ramsay Hunt syndrome type II
- Rasagiline (patient information)
- Reboxetine
- Repaglinide (patient information)
- Reserpine (patient information)
- Ribavirin (patient information)
- Rilmenidine
- Risedronate (patient information)
- Risperidone (patient information)
- Rizatriptan (patient information)
- Ropinirole (patient information)
- Rosiglitazone (patient information)
- Salmeterol oral inhalation (patient information)
- Scopolamine patch (patient information)
- Selegiline (patient information)
- Sibutramine (patient information)
- Sjogren's syndrome
- Solifenacin (patient information)
- Sorafenib (patient information)
- Spironolactone (patient information)
- Sulpiride
- Sunitinib (patient information)
- Temazepam (patient information)
- Thioridazine (patient information)
- Thiothixene Oral (patient information)
- Tolazamide (patient information)
- Tolbutamide (patient information)
- Tolterodine (patient information)
- Topiramate
- Tranylcypromine (patient information)
- Trazodone (patient information)
- Triamterene (patient information)
- Triazolam (patient information)
- Tricyclic antidepressant
- Trifluoperazine Oral (patient information)
- Trihexyphenidyl (patient information)
- Trimipramine (patient information)
- Tripelennamine
- Trospium (patient information)
- Vicodin
- Vinpocetine
- Zaleplon (patient information)
- Zenker's diverticulum
- Zimelidine
- Zoledronic Acid Injection (patient information)
- Zolmitriptan
- Zolpidem (patient information)
- Zonisamide (patient information)
- Zopiclone
- Zotepine
# Differential Diagnosis
In alphabetical order.
With parotid gland swelling
- Heerfordt's Disease
- Sicca Syndrome
- Sjögren's Syndrome
Without parotid gland swelling
- Advance age
- Alcoholism
- Antihistamines
- Antihypertensives
- Antiparkinsonian drugs
- Antispasmodics
- Atropine
- Bronchodilators
- Continuous vomiting
- Decongestants
- Diabetes Mellitus
- Diarrhea
- Diuretics
- Drugs- Cyclobenzaprine, Haloperidol
- Infections with high fever
- Lithium
- MAOIs
- Neuroleptics
- Psychogenic
- Radiation therapy
- Salivary gland surgery
- Tricyclic antidepressants
# Treatment
Treatment involves finding any correctable causes and fixing those if possible. In many cases it is not possible to correct the xerostomia itself, and treatment focuses on relieving the symptoms and preventing cavities. Patients who have endured chemotherapy usually suffer from this post- treatment.
Patients with xerostomia should avoid the use of decongestants and antihistamines, and pay careful attention to oral hygiene. Sipping sugarless fluids frequently, chewing xylitol-containing gum, and using a carboxymethyl cellulose saliva substitute as a mouthwash may help. Aquoral may be prescribed to treat xerostomia. Non-systemic relief can be found using an oxidized glycerol triesters treatment used to coat the mouth. | Xerostomia
Template:DiseaseDisorder infobox
Template:Search infobox
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [2]
# Overview
Xerostomia is the medical term for a dry mouth due to a lack of saliva. Xerostomia is sometimes colloquially called pasties or cottonmouth.
Xerostomia can cause difficulty in speech and eating. It also leads to halitosis and a dramatic rise in the number of cavities, as the protective effect of saliva is no longer present, and can make the mucosa of the mouth more vulnerable to infection. Notably, a symptom of methamphetamine abuse usually called "meth mouth" is largely caused by xerostomia.
# Causes
It may be a sign of an underlying disease, such as Sjögren's syndrome, poorly controlled diabetes, dehydration , or a side effects of medication.
Other causes of insufficient saliva include anxiety, alcohol, trauma to the salivary glands or their ducts or nerves, excessive mouth breathing, previous radiation therapy, and also a natural result of aging. The vast majority of elderly individuals will suffer xerostomia to some degree. Playing or exercising a long time outside on a hot day will often cause your saliva glands to simply dry up as your bodily fluids are concentrated elsewhere. Drugs have also been known to cause this problem, such as cannabis, and DXM.It can also be associated with rare condition like Eaton-Lambert syndrome.
## Causes by organ system
# Causes in alphabetical order
- 3-Quinuclidinyl benzilate
- Abciximab
- Acamprosate calcium
- Acitretin
- Actiq
- Adderall
- Ajulemic acid
- Albuterol
- Alfentanil Hydrochloride Injection
- Anticholinergic
- Anxiety
- Arsenic Poisoning
- Azelastine
- Benzatropine
- Benztropine Mesylate Oral
- Benzydamine
- Benzylpiperazine
- Bepridil
- Bevacizumab Injection
- Biperiden
- Botulism
- Brompheniramine
- Budesonide
- Buprenorphine
- Bupropion
- Buspirone
- Butorphanol
- Butorphanol Injection
- Calcitriol
- Calcium carbonate
- Carbamazepine
- Cetuximab Injection
- Cevimeline
- Chlordiazepoxide
- Chloropyramine
- Chlorpheniramine
- Chlorpromazine
- Chlorprothixene
- Clomipramine
- Clonazepam
- Clonidine
- Clozapine
- Codeine
- Cyclobenzaprine
- Cyproheptadine
- Dehydration
- Desloratadine
- Dextroamphetamine
- Diabetes
- Diazepam
- Dicyclomine
- Diethylpropion
- Diltiazem
- Dimenhydrinate
- Diphenhydramine
- Diphenoxylate and Atropine
- Dosulepin hydrochloride
- Doxylamine
- Duloxetine
- Eaton-Lambert syndrome
- Eribulin
- Erlotinib)
- Esomeprazole
- Estazola
- Excessive mouth breathing
- Exenatide Injection
- Fencamfamine
- Fexofenadine
- Flavoxate
- Fluacizine
- Flucytosine
- Fluphenazine
- Fosamprenavir
- Frovatriptan
- Gabapentin
- Galantamine
- Ganciclovir
- Gatifloxacin
- Glimepiride
- Glipizide
- Glyburide
- Glycopyrrolate
- Guanabenz
- Guanethidine
- Guanfacine
- Haloperidol Oral
- Hexamethonium
- Hydroxyzine
- Hyoscyamine
- Hyperglycemia
- Hyperosmolar syndrome
- Imipramine
- Insulin Aspart (rDNA Origin) Injection
- Interferon beta-1a Subcutaneous Injection
- Ipratropium Oral Inhalation
- Isocarboxazid
- Isoetharine Oral Inhalation
- Isoproterenol Oral Inhalation
- Isosorbide
- Ketorolac
- Ketotifen
- Levalbuterol Oral Inhalation
- Levodopa and Carbidopa
- Levomepromazine
- Lithium
- Lofepramine
- Loperamide
- Loratadine (patient information)
- Lorazepam (patient information)
- Loxapine Oral (patient information)
- Meperidine (patient information)
- Meropenem Injection (patient information)
- Mesalamine (patient information)
- Mesoridazine Oral (patient information)
- Metaproterenol (patient information)
- Metformin (patient information)
- Methylphenidate Transdermal (patient information)
- Metoprolol (patient information)
- Metronidazole Oral (patient information)
- Miglitol (patient information)
- Milnacipran hydrochloride
- Moclobemide
- Modafinil (patient information)
- Moxonidine
- Multiple chemical sensitivity
- Nabilone (patient information)
- Nabumetone (patient information)
- Nalbuphine injection (patient information)
- Nateglinide oral (patient information)
- Nefazodone (patient information)
- Nialamide
- Nicardipine (patient information)
- Nitroglycerin ointment (patient information)
- Nortriptyline (patient information)
- Olanzapine (patient information)
- Omeprazole (patient information)
- Orphenadrine (patient information)
- Oxaliplatin injection (patient information)
- Oxazepam (patient information)
- Oxcarbazepine (patient information)
- Peginterferon alfa-2a (patient information)
- Peginterferon alfa-2b (patient information)
- Penbutolol (patient information)
- Pergolide (patient information)
- Perphenazine oral (patient information)
- Phentermine (patient information)
- Pimozide (patient information)
- Pindolol (patient information)
- Pioglitazone (patient information)
- Pirbuterol acetate oral inhalation (patient information)
- Pizotifen
- Pramipexole (patient information)
- Prazepam (patient information)
- Pregabalin (patient information)
- Procarbazine (patient information)
- Procyclidine (patient information)
- Propafenone (patient information)
- Propantheline (patient information)
- Protriptyline (patient information)
- Quetiapine (patient information)
- Quinethazone
- Rabeprazole (patient information)
- Radiation therapy
- Ramsay Hunt syndrome type II
- Rasagiline (patient information)
- Reboxetine
- Repaglinide (patient information)
- Reserpine (patient information)
- Ribavirin (patient information)
- Rilmenidine
- Risedronate (patient information)
- Risperidone (patient information)
- Rizatriptan (patient information)
- Ropinirole (patient information)
- Rosiglitazone (patient information)
- Salmeterol oral inhalation (patient information)
- Scopolamine patch (patient information)
- Selegiline (patient information)
- Sibutramine (patient information)
- Sjogren's syndrome
- Solifenacin (patient information)
- Sorafenib (patient information)
- Spironolactone (patient information)
- Sulpiride
- Sunitinib (patient information)
- Temazepam (patient information)
- Thioridazine (patient information)
- Thiothixene Oral (patient information)
- Tolazamide (patient information)
- Tolbutamide (patient information)
- Tolterodine (patient information)
- Topiramate
- Tranylcypromine (patient information)
- Trazodone (patient information)
- Triamterene (patient information)
- Triazolam (patient information)
- Tricyclic antidepressant
- Trifluoperazine Oral (patient information)
- Trihexyphenidyl (patient information)
- Trimipramine (patient information)
- Tripelennamine
- Trospium (patient information)
- Vicodin
- Vinpocetine
- Zaleplon (patient information)
- Zenker's diverticulum
- Zimelidine
- Zoledronic Acid Injection (patient information)
- Zolmitriptan
- Zolpidem (patient information)
- Zonisamide (patient information)
- Zopiclone
- Zotepine
# Differential Diagnosis
In alphabetical order. [1] [2]
With parotid gland swelling
- Heerfordt's Disease
- Sicca Syndrome
- Sjögren's Syndrome
Without parotid gland swelling
- Advance age
- Alcoholism
- Antihistamines
- Antihypertensives
- Antiparkinsonian drugs
- Antispasmodics
- Atropine
- Bronchodilators
- Continuous vomiting
- Decongestants
- Diabetes Mellitus
- Diarrhea
- Diuretics
- Drugs- Cyclobenzaprine, Haloperidol
- Infections with high fever
- Lithium
- MAOIs
- Neuroleptics
- Psychogenic
- Radiation therapy
- Salivary gland surgery
- Tricyclic antidepressants
# Treatment
Treatment involves finding any correctable causes and fixing those if possible. In many cases it is not possible to correct the xerostomia itself, and treatment focuses on relieving the symptoms and preventing cavities. Patients who have endured chemotherapy usually suffer from this post- treatment.
Patients with xerostomia should avoid the use of decongestants and antihistamines, and pay careful attention to oral hygiene. Sipping sugarless fluids frequently, chewing xylitol-containing gum[3], and using a carboxymethyl cellulose saliva substitute as a mouthwash may help. Aquoral may be prescribed to treat xerostomia. Non-systemic relief can be found using an oxidized glycerol triesters treatment used to coat the mouth. | https://www.wikidoc.org/index.php/Ddx:Xerostomia | |
333c35dd1dcd537a7240dad3fc6220bed86efe88 | wikidoc | Erotomania | Erotomania
# Overview
Erotomania is a rare disorder in which a person holds a delusional belief that another person, usually of a higher social status, is in love with him or her.
Erotomania is also called de Clérambault's syndrome, after the France|French Gaëtan Gatian de Clérambault (1872–1934), who published a comprehensive review paper on the subject (Les Psychoses Passionelles) in 1921.
The term erotomania is also sometimes used in a less specific clinical sense meaning excessive pursuit of or preoccupation with love or sex.
# History
Early references to the condition can be found in the work of Hippocrates, Erasistratus, Plutarch and Galen. In the psychiatric literature it was first referred to in 1623 in a treatise by Jacques Ferrand (Maladie d'amour ou Mélancolie érotique) and has been variously called "old maid's psychosis", "erotic paranoia" and "erotic self-referent delusions" until the common usage of the terms erotomania and de Clérambault's syndrome.
G.E. Berrios|Berrios and Kennedy have outlined several periods of history through which the concept of erotomania has changed considerably:
- Classical times – early eighteenth century: General disease caused by unrequited love
- Early eighteenth – beginning nineteenth century: Practice of excess physical love (akin to nymphomania or satyriasis)
- Early nineteenth century – beginning twentieth century: Unrequited love as a form of mental disease
- Early twentieth century – present: Delusional belief of "being loved by someone else"
# Contemporary syndrome
The core of the syndrome is that the affected person has a delusional belief that another person, usually of higher social status, is secretly in love with them. The sufferer may also believe that the subject of their delusion secretly communicates their love by subtle methods such as body posture, arrangement of household objects and other seemingly innocuous acts (or, if the person is a public figure, through clues in the media). The object of the delusion usually has little or no contact with the delusional person, who often believes that the object initiated the fictional relationship. Erotomanic delusions are typically found as the primary symptom of delusional disorder, or in the context of schizophrenia.
Occasionally the subject of the delusion may not actually exist, although more commonly, the subjects are media figures such as popular singers, actors and politicians. Erotomania has been cited as one cause for stalking or harassment campaigns.
The assassination attempt of Ronald Reagan by John Hinckley, Jr. was reported to have been driven by an erotomanic delusion that the death of the president would cause actress Jodie Foster to publicly declare her love for Hinckley.
Late Night with David Letterman|Late night comedian David Letterman and retired astronaut Story Musgrave were the targets of delusional Margaret Mary Ray. Other reported celebrity targets of erotomania include Madonna (entertainer)|Madonna, Steven Spielberg, Barbara Mandrell, and Linda Ronstadt. | Erotomania
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Erotomania is a rare disorder in which a person holds a delusional belief that another person, usually of a higher social status, is in love with him or her.
Erotomania is also called de Clérambault's syndrome, after the France|French [[psychiatrist] Gaëtan Gatian de Clérambault (1872–1934), who published a comprehensive review paper on the subject (Les Psychoses Passionelles) in 1921.
The term erotomania is also sometimes used in a less specific clinical sense meaning excessive pursuit of or preoccupation with love or sex.
# History
Early references to the condition can be found in the work of Hippocrates, Erasistratus, Plutarch and Galen. In the psychiatric literature it was first referred to in 1623 in a treatise by Jacques Ferrand (Maladie d'amour ou Mélancolie érotique) and has been variously called "old maid's psychosis", "erotic paranoia" and "erotic self-referent delusions" until the common usage of the terms erotomania and de Clérambault's syndrome.
G.E. Berrios|Berrios and Kennedy have outlined several periods of history through which the concept of erotomania has changed considerably:
- Classical times – early eighteenth century: General disease caused by unrequited love
- Early eighteenth – beginning nineteenth century: Practice of excess physical love (akin to nymphomania or satyriasis)
- Early nineteenth century – beginning twentieth century: Unrequited love as a form of mental disease
- Early twentieth century – present: Delusional belief of "being loved by someone else"
# Contemporary syndrome
The core of the syndrome is that the affected person has a delusional belief that another person, usually of higher social status, is secretly in love with them. The sufferer may also believe that the subject of their delusion secretly communicates their love by subtle methods such as body posture, arrangement of household objects and other seemingly innocuous acts (or, if the person is a public figure, through clues in the media). The object of the delusion usually has little or no contact with the delusional person, who often believes that the object initiated the fictional relationship. Erotomanic delusions are typically found as the primary symptom of delusional disorder, or in the context of schizophrenia.
Occasionally the subject of the delusion may not actually exist, although more commonly, the subjects are media figures such as popular singers, actors and politicians. Erotomania has been cited as one cause for stalking or harassment campaigns.
The assassination attempt of Ronald Reagan by John Hinckley, Jr. was reported to have been driven by an erotomanic delusion that the death of the president would cause actress Jodie Foster to publicly declare her love for Hinckley.
Late Night with David Letterman|Late night comedian David Letterman and retired astronaut Story Musgrave were the targets of delusional Margaret Mary Ray. Other reported celebrity targets of erotomania include Madonna (entertainer)|Madonna, Steven Spielberg, Barbara Mandrell, and Linda Ronstadt. | https://www.wikidoc.org/index.php/De_Clerambault_syndrome | |
cd45c77102cef12e49f17ad1d5ce52c546ed89a5 | wikidoc | Dead space | Dead space
# Overview
In physiology, dead space is air that is inhaled by the body in breathing, but does not partake in gas exchange.
In adults, it is usually in the range of 150 mL.
# Understanding dead space
Not all the air we breathe in is able to be used for the exchange of oxygen and carbon dioxide. About a third of every resting breath is exhaled exactly as it came into the body.
Because of dead space, taking deep breaths more slowly (e.g. ten 500 mL breaths per minute) is more effective than taking shallow breaths quickly (e.g. twenty 250 mL breaths per minute). Although the amount of gas per minute is the same (5 L/min), a large proportion of the shallow breaths is dead space, and does not allow oxygen to get into the blood.
Dead space can be enlarged (and better envisaged) by breathing into a long tube. Even though one end of the tube is open to the air, when one inhales, it is mostly the carbon dioxide from expiration. Using a snorkel increases a diver's dead space in the airways.
# Components
Dead space can be divided into two components: "anatomic" and "physiologic".
## Anatomical dead space
Anatomical dead space is the gas in the conducting areas of the respiratory system, such as the mouth and trachea, where the air doesn't come to the alveoli of the lungs.
It is normally equal in milliliters to your body weight in pounds. A 150 lb (68 kg) male would have an anatomical dead space of about 150 mL. 1 mL per lb or 2.2 mL per kilogram of body weight. This is the same conversion of kilograms to pounds, except the final unit is in mL. This is about a third of the resting tidal volume (450-500 mL).
Anatomic dead space is the volume of the conducting airways. It may be measured by Fowler's Method, a nitrogen washout technique. It increases with an increase in tidal volume and is dependent on posture.
## Physiological dead space
The physiological dead space is equal to the anatomical dead space plus the alveolar dead space.
Alveolar dead space is the area in the alveoli that does get air to be exchanged, but there is not enough blood flowing through the capillaries for exchange to be effective. It is normally very small (less than 5 mL) in healthy individuals. It can increase dramatically in some lung diseases.
Physiologic dead space can be measured by Bohr's method.
An equation and example are provided below:
- VD = dead space
- VT = tidal volume
- PaCO2 = partial pressure of carbon dioxide in arteries
- PECO2 = partial pressure of carbon dioxide in exhaled air | Dead space
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
In physiology, dead space is air that is inhaled by the body in breathing, but does not partake in gas exchange.
In adults, it is usually in the range of 150 mL.[1]
# Understanding dead space
Not all the air we breathe in is able to be used for the exchange of oxygen and carbon dioxide. About a third of every resting breath is exhaled exactly as it came into the body.
Because of dead space, taking deep breaths more slowly (e.g. ten 500 mL breaths per minute) is more effective than taking shallow breaths quickly (e.g. twenty 250 mL breaths per minute). Although the amount of gas per minute is the same (5 L/min), a large proportion of the shallow breaths is dead space, and does not allow oxygen to get into the blood.
Dead space can be enlarged (and better envisaged) by breathing into a long tube. Even though one end of the tube is open to the air, when one inhales, it is mostly the carbon dioxide from expiration. Using a snorkel increases a diver's dead space in the airways.
# Components
Dead space can be divided into two components: "anatomic" and "physiologic".[2]
## Anatomical dead space
Anatomical dead space is the gas in the conducting areas of the respiratory system, such as the mouth and trachea, where the air doesn't come to the alveoli of the lungs.
It is normally equal in milliliters to your body weight in pounds. A 150 lb (68 kg) male would have an anatomical dead space of about 150 mL. 1 mL per lb or 2.2 mL per kilogram of body weight. This is the same conversion of kilograms to pounds, except the final unit is in mL. This is about a third of the resting tidal volume (450-500 mL).
Anatomic dead space is the volume of the conducting airways. It may be measured by Fowler's Method, a nitrogen washout technique.[3][4][5] It increases with an increase in tidal volume and is dependent on posture.
## Physiological dead space
The physiological dead space is equal to the anatomical dead space plus the alveolar dead space.[6]
Alveolar dead space is the area in the alveoli that does get air to be exchanged, but there is not enough blood flowing through the capillaries for exchange to be effective.[7] It is normally very small (less than 5 mL) in healthy individuals. It can increase dramatically in some lung diseases.
Physiologic dead space can be measured by Bohr's method.[8][9]
An equation and example are provided below:
- VD = dead space
- VT = tidal volume
- PaCO2 = partial pressure of carbon dioxide in arteries
- PECO2 = partial pressure of carbon dioxide in exhaled air | https://www.wikidoc.org/index.php/Dead_space | |
3e0178de76108b7962296d3c77560a0bfbc72a19 | wikidoc | Nandrolone | Nandrolone
# 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
Nandrolone is an anabolic steroid, endocrine-metabolic agent that is FDA approved for the treatment of anemia of chronic renal failure. Common adverse reactions include acne in women and prepubertal boys, female hirsutism, male pattern alopecia in women, gynecomastia in men, diarrhea, nausea, vomiting, insomnia, depression, excitability, atrophy of testis, postpubertal males, erectile dysfunction, erection finding- increased frequency, hypertrophy of clitoris, irregular periods, decreased or increased libido in men or women, priapism, enlargement penis in prepubertal males, testicular hypofunction, deepening in voice in women, drug habituation.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Nandrolone decanoate is indicated for the management of the anemia of renal insufficiency and has been shown to increase hemoglobin and red cell mass. Surgically induced anephric patients have been reported to be less responsive.
- Dosing Information
- Nandrolone decanoate injection is intended for deep intramuscular injection only, into the gluteal muscle preferably. Dosage should be based on therapeutic response and consideration of the benefit to risk ratio. Duration of therapy will depend on the response of the condition and the appearance of adverse reactions. If possible, therapy should be intermittent. Nandrolone decanoate should be regarded as adjunctive therapy and adequate quantities of nutrients should be consumed in order to obtain maximal therapeutic effects. For example, when it is used in the treatment of refractory anemia, adequate iron intake is required for a maximal response.
- Both nandrolone decanoate is administered by deep intramuscular injection. For nandrolone decanoate, the recommended dose for women is 50 to 100 milligrams per week and 100 to 200 milligrams per week for men.
- Prior to the availability of recombinant erythropoietin (epoetin), nandrolone decanoate was widely used in the treatment of ANEMIA in patients with chronic renal failure in doses of 100 to 200 milligrams intramuscularly weekly. Responses were best in patients who were well-nourished and receiving adequate dialysis.
- Recombinant epoetin is now usually preferred over androgens for initial non-transfusional therapy in these patients. The use of lower doses of epoetin in combination with nandrolone has, however, been investigated due to financial constraints. In one study, a greater increase in hematocrit was reported with combined low-dose recombinant epoetin (2000 units three times weekly) plus nandrolone decanoate (100 milligrams weekly) as compared to epoetin alone in the same doses in male hemodialysis patients. Nandrolone therapy was started simultaneously with epoetin. However, in another combination study, no additional benefit was observed when nandrolone was started at least 2 months prior to epoetin. Further studies investigating this combination are needed.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Nandrolone in adult patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Nandrolone in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Dosing Information
- The safety and effectiveness in children less than 2 years of age has not been established.
- In children 2 to 13 years of age, the dose of nandrolone decanoate is 25 to 50 milligrams every 3 to 4 weeks.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Nandrolone in pediatric patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Nandrolone in pediatric patients.
# Contraindications
- Male patients with carcinoma of the breast or with known or suspected carcinoma of the prostate.
- Carcinoma of the breast in females with hypercalcemia: androgenic anabolic steroids may stimulate osteolytic resorption of bones.
- Pregnancy, because of masculinization of the fetus.
- Nephrosis or the nephrotic phase of nephritis.
# Warnings
- PELIOSIS HEPATIS, A CONDITION IN WHICH LIVER AND SOMETIMES SPLENIC TISSUE IS REPLACED WITH BLOOD-FILLED CYSTS, HAS BEEN REPORTED IN PATIENTS RECEIVING ANDROGENIC ANABOLIC STEROID THERAPY. THESE CYSTS ARE SOMETIMES PRESENT WITH MINIMAL HEPATIC DYSFUNCTION, BUT AT OTHER TIMES THEY HAVE BEEN ASSOCIATED WITH LIVER FAILURE. THEY ARE OFTEN NOT RECOGNIZED UNTIL LIFE-THREATENING LIVER FAILURE OR INTRA-ABDOMINAL HEMORRHAGE DEVELOPS. WITHDRAWAL OF DRUG USUALLY RESULTS IN COMPLETE DISAPPEARANCE OF LESIONS. LIVER CELL TUMORS ARE ALSO REPORTED. MOST OFTEN THESE TUMORS ARE BENIGN AND ANDROGEN-DEPENDENT, BUT FATAL MALIGNANT TUMORS HAVE BEEN REPORTED. WITHDRAWAL OF DRUG OFTEN RESULTS IN REGRESSION OR CESSATION OF PROGRESSION OF THE TUMOR. HOWEVER, HEPATIC TUMORS ASSOCIATED WITH ANDROGENS OR ANABOLIC STEROIDS ARE MUCH MORE VASCULAR THAN OTHER HEPATIC TUMORS AND MAY BE SILENT UNTIL LIFE-THREATENING INTRA-ABDOMINAL HEMORRHAGE DEVELOPS. BLOOD LIPID CHANGES THAT ARE KNOWN TO BE ASSOCIATED WITH INCREASED RISK OF ATHEROSCLEROSIS ARE SEEN IN PATIENTS TREATED WITH ANDROGENS AND ANABOLIC STEROIDS. THESE CHANGES INCLUDE DECREASED HIGH-DENSITY LIPOPROTEIN AND SOMETIMES INCREASED LOW-DENSITY LIPOPROTEIN. THE CHANGES MAY BE VERY MARKED AND COULD HAVE A SERIOUS IMPACT ON THE RISK OF ATHEROSCLEROSIS AND CORONARY ARTERY DISEASE.
- Hypercalcemia may develop both spontaneously and as a result of androgen therapy in women with disseminated breast carcinoma. If it develops while on this agent, the drug should be discontinued. Caution is required in administering these agents to patients with cardiac, renal or hepatic disease. Cholestatic jaundice is associated with therapeutic use of anabolic and androgenic steroids. Edema may occur occasionally with or without congestive heart failure. Concomitant administration of adrenal steroids or ACTH may add to the edema. In children, anabolic steroid treatment may accelerate bone maturation without producing compensatory gain in linear growth. This adverse effect may result in compromised adult stature. The younger the child the greater the risk of compromising final mature height. The effect on bone maturation should be monitored by assessing bone age of the wrist and hand every six months. This drug has not been shown to be safe and effective for the enhancement of athletic performance. Because of the potential risk of serious adverse health effects, this drug should not be used for such purpose.
### Precautions
General
- Women should be observed for signs of virilization (deepening of the voice, hirsutism, acne, clitorimegaly and menstrual irregularities). Discontinuation of drug therapy at the time of evidence of mild virilism is necessary to prevent irreversible virilization. Such virilization is usual following anabolic steroid use in high doses. The insulin or oral hypoglycemic dosage may need adjustment in diabetic patients who receive anabolic steroids.
Laboratory Tests
- Women with disseminated breast carcinoma should have frequent determination of urine and serum calcium levels during the course of anabolic therapy (see WARNINGS section). If children are treated, periodic (every six months) X-ray examinations of bone age should be made during treatment to determine the rate of bone maturation and the effects of anabolic therapy on the epiphyseal centers. Hemoglobin and hematocrit should be checked periodically for polycythemia in patients who are receiving high doses of anabolic steroids. Serum lipids and high-density lipoprotein cholesterol should be determined periodically. Because of the hepatotoxicity associated with the use of 17-alpha-alkylated anabolic steroids, liver function tests should be obtained periodically.
# Adverse Reactions
## Clinical Trials Experience
Hepatic:
- Hepatocellular neoplasms and peliosis hepatis have been reported in association with long-term androgenic anabolic steroid therapy (see WARNINGS section).
Genitourinary System:
- In men.
- Prepubertal: Phallic enlargement and increased frequency of erections.
- Postpubertal: Inhibition of testicular function, testicular atrophy and oligospermia, impotence, chronic priapism, epididymitis and bladder irritability.
- In women: Clitoral enlargement, menstrual irregularities. In both sexes: Increased or decreased libido.
CNS:
- Habituation, excitation, insomnia, depression.
Gastrointestinal:
- Nausea, vomiting, diarrhea.
Hematologic:
- Bleeding in patients on concomitant anticoagulant therapy (see PRECAUTIONS, Drug Interactions).
Breast:
- Gynecomastia.
Larynx:
- Deepening of the voice in women.
Hair:
- Hirsutism and male pattern of baldness in women.
Skin:
- Acne (especially in women and prepubertal boys.)
Skeletal:
- Premature closure of epiphyses in children (see PRECAUTIONS, Pediatric use).
Fluid and Electrolytes:
- Edema, retention of serum electrolytes (sodium, chloride, potassium, phosphate, calcium).
Metabolic/Endocrine:
- Decreased glucose tolerance (see PRECAUTIONS, General), increased serum levels of low-density lipoprotein and decreased levels of high-density lipoprotein (see PRECAUTIONS, Laboratory tests), increased creatine and creatinine excretion, increased serum levels of creatinine phosphokinase (CPK). Some virilizing changes in women are irreversible even after prompt discontinuance of therapy and are not prevented by concomitant use of estrogens (see PRECAUTIONS).
### DRUG ABUSE AND DEPENDENCE
- Nandrolone decanoate injection is classified as a Schedule III controlled substance under the Anabolic Steroids Control Act of 1990.
## Postmarketing Experience
- There is limited information regarding Postmarketing Experience of Nandrolone in the drug label
# Drug Interactions
- Anticoagulants. Anabolic steroids may increase sensitivity to oral anticoagulants. Dosage of the anticoagulant may have to be decreased in order to maintain the prothrombin time at the desired therapeutic level. Patients receiving oral anticoagulant therapy require close monitoring, especially when anabolic steroids are started or stopped.
DRUG & OR LABORATORY TEST INTERACTIONS
- Anabolic steroid therapy may decrease thyroxine-binding globulin resulting in decreased total T4 serum levels and increased resin uptake of T3 and T4. Free thyroid hormone levels remain unchanged. Anabolic steroids may cause an increase in prothrombin time.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): X
Pregnancy Category X.
See CONTRAINDICATIONS section.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
- There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Nandrolone in women who are pregnant.
### Labor and Delivery
- There is no FDA guidance on use of Nandrolone during labor and delivery.
### Nursing Mothers
- It is not known whether anabolic steroids are excreted in human milk. Many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from anabolic steroids, 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 safety and efficacy of nandrolone decanoate in children with metastatic breast cancer (rarely found) has not been established. Anabolic agents may accelerate epiphyseal maturation more rapidly than linear growth in children, and the effect may continue for six months after the drug has been stopped. Therefore, therapy should be monitored by X-ray studies at six month intervals in order to avoid the risk of compromising the adult height.
### Geriatic Use
- There is no FDA guidance on the use of Nandrolone with respect to geriatric patients.
### Gender
- There is no FDA guidance on the use of Nandrolone with respect to specific gender populations.
### Race
- There is no FDA guidance on the use of Nandrolone with respect to specific racial populations.
### Renal Impairment
- There is no FDA guidance on the use of Nandrolone in patients with renal impairment.
### Hepatic Impairment
- There is no FDA guidance on the use of Nandrolone in patients with hepatic impairment.
### Females of Reproductive Potential and Males
- There is no FDA guidance on the use of Nandrolone in women of reproductive potentials and males.
### Immunocompromised Patients
- There is no FDA guidance one the use of Nandrolone in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Nandrolone decanoate injection is intended for deep intramuscular injection only, into the gluteal muscle preferably. Dosage should be based on therapeutic response and consideration of the benefit to risk ratio. Duration of therapy will depend on the response of the condition and the appearance of adverse reactions. If possible, therapy should be intermittent. Nandrolone decanoate should be regarded as adjunctive therapy and adequate quantities of nutrients should be consumed in order to obtain maximal therapeutic effects. For example, when it is used in the treatment of refractory anemia, adequate iron intake is required for a maximal response.
- A dose of 50 to 100 mg per week is recommended for women and 100 to 200 mg per week for men. Drug therapy should be discontinued if no hematologic improvement is seen within the first six months. For children from 2 to 13 years of age, the average dose is 25 to 50 mg every 3 to 4 weeks. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever the solution and container permit.
### Monitoring
- There is limited information regarding Monitoring of Nandrolone in the drug label.
# IV Compatibility
- There is limited information regarding IV Compatibility of Nandrolone in the drug label.
# Overdosage
- There is limited information regarding Chronic Overdose of Nandrolone in the drug label.
# Pharmacology
## Mechanism of Action
- Anabolic steroids are synthetic derivatives of testosterone. Certain clinical effects and adverse reactions demonstrate the androgenic properties of this class of drugs. Complete dissociation of anabolic and androgenic effects has not been achieved. The actions of anabolic steroids are therefore similar to those of male sex hormones with the possibility of causing serious disturbances of growth and sexual development if given to young children. Anabolic steroids suppress the gonadotropic functions of the pituitary and may exert a direct effect upon the testis. Anabolic steroids have been reported to increase low-density lipoproteins and decrease high-density lipoproteins. These changes revert to normal on discontinuation of treatment.
## Structure
- A sterile oleaginous solution containing per mL: Nandrolone Decanoate 200 mg with Benzyl Alcohol 5% as solubilizer/preservative, in Sesame Oil q.s. Nandrolone decanoate (C28H44O3) occurs as a fine, white to creamy white, crystalline powder. It is odorless, or may have a slight odor. Nandrolone decanoate is soluble in chloroform, in alcohol, in acetone, and in vegetable oils. It is practically insoluble in water.
## Pharmacodynamics
- There is limited information regarding Pharmacodynamics of Nandrolone in the drug label.
## Pharmacokinetics
- There is limited information regarding Pharmacokinetics of Nandrolone in the drug label.
## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
- Nandrolone decanoate has not been tested in laboratory animals for carcinogenic or mutagenic effects. Liver cell tumors have been reported in patients receiving androgenic anabolic steroid therapy (see WARNINGS section). Geriatric patients treated with anabolics may be at an increased risk for prostatic hypertrophy and prostatic carcinoma.
# Clinical Studies
- There is limited information regarding Clinical Studies of Nandrolone in the drug label.
# How Supplied
- Nandrolone Decanoate Injection USP, 200 mg per mL is available in vials of 1 mL, in cartons of 20.
## Storage
- Store at 20° to 25°C (68° to 77°F) .
- PROTECT FROM LIGHT. Store in carton until contents are used.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Information for Patients
- The physician should instruct patients to report any of the following side effects of androgenic anabolic steroids: Hoarseness, acne, changes in menstrual periods, more hair on the face, nausea, vomiting, changes in skin color, or ankle swelling.
# Precautions with Alcohol
- Alcohol-Nandrolone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
Deca-Durabolin,
Hybolin Decanoate.
# Look-Alike Drug Names
- A® — B®
# Drug Shortage Status
# Price | Nandrolone
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
Nandrolone is an anabolic steroid, endocrine-metabolic agent that is FDA approved for the treatment of anemia of chronic renal failure. Common adverse reactions include acne in women and prepubertal boys, female hirsutism, male pattern alopecia in women, gynecomastia in men, diarrhea, nausea, vomiting, insomnia, depression, excitability, atrophy of testis, postpubertal males, erectile dysfunction, erection finding- increased frequency, hypertrophy of clitoris, irregular periods, decreased or increased libido in men or women, priapism, enlargement penis in prepubertal males, testicular hypofunction, deepening in voice in women, drug habituation.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Nandrolone decanoate is indicated for the management of the anemia of renal insufficiency and has been shown to increase hemoglobin and red cell mass. Surgically induced anephric patients have been reported to be less responsive.
- Dosing Information
- Nandrolone decanoate injection is intended for deep intramuscular injection only, into the gluteal muscle preferably. Dosage should be based on therapeutic response and consideration of the benefit to risk ratio. Duration of therapy will depend on the response of the condition and the appearance of adverse reactions. If possible, therapy should be intermittent. Nandrolone decanoate should be regarded as adjunctive therapy and adequate quantities of nutrients should be consumed in order to obtain maximal therapeutic effects. For example, when it is used in the treatment of refractory anemia, adequate iron intake is required for a maximal response.
- Both nandrolone decanoate is administered by deep intramuscular injection. For nandrolone decanoate, the recommended dose for women is 50 to 100 milligrams per week and 100 to 200 milligrams per week for men.
- Prior to the availability of recombinant erythropoietin (epoetin), nandrolone decanoate was widely used in the treatment of ANEMIA in patients with chronic renal failure in doses of 100 to 200 milligrams intramuscularly weekly. Responses were best in patients who were well-nourished and receiving adequate dialysis.
- Recombinant epoetin is now usually preferred over androgens for initial non-transfusional therapy in these patients. The use of lower doses of epoetin in combination with nandrolone has, however, been investigated due to financial constraints. In one study, a greater increase in hematocrit was reported with combined low-dose recombinant epoetin (2000 units three times weekly) plus nandrolone decanoate (100 milligrams weekly) as compared to epoetin alone in the same doses in male hemodialysis patients. Nandrolone therapy was started simultaneously with epoetin. However, in another combination study, no additional benefit was observed when nandrolone was started at least 2 months prior to epoetin. Further studies investigating this combination are needed.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Nandrolone in adult patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Nandrolone in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Dosing Information
- The safety and effectiveness in children less than 2 years of age has not been established.
- In children 2 to 13 years of age, the dose of nandrolone decanoate is 25 to 50 milligrams every 3 to 4 weeks.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Nandrolone in pediatric patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Nandrolone in pediatric patients.
# Contraindications
- Male patients with carcinoma of the breast or with known or suspected carcinoma of the prostate.
- Carcinoma of the breast in females with hypercalcemia: androgenic anabolic steroids may stimulate osteolytic resorption of bones.
- Pregnancy, because of masculinization of the fetus.
- Nephrosis or the nephrotic phase of nephritis.
# Warnings
- PELIOSIS HEPATIS, A CONDITION IN WHICH LIVER AND SOMETIMES SPLENIC TISSUE IS REPLACED WITH BLOOD-FILLED CYSTS, HAS BEEN REPORTED IN PATIENTS RECEIVING ANDROGENIC ANABOLIC STEROID THERAPY. THESE CYSTS ARE SOMETIMES PRESENT WITH MINIMAL HEPATIC DYSFUNCTION, BUT AT OTHER TIMES THEY HAVE BEEN ASSOCIATED WITH LIVER FAILURE. THEY ARE OFTEN NOT RECOGNIZED UNTIL LIFE-THREATENING LIVER FAILURE OR INTRA-ABDOMINAL HEMORRHAGE DEVELOPS. WITHDRAWAL OF DRUG USUALLY RESULTS IN COMPLETE DISAPPEARANCE OF LESIONS. LIVER CELL TUMORS ARE ALSO REPORTED. MOST OFTEN THESE TUMORS ARE BENIGN AND ANDROGEN-DEPENDENT, BUT FATAL MALIGNANT TUMORS HAVE BEEN REPORTED. WITHDRAWAL OF DRUG OFTEN RESULTS IN REGRESSION OR CESSATION OF PROGRESSION OF THE TUMOR. HOWEVER, HEPATIC TUMORS ASSOCIATED WITH ANDROGENS OR ANABOLIC STEROIDS ARE MUCH MORE VASCULAR THAN OTHER HEPATIC TUMORS AND MAY BE SILENT UNTIL LIFE-THREATENING INTRA-ABDOMINAL HEMORRHAGE DEVELOPS. BLOOD LIPID CHANGES THAT ARE KNOWN TO BE ASSOCIATED WITH INCREASED RISK OF ATHEROSCLEROSIS ARE SEEN IN PATIENTS TREATED WITH ANDROGENS AND ANABOLIC STEROIDS. THESE CHANGES INCLUDE DECREASED HIGH-DENSITY LIPOPROTEIN AND SOMETIMES INCREASED LOW-DENSITY LIPOPROTEIN. THE CHANGES MAY BE VERY MARKED AND COULD HAVE A SERIOUS IMPACT ON THE RISK OF ATHEROSCLEROSIS AND CORONARY ARTERY DISEASE.
- Hypercalcemia may develop both spontaneously and as a result of androgen therapy in women with disseminated breast carcinoma. If it develops while on this agent, the drug should be discontinued. Caution is required in administering these agents to patients with cardiac, renal or hepatic disease. Cholestatic jaundice is associated with therapeutic use of anabolic and androgenic steroids. Edema may occur occasionally with or without congestive heart failure. Concomitant administration of adrenal steroids or ACTH may add to the edema. In children, anabolic steroid treatment may accelerate bone maturation without producing compensatory gain in linear growth. This adverse effect may result in compromised adult stature. The younger the child the greater the risk of compromising final mature height. The effect on bone maturation should be monitored by assessing bone age of the wrist and hand every six months. This drug has not been shown to be safe and effective for the enhancement of athletic performance. Because of the potential risk of serious adverse health effects, this drug should not be used for such purpose.
### Precautions
General
- Women should be observed for signs of virilization (deepening of the voice, hirsutism, acne, clitorimegaly and menstrual irregularities). Discontinuation of drug therapy at the time of evidence of mild virilism is necessary to prevent irreversible virilization. Such virilization is usual following anabolic steroid use in high doses. The insulin or oral hypoglycemic dosage may need adjustment in diabetic patients who receive anabolic steroids.
Laboratory Tests
- Women with disseminated breast carcinoma should have frequent determination of urine and serum calcium levels during the course of anabolic therapy (see WARNINGS section). If children are treated, periodic (every six months) X-ray examinations of bone age should be made during treatment to determine the rate of bone maturation and the effects of anabolic therapy on the epiphyseal centers. Hemoglobin and hematocrit should be checked periodically for polycythemia in patients who are receiving high doses of anabolic steroids. Serum lipids and high-density lipoprotein cholesterol should be determined periodically. Because of the hepatotoxicity associated with the use of 17-alpha-alkylated anabolic steroids, liver function tests should be obtained periodically.
# Adverse Reactions
## Clinical Trials Experience
Hepatic:
- Hepatocellular neoplasms and peliosis hepatis have been reported in association with long-term androgenic anabolic steroid therapy (see WARNINGS section).
Genitourinary System:
- In men.
- Prepubertal: Phallic enlargement and increased frequency of erections.
- Postpubertal: Inhibition of testicular function, testicular atrophy and oligospermia, impotence, chronic priapism, epididymitis and bladder irritability.
- In women: Clitoral enlargement, menstrual irregularities. In both sexes: Increased or decreased libido.
CNS:
- Habituation, excitation, insomnia, depression.
Gastrointestinal:
- Nausea, vomiting, diarrhea.
Hematologic:
- Bleeding in patients on concomitant anticoagulant therapy (see PRECAUTIONS, Drug Interactions).
Breast:
- Gynecomastia.
Larynx:
- Deepening of the voice in women.
Hair:
- Hirsutism and male pattern of baldness in women.
Skin:
- Acne (especially in women and prepubertal boys.)
Skeletal:
- Premature closure of epiphyses in children (see PRECAUTIONS, Pediatric use).
Fluid and Electrolytes:
- Edema, retention of serum electrolytes (sodium, chloride, potassium, phosphate, calcium).
Metabolic/Endocrine:
- Decreased glucose tolerance (see PRECAUTIONS, General), increased serum levels of low-density lipoprotein and decreased levels of high-density lipoprotein (see PRECAUTIONS, Laboratory tests), increased creatine and creatinine excretion, increased serum levels of creatinine phosphokinase (CPK). Some virilizing changes in women are irreversible even after prompt discontinuance of therapy and are not prevented by concomitant use of estrogens (see PRECAUTIONS).
### DRUG ABUSE AND DEPENDENCE
- Nandrolone decanoate injection is classified as a Schedule III controlled substance under the Anabolic Steroids Control Act of 1990.
## Postmarketing Experience
- There is limited information regarding Postmarketing Experience of Nandrolone in the drug label
# Drug Interactions
- Anticoagulants. Anabolic steroids may increase sensitivity to oral anticoagulants. Dosage of the anticoagulant may have to be decreased in order to maintain the prothrombin time at the desired therapeutic level. Patients receiving oral anticoagulant therapy require close monitoring, especially when anabolic steroids are started or stopped.
DRUG & OR LABORATORY TEST INTERACTIONS
- Anabolic steroid therapy may decrease thyroxine-binding globulin resulting in decreased total T4 serum levels and increased resin uptake of T3 and T4. Free thyroid hormone levels remain unchanged. Anabolic steroids may cause an increase in prothrombin time.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): X
Pregnancy Category X.
See CONTRAINDICATIONS section.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
- There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Nandrolone in women who are pregnant.
### Labor and Delivery
- There is no FDA guidance on use of Nandrolone during labor and delivery.
### Nursing Mothers
- It is not known whether anabolic steroids are excreted in human milk. Many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from anabolic steroids, 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 safety and efficacy of nandrolone decanoate in children with metastatic breast cancer (rarely found) has not been established. Anabolic agents may accelerate epiphyseal maturation more rapidly than linear growth in children, and the effect may continue for six months after the drug has been stopped. Therefore, therapy should be monitored by X-ray studies at six month intervals in order to avoid the risk of compromising the adult height.
### Geriatic Use
- There is no FDA guidance on the use of Nandrolone with respect to geriatric patients.
### Gender
- There is no FDA guidance on the use of Nandrolone with respect to specific gender populations.
### Race
- There is no FDA guidance on the use of Nandrolone with respect to specific racial populations.
### Renal Impairment
- There is no FDA guidance on the use of Nandrolone in patients with renal impairment.
### Hepatic Impairment
- There is no FDA guidance on the use of Nandrolone in patients with hepatic impairment.
### Females of Reproductive Potential and Males
- There is no FDA guidance on the use of Nandrolone in women of reproductive potentials and males.
### Immunocompromised Patients
- There is no FDA guidance one the use of Nandrolone in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Nandrolone decanoate injection is intended for deep intramuscular injection only, into the gluteal muscle preferably. Dosage should be based on therapeutic response and consideration of the benefit to risk ratio. Duration of therapy will depend on the response of the condition and the appearance of adverse reactions. If possible, therapy should be intermittent. Nandrolone decanoate should be regarded as adjunctive therapy and adequate quantities of nutrients should be consumed in order to obtain maximal therapeutic effects. For example, when it is used in the treatment of refractory anemia, adequate iron intake is required for a maximal response.
- A dose of 50 to 100 mg per week is recommended for women and 100 to 200 mg per week for men. Drug therapy should be discontinued if no hematologic improvement is seen within the first six months. For children from 2 to 13 years of age, the average dose is 25 to 50 mg every 3 to 4 weeks. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever the solution and container permit.
### Monitoring
- There is limited information regarding Monitoring of Nandrolone in the drug label.
# IV Compatibility
- There is limited information regarding IV Compatibility of Nandrolone in the drug label.
# Overdosage
- There is limited information regarding Chronic Overdose of Nandrolone in the drug label.
# Pharmacology
## Mechanism of Action
- Anabolic steroids are synthetic derivatives of testosterone. Certain clinical effects and adverse reactions demonstrate the androgenic properties of this class of drugs. Complete dissociation of anabolic and androgenic effects has not been achieved. The actions of anabolic steroids are therefore similar to those of male sex hormones with the possibility of causing serious disturbances of growth and sexual development if given to young children. Anabolic steroids suppress the gonadotropic functions of the pituitary and may exert a direct effect upon the testis. Anabolic steroids have been reported to increase low-density lipoproteins and decrease high-density lipoproteins. These changes revert to normal on discontinuation of treatment.
## Structure
- A sterile oleaginous solution containing per mL: Nandrolone Decanoate 200 mg with Benzyl Alcohol 5% as solubilizer/preservative, in Sesame Oil q.s. Nandrolone decanoate (C28H44O3) occurs as a fine, white to creamy white, crystalline powder. It is odorless, or may have a slight odor. Nandrolone decanoate is soluble in chloroform, in alcohol, in acetone, and in vegetable oils. It is practically insoluble in water.
## Pharmacodynamics
- There is limited information regarding Pharmacodynamics of Nandrolone in the drug label.
## Pharmacokinetics
- There is limited information regarding Pharmacokinetics of Nandrolone in the drug label.
## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
- Nandrolone decanoate has not been tested in laboratory animals for carcinogenic or mutagenic effects. Liver cell tumors have been reported in patients receiving androgenic anabolic steroid therapy (see WARNINGS section). Geriatric patients treated with anabolics may be at an increased risk for prostatic hypertrophy and prostatic carcinoma.
# Clinical Studies
- There is limited information regarding Clinical Studies of Nandrolone in the drug label.
# How Supplied
- Nandrolone Decanoate Injection USP, 200 mg per mL is available in vials of 1 mL, in cartons of 20.
## Storage
- Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].
- PROTECT FROM LIGHT. Store in carton until contents are used.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Information for Patients
- The physician should instruct patients to report any of the following side effects of androgenic anabolic steroids: Hoarseness, acne, changes in menstrual periods, more hair on the face, nausea, vomiting, changes in skin color, or ankle swelling.
# Precautions with Alcohol
- Alcohol-Nandrolone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
Deca-Durabolin,
Hybolin Decanoate.
# Look-Alike Drug Names
- A® — B®[1]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Deca-Durabolin | |
8862ca9ac73a688295bda693c32e5f6fb8d5f358 | wikidoc | Decaborane | Decaborane
Decaborane, also called decaborane(14) or decaboron tetradecahydride, is a stable crystalline borane with chemical formula B10H14. It forms colorless to white crystals. The B10 framework is an incomplete icosahedron.
B10H14 possesses a strong penetrating musty odor that is unique to boranes and quickly recognizable; decaborane itself smells intensely bitter, chocolate-like. When ignited it produces a bright green flame, as do other boron hydrides. It is not sensitive to moist air, although it hydrolyzes in boiling water, releasing hydrogen and boric acid solution. It is soluble in cold water.
# Synthesis
It is commonly synthesized via the pyrolysis of smaller boron hydride clusters (for example B2H6 or B5H9) under vacuum. The physical characteristics of decaborane(14) resemble those of the organic compounds naphthalene and anthracene, in that it is highly flammable and can be sublimed under vacuum at moderate temperatures. Sublimation is the most common method of purification.
# Chemical properties
Decaborane(14) is soluble in a wide variety of non-polar and moderately polar solvents including hexanes, benzene, toluene, diethyl ether, and methylene chloride. In strongly coordinating solvents (i.e. CH3CN or Me2S), decaborane(14) readily forms an adduct with the formula B10H12·2L, where L = CH3CN, Me2S).
Decaborane(14) is a Brønsted acid: in the presence of moderately strong bases, a proton can be removed to generate the anion –.
Decaborane, like pentaborane, is a powerful toxin affecting central nervous system, although considerably less toxic than pentaborane. It can be absorbed through skin.
It forms an explosive mixture with tetrachloromethane, which caused an often quoted explosion in a Malta, NY manufacturing facility in 1948 when CCl4 was used to clean the equipment.
# Applications
Decaborane ions can be used for low energy ion implantation of boron in the manufacture of semiconductors; the molecule decomposes in the plasma, yielding monoatomic boron ions. It is also used in plasma-assisted chemical vapor deposition to manufacture boron-containing thin films.
In fusion research, the absorbing nature of thin films of decaborane is used to boronize the walls of the tokamak vacuum vessel to reduce recycling of particles and impurities into the plasma and improve overall performance.
In polymer chemistry, decaborane is used as a catalyst.
Decaborane was also being used as an additive to special high-performance rocket fuels. Its derivates were investigated as well, eg. ethyl decaborane. One patented fuel composition includes vinyl decaborane-polyester copolymer. Vinyl decaborane ("dekene") is prepared by reacting decaborane with acetylene. | Decaborane
Template:Chembox new
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Decaborane, also called decaborane(14) or decaboron tetradecahydride, is a stable crystalline borane with chemical formula B10H14. It forms colorless to white crystals. The B10 framework is an incomplete icosahedron.
B10H14 possesses a strong penetrating musty odor that is unique to boranes and quickly recognizable; decaborane itself smells intensely bitter, chocolate-like. When ignited it produces a bright green flame, as do other boron hydrides. It is not sensitive to moist air, although it hydrolyzes in boiling water, releasing hydrogen and boric acid solution. It is soluble in cold water.
# Synthesis
It is commonly synthesized via the pyrolysis of smaller boron hydride clusters (for example B2H6 or B5H9) under vacuum. The physical characteristics of decaborane(14) resemble those of the organic compounds naphthalene and anthracene, in that it is highly flammable and can be sublimed under vacuum at moderate temperatures. Sublimation is the most common method of purification.
# Chemical properties
Decaborane(14) is soluble in a wide variety of non-polar and moderately polar solvents including hexanes, benzene, toluene, diethyl ether, and methylene chloride. In strongly coordinating solvents (i.e. CH3CN or Me2S), decaborane(14) readily forms an adduct with the formula B10H12·2L, where L = CH3CN, Me2S).
Decaborane(14) is a Brønsted acid: in the presence of moderately strong bases, a proton can be removed to generate the anion [B10H13]–.
Decaborane, like pentaborane, is a powerful toxin affecting central nervous system, although considerably less toxic than pentaborane. It can be absorbed through skin.
It forms an explosive mixture with tetrachloromethane, which caused an often quoted explosion in a Malta, NY manufacturing facility in 1948 when CCl4 was used to clean the equipment.[1]
# Applications
Decaborane ions can be used for low energy ion implantation of boron in the manufacture of semiconductors; the molecule decomposes in the plasma, yielding monoatomic boron ions. It is also used in plasma-assisted chemical vapor deposition to manufacture boron-containing thin films.
In fusion research, the absorbing nature of thin films of decaborane is used to boronize the walls of the tokamak vacuum vessel to reduce recycling of particles and impurities into the plasma and improve overall performance.
[2]
In polymer chemistry, decaborane is used as a catalyst.
Decaborane was also being used as an additive to special high-performance rocket fuels. Its derivates were investigated as well, eg. ethyl decaborane. One patented fuel composition includes vinyl decaborane-polyester copolymer. Vinyl decaborane ("dekene") is prepared by reacting decaborane with acetylene. [3] | https://www.wikidoc.org/index.php/Decaborane | |
7a26751abae49e071a7c95022abf0732a72d9cc4 | wikidoc | Perflutren | Perflutren
Perflutren (Optison, Protein-Type A Microspheres Injectable Suspension, USP) is a sterile non-pyrogenic suspension of microspheres of human serum albumin with perflutren for contrast enhancement during the indicated ultrasound imaging procedures. The vial contains a clear liquid lower layer and a white upper layer that, after resuspension by gentle mixing, provides a homogeneous, opaque, milky-white suspension for intravenous injection.
Perflutren is chemically characterized as 1,1,1,2,2,3,3,3-perflutren with a molecular weight of 188, an empirical formula of C3F8.
Each mL of Optison contains 5.0-8.0×108 protein-type A microspheres, 10 mg Albumin Human, USP, 0.22 ± 0.11 mg/mL perflutren, 0.2 mg N-acetyltryptophan, and 0.12 mg caprylic acid in 0.9% aqueous sodium chloride. The headspace of the vial is filled with perflutren gas. The pH is adjusted to 6.4-7.4. The protein in the microsphere shell makes up approximately 5-7% (w/w) of the total protein in the liquid. The microsphere particle size parameters are listed in Table 1.
# Clinical Pharmacology
## General
The Optison microspheres create an echogenic contrast effect in the blood.
## Pharmacokinetics
Studies in humans have evaluated the pharmacokinetics of the perflutren component of the Optison microspheres. After injection of Optison, diffusion of the perflutren gas out of the microspheres is limited by the low partition coefficient of the gas in blood that contributes to the persistence of the microspheres. The diffusion rate has not been studied.
In an anesthetized dog model, the acoustic properties of Optison were established at 0.6 mechanical index and 2.5 MHz frequency.
Neither the pharmacokinetics of the intact microspheres or of the human albumin component have been evaluated in humans.
## Metabolism
Perflutren is a stable gas that is not metabolized. The human albumin component of the microsphere is expected to be handled by the normal metabolic routes for human albumin.
## Perflutren Elimination
Following a single intravenous dose of 20 mL Optison to 10 healthy volunteers (5 men and 5 women), most of the perflutren was eliminated through the lungs within 10 minutes. The recovery was 96% ± 23% (mean ± SD), and the pulmonary elimination half-life was 1.3 ± 0.69 minutes (mean ± SD). The perflutren concentration in expired air peaked approximately 30-40 seconds after administration.
## Perflutren Protein Binding
The binding of perflutren to plasma proteins or its partitioning into blood cells have not been studied. However, perflutren protein binding is expected to be minimal due to the low partition coefficient of the gas in blood.
## Special Populations
The pharmacokinetics of Optison have not been studied in patients with hepatic or respiratory diseases.
## Gender, Age, Race
The effects of gender, age, or race on the pharmacokinetics of Optison have not been studied.
## Drug-Drug Interactions
Drug-drug interactions for Optison have not been studied.
## Pediatrics
The pharmacokinetics of Optison in pediatric patients have not been studied.
# Pharmocodynamics
The general acoustic properties of Optison are similar to those of ALBUNEX®. The acoustic impedance of the Optison microspheres is much lower than that of the blood. Therefore, impinging ultrasound waves are scattered and reflected at the microsphere-blood interface and ultimately may be visualized in the ultrasound image. At the frequencies used in adult echocardiography (2-5 MHz), the microspheres resonate which further increases the extent of ultrasound scattering and reflection.
As assessed by the unblinded investigators in clinical studies, the median duration of Optison contrast enhancement for each of the four doses of Optison (0.2, 0.5, 3.0, and 5.0 mL) were approximately one, two, four, and five minutes, respectively (see CLINICAL TRIALS section).
# Clinical Trials
The efficacy of Optison was evaluated in two identical multicenter, dose escalation, randomized, cross-over studies of Optison and ALBUNEX®. The test drugs were administered single blind and the image analysis was double blind. Eligible patients were undergoing routine echocardiography and all patients were required to have at least two of six segments of the left ventricular endocardial border that were not well delineated in the apical 4-chamber view. In these studies, the 203 patients (Study A: n=101, Study B: n=102) received at least one dose of study drug had the following characteristics: 79% men, 21% women, 64% White, 25% Black, 10% Hispanic, and 1% other race or ethnic group. The patients had a mean age of 61 years (range: 21 to 83 years), a mean weight of 196 lbs (range: 117 to 342 lbs), a mean height of 68 inches (range: 47 to 78 inches), and a mean body surface area of 2.0m2 (range: 1.4 to 2.6m2). Approximately 23% of the patients had chronic pulmonary disease, and 17% had congestive and dilated cardiomyopathy with left ventricular ejection fractions (LVEFs) of between 20% and 40% (by previous echocardiography). Patients with a LVEF of less than 20% or with New York Heart Association Class IV heart failure were not included in the studies.
The study test drugs were four doses of Optison (0.2, 0.5, 3.0 and 5.0 mL) and two doses of ALBUNEX® (0.08 and 0.22 mL/kg). The two test drugs were administered to the patients in a random sequence, with two to ten days between each drug. After non-contrast imaging, the test doses were administered in ascending order with at least ten minutes between each dose. Ultrasound settings were optimized for the baseline (non-contrast) apical four-chamber view and remained unchanged for the contrast imaging. Static echocardiographic images and video-tape segments were interpreted by a reader who was blinded to the patient's clinical history and to the identity and dose of the test drug. The primary efficacy endpoint was left ventricular endocardial border delineation, assessed before and after Optison administration, by the measurement of visualized endocardial border length. The six segments of the left ventricular endocardial border were also assessed qualitatively (i.e., not well delineated, average delineation, good delineation, excellent delineation) before and after Optison administration.
In comparison to non-contrast ultrasound, Optison significantly increased the length of endocardial border that could be visualized both at end-systole and end-diastole (see Table 2). In these patients there was a trend towards less visualization in women. Similarly, in comparison to non-contrast ultrasound, Optison significantly improved the qualitative ability to delineate each of the left ventricular segments, though the effect was less for the septal segments. As assessed by videodensitometry, Optison increased left ventricular opacification (peak intensity) in the mid-chamber and apical views (see Table 3). In subset analysis, Optison tended to enhance the quality of the spectral Doppler signal of the pulmonary veins. The imaging effects of Optison on endocardial border delineation and left ventricular opacification tended to be qualitatively similar in patients with and without pulmonary disease or dilated cardiomyopathy.
In these studies, quantitative measures of left ventricular function (e.g., ejection fraction), quantitative measurements of anatomical structures (e.g., wall thickness), or the evaluation of myocardial perfusion were not performed.
# Indications
Optison is indicated for use in patients with suboptimal echocardiograms to opacify the left ventricle and to improve the delineation of the left ventricular endocardial borders. The safety and efficacy of Optison with exercise stress or pharmacologic stress testing have not been established.
# Contraindications
Do not administer Optison to patients with known or suspected:
- Right-to-left, bi-directional, or transient right-to-left cardiac shunts,
- Worsening or clinically unstable congestive heart failure,
- Acute myocardial infarction or acute coronary syndromes,
- Serious ventricular arrhythmias or high risk for arrhythmias due to prolongation of the QT interval,
- Respiratory failure, as manifest by signs or symptoms of carbon dioxide retention or hypoxemia,
- Severe emphysema, pulmonary emboli or other conditions that cause pulmonary hypertension due to compromised pulmonary arterial vasculature, and
- Hypersensitivity to perflutren, blood, blood products, or albumin (see WARNINGS).
Do not administer Optison by intra-arterial injection.
# Warnings
## Serious Cardiopulmonary Reactions
Serious cardiopulmonary reactions, including fatalities, have occurred during or within 30 minutes following perflutren-containing microsphere administration. Assess all patients for the presence of any condition that precludes Optison administration (see CONTRAINDICATIONS). Monitor patients during and for 30 minutes following Optison administration, including vital sign measurements and electrocardiography in all patients and cutaneous oxygen saturation in patients at risk for hypoxemia. Always have resuscitation equipment and trained personnel readily available.
In postmarketing use, four patients experienced fatal cardiac arrests either during or within 30 minutes of perflutren-containing microsphere administration; one patient received the product and underwent a cardiac stress test, two patients had severe congestive heart failure and the fourth was undergoing mechanical ventilation for respiratory failure. Other uncommon but serious reactions observed during or shortly following perflutren-containing microsphere administration included cardiac or respiratory arrest, loss of consciousness, convulsions, symptomatic arrhythmias (atrial fibrillation, supraventricular tachycardia, ventricular tachycardia or fibrillation), hypotension, respiratory distress or cardiac ischemia (see ADVERSE REACTIONS).
## Anaphylactoid Reactions
Postmarketing reports of acute anaphylactoid reactions including shock, bronchospasm, upper airway swelling, loss of consciousness, urticaria and pruritus, have occurred in patients with no prior exposure to perflutren-containing microsphere products. Monitor all patients for signs and symptoms of anaphylactoid reactions (see ADVERSE REACTIONS).
## Systemic Embolization of Optison in Patients with Cardiac Shunts
In patients with right-to-left, bi-directional, or transient right-to-left cardiac shunts perflutren-containing microspheres can bypass the pulmonary particle-filtering mechanisms and directly enter the arterial circulation resulting in microvascular occlusion and ischemia. Do not administer Optison by intra-arterial injection.
## High Ultrasound Mechanical Index
High ultrasound mechanical index values may cause microsphere cavitation or rupture and lead to ventricular arrhythmias. Additionally, end-systolic triggering with high mechanical indices has been reported to cause ventricular arrhythmias. The safety of Optison at mechanical indices greater than 0.8 has not been evaluated. The safety of Optison with the use of end-systolic triggering has not been evaluated.
# Precautions
## General
This product contains albumin, a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries an extremely remote risk for transmission of viral disease. A theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD) also is considered extremely remote. No cases of transmission of viral disease or CJD have ever been identified for albumin.
## Laboratory Tests
Immunologic tests of serum immunoglobulins, cytokines, and complement were monitored in a 3 week study of 20 healthy volunteers and 30 patients who received Optison or a 1% albumin control. Clinically relevant changes in the measured parameters were not noted. In another study 5 subjects received a skin test with Optison one year after receiving Optison. One subject had a positive skin test and was not given a repeat dose of Optison.
## Information for Patients
Patients receiving Optison:
- Inform your physician or health care provider if you may be pregnant or are nursing an infant.
- Inform your physician if you ever have had an allergic or hypersensitivity reaction to blood, blood products, or albumin.
- Inform your physician or health care provider if you have a congenital heart defect.
## Carcinogenesis, Mutagenesis, and Impairment of Fertility
Animal studies were not carried out to determine the carcinogenic potential of Optison.
The result of the following genotoxicity studies with Optison were negative: 1) Salmonella/Escherichia coli reverse mutation assay, 2) in vitro mammalian chromosome aberration assay using Chinese hamster ovary cells (CHO) with and without metabolic activation, 3) CHO/HGPRT forward mutation assay, and 4) in vivo mammalian micronucleus assay.
Pregnancy Category C
Optison administered intravenously to rats during organogenesis at doses of 0.25, 5.0 and 10.0 mL/kg/day was fetotoxic at 0.25 and 5.0 mL/kg (approximately 0.2 and 5 times the recommended maximum human dose, respectively, based on body surface area). Fetotoxicity was characterized by an increased incidence of reversible delayed pelvic ossification, the incidence of which was not related to dose. Signs of maternal toxicity at 5 mL/kg included respiratory and motor signs. Maternal death occurred at 10 mL/kg. A no observable adverse effect level (NOAEL) for fetotoxicity was not determined. Teratogenic effects were not observed at doses up to 10 mL/kg/day. The NOAEL for maternal toxicity was 0.25 mL/kg.
Optison administered intravenously to rabbits during organogenesis at doses of 0.25, 2.5 and 5.0 mL/kg/day was embryofetal toxic at 2.5 and 5.0 mL/kg (approximately 5 and 10 times the recommended maximum human dose, respectively, based on body surface area). Embryofetal toxicity was characterized by a decrease in fetal body weight and an increase in embryofetal death. Teratogenic effects (cleft palates and dilation of the lateral ventricles of the brain associated with skull abnormalities and compression deformities) were observed at 2.5 mL/kg but not 5 mL/kg. Neither the incidence nor the severity of embryofetal toxicity and teratogenicity exhibited a dose-dependent relationship. Maternal toxicity (significant suppression of body weight gain, abnormal stool) was observed at 2.5 and 5.0 mL/kg with the greatest effect observed at 2.5 mL/kg. The NOAEL for embryofetal and maternal toxicity was 0.25 mL/kg (approximately 0.5 times the recommended maximum human dose).
Adequate or well-controlled studies were not conducted in pregnant women. Optison should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
## 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 Optison is administered to a nursing woman.
## Pediatric Use
Safety and efficacy have not been established in pediatric patients, or in patients with congenital heart disease (see WARNINGS).
# Adverse Reactions
## Clinical Trials Experience
Optison was administered in clinical studies in 279 patients. Of these patients there were 192 (68.8%) men and 87 (31.2%) women. The racial demographics were 199 (71.3%) Caucasian, 52 (18.6%) Black, 24 (8.6%) Hispanic, and 4 (1.4%) other racial or ethnic groups.
In these patients, 47 (16.8%) reported at least one adverse event. Of these one event was serious and required treatment with antihistamines for hypersensitivity manifestations of dizziness, nausea, flushing and temperature elevation. Deaths were not reported during the clinical studies.
Of the reported adverse reactions following the use of Optison the most frequently reported were headache (5.4%), nausea and/or vomiting (4.3%), warm sensation or flushing (3.6%), and dizziness (2.5%). The most common adverse events observed in clinical studies of Optison are given in Table 4.
Adverse events reported in < 0.5% of subjects who received Optison included: arthralgia, back pain, body or muscle aches, induration, urticaria, dry mouth, eosinophilia, palpitations, paresthesia, photophobia, premature ventricular contraction, pruritus, rash, irritableness, hypersensitivity, tinnitus, tremor, visual blurring, wheezing, oxygen saturation decline due to coughing, discoloration at the Heplock site, and burning sensation in the eyes.
Overall the reported adverse events with Optison were similar in type and frequency to those reported in the 199 patients who received ALBUNEX®.
In the clinical dose ranging studies of 40 normal volunteers, doses higher than those recommended in the DOSAGE AND ADMINISTRATION section tended to be associated with an increased frequency of reported adverse events.
# Postmarketing Experience
The following adverse reactions have been identified during the postmarketing use of perflutren-containing microsphere products. 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.
Four fatal cardiac arrests and other serious but non-fatal adverse reactions were uncommonly reported. Most of these uncommon reactions included cardiopulmonary symptoms and signs such as cardiac or respiratory arrest, hypotension, supraventricular and ventricular arrhythmias, respiratory distress or decreased oxygenation. Reports also identified neurologic reactions (loss of consciousness or convulsions) as well as anaphylactoid reactions (see WARNINGS).
# Optison Dosage and Administration
The recommended dose of Optison is 0.5 mL injected into a peripheral vein. This may be repeated for further contrast enhancement as needed. See individualization of dose below.
- The injection rate should not exceed 1 mL per second.
- Follow the Optison injection with a flush of 0.9% Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP.
- The maximum total dose should not exceed 5.0 mL in any 10 minute period.
- The maximum total dose should not exceed 8.7 mL in any one patient study.
## Individualization of Dose
Image quality in cardiac ultrasound is a function of the acoustic window which is influenced by many variables including body habitus, intervening lung tissue, adequacy of transducer skin interface and other acoustic factors. These variables may influence the ultrasound contrast effect.
If the contrast enhancement is inadequate after the dose of 0.5 mL, additional doses in increments of 0.5 mL up to 5.0 mL cumulatively in a 10 minute period may be injected intravenously up to a maximum total dose of 8.7 mL in any one patient study.
# DRUG HANDLING DIRECTIONS
FOR SINGLE USE ONLY.
Optison does not contain preservatives. Bacterial contamination with the risk of post-infusion septicemia can occur if the container has been damaged or following puncture of the rubber cap. A single vial must not be used for more than one patient. Discard unused product properly.
DO NOT USE if the container has been damaged or the protective seal and/or rubber cap have been entered.
DO NOT USE if the upper white layer is absent. This indicates that the microspheres may have been damaged and may result in poor or no echo contrast.
DO NOT INJECT air into the vial.
- Invert the Optison vial and gently rotate to resuspend the microspheres. This process will allow the product to come to room temperature before use.
- Inspect the vial for complete resuspension. Failure to adequately resuspend Optison may cause an under delivery of the microspheres, and may result in inadequate contrast.
- Do not use Optison if, after resuspension, the solution appears to be clear rather than opaque milky-white.
- Vent the Optison vial with a sterile vent spike or with a sterile 18 gauge needle before withdrawing the Optison suspension into the injection syringe.
DO NOT USE if after resuspending the Optison, the product remains clear rather than appearing opaque and milky-white.
# INJECTION PROCEDURE
The time from resuspension of the Optison to injection must not exceed one minute. If one minute is exceeded, resuspend the microspheres in the syringe by gently rotating and inverting the syringe.
Before injection, provide intravenous access in a peripheral vein with a 20-gauge or larger angiocatheter. Suggested methods of administration include: a short extension tubing, heparin lock, or intravenous line, all with a 3-way stopcock.
For short extension tubing or heparin lock: fill one syringe with 0.9% Sodium Chloride Injection, USP, and flush the line for patency before and after the injection of Optison.
For a continuous intravenous line: open an intravenous line with 0.9% Sodium Chloride Injection, USP (or 5% Dextrose Injection, USP) at a slow infusion rate to maintain vascular patency. The line should be flushed immediately after injection of Optison.
DO NOT ASPIRATE blood back into the Optison containing syringe before administration; this may promote the formation of a blood clot within the syringe. | Perflutren
Perflutren (Optison, Protein-Type A Microspheres Injectable Suspension, USP) is a sterile non-pyrogenic suspension of microspheres of human serum albumin with perflutren for contrast enhancement during the indicated ultrasound imaging procedures. The vial contains a clear liquid lower layer and a white upper layer that, after resuspension by gentle mixing, provides a homogeneous, opaque, milky-white suspension for intravenous injection.
Perflutren is chemically characterized as 1,1,1,2,2,3,3,3-perflutren with a molecular weight of 188, an empirical formula of C3F8.
Each mL of Optison contains 5.0-8.0×108 protein-type A microspheres, 10 mg Albumin Human, USP, 0.22 ± 0.11 mg/mL perflutren, 0.2 mg N-acetyltryptophan, and 0.12 mg caprylic acid in 0.9% aqueous sodium chloride. The headspace of the vial is filled with perflutren gas. The pH is adjusted to 6.4-7.4. The protein in the microsphere shell makes up approximately 5-7% (w/w) of the total protein in the liquid. The microsphere particle size parameters are listed in Table 1.
# Clinical Pharmacology
## General
The Optison microspheres create an echogenic contrast effect in the blood.
## Pharmacokinetics
Studies in humans have evaluated the pharmacokinetics of the perflutren component of the Optison microspheres. After injection of Optison, diffusion of the perflutren gas out of the microspheres is limited by the low partition coefficient of the gas in blood that contributes to the persistence of the microspheres. The diffusion rate has not been studied.
In an anesthetized dog model, the acoustic properties of Optison were established at 0.6 mechanical index and 2.5 MHz frequency.
Neither the pharmacokinetics of the intact microspheres or of the human albumin component have been evaluated in humans.
## Metabolism
Perflutren is a stable gas that is not metabolized. The human albumin component of the microsphere is expected to be handled by the normal metabolic routes for human albumin.
## Perflutren Elimination
Following a single intravenous dose of 20 mL Optison to 10 healthy volunteers (5 men and 5 women), most of the perflutren was eliminated through the lungs within 10 minutes. The recovery was 96% ± 23% (mean ± SD), and the pulmonary elimination half-life was 1.3 ± 0.69 minutes (mean ± SD). The perflutren concentration in expired air peaked approximately 30-40 seconds after administration.
## Perflutren Protein Binding
The binding of perflutren to plasma proteins or its partitioning into blood cells have not been studied. However, perflutren protein binding is expected to be minimal due to the low partition coefficient of the gas in blood.
## Special Populations
The pharmacokinetics of Optison have not been studied in patients with hepatic or respiratory diseases.
## Gender, Age, Race
The effects of gender, age, or race on the pharmacokinetics of Optison have not been studied.
## Drug-Drug Interactions
Drug-drug interactions for Optison have not been studied.
## Pediatrics
The pharmacokinetics of Optison in pediatric patients have not been studied.
# Pharmocodynamics
The general acoustic properties of Optison are similar to those of ALBUNEX®. The acoustic impedance of the Optison microspheres is much lower than that of the blood. Therefore, impinging ultrasound waves are scattered and reflected at the microsphere-blood interface and ultimately may be visualized in the ultrasound image. At the frequencies used in adult echocardiography (2-5 MHz), the microspheres resonate which further increases the extent of ultrasound scattering and reflection.
As assessed by the unblinded investigators in clinical studies, the median duration of Optison contrast enhancement for each of the four doses of Optison (0.2, 0.5, 3.0, and 5.0 mL) were approximately one, two, four, and five minutes, respectively (see CLINICAL TRIALS section).
# Clinical Trials
The efficacy of Optison was evaluated in two identical multicenter, dose escalation, randomized, cross-over studies of Optison and ALBUNEX®. The test drugs were administered single blind and the image analysis was double blind. Eligible patients were undergoing routine echocardiography and all patients were required to have at least two of six segments of the left ventricular endocardial border that were not well delineated in the apical 4-chamber view. In these studies, the 203 patients (Study A: n=101, Study B: n=102) received at least one dose of study drug had the following characteristics: 79% men, 21% women, 64% White, 25% Black, 10% Hispanic, and 1% other race or ethnic group. The patients had a mean age of 61 years (range: 21 to 83 years), a mean weight of 196 lbs (range: 117 to 342 lbs), a mean height of 68 inches (range: 47 to 78 inches), and a mean body surface area of 2.0m2 (range: 1.4 to 2.6m2). Approximately 23% of the patients had chronic pulmonary disease, and 17% had congestive and dilated cardiomyopathy with left ventricular ejection fractions (LVEFs) of between 20% and 40% (by previous echocardiography). Patients with a LVEF of less than 20% or with New York Heart Association Class IV heart failure were not included in the studies.
The study test drugs were four doses of Optison (0.2, 0.5, 3.0 and 5.0 mL) and two doses of ALBUNEX® (0.08 and 0.22 mL/kg). The two test drugs were administered to the patients in a random sequence, with two to ten days between each drug. After non-contrast imaging, the test doses were administered in ascending order with at least ten minutes between each dose. Ultrasound settings were optimized for the baseline (non-contrast) apical four-chamber view and remained unchanged for the contrast imaging. Static echocardiographic images and video-tape segments were interpreted by a reader who was blinded to the patient's clinical history and to the identity and dose of the test drug. The primary efficacy endpoint was left ventricular endocardial border delineation, assessed before and after Optison administration, by the measurement of visualized endocardial border length. The six segments of the left ventricular endocardial border were also assessed qualitatively (i.e., not well delineated, average delineation, good delineation, excellent delineation) before and after Optison administration.
In comparison to non-contrast ultrasound, Optison significantly increased the length of endocardial border that could be visualized both at end-systole and end-diastole (see Table 2). In these patients there was a trend towards less visualization in women. Similarly, in comparison to non-contrast ultrasound, Optison significantly improved the qualitative ability to delineate each of the left ventricular segments, though the effect was less for the septal segments. As assessed by videodensitometry, Optison increased left ventricular opacification (peak intensity) in the mid-chamber and apical views (see Table 3). In subset analysis, Optison tended to enhance the quality of the spectral Doppler signal of the pulmonary veins. The imaging effects of Optison on endocardial border delineation and left ventricular opacification tended to be qualitatively similar in patients with and without pulmonary disease or dilated cardiomyopathy.
In these studies, quantitative measures of left ventricular function (e.g., ejection fraction), quantitative measurements of anatomical structures (e.g., wall thickness), or the evaluation of myocardial perfusion were not performed.
# Indications
Optison is indicated for use in patients with suboptimal echocardiograms to opacify the left ventricle and to improve the delineation of the left ventricular endocardial borders. The safety and efficacy of Optison with exercise stress or pharmacologic stress testing have not been established.
# Contraindications
Do not administer Optison to patients with known or suspected:
- Right-to-left, bi-directional, or transient right-to-left cardiac shunts,
- Worsening or clinically unstable congestive heart failure,
- Acute myocardial infarction or acute coronary syndromes,
- Serious ventricular arrhythmias or high risk for arrhythmias due to prolongation of the QT interval,
- Respiratory failure, as manifest by signs or symptoms of carbon dioxide retention or hypoxemia,
- Severe emphysema, pulmonary emboli or other conditions that cause pulmonary hypertension due to compromised pulmonary arterial vasculature, and
- Hypersensitivity to perflutren, blood, blood products, or albumin (see WARNINGS).
Do not administer Optison by intra-arterial injection.
# Warnings
## Serious Cardiopulmonary Reactions
Serious cardiopulmonary reactions, including fatalities, have occurred during or within 30 minutes following perflutren-containing microsphere administration. Assess all patients for the presence of any condition that precludes Optison administration (see CONTRAINDICATIONS). Monitor patients during and for 30 minutes following Optison administration, including vital sign measurements and electrocardiography in all patients and cutaneous oxygen saturation in patients at risk for hypoxemia. Always have resuscitation equipment and trained personnel readily available.
In postmarketing use, four patients experienced fatal cardiac arrests either during or within 30 minutes of perflutren-containing microsphere administration; one patient received the product and underwent a cardiac stress test, two patients had severe congestive heart failure and the fourth was undergoing mechanical ventilation for respiratory failure. Other uncommon but serious reactions observed during or shortly following perflutren-containing microsphere administration included cardiac or respiratory arrest, loss of consciousness, convulsions, symptomatic arrhythmias (atrial fibrillation, supraventricular tachycardia, ventricular tachycardia or fibrillation), hypotension, respiratory distress or cardiac ischemia (see ADVERSE REACTIONS).
## Anaphylactoid Reactions
Postmarketing reports of acute anaphylactoid reactions including shock, bronchospasm, upper airway swelling, loss of consciousness, urticaria and pruritus, have occurred in patients with no prior exposure to perflutren-containing microsphere products. Monitor all patients for signs and symptoms of anaphylactoid reactions (see ADVERSE REACTIONS).
## Systemic Embolization of Optison in Patients with Cardiac Shunts
In patients with right-to-left, bi-directional, or transient right-to-left cardiac shunts perflutren-containing microspheres can bypass the pulmonary particle-filtering mechanisms and directly enter the arterial circulation resulting in microvascular occlusion and ischemia. Do not administer Optison by intra-arterial injection.
## High Ultrasound Mechanical Index
High ultrasound mechanical index values may cause microsphere cavitation or rupture and lead to ventricular arrhythmias. Additionally, end-systolic triggering with high mechanical indices has been reported to cause ventricular arrhythmias. The safety of Optison at mechanical indices greater than 0.8 has not been evaluated. The safety of Optison with the use of end-systolic triggering has not been evaluated.
# Precautions
## General
This product contains albumin, a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries an extremely remote risk for transmission of viral disease. A theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD) also is considered extremely remote. No cases of transmission of viral disease or CJD have ever been identified for albumin.
## Laboratory Tests
Immunologic tests of serum immunoglobulins, cytokines, and complement were monitored in a 3 week study of 20 healthy volunteers and 30 patients who received Optison or a 1% albumin control. Clinically relevant changes in the measured parameters were not noted. In another study 5 subjects received a skin test with Optison one year after receiving Optison. One subject had a positive skin test and was not given a repeat dose of Optison.
## Information for Patients
Patients receiving Optison:
- Inform your physician or health care provider if you may be pregnant or are nursing an infant.
- Inform your physician if you ever have had an allergic or hypersensitivity reaction to blood, blood products, or albumin.
- Inform your physician or health care provider if you have a congenital heart defect.
## Carcinogenesis, Mutagenesis, and Impairment of Fertility
Animal studies were not carried out to determine the carcinogenic potential of Optison.
The result of the following genotoxicity studies with Optison were negative: 1) Salmonella/Escherichia coli reverse mutation assay, 2) in vitro mammalian chromosome aberration assay using Chinese hamster ovary cells (CHO) with and without metabolic activation, 3) CHO/HGPRT forward mutation assay, and 4) in vivo mammalian micronucleus assay.
Pregnancy Category C
Optison administered intravenously to rats during organogenesis at doses of 0.25, 5.0 and 10.0 mL/kg/day was fetotoxic at 0.25 and 5.0 mL/kg (approximately 0.2 and 5 times the recommended maximum human dose, respectively, based on body surface area). Fetotoxicity was characterized by an increased incidence of reversible delayed pelvic ossification, the incidence of which was not related to dose. Signs of maternal toxicity at 5 mL/kg included respiratory and motor signs. Maternal death occurred at 10 mL/kg. A no observable adverse effect level (NOAEL) for fetotoxicity was not determined. Teratogenic effects were not observed at doses up to 10 mL/kg/day. The NOAEL for maternal toxicity was 0.25 mL/kg.
Optison administered intravenously to rabbits during organogenesis at doses of 0.25, 2.5 and 5.0 mL/kg/day was embryofetal toxic at 2.5 and 5.0 mL/kg (approximately 5 and 10 times the recommended maximum human dose, respectively, based on body surface area). Embryofetal toxicity was characterized by a decrease in fetal body weight and an increase in embryofetal death. Teratogenic effects (cleft palates and dilation of the lateral ventricles of the brain associated with skull abnormalities and compression deformities) were observed at 2.5 mL/kg but not 5 mL/kg. Neither the incidence nor the severity of embryofetal toxicity and teratogenicity exhibited a dose-dependent relationship. Maternal toxicity (significant suppression of body weight gain, abnormal stool) was observed at 2.5 and 5.0 mL/kg with the greatest effect observed at 2.5 mL/kg. The NOAEL for embryofetal and maternal toxicity was 0.25 mL/kg (approximately 0.5 times the recommended maximum human dose).
Adequate or well-controlled studies were not conducted in pregnant women. Optison should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
## 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 Optison is administered to a nursing woman.
## Pediatric Use
Safety and efficacy have not been established in pediatric patients, or in patients with congenital heart disease (see WARNINGS).
# Adverse Reactions
## Clinical Trials Experience
Optison was administered in clinical studies in 279 patients. Of these patients there were 192 (68.8%) men and 87 (31.2%) women. The racial demographics were 199 (71.3%) Caucasian, 52 (18.6%) Black, 24 (8.6%) Hispanic, and 4 (1.4%) other racial or ethnic groups.
In these patients, 47 (16.8%) reported at least one adverse event. Of these one event was serious and required treatment with antihistamines for hypersensitivity manifestations of dizziness, nausea, flushing and temperature elevation. Deaths were not reported during the clinical studies.
Of the reported adverse reactions following the use of Optison the most frequently reported were headache (5.4%), nausea and/or vomiting (4.3%), warm sensation or flushing (3.6%), and dizziness (2.5%). The most common adverse events observed in clinical studies of Optison are given in Table 4.
Adverse events reported in < 0.5% of subjects who received Optison included: arthralgia, back pain, body or muscle aches, induration, urticaria, dry mouth, eosinophilia, palpitations, paresthesia, photophobia, premature ventricular contraction, pruritus, rash, irritableness, hypersensitivity, tinnitus, tremor, visual blurring, wheezing, oxygen saturation decline due to coughing, discoloration at the Heplock site, and burning sensation in the eyes.
Overall the reported adverse events with Optison were similar in type and frequency to those reported in the 199 patients who received ALBUNEX®.
In the clinical dose ranging studies of 40 normal volunteers, doses higher than those recommended in the DOSAGE AND ADMINISTRATION section tended to be associated with an increased frequency of reported adverse events.
# Postmarketing Experience
The following adverse reactions have been identified during the postmarketing use of perflutren-containing microsphere products. 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.
Four fatal cardiac arrests and other serious but non-fatal adverse reactions were uncommonly reported. Most of these uncommon reactions included cardiopulmonary symptoms and signs such as cardiac or respiratory arrest, hypotension, supraventricular and ventricular arrhythmias, respiratory distress or decreased oxygenation. Reports also identified neurologic reactions (loss of consciousness or convulsions) as well as anaphylactoid reactions (see WARNINGS).
# Optison Dosage and Administration
The recommended dose of Optison is 0.5 mL injected into a peripheral vein. This may be repeated for further contrast enhancement as needed. See individualization of dose below.
- The injection rate should not exceed 1 mL per second.
- Follow the Optison injection with a flush of 0.9% Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP.
- The maximum total dose should not exceed 5.0 mL in any 10 minute period.
- The maximum total dose should not exceed 8.7 mL in any one patient study.
## Individualization of Dose
Image quality in cardiac ultrasound is a function of the acoustic window which is influenced by many variables including body habitus, intervening lung tissue, adequacy of transducer skin interface and other acoustic factors. These variables may influence the ultrasound contrast effect.
If the contrast enhancement is inadequate after the dose of 0.5 mL, additional doses in increments of 0.5 mL up to 5.0 mL cumulatively in a 10 minute period may be injected intravenously up to a maximum total dose of 8.7 mL in any one patient study.
# DRUG HANDLING DIRECTIONS
FOR SINGLE USE ONLY.
Optison does not contain preservatives. Bacterial contamination with the risk of post-infusion septicemia can occur if the container has been damaged or following puncture of the rubber cap. A single vial must not be used for more than one patient. Discard unused product properly.
DO NOT USE if the container has been damaged or the protective seal and/or rubber cap have been entered.
DO NOT USE if the upper white layer is absent. This indicates that the microspheres may have been damaged and may result in poor or no echo contrast.
DO NOT INJECT air into the vial.
- Invert the Optison vial and gently rotate to resuspend the microspheres. This process will allow the product to come to room temperature before use.
- Inspect the vial for complete resuspension. Failure to adequately resuspend Optison may cause an under delivery of the microspheres, and may result in inadequate contrast.
- Do not use Optison if, after resuspension, the solution appears to be clear rather than opaque milky-white.
- Vent the Optison vial with a sterile vent spike or with a sterile 18 gauge needle before withdrawing the Optison suspension into the injection syringe.
DO NOT USE if after resuspending the Optison, the product remains clear rather than appearing opaque and milky-white.
# INJECTION PROCEDURE
The time from resuspension of the Optison to injection must not exceed one minute. If one minute is exceeded, resuspend the microspheres in the syringe by gently rotating and inverting the syringe.
Before injection, provide intravenous access in a peripheral vein with a 20-gauge or larger angiocatheter. Suggested methods of administration include: a short extension tubing, heparin lock, or intravenous line, all with a 3-way stopcock.
For short extension tubing or heparin lock: fill one syringe with 0.9% Sodium Chloride Injection, USP, and flush the line for patency before and after the injection of Optison.
For a continuous intravenous line: open an intravenous line with 0.9% Sodium Chloride Injection, USP (or 5% Dextrose Injection, USP) at a slow infusion rate to maintain vascular patency. The line should be flushed immediately after injection of Optison.
DO NOT ASPIRATE blood back into the Optison containing syringe before administration; this may promote the formation of a blood clot within the syringe.
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Definity | |
a5612507e2f28987b7e3586c5bb9f91b40094fde | wikidoc | Swallowing | Swallowing
# Overview
Swallowing, known scientifically as deglutition, is the reflex in the human body that makes something pass from the mouth, to the pharynx, into the esophagus, with the shutting of the epiglottis. If this fails and the object goes through the trachea, then choking or pulmonary aspiration can occur.
# Coordination and control
The mechanism for swallowing is co-ordinated by the swallowing centre in the medulla oblongata and pons. The reflex is initiated by touch receptors in the pharynx as a bolus of food is pushed to the back of the mouth by the tongue.
Swallowing is a complex mechanism using both skeletal muscle (tongue) and smooth muscles of the pharynx and esophagus. The autonomic nervous system (ANS) coordinates this process in the pharyngeal and esophgeal phases.
# Phases
Normal swallowing consists of four phases: oral preparatory, oral, pharyngeal, and esophageal (not all sources consider oral preparatory a distinct phase).
## Oral preparatory phase
In this phase, the food is processed by mastication, combined with the movement of the tongue form a bolus to an appropriate size to pass through the pharynx and esophagus.
## Oral (or "buccal") phase
When the bolus is ready to enter the oral stage, it is first moved to the back of the tongue. Next, the anterior tongue lifts to the hard palate and retracts in a posterior direction to force the bolus to the oropharynx. Then, the posterior tongue is lifted by the mylohyoid muscles, which also elevates the soft palate and seals the nasopharynx to prevent nasal aspiration. This phase is voluntary and involves important cranial nerves: V (trigeminal), VII (facial), and XII (hypoglossal).
## Pharyngeal phase
In this phase, the bolus is advanced from the pharynx to the esophagus through peristalsis. The soft palate is elevated to the posterior nasopharyngeal wall, through the action of the levator veli palatini. The palatopharyngeal folds on each side of the pharynx are brought close together through the superior constrictor muscles, so that only a small bolus can pass. Then the larynx and hyoid are elevated and pulled forward to the epiglottis to relax the cricopharyngeus muscle. This passively shuts off its entrance and the vocal cords are pulled close together, narrowing the passageway between them. This phase is passively controlled reflexively and involves cranial nerves V, X (vagus), XI (accessory), and XII.
The respiratory centre of the medulla is directly inhibited by the swallowing centre for the very brief time that it takes to swallow. This is known as deglutition apnoea.
## Esophageal phase
The upper oesophageal sphincter relaxes to let food past, after which various striated constrictor muscles of the pharynx as well as peristalsis and relaxation of the lower esophageal sphincter sequentially push the bolus of food through the esophagus into the stomach.
In terminally ill patients, a failure of the reflex to swallow leads to a buildup of mucous or saliva in the throat and airways, producing a noise known as a death rattle, or agonal respiration.
# Clinicial significance
Swallowing becomes a great concern for the elderly since strokes and Alzheimer's disease can interfere with the ANS. Speech therapy is commonly used to correct this condition since the speech process uses the same neuromuscular structures as swallowing.
Disorders of the oral or pharyngeal phases may lead to oropharyngeal dysphagia and disorders of the esophageal may lead to esophageal dysphagia. | Swallowing
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Swallowing, known scientifically as deglutition, is the reflex in the human body that makes something pass from the mouth, to the pharynx, into the esophagus, with the shutting of the epiglottis. If this fails and the object goes through the trachea, then choking or pulmonary aspiration can occur.
# Coordination and control
The mechanism for swallowing is co-ordinated by the swallowing centre in the medulla oblongata and pons. The reflex is initiated by touch receptors in the pharynx as a bolus of food is pushed to the back of the mouth by the tongue.
Swallowing is a complex mechanism using both skeletal muscle (tongue) and smooth muscles of the pharynx and esophagus. The autonomic nervous system (ANS) coordinates this process in the pharyngeal and esophgeal phases.
# Phases
Normal swallowing consists of four phases: oral preparatory, oral, pharyngeal, and esophageal (not all sources consider oral preparatory a distinct phase).
## Oral preparatory phase
In this phase, the food is processed by mastication, combined with the movement of the tongue form a bolus to an appropriate size to pass through the pharynx and esophagus.
## Oral (or "buccal") phase
When the bolus is ready to enter the oral stage, it is first moved to the back of the tongue. Next, the anterior tongue lifts to the hard palate and retracts in a posterior direction to force the bolus to the oropharynx. Then, the posterior tongue is lifted by the mylohyoid muscles, which also elevates the soft palate and seals the nasopharynx to prevent nasal aspiration. This phase is voluntary and involves important cranial nerves: V (trigeminal), VII (facial), and XII (hypoglossal).
## Pharyngeal phase
In this phase, the bolus is advanced from the pharynx to the esophagus through peristalsis. The soft palate is elevated to the posterior nasopharyngeal wall, through the action of the levator veli palatini. The palatopharyngeal folds on each side of the pharynx are brought close together through the superior constrictor muscles, so that only a small bolus can pass. Then the larynx and hyoid are elevated and pulled forward to the epiglottis to relax the cricopharyngeus muscle. This passively shuts off its entrance and the vocal cords are pulled close together, narrowing the passageway between them. This phase is passively controlled reflexively and involves cranial nerves V, X (vagus), XI (accessory), and XII.
The respiratory centre of the medulla is directly inhibited by the swallowing centre for the very brief time that it takes to swallow. This is known as deglutition apnoea.
## Esophageal phase
The upper oesophageal sphincter relaxes to let food past, after which various striated constrictor muscles of the pharynx as well as peristalsis and relaxation of the lower esophageal sphincter sequentially push the bolus of food through the esophagus into the stomach.
In terminally ill patients, a failure of the reflex to swallow leads to a buildup of mucous or saliva in the throat and airways, producing a noise known as a death rattle, or agonal respiration.
# Clinicial significance
Swallowing becomes a great concern for the elderly since strokes and Alzheimer's disease can interfere with the ANS. Speech therapy is commonly used to correct this condition since the speech process uses the same neuromuscular structures as swallowing.
Disorders of the oral or pharyngeal phases may lead to oropharyngeal dysphagia and disorders of the esophageal may lead to esophageal dysphagia. | https://www.wikidoc.org/index.php/Deglutition | |
26040eef5cb265ea5b446732893e681cf8929ea0 | wikidoc | Hygroscopy | Hygroscopy
Hygroscopy is the ability of a substance to attract water molecules from the surrounding environment through either absorption or adsorption.
Hygroscopic substances include honey, glycerin, ethanol, methanol, concentrated sulfuric acid, and concentrated sodium hydroxide (lye). Calcium chloride is so hygroscopic that it eventually dissolves in the water it absorbs: this property is called deliquescence (see below). Because of their affinity for atmospheric moisture, hygroscopic materials may need to be stored in sealed containers. When added to foods or other materials for the express purpose of maintaining moisture content, such substances are known as humectants.
Materials and compounds exhibit different hygroscopic properties, and this difference can lead to detrimental effects, such as stress concentration in composite materials. The amount a particular material or compound is affected by ambient moisture may be considered its coefficient of hygroscopic expansion (CHE) or coefficient of hygroscopic contraction (CHC)—the difference between the two terms being a difference in sign convention and a difference in point of view as to whether the difference in moisture leads to contraction or expansion.
A common example where difference in this hygroscopic property can be seen is in a paperback book cover. Often in a relatively moist environment the book cover will curl away from the rest of the book. The unlaminated side of the cover absorbs more moisture than the laminated side and increased in area, causing a stress that curls the cover toward the laminated side. This is similar to the function of a bi-metallic strip.
The similar sounding but unrelated word hydroscopic is sometimes used in error for hygroscopic. A hydroscope is an optical device used for making observations deep under water.
# Biology
The seeds of some grasses have hygroscopic extensions which bend with changes in humidity, enabling them to disperse over the ground. An example is Needle-and-Thread, Hesperostipa comata. Each seed has an awn that twists several turns when the seed is released. Increased moisture causes it to untwist, and upon drying to twist again; the seed is drilled into the ground. Children in the west call this the "clock plant".
# Deliquescence
Deliquescent materials are substances (mostly salts) which have a strong affinity for moisture and will absorb relatively large amounts of water from the atmosphere if exposed to it, forming a liquid solution. Deliquescent salts include calcium chloride, magnesium chloride, zinc chloride, and the strong base sodium hydroxide. They are often used as desiccants. | Hygroscopy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Hygroscopy is the ability of a substance to attract water molecules from the surrounding environment through either absorption or adsorption.
Hygroscopic substances include honey, glycerin, ethanol, methanol, concentrated sulfuric acid, and concentrated sodium hydroxide (lye). Calcium chloride is so hygroscopic that it eventually dissolves in the water it absorbs: this property is called deliquescence (see below). Because of their affinity for atmospheric moisture, hygroscopic materials may need to be stored in sealed containers. When added to foods or other materials for the express purpose of maintaining moisture content, such substances are known as humectants.
Materials and compounds exhibit different hygroscopic properties, and this difference can lead to detrimental effects, such as stress concentration in composite materials. The amount a particular material or compound is affected by ambient moisture may be considered its coefficient of hygroscopic expansion (CHE) or coefficient of hygroscopic contraction (CHC)—the difference between the two terms being a difference in sign convention and a difference in point of view as to whether the difference in moisture leads to contraction or expansion.
A common example where difference in this hygroscopic property can be seen is in a paperback book cover. Often in a relatively moist environment the book cover will curl away from the rest of the book. The unlaminated side of the cover absorbs more moisture than the laminated side and increased in area, causing a stress that curls the cover toward the laminated side. This is similar to the function of a bi-metallic strip.
The similar sounding but unrelated word hydroscopic is sometimes used in error for hygroscopic. A hydroscope is an optical device used for making observations deep under water.
# Biology
The seeds of some grasses have hygroscopic extensions which bend with changes in humidity, enabling them to disperse over the ground. An example is Needle-and-Thread, Hesperostipa comata. Each seed has an awn that twists several turns when the seed is released. Increased moisture causes it to untwist, and upon drying to twist again; the seed is drilled into the ground. Children in the west call this the "clock plant".
# Deliquescence
Deliquescent materials are substances (mostly salts) which have a strong affinity for moisture and will absorb relatively large amounts of water from the atmosphere if exposed to it, forming a liquid solution. Deliquescent salts include calcium chloride, magnesium chloride, zinc chloride, and the strong base sodium hydroxide. They are often used as desiccants. | https://www.wikidoc.org/index.php/Deliquescence | |
c62f534809d72ee43a21768909168b7480c83aa7 | wikidoc | Delphinium | Delphinium
Delphinium is a genus of about 250 species of annual, biennial or perennial flowering plants in the buttercup family Ranunculaceae, native throughout the Northern Hemisphere and also on the high mountains of tropical Africa. The common name, shared with the closely related genus Consolida, is Larkspur.
The leaves are deeply lobed with 3-7 toothed, pointed lobes. The main flowering stem is erect, and varies greatly in size between the species, from 10 cm in some alpine species, up to 2 m tall in the larger meadowland species; it is topped by many flowers, varying between purple, blue, red, yellow or white. The flower has five petals which grow together to form a hollow flower with a spur at the end, which gives the plant its name. The seeds are small and shiny black. The plants flower from late spring to late summer, and are pollinated by butterflies and bumble bees. Despite the toxicity, Delphinium species are used as food plants by the larvae of some Lepidoptera species including Dot Moth and Small Angle Shades.
Other names are, lark's heel (Shakespeare), lark's claw and knight's spur. The scientific name is taken from Dioscorides and describes the shape of the bud, which is thought to look like a (rather fat) dolphin.
The Forking Larkspur (Delphinium consolida) prefers chalky loams. It grows wild in cornfields, but has become very rare nowadays. The flowers are commonly purple, but a white variety exists as well.
Baker's larkspur (Delphinium bakeri) and Yellow larkspur (D. luteum), both native to very restricted areas of California, are highly endangered species.
# Cultivation and uses
Many species are cultivated as garden plants, with numerous cultivars having been selected for their denser, more prominent flowers.
All parts of the plant contain an alkaloid delphinine and are very poisonous, causing vomiting when eaten, and death in larger amounts. In small amounts, extracts of the plant have been used in herbal medicine. Gerard's herball reports that drinking the seed of larkspur was thought to help against the stings of scorpions, and that other poisonous animals could not move when covered by the herb, but does not believe it himself. Grieve's herbal reports that the seeds can be used against parasites, especially lice and their nits in the hair. A tincture is used against asthma and dropsy. The juice of the flowers, mixed with alum, gives a blue ink.
The plant was connected to Saint Odile and in popular medicine used against eye-diseases. It was one of the herbs used on the feast of St. John and as such warded against lightning. In Transylvania, it was used to keep witches from the stables, probably because of its blue color.
Larkspur, especially tall larkspur, is a significant cause of cattle poisoning on rangelands in the western United States. Larkspur is more common in high-elevation areas, and many ranchers will delay moving cattle onto such ranges until late summer when the toxicity of the plants is reduced.
# Species
About 250 species, including:
- Delphinium alabamicum : Alabama Larkspur
- Delphinium alpestre : Colorado Larkspur
- Delphinium altissimum
- Delphinium andersonii : Anderson's Larkspur
- Delphinium andesicola : Chiricahua Mountain Larkspur
- Delphinia antoninum : Tracy's Larkspur
- Delphinium bakeri: Baker's Delphinium
- Delphinium barbeyi : Subalpine Larkspur
- Delphinium basalticum : Basalt Larkspur
- Delphinium bicolor : Little Larkspur
- Delphinium brachycentrum : Northern Larkspur
- Delphinium brownii
- Delphinium brunonianum
- Delphinium bulleyanum
- Delphinium caeruleum
- Delphinium californicum : California Larkspur
- Delphinium cardinale
- Delphinium carolinianum : Carolina Larkspur
- Delphinium cashmerianum
- Delphinium chamissonis : Chamisso's Larkspur
- Delphinium cheilanthum
- Delphinium consolida
- Delphinium corymbosum
- Delphinium decorum : Coastal Larkspur
- Delphinium delavayi
- Delphinium denudatum
- Delphinium depauperatum : Slim Larkspur
- Delphinium dictyocarpum
- Delphinium distichum : Twospike Larkspur
- Delphinium duhmbergii
- Delphinium elatum : Candle Larkspur
- Delphinium exaltatum : Tall Larkspur
- Delphinium fissum
- Delphinium formosum
- Delphinium geraniifolium : Clark Valley Larkspur
- Delphinium geyeri : Geyer's Larkspur
- Delphinium glareosum : Olympic Larkspur
- Delphinium glaucescens : Smooth Larkspur
- Delphinium glaucum : Sierra Larkpsur
- Delphinium gracilentum : Pine Forest Larkspur
- Delphinium grandiflorum : Siberian Larkspur
- Delphinium gypsophilum : Pinoche Creek Larkspur
- Delphinium hansenii : Eldorado Larkspur
- Delphinium hesperium : Foothill Larkspur
- Delphinium hutchinsoniae : Monterey Larkspur
- Delphinium hybridum
- Delphinium inopinum : Unexpected Larkspur
- Delphinium leroyi
- Delphinium leucophaeum
- Delphinium likiangense
- Delphinium linarioides
- Delphinium lineapetalum : Thinpetal Larkspur
- Delphinium luteum : Yellow Larkspur
- Delphinium maackianum
- Delphinium macrocentron
- Delphinium madrense : Sierra Madre Larkspur
- Delphinium menziesii : Menzies' Larkspur
- Delphinium multiplex : Kittitas Larkspur
- Delphinium muscosum
- Delphinium nelsonii
- Delphinium newtonianum : Newton's Larkspur
- Delphinium novomexicanum : White Mountain Larkspur
- Delphinium nudicaule : Red Larkspur
- Delphinium nuttallianum : Twolobe Larkspur
- Delphinium nuttallii : Upland Larkspur
- Delphinium occidentale: Subalpine Larkspur
- Delphinium oxysepalum
- Delphinium parishii : Desert Larkspur
- Delphinium parryi : San Bernardino Larkspur
- Delphinium patens : Zigzag Larkspur
- Delphinium peregrinum
- Delphinium pictum
- Delphinium polycladon : Mountain Marsh Larkspur
- Delphinium przewalskii
- Delphinium purpusii : Kern County Larkspur
- Delphinium pylzowii
- Delphinium ramosum : Mountain Larkspur
- Delphinium recurvatum : Byron Larkspur
- Delphinium requienii
- Delphinium robustum : Wahatoya Creek Larkspur
- Delphinium roylei
- Delphinium sapellonis : Sapello Canyon Larkspur
- Delphinium scaposum : Tall Mountain Larkspur
- Delphinium scopulorum : Rocky Mountain Larkspur
- Delphinium semibarbatum
- Delphinium speciosum
- Delphinium stachydeum : Spiked Larkspur
- Delphinium staphisagria
- Delphinium sutchuense
- Delphinium sutherlandii : Sutherland's Larkspur
- Delphinium tatsienense
- Delphinium treleasei : Glade Larkspur
- Delphinium tricorne : Dwarf Larkspur
- Delphinium triste
- Delphinium trolliifolium : Columbian Larkspur
- Delphinium uliginosum : Swamp Larkspur
- Delphinium umbraculorum : Umbrella Larkspur
- Delphinium variegatum : Royal Larkspur
- Delphinium verdunense
- Delphinium vestitum
- Delphinium villosum
- Delphinium virescens
- Delphinium viridescens : Wenatchee Larkspur
- Delphinium viride
- Delphinium wootonii : Organ Mountain Larkspur
- Delphinium xantholeucum : Yellow-white Larkspur
- Delphinium yunnanense
- Delphinium zalil : Zalil
de:Rittersporne
eo:Delfinio
it:Delphinium
lt:Pentinius
nl:Ridderspoor
no:Ridderspore (Delphinium)
sq:Delphinium | Delphinium
Delphinium is a genus of about 250 species of annual, biennial or perennial flowering plants in the buttercup family Ranunculaceae, native throughout the Northern Hemisphere and also on the high mountains of tropical Africa. The common name, shared with the closely related genus Consolida, is Larkspur.
The leaves are deeply lobed with 3-7 toothed, pointed lobes. The main flowering stem is erect, and varies greatly in size between the species, from 10 cm in some alpine species, up to 2 m tall in the larger meadowland species; it is topped by many flowers, varying between purple, blue, red, yellow or white. The flower has five petals which grow together to form a hollow flower with a spur at the end, which gives the plant its name. The seeds are small and shiny black. The plants flower from late spring to late summer, and are pollinated by butterflies and bumble bees. Despite the toxicity, Delphinium species are used as food plants by the larvae of some Lepidoptera species including Dot Moth and Small Angle Shades.
Other names are, lark's heel (Shakespeare), lark's claw and knight's spur. The scientific name is taken from Dioscorides and describes the shape of the bud, which is thought to look like a (rather fat) dolphin.
The Forking Larkspur (Delphinium consolida) prefers chalky loams. It grows wild in cornfields, but has become very rare nowadays. The flowers are commonly purple, but a white variety exists as well.
Baker's larkspur (Delphinium bakeri) and Yellow larkspur (D. luteum), both native to very restricted areas of California, are highly endangered species.
# Cultivation and uses
Many species are cultivated as garden plants, with numerous cultivars having been selected for their denser, more prominent flowers.
All parts of the plant contain an alkaloid delphinine and are very poisonous, causing vomiting when eaten, and death in larger amounts. In small amounts, extracts of the plant have been used in herbal medicine. Gerard's herball reports that drinking the seed of larkspur was thought to help against the stings of scorpions, and that other poisonous animals could not move when covered by the herb, but does not believe it himself. Grieve's herbal reports that the seeds can be used against parasites, especially lice and their nits in the hair. A tincture is used against asthma and dropsy. The juice of the flowers, mixed with alum, gives a blue ink.
The plant was connected to Saint Odile and in popular medicine used against eye-diseases. It was one of the herbs used on the feast of St. John and as such warded against lightning. In Transylvania, it was used to keep witches from the stables, probably because of its blue color.
Larkspur, especially tall larkspur, is a significant cause of cattle poisoning on rangelands in the western United States. Larkspur is more common in high-elevation areas, and many ranchers will delay moving cattle onto such ranges until late summer when the toxicity of the plants is reduced.
# Species
About 250 species, including:
Template:Col-start
- Delphinium alabamicum : Alabama Larkspur
- Delphinium alpestre : Colorado Larkspur
- Delphinium altissimum
- Delphinium andersonii : Anderson's Larkspur
- Delphinium andesicola : Chiricahua Mountain Larkspur
- Delphinia antoninum : Tracy's Larkspur
- Delphinium bakeri: Baker's Delphinium
- Delphinium barbeyi : Subalpine Larkspur
- Delphinium basalticum : Basalt Larkspur
- Delphinium bicolor : Little Larkspur
- Delphinium brachycentrum : Northern Larkspur
- Delphinium brownii
- Delphinium brunonianum
- Delphinium bulleyanum
- Delphinium caeruleum
- Delphinium californicum : California Larkspur
- Delphinium cardinale
- Delphinium carolinianum : Carolina Larkspur
- Delphinium cashmerianum
- Delphinium chamissonis : Chamisso's Larkspur
- Delphinium cheilanthum
- Delphinium consolida
- Delphinium corymbosum
- Delphinium decorum : Coastal Larkspur
- Delphinium delavayi
- Delphinium denudatum
- Delphinium depauperatum : Slim Larkspur
- Delphinium dictyocarpum
- Delphinium distichum : Twospike Larkspur
- Delphinium duhmbergii
- Delphinium elatum : Candle Larkspur
- Delphinium exaltatum : Tall Larkspur
- Delphinium fissum
- Delphinium formosum
- Delphinium geraniifolium : Clark Valley Larkspur
- Delphinium geyeri : Geyer's Larkspur
- Delphinium glareosum : Olympic Larkspur
- Delphinium glaucescens : Smooth Larkspur
- Delphinium glaucum : Sierra Larkpsur
- Delphinium gracilentum : Pine Forest Larkspur
- Delphinium grandiflorum : Siberian Larkspur
- Delphinium gypsophilum : Pinoche Creek Larkspur
- Delphinium hansenii : Eldorado Larkspur
- Delphinium hesperium : Foothill Larkspur
- Delphinium hutchinsoniae : Monterey Larkspur
- Delphinium hybridum
- Delphinium inopinum : Unexpected Larkspur
- Delphinium leroyi
- Delphinium leucophaeum
- Delphinium likiangense
- Delphinium linarioides
- Delphinium lineapetalum : Thinpetal Larkspur
- Delphinium luteum : Yellow Larkspur
- Delphinium maackianum
- Delphinium macrocentron
- Delphinium madrense : Sierra Madre Larkspur
- Delphinium menziesii : Menzies' Larkspur
- Delphinium multiplex : Kittitas Larkspur
- Delphinium muscosum
- Delphinium nelsonii
- Delphinium newtonianum : Newton's Larkspur
- Delphinium novomexicanum : White Mountain Larkspur
- Delphinium nudicaule : Red Larkspur
- Delphinium nuttallianum : Twolobe Larkspur
- Delphinium nuttallii : Upland Larkspur
- Delphinium occidentale: Subalpine Larkspur
- Delphinium oxysepalum
- Delphinium parishii : Desert Larkspur
- Delphinium parryi : San Bernardino Larkspur
- Delphinium patens : Zigzag Larkspur
- Delphinium peregrinum
- Delphinium pictum
- Delphinium polycladon : Mountain Marsh Larkspur
- Delphinium przewalskii
- Delphinium purpusii : Kern County Larkspur
- Delphinium pylzowii
- Delphinium ramosum : Mountain Larkspur
- Delphinium recurvatum : Byron Larkspur
- Delphinium requienii
- Delphinium robustum : Wahatoya Creek Larkspur
- Delphinium roylei
- Delphinium sapellonis : Sapello Canyon Larkspur
- Delphinium scaposum : Tall Mountain Larkspur
- Delphinium scopulorum : Rocky Mountain Larkspur
- Delphinium semibarbatum
- Delphinium speciosum
- Delphinium stachydeum : Spiked Larkspur
- Delphinium staphisagria
- Delphinium sutchuense
- Delphinium sutherlandii : Sutherland's Larkspur
- Delphinium tatsienense
- Delphinium treleasei : Glade Larkspur
- Delphinium tricorne : Dwarf Larkspur
- Delphinium triste
- Delphinium trolliifolium : Columbian Larkspur
- Delphinium uliginosum : Swamp Larkspur
- Delphinium umbraculorum : Umbrella Larkspur
- Delphinium variegatum : Royal Larkspur
- Delphinium verdunense
- Delphinium vestitum
- Delphinium villosum
- Delphinium virescens
- Delphinium viridescens : Wenatchee Larkspur
- Delphinium viride
- Delphinium wootonii : Organ Mountain Larkspur
- Delphinium xantholeucum : Yellow-white Larkspur
- Delphinium yunnanense
- Delphinium zalil : Zalil
de:Rittersporne
eo:Delfinio
it:Delphinium
lt:Pentinius
nl:Ridderspoor
no:Ridderspore (Delphinium)
sq:Delphinium
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Delphinium | |
8db6907606671c3c297f766c0e4fdb6af5194ca7 | wikidoc | Delta-F508 | Delta-F508
ΔF508 is a specific mutation within the human genome. The mutation--a deletion of three base pairs (T, T, T) which form the codon for phenylalanine (F) at the 508 position--prevents a protein called the cystic fibrosis transmembrane conductance regulator (CFTR) from obtaining its normal position. Having two copies of this mutation, inherited from both parents, is the leading cause of cystic fibrosis (CF).
# Prevalence
ΔF508 is present in approximately one in 30 caucasians. Scientists have estimated that the mutation occurred over 52,000 years ago in Northern Europe. From an evolutionary standpoint the mutation's negative effects (see below) are outweighed by the fact that it reduces water-loss during cholera, a common cause of death in Europe when the mutation first appeared.
# Effects
The CFTR protein--when in the proper position--opens channels in the cell wall which release chloride ions in the cells. This causes osmosis to draw water out of the cell. The ΔF508 mutation can prevent the CFTR from moving into its proper position in the cell.
## Heterozygous carriers
Being a 'carrier' (having a single copy of ΔF508) results in decreased water loss during diarrhea. This prevents dehydration, and vastly increases the chances of surviving cholera.
If two carriers of the gene mate, their offspring will have a 25% chance of having two copies of the mutation (see also Mendelian inheritance). Generally ΔF508 carriers are symptom free, however when combined with other mutations, varying degrees of CF-like symptoms can appear (see below).
## Homozygous genotype
Having a pair of genes with the ΔF508 mutation prevents the CFTR protein from obtaining its normal position in the cell membranes. This causes increased water retention in cells, and a variety of effects on the body:
- Thicker mucous membranes in many parts of the body
- Congenital Bilateral Absence of the Vas deferens (CBAVD) due to increased mucus thickness during fetal development
- Pancreatic insufficiency, due to blockage of the pancreatic duct with mucus
This collection of symptoms is called cystic fibrosis, however ΔF508 is not the only mutation that causes CF.
## Heterozygous carriers with other mutations
Approximately 70% of cystic fibrosis cases in Europe are due to Double ΔF508 (this varies widely by region). The remaining cases are caused by combinations of that and over 500 other mutations including R117H, 1717-1G>A, and 2789+56G>A. These mutations, when combined with each other or ΔF508, cause CF symptoms. The genotype is not strongly correlated with severity of the CF, however specific symptoms have been linked to certain mutations. | Delta-F508
ΔF508 is a specific mutation within the human genome. The mutation--a deletion of three base pairs (T, T, T) which form the codon for phenylalanine (F) at the 508 position--prevents a protein called the cystic fibrosis transmembrane conductance regulator (CFTR) from obtaining its normal position. Having two copies of this mutation, inherited from both parents, is the leading cause of cystic fibrosis (CF).
# Prevalence
ΔF508 is present in approximately one in 30 caucasians. Scientists have estimated that the mutation occurred over 52,000 years ago in Northern Europe. From an evolutionary standpoint the mutation's negative effects (see below) are outweighed by the fact that it reduces water-loss during cholera, a common cause of death in Europe when the mutation first appeared.
# Effects
The CFTR protein--when in the proper position--opens channels in the cell wall which release chloride ions in the cells. This causes osmosis to draw water out of the cell. The ΔF508 mutation can prevent the CFTR from moving into its proper position in the cell.
## Heterozygous carriers
Being a 'carrier' (having a single copy of ΔF508) results in decreased water loss during diarrhea. This prevents dehydration, and vastly increases the chances of surviving cholera.
If two carriers of the gene mate, their offspring will have a 25% chance of having two copies of the mutation (see also Mendelian inheritance). Generally ΔF508 carriers are symptom free, however when combined with other mutations, varying degrees of CF-like symptoms can appear (see below).
## Homozygous genotype
Having a pair of genes with the ΔF508 mutation prevents the CFTR protein from obtaining its normal position in the cell membranes. This causes increased water retention in cells, and a variety of effects on the body:
- Thicker mucous membranes in many parts of the body
- Congenital Bilateral Absence of the Vas deferens (CBAVD) due to increased mucus thickness during fetal development
- Pancreatic insufficiency, due to blockage of the pancreatic duct with mucus
This collection of symptoms is called cystic fibrosis, however ΔF508 is not the only mutation that causes CF.
## Heterozygous carriers with other mutations
Approximately 70% of cystic fibrosis cases in Europe are due to Double ΔF508 (this varies widely by region). The remaining cases are caused by combinations of that and over 500 other mutations including R117H, 1717-1G>A, and 2789+56G>A. These mutations, when combined with each other or ΔF508, cause CF symptoms. The genotype is not strongly correlated with severity of the CF, however specific symptoms have been linked to certain mutations. | https://www.wikidoc.org/index.php/Delta-F508 | |
805e4c8e14149a1e0bab75fce6083d33a15aed50 | wikidoc | Delta wave | Delta wave
In both cardiology and neurology, there are references to the "Delta wave".
# Cardiology
A delta wave can be observed in patients with Wolff-Parkinson-White syndrome.
Wolff-Parkinson-White syndrome (WPW) is a syndrome of pre-excitation of the ventricles of the heart due to an accessory pathway known as the Bundle of Kent. This accessory pathway is an abnormal electrical communication from the atria to the ventricles.
The incidence of WPW syndrome is between 0.1 and 3% of the general population.
While the vast majority of individuals with WPW syndrome remain asymptomatic throughout their entire lives, there is a risk of sudden death associated with the syndrome. Sudden death due to WPW syndrome is rare (incidence of less than 0.6%), and is due to the effect of the accessory pathway on tachyarrhythmias in these individuals.
# Pathophysiology
In normal individuals, electrical activity in the heart is initiated in the sinoatrial (SA) node (located in the right atrium), propagates to the atrioventricular (AV) node, and then through the bundle of His to the ventricles of the heart. (See electrical conduction system of the heart).
The AV node acts as a gatekeeper, limiting the electrical activity that reaches the ventricles of the heart. This function of the AV node is important, because if the signals generated in the atria of the heart were to increase in rate (as they do during atrial fibrillation or atrial flutter), the AV node will limit the electrical activity that conducts to the ventricles. For instance, if the atria are electrically activated at 300 beats per minute, half those electrical impulses are blocked by the AV node, so that the ventricles are activated at 150 beats per minute (giving a pulse of 150 beats per minute). Another important property of the AV node is that it slows down individual electrical impulses. This is manifest on the ECG as the PR interval, the time from activation of the atria (manifest as the P wave) and activation of the ventricles (manifest as the QRS complex).
Individuals with WPW syndrome have an accessory pathway that connects the atria and the ventricles, in addition to the AV node. This accessory pathway is known as the bundle of Kent. This accessory pathway does not share the rate-slowing properties of the AV node, and may conduct electrical activity at a significantly higher rate than the AV node. For instance, in the example above, if an individual had an atrial rate of 300 beats per minute, the accessory bundle may conduct all the electrical impulses from the atria to the ventricles, causing the ventricles to activate at 300 beats per minute. Extremely fast heart rates are potentially dangerous, and can cause hemodynamic instability. In some cases, the combination of an accessory pathway and cardiac arrhythmias can trigger ventricular fibrillation, a leading cause of sudden cardiac death.
# Diagnosis
WPW syndrome is commonly diagnosed on the basis of the surface ECG in an asymptomatic individual. In this case it is manifested as a delta wave, which is a slurred upstroke in the QRS complex that is associated with a short PR interval. The short PR interval and slurring of the QRS complex is actually the impulse making it through to the ventricles prematurely (across the accessory pathway) without the usual delay experienced in the AV node.
If the patient experiences episodes of atrial fibrillation, the ECG will show a rapid polymorphic wide-complex tachycardia (without turning of the points). This combination of atrial fibrillation and WPW is considered dangerous, and most antiarrhythmic drugs are contraindicated.
When an individual is in normal sinus rhythm, the ECG characteristics of WPW syndrome are a short PR interval, widened QRS complex (greater than 120 ms in length) with slurred upstroke of the QRS complex, and secondary repolarization changes reflected in ST segment-T wave changes.
In individuals with WPW syndrome, electrical activity that is initiated in the SA node travels through the accessory pathway as well as through the AV node to activate the ventricles via both pathways. Since the accessory pathway does not have the impulse slowing properties of the AV node, the electrical impulse first activates the ventricles via the accessory pathway, and immediately afterwards via the AV node. This gives the short PR interval and slurred upstroke to the QRS complex known as the delta wave.
Patients with WPW often exhibit more than one accessory pathway, and in some patients as many as eight additional abnormal pathways can be found. This has been seen in individuals with Ebstein's anomaly.
Wolff-Parkinson-White syndrome is sometimes associated with Leber's hereditary optic neuropathy (LHON), a form of mitochondrial disease.
# Neurology
A delta wave is a large, slow (2 Hz or less) brain wave recorded with an EEG and is usually associated with deep sleep.
Delta activity is characterized by frequencies under 3 Hz and is absent in awake healthy adults, but is physiological and normal in awake children under the age of 13. Delta waves are also naturally present in stage three and four of sleep (deep sleep) but not in stages 1, 2, and rapid eye movement (REM) of sleep. Finally, delta rhythm can be observed in cases of brain injury and comatic patients.
Human non-rapid eye movement (NREM) sleep is divided in the categories 2, 3, and 4 by the percentage of slow waves. | Delta wave
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
In both cardiology and neurology, there are references to the "Delta wave".
# Cardiology
A delta wave can be observed in patients with Wolff-Parkinson-White syndrome.
Wolff-Parkinson-White syndrome (WPW) is a syndrome of pre-excitation of the ventricles of the heart due to an accessory pathway known as the Bundle of Kent. This accessory pathway is an abnormal electrical communication from the atria to the ventricles.
The incidence of WPW syndrome is between 0.1 and 3% of the general population.[1][2][3]
While the vast majority of individuals with WPW syndrome remain asymptomatic throughout their entire lives, there is a risk of sudden death associated with the syndrome. Sudden death due to WPW syndrome is rare (incidence of less than 0.6%[3][4]), and is due to the effect of the accessory pathway on tachyarrhythmias in these individuals.
# Pathophysiology
In normal individuals, electrical activity in the heart is initiated in the sinoatrial (SA) node (located in the right atrium), propagates to the atrioventricular (AV) node, and then through the bundle of His to the ventricles of the heart. (See electrical conduction system of the heart).
The AV node acts as a gatekeeper, limiting the electrical activity that reaches the ventricles of the heart. This function of the AV node is important, because if the signals generated in the atria of the heart were to increase in rate (as they do during atrial fibrillation or atrial flutter), the AV node will limit the electrical activity that conducts to the ventricles. For instance, if the atria are electrically activated at 300 beats per minute, half those electrical impulses are blocked by the AV node, so that the ventricles are activated at 150 beats per minute (giving a pulse of 150 beats per minute). Another important property of the AV node is that it slows down individual electrical impulses. This is manifest on the ECG as the PR interval, the time from activation of the atria (manifest as the P wave) and activation of the ventricles (manifest as the QRS complex).
Individuals with WPW syndrome have an accessory pathway that connects the atria and the ventricles, in addition to the AV node. This accessory pathway is known as the bundle of Kent. This accessory pathway does not share the rate-slowing properties of the AV node, and may conduct electrical activity at a significantly higher rate than the AV node. For instance, in the example above, if an individual had an atrial rate of 300 beats per minute, the accessory bundle may conduct all the electrical impulses from the atria to the ventricles, causing the ventricles to activate at 300 beats per minute. Extremely fast heart rates are potentially dangerous, and can cause hemodynamic instability. In some cases, the combination of an accessory pathway and cardiac arrhythmias can trigger ventricular fibrillation, a leading cause of sudden cardiac death.
# Diagnosis
WPW syndrome is commonly diagnosed on the basis of the surface ECG in an asymptomatic individual. In this case it is manifested as a delta wave, which is a slurred upstroke in the QRS complex that is associated with a short PR interval. The short PR interval and slurring of the QRS complex is actually the impulse making it through to the ventricles prematurely (across the accessory pathway) without the usual delay experienced in the AV node.
If the patient experiences episodes of atrial fibrillation, the ECG will show a rapid polymorphic wide-complex tachycardia (without turning of the points). This combination of atrial fibrillation and WPW is considered dangerous, and most antiarrhythmic drugs are contraindicated.
When an individual is in normal sinus rhythm, the ECG characteristics of WPW syndrome are a short PR interval, widened QRS complex (greater than 120 ms in length) with slurred upstroke of the QRS complex, and secondary repolarization changes reflected in ST segment-T wave changes.
In individuals with WPW syndrome, electrical activity that is initiated in the SA node travels through the accessory pathway as well as through the AV node to activate the ventricles via both pathways. Since the accessory pathway does not have the impulse slowing properties of the AV node, the electrical impulse first activates the ventricles via the accessory pathway, and immediately afterwards via the AV node. This gives the short PR interval and slurred upstroke to the QRS complex known as the delta wave.
Patients with WPW often exhibit more than one accessory pathway, and in some patients as many as eight additional abnormal pathways can be found. This has been seen in individuals with Ebstein's anomaly.
Wolff-Parkinson-White syndrome is sometimes associated with Leber's hereditary optic neuropathy (LHON), a form of mitochondrial disease.[5]
# Neurology
A delta wave is a large, slow (2 Hz or less) brain wave recorded with an EEG and is usually associated with deep sleep.
Delta activity is characterized by frequencies under 3 Hz and is absent in awake healthy adults, but is physiological and normal in awake children under the age of 13. Delta waves are also naturally present in stage three and four of sleep (deep sleep) but not in stages 1, 2, and rapid eye movement (REM) of sleep. Finally, delta rhythm can be observed in cases of brain injury and comatic patients.
Human non-rapid eye movement (NREM) sleep is divided in the categories 2, 3, and 4 by the percentage of slow waves. | https://www.wikidoc.org/index.php/Delta-wave | |
aa580c57f7620adb2f896e178f980bc850106549 | wikidoc | Nordazepam | Nordazepam
# Overview
Nordazepam (marketed under brand names Stilny®, Madar®, Vegesan®, and Calmday®), also known as nordiazepam and desmethyldiazepam, is a 1,4-benzodiazepine derivative. Like other benzodiazepine derivatives, it has anticonvulsant, anxiolytic, muscle relaxant and sedative properties. However, it is used primarily in the treatment of anxiety. It is an active metabolite of diazepam, chlordiazepoxide, clorazepate, prazepam, and medazepam.
# Side effects
Common side effects of nordazepam include somnolence, which is more common in elderly patients and/or people on high dose regimens. Hypotonia, which is much less common, is also associated with high doses and/or old age.
# Interactions
Benzodiazepines including N-desmethyldiazepam (nordazepam) may inhibit the glucuronidation of morphine leading to increased levels of and prolongation of the effects of morphine.
# Abuse
Nordazepam and other sedative hypnotic drugs are detected frequently in cases of people suspected of driving under the influence of drugs. Other benzodiazepines and zolpidem and zopiclone are also found in high numbers of suspected drugged drivers. Many drivers have blood levels far exceeding the therapeutic dose range suggesting a high degree of abuse potential for benzodiazepines and zolpidem and zopiclone. | Nordazepam
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Nordazepam (marketed under brand names Stilny®, Madar®, Vegesan®, and Calmday®), also known as nordiazepam and desmethyldiazepam, is a 1,4-benzodiazepine derivative. Like other benzodiazepine derivatives, it has anticonvulsant, anxiolytic, muscle relaxant and sedative properties. However, it is used primarily in the treatment of anxiety. It is an active metabolite of diazepam, chlordiazepoxide, clorazepate, prazepam, and medazepam.[1]
# Side effects
Common side effects of nordazepam include somnolence, which is more common in elderly patients and/or people on high dose regimens. Hypotonia, which is much less common, is also associated with high doses and/or old age.
# Interactions
Benzodiazepines including N-desmethyldiazepam (nordazepam) may inhibit the glucuronidation of morphine leading to increased levels of and prolongation of the effects of morphine.[2]
# Abuse
Nordazepam and other sedative hypnotic drugs are detected frequently in cases of people suspected of driving under the influence of drugs. Other benzodiazepines and zolpidem and zopiclone are also found in high numbers of suspected drugged drivers. Many drivers have blood levels far exceeding the therapeutic dose range suggesting a high degree of abuse potential for benzodiazepines and zolpidem and zopiclone.[3]
# External links
- Inchem - Nordazepam | https://www.wikidoc.org/index.php/Demethyldiazepam | |
6049405b3b0af2620709ab67548e9f761a99f00b | wikidoc | Demography | Demography
Demography is the statistical study of all populations. It can be a general science that can be applied to any kind of dynamic population, that is, one that changes over time or space (see population dynamics). It encompasses the study of the size, structure and distribution of populations, and spatial and/or temporal changes in them in response to birth, death, migration and aging.
Human demography is the most well known discipline of demography, and typically what people refer to when using the term demography. Demographic analysis can be applied to whole societies or to groups defined by criteria such as education, nationality, religion and ethnicity. In academia, demography is often regarded as a branch of either economics or sociology. Formal demography limits its object of study to the measurement of populations processes, while the more broad field of social demography population studies also analyze the relationships between economic, social, cultural and biological processes influencing a population.
The term demographics is often used erroneously for demography, but refers rather to selected population characteristics as used in government, marketing or opinion research, or the demographic profiles used in such research.
# Data and methods
There are two methods of data collection: direct and indirect. Direct data come from vital statistics registries that track all births and deaths as well as certain changes in legal status such as marriage, divorce, and migration (registration of place of residence). In developed countries with good registration systems (such as the United States and much of Europe), registry statistics are the best method for estimating the number of births and deaths.
The census is the other common direct method of collecting demographic data. A census is usually conducted by a national government and attempts to enumerate every person in a country. However, in contrast to vital statistics data, which are typically collected continuously and summarized on an annual basis, censuses typically occur only every 10 years or so, and thus are not usually the best source of data on births and deaths. Analyses are conducted after a census to estimate how much over or undercounting took place. Censuses do more than just count people. They also typically collect information about families or households, as well as about such individual characteristics as age, sex, marital status, literacy/education, employment status and occupation, and geographical location. They may also collect data on migration (or place of birth or of previous residence), language, religion, nationality (or ethnicity or race), and citizenship. In countries in which the vital registration system may be incomplete, the censuses are also used as a direct source of information about fertility and mortality; for example the censuses of the People's Republic of China gather information on births and deaths that occurred in the 18 months immediately preceding the census.
Indirect methods of data collections are required in countries where full data are not available, such as is the case in much of the developing world. One of these techniques is the sister method, where survey researchers ask women how many of their sisters have died or had children and at what age. With these surveys, researchers can then indirectly estimate birth or death rates for the entire population. Other indirect methods include asking people about siblings, parents, and children.
There are a variety of demographic methods for modeling population processes. They include models of mortality (including the life table, Gompertz models, hazard models, Cox proportional hazards models, multiple decrement life tables, Brass relational logits), fertility (Hernes model, Coale-Trussell models, parity progression ratios), marriage (Singulate Mean at Marriage, Page model), disability (Sullivan's method, multistate life tables), population projections ( Lee Carter, the Leslie Matrix), and population momentum (Keyfitz).
# Important concepts
Important concepts in demography include-:
- The crude birth rate, the annual number of live births per thousand people.
- The general fertility rate, the annual number of live births per 1000 women of childbearing age (often taken to be from 15 to 49 years old, but sometimes from 15 to 44).
- age-specific fertility rates, the annual number of live births per 1000 women in particular age groups (usually age 15-19, 20-24 etc.)
- The crude death rate, the annual number of deaths per 1000 people.
- The infant mortality rate, the annual number of deaths of children less than 1 year old per 1000 live births.
- The expectation of life (or life expectancy), the number of years which an individual at a given age could expect to live at present mortality levels.
- The total fertility rate, the number of live births per woman completing her reproductive life, if her childbearing at each age reflected current age-specific fertility rates.
- The gross reproduction rate, the number of daughters who would be born to a woman completing her reproductive life at current age-specific fertility rates.
- The net reproduction ratio is the expected number of daughters, per newborn prospective mother, who may or may not survive to and through the ages of childbearing.
Note that the crude death rate as defined above and applied to a whole population can give a misleading impression. For example, the number of deaths per 1000 people can be higher for developed nations than in less-developed countries, despite standards of health being better in developed countries. This is because developed countries have relatively more older people, who are more likely to die in a given year, so that the overall mortality rate can be higher even if the mortality rate at any given age is lower. A more complete picture of mortality is given by a life table which summarises mortality separately at each age. A life table is necessary to give a good estimate of life expectancy.
The fertility rates can also give a misleading impression that a population is growing faster than it in fact is, because measurement of fertility rates only involves the reproductive rate of women, and does not adjust for the sex ratio. For example, if a population has a total fertility rate of 4.0 but the sex ratio is 66/34 (twice as many men as women), this population is actually growing at a slower natural increase rate than would a population having a fertility rate of 3.0 and a sex ratio of 50/50. This distortion is greatest in India and Myanmar, and is present in China as well.
# Basic demographic equation
Suppose that a country (or other entity) contains Populationt persons at time t.
What is the size of the population at time t + 1 ?
Natural increase from time t to t + 1:
Net migration from time t to t + 1:
This basic equation can also be applied to subpopulations. For example, the population size of ethnic groups or nationalities within a given society or country is subject to the same sources of change. However, when dealing with ethnic groups, "net migration" might have to be subdivided into physical migration and ethnic reidentification (assimilation). Individuals who change their ethnic self-labels or whose ethnic classification in government statistics changes over time may be thought of as migrating or moving from one population subcategory to another.
More generally, while the basic demographic equation holds true by definition, in practice the recording and counting of events (births, deaths, immigration, emigration) and the enumeration of the total population size are subject to error. So allowance needs to be made for error in the underlying statistics when any accounting of population size or change is made.
# History
Ibn Khaldun (1332-1406) is regarded as the "father of demography" for his economic analysis of social organization which produced the first scientific and theoretical work on population, development, and group dynamics. His
Muqaddimah also laid the groundwork for his observation of the role of state, communication and propaganda in history.
The Natural and Political Observations ... upon the Bills of Mortality (1662) of John Graunt contains a primitive form of life table. Mathematicians, such as Edmond Halley, developed the life table as the basis for life insurance mathematics. Richard Price was credited with the first textbook on life contingencies published in 1771, followed later by Augustus de Morgan, ‘On the Application of Probabilities to Life Contingencies’, (1838).
At the end of the 18th century, Thomas Malthus concluded that, if unchecked, populations would be subject to exponential growth. He feared that population growth would tend to outstrip growth in food production, leading to ever increasing famine and poverty (see Malthusian catastrophe); he is seen as the intellectual father of ideas of overpopulation and the limits to growth. Later more sophisticated and realistic models were presented by e.g. Benjamin Gompertz and Verhulst.
# The demographic transition
Contrary to Malthus' predictions (though in line with his thoughts on moral restraint), natural population growth in most developed countries has diminished to close to zero, without being held in check by famine or lack of resources, as people in developed nations have shown a tendency to have fewer children. The fall in population growth has occurred despite large rises in life expectancy in these countries. This pattern of population growth, with slow (or no) growth in post-industrial societies, followed by fast growth as the society develops and industrialises, followed by slow growth again as it becomes more affluent, is known as the demographic transition.
Similar trends are now becoming visible in ever more developing countries, so that far from spiralling out of control, world population growth is expected to slow markedly in the next century, coming to an eventual standstill or even declining. The change is likely to be accompanied by major shifts in the proportion of world population in particular regions. The United Nations Population Division expects the absolute number of infants and toddlers in the world to begin to fall by 2015, and the number of children under 15 by 2025. The figure in this section shows the latest (2004) UN projections of world population out to the year 2150 (red = high, orange = medium, green = low). The UN "medium" projection shows world population reaching an approximate equilibrium at 9 billion by 2075. Working independently, demographers at the International Institute for Applied Systems Analysis in Austria expect world population to peak at 9 billion by 2070. Throughout the 21st century, the average age of the population is likely to continue to rise.
# The Science of Population
Populations change through three processes: fertility, mortality, and migration. Fertility involves the number of children that women have and is to be contrasted with fecundity (a woman's childbearing potential). Mortality is the study of the causes, consequences, and measurement of processes affecting death to members of the population. Demographers most commonly study mortality using the Life Table, a statistical device which provides information about the mortality conditions (most notably the life expectancy) in the population. Migration refers to the movement of persons from an origin place to a destination place across some pre-defined, political boundary. Migration researchers do not designate movements 'migrations' unless they are somewhat permanent. Thus demographers do not consider tourists and travelers to be migrating. While demographers who study migration typically do so through census data on place of residence, indirect sources of data including tax forms and labor force surveys are also important.
Demography is today widely taught in many universities across the world, attracting students with initial training in social sciences, statistics or health. Being at the crossroads of several disciplines such as geography, economics, sociology or epidemiology, demography offers tools to approach a large range of population issues by combining a more technical quantitative approach that represents the core of the discipline with many other methods borrowed from social or other sciences. Demographic research is conducted in universities, in research institutes as well as in statistical departments and in several international agencies. Population institutions are part of the Cicred (International Committee for Coordination of Demographic Research) network while most individual scientists engaged in demographic research are members of the IUSSP (International Union for the Scientific Study of Population).
# Notes
- ↑ Andrew Hinde Demographic Methods Ch. 1 ISBN 0-340-71892-7
- ↑ See, for example, Barbara A. Anderson and Brian D. Silver, "Estimating Russification of Ethnic Identity Among Non-Russians in the USSR," Demography, Vol. 20, No. 4 (Nov., 1983): 461-489.
- ↑ H. Mowlana (2001). "Information in the Arab World", Cooperation South Journal 1.
- ↑ “Our Yesterdays: the History of the Actuarial Profession in North America, 1809-1979,” by E.J. (Jack) Moorhead, FSA, ( 1/23/10 – 2/21/04), published by the Society of Actuaries as part of the profession’s centennial celebration in 1989.
- ↑ The History of Insurance, Vol 3, Edited by David Jenkins and Takau Yoneyama (1 85196 527 0): 8 Volume Set: ( 2000) Availability: Japan: Kinokuniya)
- ↑ John Bongaarts. The Fertility-Inhibiting Effects of the Intermediate Fertility Variables. Studies in Family Planning, Vol. 13, No. 6/7. (Jun. - Jul., 1982), pp. 179-189.
- ↑ Donald T. Rowland Demographic Methods and Concepts Ch. 11 ISBN 0-19-875263-6 | Demography
Demography is the statistical study of all populations. It can be a general science that can be applied to any kind of dynamic population, that is, one that changes over time or space (see population dynamics). It encompasses the study of the size, structure and distribution of populations, and spatial and/or temporal changes in them in response to birth, death, migration and aging.
Human demography is the most well known discipline of demography, and typically what people refer to when using the term demography. Demographic analysis can be applied to whole societies or to groups defined by criteria such as education, nationality, religion and ethnicity. In academia, demography is often regarded as a branch of either economics or sociology. Formal demography limits its object of study to the measurement of populations processes, while the more broad field of social demography population studies also analyze the relationships between economic, social, cultural and biological processes influencing a population.[1]
The term demographics is often used erroneously for demography, but refers rather to selected population characteristics as used in government, marketing or opinion research, or the demographic profiles used in such research.
# Data and methods
There are two methods of data collection: direct and indirect. Direct data come from vital statistics registries that track all births and deaths as well as certain changes in legal status such as marriage, divorce, and migration (registration of place of residence). In developed countries with good registration systems (such as the United States and much of Europe), registry statistics are the best method for estimating the number of births and deaths.
The census is the other common direct method of collecting demographic data. A census is usually conducted by a national government and attempts to enumerate every person in a country. However, in contrast to vital statistics data, which are typically collected continuously and summarized on an annual basis, censuses typically occur only every 10 years or so, and thus are not usually the best source of data on births and deaths. Analyses are conducted after a census to estimate how much over or undercounting took place. Censuses do more than just count people. They also typically collect information about families or households, as well as about such individual characteristics as age, sex, marital status, literacy/education, employment status and occupation, and geographical location. They may also collect data on migration (or place of birth or of previous residence), language, religion, nationality (or ethnicity or race), and citizenship. In countries in which the vital registration system may be incomplete, the censuses are also used as a direct source of information about fertility and mortality; for example the censuses of the People's Republic of China gather information on births and deaths that occurred in the 18 months immediately preceding the census.
Indirect methods of data collections are required in countries where full data are not available, such as is the case in much of the developing world. One of these techniques is the sister method, where survey researchers ask women how many of their sisters have died or had children and at what age. With these surveys, researchers can then indirectly estimate birth or death rates for the entire population. Other indirect methods include asking people about siblings, parents, and children.
There are a variety of demographic methods for modeling population processes. They include models of mortality (including the life table, Gompertz models, hazard models, Cox proportional hazards models, multiple decrement life tables, Brass relational logits), fertility (Hernes model, Coale-Trussell models, parity progression ratios), marriage (Singulate Mean at Marriage, Page model), disability (Sullivan's method, multistate life tables), population projections ( Lee Carter, the Leslie Matrix), and population momentum (Keyfitz).
# Important concepts
Important concepts in demography include-:
- The crude birth rate, the annual number of live births per thousand people.
- The general fertility rate, the annual number of live births per 1000 women of childbearing age (often taken to be from 15 to 49 years old, but sometimes from 15 to 44).
- age-specific fertility rates, the annual number of live births per 1000 women in particular age groups (usually age 15-19, 20-24 etc.)
- The crude death rate, the annual number of deaths per 1000 people.
- The infant mortality rate, the annual number of deaths of children less than 1 year old per 1000 live births.
- The expectation of life (or life expectancy), the number of years which an individual at a given age could expect to live at present mortality levels.
- The total fertility rate, the number of live births per woman completing her reproductive life, if her childbearing at each age reflected current age-specific fertility rates.
- The gross reproduction rate, the number of daughters who would be born to a woman completing her reproductive life at current age-specific fertility rates.
- The net reproduction ratio is the expected number of daughters, per newborn prospective mother, who may or may not survive to and through the ages of childbearing.
Note that the crude death rate as defined above and applied to a whole population can give a misleading impression. For example, the number of deaths per 1000 people can be higher for developed nations than in less-developed countries, despite standards of health being better in developed countries. This is because developed countries have relatively more older people, who are more likely to die in a given year, so that the overall mortality rate can be higher even if the mortality rate at any given age is lower. A more complete picture of mortality is given by a life table which summarises mortality separately at each age. A life table is necessary to give a good estimate of life expectancy.
The fertility rates can also give a misleading impression that a population is growing faster than it in fact is, because measurement of fertility rates only involves the reproductive rate of women, and does not adjust for the sex ratio. For example, if a population has a total fertility rate of 4.0 but the sex ratio is 66/34 (twice as many men as women), this population is actually growing at a slower natural increase rate than would a population having a fertility rate of 3.0 and a sex ratio of 50/50. This distortion is greatest in India and Myanmar, and is present in China as well.
# Basic demographic equation
Suppose that a country (or other entity) contains Populationt persons at time t.
What is the size of the population at time t + 1 ?
Natural increase from time t to t + 1:
Net migration from time t to t + 1:
This basic equation can also be applied to subpopulations. For example, the population size of ethnic groups or nationalities within a given society or country is subject to the same sources of change. However, when dealing with ethnic groups, "net migration" might have to be subdivided into physical migration and ethnic reidentification (assimilation). Individuals who change their ethnic self-labels or whose ethnic classification in government statistics changes over time may be thought of as migrating or moving from one population subcategory to another.[2]
More generally, while the basic demographic equation holds true by definition, in practice the recording and counting of events (births, deaths, immigration, emigration) and the enumeration of the total population size are subject to error. So allowance needs to be made for error in the underlying statistics when any accounting of population size or change is made.
# History
Ibn Khaldun (1332-1406) is regarded as the "father of demography" for his economic analysis of social organization which produced the first scientific and theoretical work on population, development, and group dynamics. His
Muqaddimah also laid the groundwork for his observation of the role of state, communication and propaganda in history.[3]
The Natural and Political Observations ... upon the Bills of Mortality (1662) of John Graunt contains a primitive form of life table. Mathematicians, such as Edmond Halley, developed the life table as the basis for life insurance mathematics. Richard Price was credited with the first textbook on life contingencies published in 1771,[4] followed later by Augustus de Morgan, ‘On the Application of Probabilities to Life Contingencies’, (1838).[5]
At the end of the 18th century, Thomas Malthus concluded that, if unchecked, populations would be subject to exponential growth. He feared that population growth would tend to outstrip growth in food production, leading to ever increasing famine and poverty (see Malthusian catastrophe); he is seen as the intellectual father of ideas of overpopulation and the limits to growth. Later more sophisticated and realistic models were presented by e.g. Benjamin Gompertz and Verhulst.
# The demographic transition
Contrary to Malthus' predictions (though in line with his thoughts on moral restraint), natural population growth in most developed countries has diminished to close to zero, without being held in check by famine or lack of resources, as people in developed nations have shown a tendency to have fewer children. The fall in population growth has occurred despite large rises in life expectancy in these countries. This pattern of population growth, with slow (or no) growth in post-industrial societies, followed by fast growth as the society develops and industrialises, followed by slow growth again as it becomes more affluent, is known as the demographic transition.
Similar trends are now becoming visible in ever more developing countries, so that far from spiralling out of control, world population growth is expected to slow markedly in the next century, coming to an eventual standstill or even declining. The change is likely to be accompanied by major shifts in the proportion of world population in particular regions. The United Nations Population Division expects the absolute number of infants and toddlers in the world to begin to fall by 2015, and the number of children under 15 by 2025. The figure in this section shows the latest (2004) UN projections of world population out to the year 2150 (red = high, orange = medium, green = low). The UN "medium" projection shows world population reaching an approximate equilibrium at 9 billion by 2075. Working independently, demographers at the International Institute for Applied Systems Analysis in Austria expect world population to peak at 9 billion by 2070. Throughout the 21st century, the average age of the population is likely to continue to rise.
# The Science of Population
Populations change through three processes: fertility, mortality, and migration. Fertility involves the number of children that women have and is to be contrasted with fecundity (a woman's childbearing potential).[6] Mortality is the study of the causes, consequences, and measurement of processes affecting death to members of the population. Demographers most commonly study mortality using the Life Table, a statistical device which provides information about the mortality conditions (most notably the life expectancy) in the population.[7] Migration refers to the movement of persons from an origin place to a destination place across some pre-defined, political boundary. Migration researchers do not designate movements 'migrations' unless they are somewhat permanent. Thus demographers do not consider tourists and travelers to be migrating. While demographers who study migration typically do so through census data on place of residence, indirect sources of data including tax forms and labor force surveys are also important.[8]
Demography is today widely taught in many universities across the world, attracting students with initial training in social sciences, statistics or health. Being at the crossroads of several disciplines such as geography, economics, sociology or epidemiology, demography offers tools to approach a large range of population issues by combining a more technical quantitative approach that represents the core of the discipline with many other methods borrowed from social or other sciences. Demographic research is conducted in universities, in research institutes as well as in statistical departments and in several international agencies. Population institutions are part of the Cicred (International Committee for Coordination of Demographic Research) network while most individual scientists engaged in demographic research are members of the IUSSP (International Union for the Scientific Study of Population).
# Notes
- ↑ Andrew Hinde Demographic Methods Ch. 1 ISBN 0-340-71892-7
- ↑ See, for example, Barbara A. Anderson and Brian D. Silver, "Estimating Russification of Ethnic Identity Among Non-Russians in the USSR," Demography, Vol. 20, No. 4 (Nov., 1983): 461-489.
- ↑ H. Mowlana (2001). "Information in the Arab World", Cooperation South Journal 1.
- ↑ “Our Yesterdays: the History of the Actuarial Profession in North America, 1809-1979,” by E.J. (Jack) Moorhead, FSA, ( 1/23/10 – 2/21/04), published by the Society of Actuaries as part of the profession’s centennial celebration in 1989.
- ↑ The History of Insurance, Vol 3, Edited by David Jenkins and Takau Yoneyama (1 85196 527 0): 8 Volume Set: ( 2000) Availability: Japan: Kinokuniya)
- ↑ John Bongaarts. The Fertility-Inhibiting Effects of the Intermediate Fertility Variables. Studies in Family Planning, Vol. 13, No. 6/7. (Jun. - Jul., 1982), pp. 179-189.
- ↑ http://www.cdc.gov/nchs/products/pubs/pubd/lftbls/lftbls.htm
- ↑ Donald T. Rowland Demographic Methods and Concepts Ch. 11 ISBN 0-19-875263-6 | https://www.wikidoc.org/index.php/Demography | |
e3a47b799f71fd3d8f896e0c9052b4fe1b60688a | wikidoc | Denatonium | Denatonium
Denatonium, usually available as denatonium benzoate (under trade names such as Bitrex or Aversion) and as denatonium saccharide, is the most bitter compound known to date.
It was discovered in 1958 during research on local anesthetics by Macfarlan Smith of Edinburgh, Scotland, and registered under the trademark Bitrex. Dilutions of as little as 10 ppm are unbearably bitter to most humans. Denatonium salts are usually colorless and odorless solids but are often traded as solutions. They are used as aversive agents to prevent accidental ingestion. Denatonium is used in denatured alcohol, antifreeze, nail biting preventions, animal repellents, liquid soaps, and shampoos. It is not known to pose any long-term health risks although exposure may be irritating and unpleasant.
An amusing anecdote relates how one of the researchers at Atomergic Chemetals Corp. in Plainview, New York, went home without realising that he had a tiny trace of denatonium saccharide on the outside of his lip. When he kissed his wife, she almost vomited.
# Structure and physical properties
Denatonium is a quaternary ammonium cation. It is a compound of a salt with an inert anion like benzoate or saccharide. The structure of denatonium is related to the local anesthetic lidocaine, differing only by the addition of a benzyl group to the amino nitrogen.
# Applications
The bitterness of the compound guides most applications of denatonium. Denatonium benzoate is used to denature ethanol so that it is not taxed as an alcoholic beverage. One designation in particular, SD-40B, indicates that ethanol has been denatured using denatonium benzoate. In fact, the common name for this chemical, denatonium alludes to this application.
Denatonium also discourages consumption of harmful alcohols like methyl alcohol and ethylene glycol. Denatonium is therefore often used in rubbing alcohol as an inactive ingredient. It is also added to all kinds of harmful liquids including solvents, paints, varnishes, toiletries, and other household products.
Since 1995, when the State of Oregon required that denatonium benzoate be added to antifreeze and windshield wiper fluid, the compound has been increasingly found in these substances throughout the world. The addition is credited with saving children and animals who might otherwise drink sweet antifreeze or wiper fluid and get ethylene glycol or methanol poisoning respectively.
Other uses include nail polish for preventing nail biting, and as animal repellent (especially for big game like deer).
Non-human animals are known to have different sensitivities to the effects of denatonium. It has been used to safeguard rat poisons from human consumption, so presumably rats are not deterred by it, although there is evidence that a small percentage of rodents do avoid such baits. Some cats have been known to be tempted by them — it may not be as effective a deterrent for cats as it is for humans, or perhaps some cats are not deterred due to a genetic factor similar to that affecting human perceptions of the taste of phenylthiocarbamide.
It is soon to be used on all Bindeez toys in response to the incident where two children experienced a coma after ingesting the small beads. It was later discovered that it contained a chemical which metabolizes to GHB, a drug with alcohol-like effects in small doses. Though that problem is unlikely to reoccur, the bitter substance will be used to prevent future ingestion and choking. | Denatonium
Template:Chembox new
Denatonium, usually available as denatonium benzoate (under trade names such as Bitrex or Aversion) and as denatonium saccharide, is the most bitter compound known to date.
It was discovered in 1958 during research on local anesthetics by Macfarlan Smith of Edinburgh, Scotland, and registered under the trademark Bitrex.[1][2] Dilutions of as little as 10 ppm are unbearably bitter to most humans. Denatonium salts are usually colorless and odorless solids but are often traded as solutions. They are used as aversive agents to prevent accidental ingestion. Denatonium is used in denatured alcohol,[3] antifreeze, nail biting preventions, animal repellents, liquid soaps, and shampoos. It is not known to pose any long-term health risks although exposure may be irritating and unpleasant.
An amusing anecdote relates how one of the researchers at Atomergic Chemetals Corp. in Plainview, New York, went home without realising that he had a tiny trace of denatonium saccharide on the outside of his lip. When he kissed his wife, she almost vomited.[4]
# Structure and physical properties
Denatonium is a quaternary ammonium cation. It is a compound of a salt with an inert anion like benzoate or saccharide. The structure of denatonium is related to the local anesthetic lidocaine, differing only by the addition of a benzyl group to the amino nitrogen.
# Applications
The bitterness of the compound guides most applications of denatonium. Denatonium benzoate is used to denature ethanol so that it is not taxed as an alcoholic beverage. One designation in particular, SD-40B, indicates that ethanol has been denatured using denatonium benzoate. In fact, the common name for this chemical, denatonium alludes to this application.
Denatonium also discourages consumption of harmful alcohols like methyl alcohol and ethylene glycol. Denatonium is therefore often used in rubbing alcohol as an inactive ingredient. It is also added to all kinds of harmful liquids including solvents, paints, varnishes, toiletries, and other household products.
Since 1995, when the State of Oregon required that denatonium benzoate be added to antifreeze and windshield wiper fluid, the compound has been increasingly found in these substances throughout the world. The addition is credited with saving children and animals who might otherwise drink sweet antifreeze or wiper fluid and get ethylene glycol or methanol poisoning respectively.
Other uses include nail polish for preventing nail biting, and as animal repellent (especially for big game like deer).
Non-human animals are known to have different sensitivities to the effects of denatonium. It has been used to safeguard rat poisons from human consumption, so presumably rats are not deterred by it, although there is evidence that a small percentage of rodents do avoid such baits.[citation needed] Some cats have been known to be tempted by them — it may not be as effective a deterrent for cats as it is for humans, or perhaps some cats are not deterred due to a genetic factor similar to that affecting human perceptions of the taste of phenylthiocarbamide.[citation needed]
It is soon to be used on all Bindeez toys in response to the incident where two children experienced a coma after ingesting the small beads. It was later discovered that it contained a chemical which metabolizes to GHB, a drug with alcohol-like effects in small doses. Though that problem is unlikely to reoccur, the bitter substance will be used to prevent future ingestion and choking.[citation needed] | https://www.wikidoc.org/index.php/Denatonium | |
7e59bb0afb11c4672cbefcc21ae8b60f0a01cb0a | wikidoc | Dental dam | Dental dam
# Overview
Dental dams or rubber dams are essentially rectangular sheets of latex used in dentistry, specifically endodontic therapy. They are also used during sexual activities as a safer sex technique.
# In dentistry
A dental dam, also known as in Europe as a "Kofferdamm" (from German), is used mainly in endodontic treatment and when putting fillings into teeth. They are often made from thin latex rubber, and because of possible latex allergy, they are also available in silicone.
The main function is to isolate the tooth being treated from its environment, in particular from the bacteria in the oral cavity. The rubber dam is held over individual teeth or groups of teeth by appropriate clips or threads (ligatures) along the edge of the gum. The tooth crown stands out from the rubber dam through individual holes made by hole pliers, and permits a clean and dry treatment of the appropriate tooth without admission of blood and saliva.
Routine use of dental dams is not always appropriate because of some difficulties: communication with the patient is strongly reduced and the patient may feel restricted.
# For oral sex
When held over the vulva or anus, an unpierced, intact dental dam protects both the person performing oral sex on those body parts and the person receiving it from potential harm from sexually transmitted diseases. | Dental dam
# Overview
Dental dams or rubber dams are essentially rectangular sheets of latex used in dentistry, specifically endodontic therapy. They are also used during sexual activities as a safer sex technique.
# In dentistry
A dental dam, also known as in Europe as a "Kofferdamm" (from German), is used mainly in endodontic treatment and when putting fillings into teeth. They are often made from thin latex rubber, and because of possible latex allergy, they are also available in silicone.
The main function is to isolate the tooth being treated from its environment, in particular from the bacteria in the oral cavity. The rubber dam is held over individual teeth or groups of teeth by appropriate clips or threads (ligatures) along the edge of the gum. The tooth crown stands out from the rubber dam through individual holes made by hole pliers, and permits a clean and dry treatment of the appropriate tooth without admission of blood and saliva.
Routine use of dental dams is not always appropriate because of some difficulties: communication with the patient is strongly reduced and the patient may feel restricted.
# For oral sex
When held over the vulva or anus, an unpierced, intact dental dam protects both the person performing oral sex on those body parts and the person receiving it from potential harm from sexually transmitted diseases.
# External links
- SexInfo's "How to Make a Dental Dam Using a Condom"
- How to use a Dental Dam for sex
- Sgfelken.com (commercial) website provides a description and pictures about dental dams and its medical and sexual usage.
de:Kofferdam (Zahnmedizin)
de:Lecktuch
nl:Rubberdam
Template:WH
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Dental_dam | |
4affedebb772ec93396b8a68d3c429e0ba469768 | wikidoc | Nucleotide | Nucleotide
A nucleotide is a chemical compound that consists of 3 portions: a heterocyclic base, a sugar, and one or more phosphate groups. In the most common nucleotides the base is a derivative of purine or pyrimidine, and the sugar is the pentose (five-carbon sugar) deoxyribose or ribose. Nucleotides are the monomers of nucleic acids, with three or more bonding together in order to form a nucleic acid.
Nucleotides are the structural units of RNA, DNA, and several cofactors - CoA, flavin adenine dinucleotide, flavin mononucleotide, adenosine triphosphate and nicotinamide adenine dinucleotide phosphate. In the cell they have important roles in metabolism and signaling.
## Nucleotides
## Deoxynucleotides
NOTE:
If in place of ribose , the sugar deoxyribose is present the prefix `deoxy` may be added before the name of the nucleoside in all cases except thymidine.
# Synthesis
Salvage synthesis refers to the reuse of parts of nucleotides in resynthesizing new nucleotides. Salvage synthesis requires both breakdown and synthesis reactions in order to exchange the useful parts.
## Natural
### Purine ribonucleotides
By using a variety of isotopically labelled compounds it was demonstrated that the sources of the atoms in purines are as follows:
The de novo synthesis of purine nucleotides by which these precursors are incorporated into the purine ring, proceeds by a 10 step pathway to the branch point intermediate IMP, the nucleotide of the base hypoxanthine. AMP and GMP are subsequently synthesized from this intermediate via separate, two step each, pathways. Thus purine moieties are initially formed as part of the ribonucleotides rather than as free bases.
Six enzymes take part in IMP synthesis. Three of them are multifunctional:
- GART (reactions 2, 3, and 5)
- PAICS (reactions 6, and 7)
- ATIC (reactions 9, and 10)
Reaction 1. The pathway starts with the formation of PRPP. PRPS1 is the enzyme that activates R5P, which is primarily formed by the pentose phosphate pathway, to PRPP by reacting it with ATP. The reaction is unusual in that a pyrophosphoryl group is directly transferred from ATP to C1 of R5P and that the product has the α configuration about C1. This reaction is also shared with the pathways for the synthesis of the pyrimidine nucleotides, Trp, and His. As a result of being on (a) such (a) major metabolic crossroad and the use of energy, this reaction is highly regulated.
Reaction 2. In the first reaction unique to purine nucleotide biosynthesis, PPAT catalyzes the displacement of PRPP's pyrophosphate group (PPi) by Gln's amide nitrogen. The reaction occurs with the inversion of configuration about ribose C1, thereby forming β-5-phosphorybosylamine (5-PRA) and establishing the anomeric form of the future nucleotide. This reaction which is driven to completion by the subsequent hydrolysis of the released PPi, is the pathway's flux generating step and is therefore regulated too.
Reaction 3.
### Pyrimidine ribonucleotides
## Protection Chemistry
Nucleic acids can be synthesised in the lab. using protecting groups, typically this is achieved by protecting a purified nucleoside or nucleobase, a protected base is called a phosphoramidite. these can be used to obtain analogues not present in nature and/or to create an oligonucleotide. | Nucleotide
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
A nucleotide is a chemical compound that consists of 3 portions: a heterocyclic base, a sugar, and one or more phosphate groups. In the most common nucleotides the base is a derivative of purine or pyrimidine, and the sugar is the pentose (five-carbon sugar) deoxyribose or ribose. Nucleotides are the monomers of nucleic acids, with three or more bonding together in order to form a nucleic acid.
Nucleotides are the structural units of RNA, DNA, and several cofactors - CoA, flavin adenine dinucleotide, flavin mononucleotide, adenosine triphosphate and nicotinamide adenine dinucleotide phosphate. In the cell they have important roles in metabolism and signaling.
## Nucleotides
## Deoxynucleotides
NOTE:
If in place of ribose , the sugar deoxyribose is present the prefix `deoxy` may be added before the name of the nucleoside in all cases except thymidine.
# Synthesis
Salvage synthesis refers to the reuse of parts of nucleotides in resynthesizing new nucleotides. Salvage synthesis requires both breakdown and synthesis reactions in order to exchange the useful parts.
## Natural
### Purine ribonucleotides
By using a variety of isotopically labelled compounds it was demonstrated that the sources of the atoms in purines are as follows:
The de novo synthesis of purine nucleotides by which these precursors are incorporated into the purine ring, proceeds by a 10 step pathway to the branch point intermediate IMP, the nucleotide of the base hypoxanthine. AMP and GMP are subsequently synthesized from this intermediate via separate, two step each, pathways. Thus purine moieties are initially formed as part of the ribonucleotides rather than as free bases.
Six enzymes take part in IMP synthesis. Three of them are multifunctional:
- GART (reactions 2, 3, and 5)
- PAICS (reactions 6, and 7)
- ATIC (reactions 9, and 10)
Reaction 1. The pathway starts with the formation of PRPP. PRPS1 is the enzyme that activates R5P, which is primarily formed by the pentose phosphate pathway, to PRPP by reacting it with ATP. The reaction is unusual in that a pyrophosphoryl group is directly transferred from ATP to C1 of R5P and that the product has the α configuration about C1. This reaction is also shared with the pathways for the synthesis of the pyrimidine nucleotides, Trp, and His. As a result of being on (a) such (a) major metabolic crossroad and the use of energy, this reaction is highly regulated.
Reaction 2. In the first reaction unique to purine nucleotide biosynthesis, PPAT catalyzes the displacement of PRPP's pyrophosphate group (PPi) by Gln's amide nitrogen. The reaction occurs with the inversion of configuration about ribose C1, thereby forming β-5-phosphorybosylamine (5-PRA) and establishing the anomeric form of the future nucleotide. This reaction which is driven to completion by the subsequent hydrolysis of the released PPi, is the pathway's flux generating step and is therefore regulated too.
Reaction 3.
### Pyrimidine ribonucleotides
## Protection Chemistry
Nucleic acids can be synthesised in the lab. using protecting groups, typically this is achieved by protecting a purified nucleoside or nucleobase, a protected base is called a phosphoramidite. these can be used to obtain analogues not present in nature and/or to create an oligonucleotide. | https://www.wikidoc.org/index.php/Deoxynucleotide | |
a12592c0e8509028847db14504a06ebc5d8743b1 | wikidoc | Desflurane | Desflurane
# Disclaimer
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# Overview
Desflurane is a general anesthetic that is FDA approved for the {{{indicationType}}} of general anesthesia. Common adverse reactions include gastrointestinal: nausea (27% ), vomiting (16% ), respiratory: cough ( adult induction, 22% to 34% ), interrupted breathing (adult induction, 30% to 39%; adult and intubated pediatric maintenance, greater than 1% ).
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- General anesthesia: induction, initial inhaled concentration of 3% in oxygen or nitrous oxide/oxygen, increased by 0.5% to 1% increments every 2 to 3 breaths or as tolerated (end tidal concentrations 4% to 11%) inspired concentrations greater than 12% have been safely administered during induction and may require a reduction of nitrous oxide or air.
- General anesthesia: maintenance, inhaled concentrations of 2.5% to 8.5% with or without concomitant nitrous oxide; dosage must be individualized based on patient response.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information about Off-Label Guideline-Supported Use of Desflurane in adult patients.
### Non–Guideline-Supported Use
There is limited information about Off-Label Non–Guideline-Supported Use of Desflurane in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- General anesthesia: maintenance, inhaled in concentrations of 5.2% to 10% with or without concomitant nitrous oxide; dosage must be individualized based on patient response
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information about Off-Label Guideline-Supported Use of Desflurane in pediatric patients.
### Non–Guideline-Supported Use
There is limited information about Off-Label Non–Guideline-Supported Use of Desflurane in pediatric patients.
# Contraindications
- The use of desflurane (desflurane, USP) is contraindicated in the following conditions:
- Known or suspected genetic susceptibility to malignant hyperthermia.
- Patients in whom general anesthesia is contraindicated.
- Induction of anesthesia in pediatric patients.
- Patients with known sensitivity to desflurane (desflurane, USP) or to other halogenated agents .
- Patients with a history of confirmed hepatitis or with a history of unexplained moderate to severe hepatic dysfunction (e.g., jaundice associated with fever and/or eosinophilia) after anesthesia with desflurane (desflurane, USP) or other halogenated agents .
# Warnings
- In susceptible individuals, potent inhalation anesthetic agents may trigger a skeletal muscle hypermetabolic state leading to high oxygen demand and the clinical syndrome known as malignant hyperthermia. In genetically susceptible pigs, desflurane induced malignant hyperthermia. The clinical syndrome is signaled by hypercapnia, and may include muscle rigidity, tachycardia, tachypnea, cyanosis, arrhythmias, and/or unstable blood pressure. Some of these nonspecific signs may also appear during light anesthesia: acute hypoxia, hypercapnia, and hypovolemia.
- Treatment of malignant hyperthermia includes discontinuation of triggering agents, administration of intravenous dantrolene sodium, and application of supportive therapy. (Consult prescribing information for dantrolene sodium intravenous for additional information on patient management.) Renal failure may appear later, and urine flow should be monitored and sustained if possible.
- Fatal outcome of malignant hyperthermia has been reported with desflurane.
- Use of inhaled anesthetic agents has been associated with rare increases in serum potassium levels that have resulted in cardiac arrhythmias and death in pediatric patients during the postoperative period. Patients with latent as well as overt neuromuscular disease, particularly Duchenne muscular dystrophy, appear to be most vulnerable. Concomitant use of succinylcholine has been associated with most, but not all, of these cases. These patients also experienced significant elevations in serum creatinine kinase levels and, in some cases, changes in urine consistent with myoglobinuria. Despite the similarity in presentation to malignant hyperthermia, none of these patients exhibited signs or symptoms of muscle rigidity or hypermetabolic state. Early and aggressive intervention to treat the hyperkalemia and resistant arrhythmias is recommended, as is subsequent evaluation for latent neuromuscular disease.
- Due to the limited data available in non-intubated pediatric patients, Desflurane (desflurane, USP) is not approved for maintenance of anesthesia in non-intubated children due to an increased incidence of respiratory adverse reactions, including coughing, laryngospasm and secretions .
- Caution should be exercised should Desflurane (desflurane, USP) be used for maintenance of anesthesia with laryngeal mask airway (LMA™ mask) in children, in particular for children 6 years old or younger because of the increased potential for adverse respiratory reactions, e.g. coughing and laryngospasm, especially with removal of the LMA™ mask under deep anesthesia .
- Caution should be exercised when Desflurane (desflurane, USP) is used for maintenance of anesthesia in children with asthma or a history of recent upper airway infection due to the potential for airway narrowing and increases in airway resistance.
- Desflurane like some other inhalation anesthetics, can react with desiccated carbon dioxide (CO2) absorbents to produce carbon monoxide that may result in elevated levels of carboxyhemoglobin in some patients. Case reports suggest that barium hydroxide lime and soda lime become desiccated when fresh gases are passed through the CO2 canister at high flow rates over many hours or days. When a clinician suspects that CO2 absorbent may be desiccated, it should be replaced before the administration of desflurane (desflurane, USP).
- With the use of halogenated anesthetics, disruption of hepatic function, icterus and fatal liver necrosis have been reported; such reactions appear to indicate hypersensitivity. As with other halogenated anesthetic agents, desflurane (desflurane, USP) may cause sensitivity hepatitis in patients who have been sensitized by previous exposure to halogenated anesthetics . Cirrhosis, viral hepatitis or other pre-existing hepatic disease may be a reason to select an anesthetic other than a halogenated anesthetic. As with all halogenated anesthetics, repeated anesthesia within a short period of time should be approached with caution.
- Transient elevations in glucose and white blood cell count may occur as with use of other anesthetic agents.
# Adverse Reactions
## Clinical Trials Experience
- Adverse event information is derived from controlled clinical trials, the majority of which were conducted in the United States. The studies were conducted using a variety of premedications, other anesthetics, and surgical procedures of varying length. Most adverse events reported were mild and transient, and may reflect the surgical procedures, patient characteristics (including disease) and/or medications administered.
- Of the 2,143 patients exposed to Desflurane (desflurane, USP) in clinical trials, 370 adults and 152 children were induced with desflurane alone and 987 patients were maintained principally with desflurane. The frequencies given reflect the percent of patients with the event. Each patient was counted once for each type of adverse event. They are presented in alphabetical order according to body system.
- Frequency of Events Occurring in Less Than 1% of Patients
(in Reports Deemed “Probably Causally Related”)
- Reported in 3 or more patients, regardless of severity
- Adverse reactions reported only from postmarketing experience or in the literature, not seen in clinical trials, are considered rare and are italicized.
## Postmarketing Experience
- The following adverse reactions have been identified during post-approval use of desflurane (desflurane, USP). Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- Coagulopathy
- Hyperkalemia, Hypokalemia, metabolic acidosis
- Convulsion
- Ocular icterus
- Cardiac arrest, Torsade de pointes, ventricular failure, ventricular hypokinesia, Atrial fibrillation
- Malignant hypertension, hemorrhage, hypotension, shock
- Respiratory arrest, respiratory failure, respiratory distress, bronchospasm, hemoptysis
- Pancreatitis acute, abdominal pain
- Hepatic failure, hepatic necrosis, Hepatitis, cytolytic hepatitis, cholestasis, jaundice, hepatic function abnormal, liver disorder
- Urticaria, erythema
- Rhabdomyolysis
- Hyperthermia malignant, asthenia, malaise
- Electrocardiogram ST-T change, electrocardiogram T-wave inversion, tranaminases increased, alanine aminotransferase increased, aspartate aminotransferase increased, Blood bilirubin increased, coagulation test abnormal, ammonia increased
- Tachyarrhythmia, palpitations, eye burns, blindness transient, encephalopathy, ulcerative keratitis, ocular hyperemia, visual acuity reduced, eye irritation, eye pain, dizziness, migraine, fatigue, accidental exposure, skin burning sensation, drug administration error
- All of reactions categorized within this SOC were accidental exposures to non-patients.
# Drug Interactions
- No clinically significant adverse interactions with commonly used preanesthetic drugs, or drugs used during anesthesia (muscle relaxants, intravenous agents, and local anesthetic agents) were reported in clinical trials. The effect of desflurane (desflurane, USP) on the disposition of other drugs has not been determined. Similar to isoflurane, desflurane (desflurane, USP) does not predispose to premature ventricular arrhythmias in the presence of exogenously infused epinephrine in swine.
- Benzodiazepines and opioids decrease the amount of desflurane (MAC) needed to produce anesthesia. This effect is shown in Table 3 for intravenous midazolam (25-50 µg/kg) and intravenous fentanyl (3-6 µg/kg) in patients of two different age groups
- Anesthetic concentrations of desflurane at equilibrium (administered for 15 or more minutes before testing) reduced the ED95 of succinylcholine by approximately 30% and that of atracurium and pancuronium by approximately 50% compared to N2O/opioid anesthesia (see Table 4). The effect of desflurane on duration of nondepolarizing neuromuscular blockade has not been studied.
- Dosage reduction of neuromuscular blocking agents during induction of anesthesia may result in delayed onset of conditions suitable for endotracheal intubation or inadequate muscle relaxation, because potentiation of neuromuscular blocking agents requires equilibration of muscle with the delivered partial pressure of desflurane (desflurane, USP).
- Among nondepolarizing drugs, pancuronium, atracurium, and vecuronium interactions have been studied. In the absence of specific guidelines:
- For endotracheal intubation, do not reduce the dose of nondepolarizing muscle relaxants or succinylcholine.
- During maintenance of anesthesia, the dose of nondepolarizing muscle relaxants is likely to be reduced compared to that during N2O/opioid anesthesia. Administration of supplemental doses of muscle relaxants should be guided by the response to nerve stimulation.
- Concomitant administration of N2O reduces the MAC of desflurane (desflurane, USP) .
- Concomitant use of beta blockers may exaggerate the cardiovascular effects of inhalational anesthetics, including hypotension and negative inotropic effects.
- Concomitant use of MAO inhibitors and inhalational anesthetics may increase the risk of hemodynamic instability during surgery or medical procedures.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
- There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Reproduction studies have been performed in rats at doses up to at 1 MAC hour for a minimum of 21 days and have revealed no evidence of impaired fertility or harm to the fetus due to desflurane (desflurane, USP).
- No teratogenic effect was observed at approximately 10 and 13 cumulative MAC-Hour exposures at 1 MAC-Hour per day during organogenesis in rats or rabbits. At higher doses increased incidences of post-implantation loss and maternal toxicity were observed. However, at 10 MAC-Hours cumulative exposure in rats, about 6% decrease in the weight of male pups was observed at preterm caesarean delivery.
- Rats exposed to desflurane (desflurane, USP) at 1 MAC-Hour per day from gestation day 15 to lactation day 21, did not show signs of dystocia. - Body weights of pups delivered by these dams at birth and during lactation were comparable to that of control pups. No treatment related behavioral changes were reported in these pups during lactation.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Desflurane in women who are pregnant.
### Labor and Delivery
- The safety of desflurane (desflurane, USP) during labor or delivery has not been demonstrated. desflurane (desflurane, USP) is a uterine-relaxant.
### 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 desflurane (desflurane, USP) is administered to a nursing woman.
### Pediatric Use
- Respiratory Adverse Reactions in Pediatric Patients
- Desflurane (desflurane, USP) is indicated for maintenance of anesthesia in infants and children after induction of anesthesia with agents other than desflurane (desflurane, USP), and tracheal intubation.
- Due to limited data available in non-intubated pediatric patients, desflurane (desflurane, USP) is not approved for maintenance of anesthesia in non-intubated children due to an increased incidence of respiratory adverse reactions, including coughing (26%), laryngospasm (13%) and secretions (12%) .
- Caution should be exercised should desflurane (desflurane, USP) be used for maintenance anesthesia with laryngeal mask airway (LMA™ mask) in children, in particular for children 6 years old or younger because of the increased potential for adverse respiratory reactions, e.g. coughing and laryngospasm, especially with removal of the LMA™ mask under deep anesthesia .
- Caution should be exercised when Desflurane (desflurane, USP) is used for maintenance of anesthesia in children with asthma or a history of recent upper airway infection due to the potential for airway narrowing and increases in airway resistance.
### Geriatic Use
- The minimum alveolar concentration (MAC) of desflurane (desflurane, USP) decreases with increasing patient age. The dose should be adjusted accordingly. The average MAC for Desflurane (desflurane, USP) in a 70 year old patient is two-thirds the MAC for a 20 year old patient .
### Gender
There is no FDA guidance on the use of Desflurane with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Desflurane with respect to specific racial populations.
### Renal Impairment
- Concentrations of 1-4% desflurane (desflurane, USP) in nitrous oxide/oxygen have been used in patients with chronic renal or hepatic impairment and during renal transplantation surgery.
- Because of minimal metabolism, a need for dose adjustment in patients with renal and hepatic impairment is not to be expected.
- Nine patients receiving desflurane (N=9) were compared to 9 patients receiving isoflurane, all with chronic renal insufficiency (serum creatinine 1.5-6.9 mg/dL). No differences in hematological or biochemical tests, including renal function evaluation, were seen between the two groups. Similarly, no differences were found in a comparison of patients receiving either desflurane (N=28) or isoflurane (N=30) undergoing renal transplant.
### Hepatic Impairment
- Eight patients receiving desflurane (desflurane, USP) were compared to six patients receiving isoflurane, all with chronic hepatic disease (viral hepatitis, alcoholic hepatitis, or cirrhosis). No differences in hematological or biochemical tests, including hepatic enzymes and hepatic function evaluation, were seen.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Desflurane in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Desflurane in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Desflurane Administration in the drug label.
### Monitoring
There is limited information regarding Desflurane Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Desflurane and IV administrations.
# Overdosage
- The symptoms of overdosage of desflurane (desflurane, USP) can present as a deepening of anesthesia, cardiac and/or respiratory depression in spontaneously breathing patients, and cardiac depression in ventilated patients in whom hypercapnia and hypoxia may occur only at a late stage. In the event of overdosage, or suspected overdosage, take the following actions: discontinue administration of desflurane (desflurane, USP), maintain a patent airway, initiate assisted or controlled ventilation with oxygen, and maintain adequate cardiovascular function.
# Pharmacology
## Mechanism of Action
There is limited information regarding Desflurane Mechanism of Action in the drug label.
## Structure
- Desflurane (desflurane, USP), a nonflammable liquid administered via vaporizer, is a general inhalation anesthetic. It is (±)1,2,2,2-tetrafluoroethyl difluoromethyl ether:
- Desflurane (desflurane, USP) is nonflammable as defined by the requirements of International Electrotechnical Commission 601-2-13.
- Desflurane (desflurane, USP) is a colorless, volatile liquid below 22.8°C. Data indicate that Desflurane (desflurane, USP) is stable when stored under normal room lighting conditions according to instructions.
- Desflurane (desflurane, USP) is chemically stable. The only known degradation reaction is through prolonged direct contact with soda lime producing low levels of fluoroform (CHF3). The amount of CHF3 obtained is similar to that produced with MAC-equivalent doses of isoflurane. No discernible degradation occurs in the presence of strong acids.
- Desflurane (desflurane, USP) does not corrode stainless steel, brass, aluminum, anodized aluminum, nickel plated brass, copper, or beryllium
## Pharmacodynamics
- Changes in the clinical effects of Desflurane (desflurane, USP) rapidly follow changes in the inspired concentration. The duration of anesthesia and selected recovery measures for Desflurane (desflurane, USP) are given in the following tables:
- In 178 female outpatients undergoing laparoscopy, premedicated with fentanyl (1.5-2.0 µg/kg), anesthesia was initiated with propofol 2.5 mg/kg, desflurane/N2O 60% in O2 or desflurane/O2 alone. Anesthesia was maintained with either propofol 1.5-9.0 mg/kg/hr, desflurane 2.6-8.4% in N2O 60% in O2, or desflurane 3.1-8.9% in O2.
- In 88 unpremedicated outpatients, anesthesia was initiated with thiopental 3-9 mg/kg or desflurane in O2. Anesthesia was maintained with isoflurane 0.7-1.4% in N2O 60%, desflurane 1.8-7.7% in N2O 60%, or desflurane 4.4-11.9% in O2.
- Recovery from anesthesia was assessed at 30, 60, and 90 minutes following 0.5 MAC desflurane (3%) or isoflurane (0.6%) in N2O 60% using subjective and objective tests. At 30 minutes after anesthesia, only 43% of patients in the isoflurane group were able to perform the psychometric tests compared to 76% in the Desflurane (desflurane, USP) group (p < 0.05).
- Desflurane (desflurane, USP) was studied in twelve volunteers receiving no other drugs. Hemodynamic effects during controlled ventilation (PaCO2 38 mm Hg) were:
- When the same volunteers breathed spontaneously during desflurane anesthesia, systemic vascular resistance and mean arterial blood pressure decreased; cardiac index, heart rate, stroke volume, and central venous pressure (CVP) increased compared to values when the volunteers were conscious. Cardiac index, stroke volume, and CVP were greater during spontaneous ventilation than during controlled ventilation.
- During spontaneous ventilation in the same volunteers, increasing the concentration of Desflurane (desflurane, USP) from 3% to 12% decreased tidal volume and increased arterial carbon dioxide tension and respiratory rate. The combination of N2O 60% with a given concentration of desflurane gave results similar to those with desflurane alone. Respiratory depression produced by desflurane is similar to that produced by other potent inhalation agents.
- The use of desflurane concentrations higher than 1.5 MAC may produce apnea.
## Pharmacokinetics
- Due to the volatile nature of desflurane in plasma samples, the washin-washout profile of desflurane was used as a surrogate of plasma pharmacokinetics. Desflurane (desflurane, USP) is a volatile liquid inhalation anesthetic minimally biotransformed in the liver in humans. Less than 0.02% of the desflurane absorbed can be recovered as urinary metabolites (compared to 0.2% for isoflurane). Eight healthy male volunteers first breathed 70% N2O/30% O2 for 30 minutes and then a mixture of desflurane 2.0%, isoflurane 0.4%, and halothane 0.2% for another 30 minutes. During this time, inspired and end-tidal concentrations (FI and FA) were measured. The FA/FI (washin) value at 30 minutes for desflurane was 0.91, compared to 1.00 for N2O, 0.74 for isoflurane, and 0.58 for halothane (see Figure 2). The washin rates for halothane and isoflurane were similar to literature values. The washin was faster for desflurane than for isoflurane and halothane at all time points. The FA/FAO (washout) value at 5 minutes was 0.12 for desflurane, 0.22 for isoflurane, and 0.25 for halothane (see Figure 3). The washout for desflurane was more rapid than that for isoflurane and halothane at all elimination time points. By 5 days, the FA/FAO for desflurane is 1/20th of that for halothane or isoflurane.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
- Animal carcinogenicity studies have not been performed with Desflurane (desflurane, USP). In vitro and in vivo genotoxicity studies did not demonstrate mutagenicity or chromosomal damage by Desflurane (desflurane, USP). Tests for genotoxicity included the Ames mutation assay, the metaphase analysis of human lymphocytes, and the mouse micronucleus assay.
- Fertility was not affected after 1 MAC-Hour per day exposure (cumulative 63 and 14 MAC-Hours for males and females, respectively). At higher doses, parental toxicity (mortalities and reduced weight gain) was observed which could affect fertility.
# Clinical Studies
- The efficacy of Desflurane (desflurane, USP) was evaluated in 1,843 patients including ambulatory (N=1,061), cardiovascular (N=277), geriatric (N=103), neurosurgical (N=40), and pediatric (N=235) patients. Clinical experience with these patients and with 1,087 control patients in these studies not receiving Desflurane (desflurane, USP) is described below. Although Desflurane (desflurane, USP) can be used in adults for the inhalation induction of anesthesia via mask, it produces a high incidence of respiratory irritation (coughing, breathholding, apnea, increased secretions, laryngospasm). Oxyhemoglobin saturation below 90% occurred in 6% of patients (from pooled data, N = 370 adults).
- Desflurane (desflurane, USP) plus N2O was compared to isoflurane plus N2O in multicenter studies (21 sites) of 792 ASA physical status I, II, or III patients aged 18-76 years (median 32).
- Anesthetic induction begun with thiopental and continued with Desflurane (desflurane, USP) was associated with a 7% incidence of oxyhemoglobin saturation of 90% or less (from pooled data, N = 307) compared with 5% in patients in whom anesthesia was induced with thiopental and isoflurane (from pooled data, N = 152).
- Desflurane (desflurane, USP) with or without N2O or other anesthetics was generally well tolerated. There were no differences between Desflurane (desflurane, USP) and the other anesthetics studied in the times that patients were judged fit for discharge.
- In one outpatient study, patients received a standardized anesthetic consisting of thiopental 4.2-4.4 mg/kg, fentanyl 3.5-4.0 µg/kg, vecuronium 0.05-0.07 mg/kg, and N2O 60% in oxygen with either desflurane 3% or isoflurane 0.6%. Emergence times were significantly different; but times to sit up and discharge were not different (see Table 5).
- Desflurane (desflurane, USP) was compared to isoflurane, sufentanil or fentanyl for the anesthetic management of coronary artery bypass graft (CABG), abdominal aortic aneurysm, peripheral vascular and carotid endarterectomy surgery in 7 studies at 15 centers involving a total of 558 patients. In all patients except the desflurane vs. sufentanil study, the volatile anesthetics were supplemented with intravenous opioids, usually fentanyl. Blood pressure and heart rate were controlled by changes in concentration of the volatile anesthetics or opioids and cardiovascular drugs if necessary. Oxygen (100%) was the carrier gas in 253 of 277 desflurane cases (24 of 277 received N2O/O2).
- No differences were found in cardiovascular outcome (death, myocardial infarction, ventricular tachycardia or fibrillation, heart failure) among desflurane and the other anesthetics.
- Desflurane (desflurane, USP) should not be used as the sole agent for anesthetic induction in patients with coronary artery disease or any patients where increases in heart rate or blood pressure are undesirable. In the desflurane vs. sufentanil study, anesthetic induction with desflurane without opioids was associated with new transient ischemia in 14 patients vs. 0 in the sufentanil group. In the desflurane group, mean heart rate, arterial pressure, and pulmonary blood pressure increased and stroke volume decreased in contrast to no change in the sufentanil group. Cardiovascular drugs were used frequently in both groups: especially esmolol in the desflurane group (56% vs. 0%) and phenylephrine in the sufentanil group (43% vs. 27%). When 10 µg/kg of fentanyl was used to supplement induction of anesthesia at one other center, continuous 2-lead ECG analysis showed a low incidence of myocardial ischemia and no difference between desflurane and isoflurane. If desflurane is to be used in patients with coronary artery disease, it should be used in combination with other medications for induction of anesthesia, preferably intravenous opioids and hypnotics.
- In studies where Desflurane (desflurane, USP) or isoflurane anesthesia was supplemented with fentanyl, there were no differences in hemodynamic variables or the incidence of myocardial ischemia in the patients anesthetized with desflurane compared to those anesthetized with isoflurane.
- During the precardiopulmonary bypass period, in the desflurane vs. sufentanil study where the desflurane patients received no intravenous opioid, more desflurane patients required cardiovascular adjuvants to control hemodynamics than the sufentanil patients. During this period, the incidence of ischemia detected by ECG or echocardiography was not statistically different between desflurane (18 of 99) and sufentanil (9 of 98) groups. However, the duration and severity of ECG-detected myocardial ischemia was significantly less in the desflurane group. The incidence of myocardial ischemia after cardiopulmonary bypass and in the ICU did not differ between groups.
### Geriatric Surgery
- Desflurane (desflurane, USP) plus N2O was compared to isoflurane plus N2O in a multicenter study (6 sites) of 203 ASA physical status II or III elderly patients, aged 57-91 years (median 71).
- Most patients were premedicated with fentanyl (mean 2 µg/kg), preoxygenated, and received thiopental (mean 4.3 mg/kg IV) or thiamylal (mean 4 mg/kg IV) followed by succinylcholine (mean 1.4 mg/kg IV) for intubation.
- Heart rate and arterial blood pressure remained within 20% of preinduction baseline values during administration of Desflurane (desflurane, USP) 0.5-7.7% (average 3.6%) with 50-60% N2O. Induction, maintenance, and recovery cardiovascular measurements did not differ from those during isoflurane/N2O administration nor did the postoperative incidence of nausea and vomiting differ. The most common cardiovascular adverse event was hypotension occurring in 8% of the desflurane patients and 6% of the isoflurane patients.
### Neurosurgery
- Desflurane (desflurane, USP) was studied in 38 patients aged 26-76 years (median 48 years), ASA physical status II or III undergoing neurosurgical procedures for intracranial lesions.
- Induction consisted of standard neuroanesthetic techniques including hyperventilation and thiopental.
- No change in cerebrospinal fluid pressure (CSFP) was observed in 8 patients who had intracranial tumors when the dose of Desflurane (desflurane, USP) was 0.5 MAC in N2O 50%. In another study of 9 patients with intracranial tumors, 0.8 MAC desflurane/air/O2 did not increase CSFP above post induction baseline values. In a different study of 10 patients receiving 1.1 MAC desflurane/air/O2, CSFP increased 7 mm Hg (range 3-13 mm Hg increase, with final values of 11-26 mm Hg) above the pre-drug values.
- All volatile anesthetics may increase intracranial pressure in patients with intracranial space occupying lesions. In such patients, Desflurane (desflurane, USP) should be administered at 0.8 MAC or less, and in conjunction with a barbiturate induction and hyperventilation (hypocapnia) in the period before cranial decompression. Appropriate attention must be paid to maintain cerebral perfusion pressure. The use of a lower dose of Desflurane (desflurane, USP) and the administration of a barbiturate and mannitol would be predicted to lessen the effect of desflurane on CSFP.
- Under hypocapnic conditions (PaCO2 27 mm Hg) Desflurane (desflurane, USP) 1 and 1.5 MAC did not increase cerebral blood flow (CBF) in 9 patients undergoing craniotomies. CBF reactivity to increasing PaCO2 from 27 to 35 mm Hg was also maintained at 1.25 MAC desflurane/air/O2.
- In a clinical safety trial conducted in children aged 2 to 16 years (mean 7.4 years), following induction with another agent, Desflurane (desflurane, USP) and isoflurane (in N2O/O2) were compared when delivered via face mask or laryngeal mask airway (LMA™ mask) for maintenance of anesthesia, after induction with intravenous propofol or inhaled sevoflurane, in order to assess the relative incidence of respiratory adverse events.
- Desflurane (desflurane, USP) was associated with higher rates (compared with isoflurane) of coughing, laryngospasm and secretions with an overall rate of respiratory events of 39%. Of the pediatric patients exposed to desflurane, 5% experienced severe laryngospasm (associated with significant desaturation; i.e. SpO2 of 15 seconds, or requiring succinylcholine), across all ages, 2-16 years old. Individual age group incidences of severe laryngospasm were 9% for 2-6 years old, 1% for 7-11 years old, and 1% for 12-16 years old. Removal of LMA™ mask under deep anesthesia (MAC range 0.6 – 2.3 with a mean of 1.12 MAC) was associated with a further increase in frequency of respiratory adverse events as compared to awake LMA™ mask removal or LMA™ mask removal under deep anesthesia with the comparator. The frequency and severity of non-respiratory adverse events were comparable between the two groups.
- The incidence of respiratory events under these conditions was highest in children aged 2-6 years. Therefore, similar studies in children under the age of 2 years were not initiated.
# How Supplied
- Desflurane (desflurane, USP) is available in an amber-colored glass bottle or an aluminum bottle containing 240 mL of desflurane as follows:
## Storage
- Store at room temperature, 15°-30°C (59°-86°F). Desflurane (desflurane, USP) has been demonstrated to be stable for the period defined by the expiration dating on the label. The bottle should be recapped after each use of Desflurane (desflurane, USP).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Medications they are taking, including herbal supplements
- Drug allergies, including allergic reactions to anesthetic agents (including hepatic sensitivity)
- Any history of severe reactions to prior administration of anesthetic
- If the patient or a member of the patient’s family has a history of malignant hyperthermia or if the patient has a history of Duchenne muscular dystrophy or other latent neuromuscular disease
- Post-operative nausea and vomiting and respiratory adverse effects including coughing.
- There is no information of the effects of Desflurane (desflurane, USP) following anesthesia on the ability to operate an automobile or other heavy machinery. However, patients should be advised that the ability to perform such tasks may be impaired after receiving anesthetic agents.
- Baxter and Suprane are registered trademarks of Baxter International Inc.
# Precautions with Alcohol
Alcohol-Desflurane interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
There is limited information regarding Desflurane Brand Names in the drug label.
# Look-Alike Drug Names
There is limited information regarding Desflurane Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Desflurane
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Chetan Lokhande, M.B.B.S [2]
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# Overview
Desflurane is a general anesthetic that is FDA approved for the {{{indicationType}}} of general anesthesia. Common adverse reactions include gastrointestinal: nausea (27% ), vomiting (16% ), respiratory: cough ( adult induction, 22% to 34% ), interrupted breathing (adult induction, 30% to 39%; adult and intubated pediatric maintenance, greater than 1% ).
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- General anesthesia: induction, initial inhaled concentration of 3% in oxygen or nitrous oxide/oxygen, increased by 0.5% to 1% increments every 2 to 3 breaths or as tolerated (end tidal concentrations 4% to 11%) inspired concentrations greater than 12% have been safely administered during induction and may require a reduction of nitrous oxide or air.
- General anesthesia: maintenance, inhaled concentrations of 2.5% to 8.5% with or without concomitant nitrous oxide; dosage must be individualized based on patient response.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information about Off-Label Guideline-Supported Use of Desflurane in adult patients.
### Non–Guideline-Supported Use
There is limited information about Off-Label Non–Guideline-Supported Use of Desflurane in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- General anesthesia: maintenance, inhaled in concentrations of 5.2% to 10% with or without concomitant nitrous oxide; dosage must be individualized based on patient response
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information about Off-Label Guideline-Supported Use of Desflurane in pediatric patients.
### Non–Guideline-Supported Use
There is limited information about Off-Label Non–Guideline-Supported Use of Desflurane in pediatric patients.
# Contraindications
- The use of desflurane (desflurane, USP) is contraindicated in the following conditions:
- Known or suspected genetic susceptibility to malignant hyperthermia.
- Patients in whom general anesthesia is contraindicated.
- Induction of anesthesia in pediatric patients.
- Patients with known sensitivity to desflurane (desflurane, USP) or to other halogenated agents [see Warnings and Precautions (5.5)].
- Patients with a history of confirmed hepatitis or with a history of unexplained moderate to severe hepatic dysfunction (e.g., jaundice associated with fever and/or eosinophilia) after anesthesia with desflurane (desflurane, USP) or other halogenated agents [see Warnings and Precautions].
# Warnings
- In susceptible individuals, potent inhalation anesthetic agents may trigger a skeletal muscle hypermetabolic state leading to high oxygen demand and the clinical syndrome known as malignant hyperthermia. In genetically susceptible pigs, desflurane induced malignant hyperthermia. The clinical syndrome is signaled by hypercapnia, and may include muscle rigidity, tachycardia, tachypnea, cyanosis, arrhythmias, and/or unstable blood pressure. Some of these nonspecific signs may also appear during light anesthesia: acute hypoxia, hypercapnia, and hypovolemia.
- Treatment of malignant hyperthermia includes discontinuation of triggering agents, administration of intravenous dantrolene sodium, and application of supportive therapy. (Consult prescribing information for dantrolene sodium intravenous for additional information on patient management.) Renal failure may appear later, and urine flow should be monitored and sustained if possible.
- Fatal outcome of malignant hyperthermia has been reported with desflurane.
- Use of inhaled anesthetic agents has been associated with rare increases in serum potassium levels that have resulted in cardiac arrhythmias and death in pediatric patients during the postoperative period. Patients with latent as well as overt neuromuscular disease, particularly Duchenne muscular dystrophy, appear to be most vulnerable. Concomitant use of succinylcholine has been associated with most, but not all, of these cases. These patients also experienced significant elevations in serum creatinine kinase levels and, in some cases, changes in urine consistent with myoglobinuria. Despite the similarity in presentation to malignant hyperthermia, none of these patients exhibited signs or symptoms of muscle rigidity or hypermetabolic state. Early and aggressive intervention to treat the hyperkalemia and resistant arrhythmias is recommended, as is subsequent evaluation for latent neuromuscular disease.
- Due to the limited data available in non-intubated pediatric patients, Desflurane (desflurane, USP) is not approved for maintenance of anesthesia in non-intubated children due to an increased incidence of respiratory adverse reactions, including coughing, laryngospasm and secretions [see Clinical Studies ].
- Caution should be exercised should Desflurane (desflurane, USP) be used for maintenance of anesthesia with laryngeal mask airway (LMA™ mask) in children, in particular for children 6 years old or younger because of the increased potential for adverse respiratory reactions, e.g. coughing and laryngospasm, especially with removal of the LMA™ mask under deep anesthesia [see Clinical Studies].
- Caution should be exercised when Desflurane (desflurane, USP) is used for maintenance of anesthesia in children with asthma or a history of recent upper airway infection due to the potential for airway narrowing and increases in airway resistance.
- Desflurane like some other inhalation anesthetics, can react with desiccated carbon dioxide (CO2) absorbents to produce carbon monoxide that may result in elevated levels of carboxyhemoglobin in some patients. Case reports suggest that barium hydroxide lime and soda lime become desiccated when fresh gases are passed through the CO2 canister at high flow rates over many hours or days. When a clinician suspects that CO2 absorbent may be desiccated, it should be replaced before the administration of desflurane (desflurane, USP).
- With the use of halogenated anesthetics, disruption of hepatic function, icterus and fatal liver necrosis have been reported; such reactions appear to indicate hypersensitivity. As with other halogenated anesthetic agents, desflurane (desflurane, USP) may cause sensitivity hepatitis in patients who have been sensitized by previous exposure to halogenated anesthetics [see Contraindications]. Cirrhosis, viral hepatitis or other pre-existing hepatic disease may be a reason to select an anesthetic other than a halogenated anesthetic. As with all halogenated anesthetics, repeated anesthesia within a short period of time should be approached with caution.
- Transient elevations in glucose and white blood cell count may occur as with use of other anesthetic agents.
# Adverse Reactions
## Clinical Trials Experience
- Adverse event information is derived from controlled clinical trials, the majority of which were conducted in the United States. The studies were conducted using a variety of premedications, other anesthetics, and surgical procedures of varying length. Most adverse events reported were mild and transient, and may reflect the surgical procedures, patient characteristics (including disease) and/or medications administered.
- Of the 2,143 patients exposed to Desflurane (desflurane, USP) in clinical trials, 370 adults and 152 children were induced with desflurane alone and 987 patients were maintained principally with desflurane. The frequencies given reflect the percent of patients with the event. Each patient was counted once for each type of adverse event. They are presented in alphabetical order according to body system.
- Frequency of Events Occurring in Less Than 1% of Patients
(in Reports Deemed “Probably Causally Related”)
- Reported in 3 or more patients, regardless of severity
- Adverse reactions reported only from postmarketing experience or in the literature, not seen in clinical trials, are considered rare and are italicized.
## Postmarketing Experience
- The following adverse reactions have been identified during post-approval use of desflurane (desflurane, USP). Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- Coagulopathy
- Hyperkalemia, Hypokalemia, metabolic acidosis
- Convulsion
- Ocular icterus
- Cardiac arrest, Torsade de pointes, ventricular failure, ventricular hypokinesia, Atrial fibrillation
- Malignant hypertension, hemorrhage, hypotension, shock
- Respiratory arrest, respiratory failure, respiratory distress, bronchospasm, hemoptysis
- Pancreatitis acute, abdominal pain
- Hepatic failure, hepatic necrosis, Hepatitis, cytolytic hepatitis, cholestasis, jaundice, hepatic function abnormal, liver disorder
- Urticaria, erythema
- Rhabdomyolysis
- Hyperthermia malignant, asthenia, malaise
- Electrocardiogram ST-T change, electrocardiogram T-wave inversion, tranaminases increased, alanine aminotransferase increased, aspartate aminotransferase increased, Blood bilirubin increased, coagulation test abnormal, ammonia increased
- Tachyarrhythmia, palpitations, eye burns, blindness transient, encephalopathy, ulcerative keratitis, ocular hyperemia, visual acuity reduced, eye irritation, eye pain, dizziness, migraine, fatigue, accidental exposure, skin burning sensation, drug administration error
- All of reactions categorized within this SOC were accidental exposures to non-patients.
# Drug Interactions
- No clinically significant adverse interactions with commonly used preanesthetic drugs, or drugs used during anesthesia (muscle relaxants, intravenous agents, and local anesthetic agents) were reported in clinical trials. The effect of desflurane (desflurane, USP) on the disposition of other drugs has not been determined. Similar to isoflurane, desflurane (desflurane, USP) does not predispose to premature ventricular arrhythmias in the presence of exogenously infused epinephrine in swine.
- Benzodiazepines and opioids decrease the amount of desflurane (MAC) needed to produce anesthesia. This effect is shown in Table 3 for intravenous midazolam (25-50 µg/kg) and intravenous fentanyl (3-6 µg/kg) in patients of two different age groups
- Anesthetic concentrations of desflurane at equilibrium (administered for 15 or more minutes before testing) reduced the ED95 of succinylcholine by approximately 30% and that of atracurium and pancuronium by approximately 50% compared to N2O/opioid anesthesia (see Table 4). The effect of desflurane on duration of nondepolarizing neuromuscular blockade has not been studied.
- Dosage reduction of neuromuscular blocking agents during induction of anesthesia may result in delayed onset of conditions suitable for endotracheal intubation or inadequate muscle relaxation, because potentiation of neuromuscular blocking agents requires equilibration of muscle with the delivered partial pressure of desflurane (desflurane, USP).
- Among nondepolarizing drugs, pancuronium, atracurium, and vecuronium interactions have been studied. In the absence of specific guidelines:
- For endotracheal intubation, do not reduce the dose of nondepolarizing muscle relaxants or succinylcholine.
- During maintenance of anesthesia, the dose of nondepolarizing muscle relaxants is likely to be reduced compared to that during N2O/opioid anesthesia. Administration of supplemental doses of muscle relaxants should be guided by the response to nerve stimulation.
- Concomitant administration of N2O reduces the MAC of desflurane (desflurane, USP) [see Dosage and Administration (2), Table 1].
- Concomitant use of beta blockers may exaggerate the cardiovascular effects of inhalational anesthetics, including hypotension and negative inotropic effects.
- Concomitant use of MAO inhibitors and inhalational anesthetics may increase the risk of hemodynamic instability during surgery or medical procedures.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
- There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Reproduction studies have been performed in rats at doses up to at 1 MAC hour for a minimum of 21 days and have revealed no evidence of impaired fertility or harm to the fetus due to desflurane (desflurane, USP).
- No teratogenic effect was observed at approximately 10 and 13 cumulative MAC-Hour exposures at 1 MAC-Hour per day during organogenesis in rats or rabbits. At higher doses increased incidences of post-implantation loss and maternal toxicity were observed. However, at 10 MAC-Hours cumulative exposure in rats, about 6% decrease in the weight of male pups was observed at preterm caesarean delivery.
- Rats exposed to desflurane (desflurane, USP) at 1 MAC-Hour per day from gestation day 15 to lactation day 21, did not show signs of dystocia. * Body weights of pups delivered by these dams at birth and during lactation were comparable to that of control pups. No treatment related behavioral changes were reported in these pups during lactation.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Desflurane in women who are pregnant.
### Labor and Delivery
- The safety of desflurane (desflurane, USP) during labor or delivery has not been demonstrated. desflurane (desflurane, USP) is a uterine-relaxant.
### 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 desflurane (desflurane, USP) is administered to a nursing woman.
### Pediatric Use
- Respiratory Adverse Reactions in Pediatric Patients
- Desflurane (desflurane, USP) is indicated for maintenance of anesthesia in infants and children after induction of anesthesia with agents other than desflurane (desflurane, USP), and tracheal intubation.
- Due to limited data available in non-intubated pediatric patients, desflurane (desflurane, USP) is not approved for maintenance of anesthesia in non-intubated children due to an increased incidence of respiratory adverse reactions, including coughing (26%), laryngospasm (13%) and secretions (12%) [see Clinical Studies].
- Caution should be exercised should desflurane (desflurane, USP) be used for maintenance anesthesia with laryngeal mask airway (LMA™ mask) in children, in particular for children 6 years old or younger because of the increased potential for adverse respiratory reactions, e.g. coughing and laryngospasm, especially with removal of the LMA™ mask under deep anesthesia [see Clinical Studies].
- Caution should be exercised when Desflurane (desflurane, USP) is used for maintenance of anesthesia in children with asthma or a history of recent upper airway infection due to the potential for airway narrowing and increases in airway resistance.
### Geriatic Use
- The minimum alveolar concentration (MAC) of desflurane (desflurane, USP) decreases with increasing patient age. The dose should be adjusted accordingly. The average MAC for Desflurane (desflurane, USP) in a 70 year old patient is two-thirds the MAC for a 20 year old patient [see Dosage and Administration Table 1 and Clinical Studies].
### Gender
There is no FDA guidance on the use of Desflurane with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Desflurane with respect to specific racial populations.
### Renal Impairment
- Concentrations of 1-4% desflurane (desflurane, USP) in nitrous oxide/oxygen have been used in patients with chronic renal or hepatic impairment and during renal transplantation surgery.
- Because of minimal metabolism, a need for dose adjustment in patients with renal and hepatic impairment is not to be expected.
- Nine patients receiving desflurane (N=9) were compared to 9 patients receiving isoflurane, all with chronic renal insufficiency (serum creatinine 1.5-6.9 mg/dL). No differences in hematological or biochemical tests, including renal function evaluation, were seen between the two groups. Similarly, no differences were found in a comparison of patients receiving either desflurane (N=28) or isoflurane (N=30) undergoing renal transplant.
### Hepatic Impairment
- Eight patients receiving desflurane (desflurane, USP) were compared to six patients receiving isoflurane, all with chronic hepatic disease (viral hepatitis, alcoholic hepatitis, or cirrhosis). No differences in hematological or biochemical tests, including hepatic enzymes and hepatic function evaluation, were seen.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Desflurane in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Desflurane in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Desflurane Administration in the drug label.
### Monitoring
There is limited information regarding Desflurane Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Desflurane and IV administrations.
# Overdosage
- The symptoms of overdosage of desflurane (desflurane, USP) can present as a deepening of anesthesia, cardiac and/or respiratory depression in spontaneously breathing patients, and cardiac depression in ventilated patients in whom hypercapnia and hypoxia may occur only at a late stage. In the event of overdosage, or suspected overdosage, take the following actions: discontinue administration of desflurane (desflurane, USP), maintain a patent airway, initiate assisted or controlled ventilation with oxygen, and maintain adequate cardiovascular function.
# Pharmacology
## Mechanism of Action
There is limited information regarding Desflurane Mechanism of Action in the drug label.
## Structure
- Desflurane (desflurane, USP), a nonflammable liquid administered via vaporizer, is a general inhalation anesthetic. It is (±)1,2,2,2-tetrafluoroethyl difluoromethyl ether:
- Desflurane (desflurane, USP) is nonflammable as defined by the requirements of International Electrotechnical Commission 601-2-13.
- Desflurane (desflurane, USP) is a colorless, volatile liquid below 22.8°C. Data indicate that Desflurane (desflurane, USP) is stable when stored under normal room lighting conditions according to instructions.
- Desflurane (desflurane, USP) is chemically stable. The only known degradation reaction is through prolonged direct contact with soda lime producing low levels of fluoroform (CHF3). The amount of CHF3 obtained is similar to that produced with MAC-equivalent doses of isoflurane. No discernible degradation occurs in the presence of strong acids.
- Desflurane (desflurane, USP) does not corrode stainless steel, brass, aluminum, anodized aluminum, nickel plated brass, copper, or beryllium
## Pharmacodynamics
- Changes in the clinical effects of Desflurane (desflurane, USP) rapidly follow changes in the inspired concentration. The duration of anesthesia and selected recovery measures for Desflurane (desflurane, USP) are given in the following tables:
- In 178 female outpatients undergoing laparoscopy, premedicated with fentanyl (1.5-2.0 µg/kg), anesthesia was initiated with propofol 2.5 mg/kg, desflurane/N2O 60% in O2 or desflurane/O2 alone. Anesthesia was maintained with either propofol 1.5-9.0 mg/kg/hr, desflurane 2.6-8.4% in N2O 60% in O2, or desflurane 3.1-8.9% in O2.
- In 88 unpremedicated outpatients, anesthesia was initiated with thiopental 3-9 mg/kg or desflurane in O2. Anesthesia was maintained with isoflurane 0.7-1.4% in N2O 60%, desflurane 1.8-7.7% in N2O 60%, or desflurane 4.4-11.9% in O2.
- Recovery from anesthesia was assessed at 30, 60, and 90 minutes following 0.5 MAC desflurane (3%) or isoflurane (0.6%) in N2O 60% using subjective and objective tests. At 30 minutes after anesthesia, only 43% of patients in the isoflurane group were able to perform the psychometric tests compared to 76% in the Desflurane (desflurane, USP) group (p < 0.05).
- Desflurane (desflurane, USP) was studied in twelve volunteers receiving no other drugs. Hemodynamic effects during controlled ventilation (PaCO2 38 mm Hg) were:
- When the same volunteers breathed spontaneously during desflurane anesthesia, systemic vascular resistance and mean arterial blood pressure decreased; cardiac index, heart rate, stroke volume, and central venous pressure (CVP) increased compared to values when the volunteers were conscious. Cardiac index, stroke volume, and CVP were greater during spontaneous ventilation than during controlled ventilation.
- During spontaneous ventilation in the same volunteers, increasing the concentration of Desflurane (desflurane, USP) from 3% to 12% decreased tidal volume and increased arterial carbon dioxide tension and respiratory rate. The combination of N2O 60% with a given concentration of desflurane gave results similar to those with desflurane alone. Respiratory depression produced by desflurane is similar to that produced by other potent inhalation agents.
- The use of desflurane concentrations higher than 1.5 MAC may produce apnea.
## Pharmacokinetics
- Due to the volatile nature of desflurane in plasma samples, the washin-washout profile of desflurane was used as a surrogate of plasma pharmacokinetics. Desflurane (desflurane, USP) is a volatile liquid inhalation anesthetic minimally biotransformed in the liver in humans. Less than 0.02% of the desflurane absorbed can be recovered as urinary metabolites (compared to 0.2% for isoflurane). Eight healthy male volunteers first breathed 70% N2O/30% O2 for 30 minutes and then a mixture of desflurane 2.0%, isoflurane 0.4%, and halothane 0.2% for another 30 minutes. During this time, inspired and end-tidal concentrations (FI and FA) were measured. The FA/FI (washin) value at 30 minutes for desflurane was 0.91, compared to 1.00 for N2O, 0.74 for isoflurane, and 0.58 for halothane (see Figure 2). The washin rates for halothane and isoflurane were similar to literature values. The washin was faster for desflurane than for isoflurane and halothane at all time points. The FA/FAO (washout) value at 5 minutes was 0.12 for desflurane, 0.22 for isoflurane, and 0.25 for halothane (see Figure 3). The washout for desflurane was more rapid than that for isoflurane and halothane at all elimination time points. By 5 days, the FA/FAO for desflurane is 1/20th of that for halothane or isoflurane.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
- Animal carcinogenicity studies have not been performed with Desflurane (desflurane, USP). In vitro and in vivo genotoxicity studies did not demonstrate mutagenicity or chromosomal damage by Desflurane (desflurane, USP). Tests for genotoxicity included the Ames mutation assay, the metaphase analysis of human lymphocytes, and the mouse micronucleus assay.
- Fertility was not affected after 1 MAC-Hour per day exposure (cumulative 63 and 14 MAC-Hours for males and females, respectively). At higher doses, parental toxicity (mortalities and reduced weight gain) was observed which could affect fertility.
# Clinical Studies
- The efficacy of Desflurane (desflurane, USP) was evaluated in 1,843 patients including ambulatory (N=1,061), cardiovascular (N=277), geriatric (N=103), neurosurgical (N=40), and pediatric (N=235) patients. Clinical experience with these patients and with 1,087 control patients in these studies not receiving Desflurane (desflurane, USP) is described below. Although Desflurane (desflurane, USP) can be used in adults for the inhalation induction of anesthesia via mask, it produces a high incidence of respiratory irritation (coughing, breathholding, apnea, increased secretions, laryngospasm). Oxyhemoglobin saturation below 90% occurred in 6% of patients (from pooled data, N = 370 adults).
- Desflurane (desflurane, USP) plus N2O was compared to isoflurane plus N2O in multicenter studies (21 sites) of 792 ASA physical status I, II, or III patients aged 18-76 years (median 32).
- Anesthetic induction begun with thiopental and continued with Desflurane (desflurane, USP) was associated with a 7% incidence of oxyhemoglobin saturation of 90% or less (from pooled data, N = 307) compared with 5% in patients in whom anesthesia was induced with thiopental and isoflurane (from pooled data, N = 152).
- Desflurane (desflurane, USP) with or without N2O or other anesthetics was generally well tolerated. There were no differences between Desflurane (desflurane, USP) and the other anesthetics studied in the times that patients were judged fit for discharge.
- In one outpatient study, patients received a standardized anesthetic consisting of thiopental 4.2-4.4 mg/kg, fentanyl 3.5-4.0 µg/kg, vecuronium 0.05-0.07 mg/kg, and N2O 60% in oxygen with either desflurane 3% or isoflurane 0.6%. Emergence times were significantly different; but times to sit up and discharge were not different (see Table 5).
- Desflurane (desflurane, USP) was compared to isoflurane, sufentanil or fentanyl for the anesthetic management of coronary artery bypass graft (CABG), abdominal aortic aneurysm, peripheral vascular and carotid endarterectomy surgery in 7 studies at 15 centers involving a total of 558 patients. In all patients except the desflurane vs. sufentanil study, the volatile anesthetics were supplemented with intravenous opioids, usually fentanyl. Blood pressure and heart rate were controlled by changes in concentration of the volatile anesthetics or opioids and cardiovascular drugs if necessary. Oxygen (100%) was the carrier gas in 253 of 277 desflurane cases (24 of 277 received N2O/O2).
- No differences were found in cardiovascular outcome (death, myocardial infarction, ventricular tachycardia or fibrillation, heart failure) among desflurane and the other anesthetics.
- Desflurane (desflurane, USP) should not be used as the sole agent for anesthetic induction in patients with coronary artery disease or any patients where increases in heart rate or blood pressure are undesirable. In the desflurane vs. sufentanil study, anesthetic induction with desflurane without opioids was associated with new transient ischemia in 14 patients vs. 0 in the sufentanil group. In the desflurane group, mean heart rate, arterial pressure, and pulmonary blood pressure increased and stroke volume decreased in contrast to no change in the sufentanil group. Cardiovascular drugs were used frequently in both groups: especially esmolol in the desflurane group (56% vs. 0%) and phenylephrine in the sufentanil group (43% vs. 27%). When 10 µg/kg of fentanyl was used to supplement induction of anesthesia at one other center, continuous 2-lead ECG analysis showed a low incidence of myocardial ischemia and no difference between desflurane and isoflurane. If desflurane is to be used in patients with coronary artery disease, it should be used in combination with other medications for induction of anesthesia, preferably intravenous opioids and hypnotics.
- In studies where Desflurane (desflurane, USP) or isoflurane anesthesia was supplemented with fentanyl, there were no differences in hemodynamic variables or the incidence of myocardial ischemia in the patients anesthetized with desflurane compared to those anesthetized with isoflurane.
- During the precardiopulmonary bypass period, in the desflurane vs. sufentanil study where the desflurane patients received no intravenous opioid, more desflurane patients required cardiovascular adjuvants to control hemodynamics than the sufentanil patients. During this period, the incidence of ischemia detected by ECG or echocardiography was not statistically different between desflurane (18 of 99) and sufentanil (9 of 98) groups. However, the duration and severity of ECG-detected myocardial ischemia was significantly less in the desflurane group. The incidence of myocardial ischemia after cardiopulmonary bypass and in the ICU did not differ between groups.
### Geriatric Surgery
- Desflurane (desflurane, USP) plus N2O was compared to isoflurane plus N2O in a multicenter study (6 sites) of 203 ASA physical status II or III elderly patients, aged 57-91 years (median 71).
- Most patients were premedicated with fentanyl (mean 2 µg/kg), preoxygenated, and received thiopental (mean 4.3 mg/kg IV) or thiamylal (mean 4 mg/kg IV) followed by succinylcholine (mean 1.4 mg/kg IV) for intubation.
- Heart rate and arterial blood pressure remained within 20% of preinduction baseline values during administration of Desflurane (desflurane, USP) 0.5-7.7% (average 3.6%) with 50-60% N2O. Induction, maintenance, and recovery cardiovascular measurements did not differ from those during isoflurane/N2O administration nor did the postoperative incidence of nausea and vomiting differ. The most common cardiovascular adverse event was hypotension occurring in 8% of the desflurane patients and 6% of the isoflurane patients.
### Neurosurgery
- Desflurane (desflurane, USP) was studied in 38 patients aged 26-76 years (median 48 years), ASA physical status II or III undergoing neurosurgical procedures for intracranial lesions.
- Induction consisted of standard neuroanesthetic techniques including hyperventilation and thiopental.
- No change in cerebrospinal fluid pressure (CSFP) was observed in 8 patients who had intracranial tumors when the dose of Desflurane (desflurane, USP) was 0.5 MAC in N2O 50%. In another study of 9 patients with intracranial tumors, 0.8 MAC desflurane/air/O2 did not increase CSFP above post induction baseline values. In a different study of 10 patients receiving 1.1 MAC desflurane/air/O2, CSFP increased 7 mm Hg (range 3-13 mm Hg increase, with final values of 11-26 mm Hg) above the pre-drug values.
- All volatile anesthetics may increase intracranial pressure in patients with intracranial space occupying lesions. In such patients, Desflurane (desflurane, USP) should be administered at 0.8 MAC or less, and in conjunction with a barbiturate induction and hyperventilation (hypocapnia) in the period before cranial decompression. Appropriate attention must be paid to maintain cerebral perfusion pressure. The use of a lower dose of Desflurane (desflurane, USP) and the administration of a barbiturate and mannitol would be predicted to lessen the effect of desflurane on CSFP.
- Under hypocapnic conditions (PaCO2 27 mm Hg) Desflurane (desflurane, USP) 1 and 1.5 MAC did not increase cerebral blood flow (CBF) in 9 patients undergoing craniotomies. CBF reactivity to increasing PaCO2 from 27 to 35 mm Hg was also maintained at 1.25 MAC desflurane/air/O2.
- In a clinical safety trial conducted in children aged 2 to 16 years (mean 7.4 years), following induction with another agent, Desflurane (desflurane, USP) and isoflurane (in N2O/O2) were compared when delivered via face mask or laryngeal mask airway (LMA™ mask) for maintenance of anesthesia, after induction with intravenous propofol or inhaled sevoflurane, in order to assess the relative incidence of respiratory adverse events.
- Desflurane (desflurane, USP) was associated with higher rates (compared with isoflurane) of coughing, laryngospasm and secretions with an overall rate of respiratory events of 39%. Of the pediatric patients exposed to desflurane, 5% experienced severe laryngospasm (associated with significant desaturation; i.e. SpO2 of <90% for >15 seconds, or requiring succinylcholine), across all ages, 2-16 years old. Individual age group incidences of severe laryngospasm were 9% for 2-6 years old, 1% for 7-11 years old, and 1% for 12-16 years old. Removal of LMA™ mask under deep anesthesia (MAC range 0.6 – 2.3 with a mean of 1.12 MAC) was associated with a further increase in frequency of respiratory adverse events as compared to awake LMA™ mask removal or LMA™ mask removal under deep anesthesia with the comparator. The frequency and severity of non-respiratory adverse events were comparable between the two groups.
- The incidence of respiratory events under these conditions was highest in children aged 2-6 years. Therefore, similar studies in children under the age of 2 years were not initiated.
# How Supplied
- Desflurane (desflurane, USP) is available in an amber-colored glass bottle or an aluminum bottle containing 240 mL of desflurane as follows:
## Storage
- Store at room temperature, 15°-30°C (59°-86°F). Desflurane (desflurane, USP) has been demonstrated to be stable for the period defined by the expiration dating on the label. The bottle should be recapped after each use of Desflurane (desflurane, USP).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Medications they are taking, including herbal supplements
- Drug allergies, including allergic reactions to anesthetic agents (including hepatic sensitivity)
- Any history of severe reactions to prior administration of anesthetic
- If the patient or a member of the patient’s family has a history of malignant hyperthermia or if the patient has a history of Duchenne muscular dystrophy or other latent neuromuscular disease
- Post-operative nausea and vomiting and respiratory adverse effects including coughing.
- There is no information of the effects of Desflurane (desflurane, USP) following anesthesia on the ability to operate an automobile or other heavy machinery. However, patients should be advised that the ability to perform such tasks may be impaired after receiving anesthetic agents.
- Baxter and Suprane are registered trademarks of Baxter International Inc.
# Precautions with Alcohol
Alcohol-Desflurane interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
There is limited information regarding Desflurane Brand Names in the drug label.
# Look-Alike Drug Names
There is limited information regarding Desflurane Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Desflurane | |
3c3f46949719a464e3226cd3ceb7275c42fc9fca | wikidoc | Desiccator | Desiccator
Desiccators are sealable enclosures containing desiccants used for preserving moisture-sensitive items. A common use for desiccators are to protect hygroscopic chemicals from humidity.
The contents of desiccators are exposed to atmospheric moisture whenever the desiccators are opened. It also requires some time to achieve a low humidity. Hence they are not appropriate for storing chemicals which react quickly or violently with atmospheric moisture. A glovebox or Schlenk-type apparatus may be more suitable for these purposes.
# Laboratory use
In laboratory use, the most common desiccators are circular, and made of heavy glass. There is usually a removable platform on which the items to be stored are placed. The desiccant, usually an otherwise-inert solid such as silica gel, fills the space under the platform.
A stopcock may be included to permit the desiccator to be evacuated. Such models are usually known as vacuum desiccators. When a vacuum is to be applied, it is a common practice to criss-cross the vacuum desiccator with tape, or to place it behind a screen to minimize damage or injury caused by an implosion.
To maintain a good seal, vacuum grease is usually applied to the flanges. | Desiccator
Desiccators are sealable enclosures containing desiccants used for preserving moisture-sensitive items. A common use for desiccators are to protect hygroscopic chemicals from humidity.
The contents of desiccators are exposed to atmospheric moisture whenever the desiccators are opened. It also requires some time to achieve a low humidity. Hence they are not appropriate for storing chemicals which react quickly or violently with atmospheric moisture. A glovebox or Schlenk-type apparatus may be more suitable for these purposes.
# Laboratory use
In laboratory use, the most common desiccators are circular, and made of heavy glass. There is usually a removable platform on which the items to be stored are placed. The desiccant, usually an otherwise-inert solid such as silica gel, fills the space under the platform.
A stopcock may be included to permit the desiccator to be evacuated. Such models are usually known as vacuum desiccators. When a vacuum is to be applied, it is a common practice to criss-cross the vacuum desiccator with tape, or to place it behind a screen to minimize damage or injury caused by an implosion.
To maintain a good seal, vacuum grease is usually applied to the flanges. | https://www.wikidoc.org/index.php/Desiccator | |
cf55392ae033d09b3356938c0c787c7782707031 | wikidoc | Deslorelin | Deslorelin
# Overview
Deslorelin acetate is an injectable gonadotropin releasing hormone super-agonist (GnRH agonist) also known as an LHRH agonist. It stops the production of sex hormones (testosterone and oestrogen).
Deslorelin Acetate is marketed by Peptech with the brand name Ovuplant. It is currently approved for use in veterinary medicine and is used to induce ovulation in mares as part of the artificial insemination process. It is also used to stabilize high-risk pregnancies, mainly of livestock. Unlike other GnRH agonists, which are mainly used to inhibit luteinizing hormone and follicle-stimulating hormone by their ultimate downregulation of the pituitary gland, Deslorelin is primarily used for the initial flare effect upon the pituitary, and its associated surge of LH secretion.
# Pharmacokinetics
Deslorelin is a synthetic analogue of a naturally occurring luteinising-hormone releasing hormone (LHRH). Bioavailability is almost complete.
# Clinical trials
Deslorelin was successfully trialed in the US and was approved for veterinary use under certain circumstances. In Europe, it was approved for use in equine assisted reproduction.
It is also being trialed in humans to study its efficacy in treatment of breast cancer in women, and in treating precocious puberty and congenital adrenal hyperplasia in male and female children.
As of August 2011 this drug was not approved for general use in the US, other than within approved clinical trials. Orphan drug status has been designated in the US, though approval had not been issued as of 2011. | Deslorelin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Deslorelin acetate is an injectable gonadotropin releasing hormone super-agonist (GnRH agonist) also known as an LHRH agonist. It stops the production of sex hormones (testosterone and oestrogen).
Deslorelin Acetate is marketed by Peptech with the brand name Ovuplant.[1] It is currently approved for use in veterinary medicine and is used to induce ovulation in mares as part of the artificial insemination process. It is also used to stabilize high-risk pregnancies, mainly of livestock. Unlike other GnRH agonists, which are mainly used to inhibit luteinizing hormone and follicle-stimulating hormone by their ultimate downregulation of the pituitary gland, Deslorelin is primarily used for the initial flare effect upon the pituitary, and its associated surge of LH secretion.
# Pharmacokinetics
Deslorelin is a synthetic analogue of a naturally occurring luteinising-hormone releasing hormone (LHRH). Bioavailability is almost complete.
# Clinical trials
Deslorelin was successfully trialed in the US and was approved for veterinary use under certain circumstances. In Europe, it was approved for use in equine assisted reproduction.[2]
It is also being trialed in humans to study its efficacy in treatment of breast cancer in women,[3] and in treating precocious puberty and congenital adrenal hyperplasia in male and female children.[4]
As of August 2011 this drug was not approved for general use in the US, other than within approved clinical trials. Orphan drug status has been designated in the US, though approval had not been issued as of 2011.[5] | https://www.wikidoc.org/index.php/Deslorelin | |
ac3a05b70cd71e8ef9eaae40c5c6d744cb5ce980 | wikidoc | Desorption | Desorption
Desorption is a phenomenon whereby a substance is released from or through a surface. The process is the opposite of sorption (that is, adsorption and absorption). This occurs in a system being in the state of sorption equilibrium between bulk phase (fluid, i.e. gas or liquid solution) and an adsorbing surface (solid or boundary separating two fluids). When the concentration (or pressure) of substance in the bulk phase is lowered, some of the sorbed substance changes to the bulk state.
In chemistry, especially chromatography, desorption is the ability for a chemical to move with the mobile phase. The more a chemical desorbs, the less likely it will adsorb, thus instead of sticking to the stationary phase, the chemical moves up with the solvent front.
In chemical separation processes, stripping is also referred to as desorption as one component of a liquid stream moves by mass transfer into a vapor phase through the liquid-vapor interface.
After adsorption, the adsorbed chemical will remain on the substrate nearly indefinitely, provided the temperature remains low. However,as the temperature rises, so does the likelihood of desorption occurring. The general equation for the rate of desorption is:
R = r N^x,
where r is the rate constant for desorption, N is the concentration of the adsorbed material, and x is the kinetic order of desorption.
Usually, the order of the desorption can be predicted by the number of elementary steps involved:
Atomic or simple molecular desorption will typically be a first-order process (i.e. a simple molecule on the surface of the substrate desorbs into a gaseous form).
Recombinative molecular desorption will generally be a second-order process (i.e. two hydrogen atoms on the surface desorb and form a gaseous H2 molecule).
The rate constant r may be expressed in the form:
r = A exp(-E/kT)
where A is the "attempt frequency" (often the Greek letter nu), the chance of the adsorbed molecule overcoming its potential barrier to desorption, E is the activation energy of desorption, k is Boltzmann's constant, and T is the temperature.
de:Desorption
uk:Десорбція | Desorption
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Desorption is a phenomenon whereby a substance is released from or through a surface. The process is the opposite of sorption (that is, adsorption and absorption). This occurs in a system being in the state of sorption equilibrium between bulk phase (fluid, i.e. gas or liquid solution) and an adsorbing surface (solid or boundary separating two fluids). When the concentration (or pressure) of substance in the bulk phase is lowered, some of the sorbed substance changes to the bulk state.
In chemistry, especially chromatography, desorption is the ability for a chemical to move with the mobile phase. The more a chemical desorbs, the less likely it will adsorb, thus instead of sticking to the stationary phase, the chemical moves up with the solvent front.
In chemical separation processes, stripping is also referred to as desorption as one component of a liquid stream moves by mass transfer into a vapor phase through the liquid-vapor interface.
After adsorption, the adsorbed chemical will remain on the substrate nearly indefinitely, provided the temperature remains low. However,as the temperature rises, so does the likelihood of desorption occurring. The general equation for the rate of desorption is:
<math>R = r N^x</math>,
where r is the rate constant for desorption, N is the concentration of the adsorbed material, and x is the kinetic order of desorption.
Usually, the order of the desorption can be predicted by the number of elementary steps involved:
Atomic or simple molecular desorption will typically be a first-order process (i.e. a simple molecule on the surface of the substrate desorbs into a gaseous form).
Recombinative molecular desorption will generally be a second-order process (i.e. two hydrogen atoms on the surface desorb and form a gaseous H2 molecule).
The rate constant r may be expressed in the form:
<math>r = A exp(-E/kT)</math>
where A is the "attempt frequency" (often the Greek letter nu), the chance of the adsorbed molecule overcoming its potential barrier to desorption, E is the activation energy of desorption, k is Boltzmann's constant, and T is the temperature.
Template:Physics-stub
de:Desorption
uk:Десорбція
Template:WS | https://www.wikidoc.org/index.php/Desorption | |
0f2a07c37b779de6375ce7197125739fe841eeb3 | wikidoc | Detomidine | Detomidine
# Overview
Detomidine is an imidazole derivative and alpha2-adrenergic agonist, used as a large animal sedative,primarily used in horses. Usually available as detomidine hydrochloride. This is a prescription medication available to veterinarians sold inder the trade name Domosedan.
# Properties
Detomidine is a sedative with analgesic properties. Alpha2-adrenergic agonists produce dose-dependent sedative and analgesic effects, mediatated by activation of alpha-2 catecholamine receptors, thus inducing a negative feedback response, reducing production of excitatory neurotransmitters. Due to inhibition of the sympathetic nervous system, detomidine also has cardiac and respiratory effects and an antidiuretic action.
# Effects
A profound lethargy and characteristic lowering of the head with reduced sensitivity to environmental stimuli (sounds, etc.) are seen with detomidine. A short period of in-coordination is characteristically followed by immobility and a firm stance with front legs spread. Following administration there is an initial increase in blood pressure, followed by bradycardia and second degree atrioventricular block (this is not pathologic in horses). The horse commonly sweats to excess, especially on the flanks and neck. Other side effects reported include pilo erection (hair standing erect), ataxia, salivation, slight muscle tremors, and (rarely) penile prolapse.
# Uses
Sedation and anaesthetic premedication in horses and other large animals, commonly combined with butorphanol for increased analgesia and depth of sedation. In conjunction with ketamine it may also be used for intravenous anaesthesia of short duration. Detomidine is only licenced for use in horses at the present time.
The drug is normally administered by the intravenous route, and is fastest and most efficient when given i/v (usually 2-5 minutes to take effect, although this is highly dependent upon the individual and the environment. Some horses are highly resistant to sedation!). However, in recalcitrant animals, detomidine may be administered by the intramuscular or sublingual routes. The dose range advised by the manufacturers is 20-40 mcg/kg i/v for moderate sedation. This dose may need to be higher if given i/m.
# Cautions
As detomidine is an arrhythmogenic agent, extreme care should be exercised in horses with cardiac disease, and in the concurrent administration of other arrhythmogenics. The concurrent use of potentiated sulphonamide antibiotics is considered particularly dangerous. | Detomidine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Detomidine is an imidazole derivative and alpha2-adrenergic agonist, used as a large animal sedative,primarily used in horses. Usually available as detomidine hydrochloride. This is a prescription medication available to veterinarians sold inder the trade name Domosedan.
# Properties
Detomidine is a sedative with analgesic properties. Alpha2-adrenergic agonists produce dose-dependent sedative and analgesic effects, mediatated by activation of alpha-2 catecholamine receptors, thus inducing a negative feedback response, reducing production of excitatory neurotransmitters. Due to inhibition of the sympathetic nervous system, detomidine also has cardiac and respiratory effects and an antidiuretic action.
# Effects
A profound lethargy and characteristic lowering of the head with reduced sensitivity to environmental stimuli (sounds, etc.) are seen with detomidine. A short period of in-coordination is characteristically followed by immobility and a firm stance with front legs spread. Following administration there is an initial increase in blood pressure, followed by bradycardia and second degree atrioventricular block (this is not pathologic in horses). The horse commonly sweats to excess, especially on the flanks and neck. Other side effects reported include pilo erection (hair standing erect), ataxia, salivation, slight muscle tremors, and (rarely) penile prolapse.
# Uses
Sedation and anaesthetic premedication in horses and other large animals, commonly combined with butorphanol for increased analgesia and depth of sedation. In conjunction with ketamine it may also be used for intravenous anaesthesia of short duration. Detomidine is only licenced for use in horses at the present time.
The drug is normally administered by the intravenous route, and is fastest and most efficient when given i/v (usually 2-5 minutes to take effect, although this is highly dependent upon the individual and the environment. Some horses are highly resistant to sedation!). However, in recalcitrant animals, detomidine may be administered by the intramuscular or sublingual routes. The dose range advised by the manufacturers is 20-40 mcg/kg i/v for moderate sedation. This dose may need to be higher if given i/m.
# Cautions
As detomidine is an arrhythmogenic agent, extreme care should be exercised in horses with cardiac disease, and in the concurrent administration of other arrhythmogenics. The concurrent use of potentiated sulphonamide antibiotics is considered particularly dangerous. | https://www.wikidoc.org/index.php/Detomidine | |
1ca34c6ff553c10f6f48fb7689fbeac6dde5c729 | wikidoc | Gliclazide | Gliclazide
# Overview
Gliclazide is an oral hypoglycemic (anti-diabetic drug) and is classified as a sulfonylurea. It is marketed as Diamicron MR®.
DIAMICRON MR is also distributed as:
Diabeton MR, Diamicron 30mg, Diamicron LM 30mg, Diamicron MR 30 mg, Diamicron Uno 30mg, Dianormax MR, Diaprel MR and Uni Diamicron.
# Form and Composition:
Each tablet contains 80 mg of gliclazide.
Not marketed in the United States.
# Indication:
Control of hyperglycemia in gliclazide responsive diabetes mellitus of stable, mild, non-ketosis prone, maturity onset or adult type which cannot be controlled by proper dietary management and exercise, or when insulin therapy is not appropriate.
# Dosage:
40 to 240 mg depending on response, once or twice daily before food, no more that 160 mg at a time.
# Properties:
Hypoglycemic sulfonylurea, restoring first peak of insulin secretion, increasing insulin sensitivity.
Glycemia-independent hemovascular effects, antioxidant effect.
No active circulating metabolites.
# Contraindications:
type 1 diabetes,
hypersensitivity to sulfonylureas,
severe renal or hepatic failure,
pregnancy and lactation,
miconazole coprescription.
# Interactions:
Hyperglycemic action may be caused by danazol, chlorpromazine, glucocorticoids, progestogens, β-2 agonists.
Its hypoglycemic action may be potentiated by phenylbutazone, alcohol, fluconazole, β-blockers, possibly ACE inhibitors.
# Adverse effects:
Hypoglycemia, gastrointestinal disturbance (reported), skin reactions (rare), hematological disorders (rare), hepatic enzyme rises (exceptional).
# Overdosage:
Possible severe hypoglycemia requiring urgent IV glucose and monitoring. | Gliclazide
# Overview
Gliclazide is an oral hypoglycemic (anti-diabetic drug) and is classified as a sulfonylurea. It is marketed as Diamicron MR®.
DIAMICRON MR is also distributed as:
Diabeton MR, Diamicron 30mg, Diamicron LM 30mg, Diamicron MR 30 mg, Diamicron Uno 30mg, Dianormax MR, Diaprel MR and Uni Diamicron.
# Form and Composition:
Each tablet contains 80 mg of gliclazide.
Not marketed in the United States.
# Indication:
Control of hyperglycemia in gliclazide responsive diabetes mellitus of stable, mild, non-ketosis prone, maturity onset or adult type which cannot be controlled by proper dietary management and exercise, or when insulin therapy is not appropriate.
# Dosage:
40 to 240 mg depending on response, once or twice daily before food, no more that 160 mg at a time.
# Properties:
Hypoglycemic sulfonylurea, restoring first peak of insulin secretion, increasing insulin sensitivity.
Glycemia-independent hemovascular effects, antioxidant effect.
No active circulating metabolites.
# Contraindications:
type 1 diabetes,
hypersensitivity to sulfonylureas,
severe renal or hepatic failure,
pregnancy and lactation,
miconazole coprescription.
# Interactions:
Hyperglycemic action may be caused by danazol, chlorpromazine, glucocorticoids, progestogens, β-2 agonists.
Its hypoglycemic action may be potentiated by phenylbutazone, alcohol, fluconazole, β-blockers, possibly ACE inhibitors.
# Adverse effects:
Hypoglycemia, gastrointestinal disturbance (reported), skin reactions (rare), hematological disorders (rare), hepatic enzyme rises (exceptional).
# Overdosage:
Possible severe hypoglycemia requiring urgent IV glucose and monitoring.
# External links
- Official site for Diamicron MR
Template:Oral hypoglycemics
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Diabeton_MR | |
970cc9d14a3dac4cd143940141a1dd37927e7321 | wikidoc | Diabulimia | Diabulimia
# Overview
Diabulimia (a portmanteau of diabetes and bulimia) refers to people with Type 1 diabetes who omit their insulin injections for the purpose of weight loss. Without the insulin injections, blood sugar levels rise as the cells cannot take in glucose. The body, in an attempt to lower the blood sugar, spills excess glucose into the urine.
Prior to a diagnosis of Type 1 diabetes there is a weight loss but, upon diagnosis, a person with Type 1 diabetes is put on insulin injections, a more controlled diet, and several blood sugar checks a day. The weight that was lost is quickly gained back. However, someone who realizes that omitting or severely reducing insulin dosages leads to weight loss may be tempted to do so, especially if the individual believes they are overweight. Omitting insulin injections does have the effect of losing weight, even though appetite and thirst increase, as well as urine volume.
Often, people with Type 1 diabetes who omit insulin injections will have already been diagnosed with an eating disorder such as anorexia nervosa, bulimia nervosa and/or compulsive eating. In cases where a person with Type 1 diabetes has another eating disorder, there is a tendency to discuss the other eating disorders more openly than they do about diabulimia as many people with diabetes are not happy that they have lost control of their diabetes. These individuals are often not aware that diabulimia is more common than what they think and is also very difficult to overcome. Unlike anorexia and bulimia, diabulimia only sometimes requires the afflicted individual to stop caring for a medical condition. Unlike vomiting or starving, there is sometimes no action or willpower involved. Diabulimia may be more appealing to individuals who want to lose weight and do not want to feel hungry, or to not engage in vomiting in order to purge. Often there is an obsessive compulsive urge to engage in this activity for the purpose of emotional disassociation or a need to satisfy feelings of 'control'.
This condition can be triggered or exacerbated by the need for constant vigilance in regard to food, weight and glycemic control. In adolescents "the need for parental control over the young Diabetic's life, and the increased weight gain that insulin treatment can cause, may all play roles in the increased risk for onset of Anorexia and/or Bulimia." (Something Fishy website) The frustration of hard to control blood sugars and their subsequent effects on weight and self perception (altered by dealing with a chronic illness) can also be damaging to self esteem and body image.
A person with diabulimia, especially if not caught and treated early, is likely to suffer the extent of diabetes earlier than a person with diabetes who is maintaining their diabetes in a healthy manner. The extent of diabetes include renal failure, blindness and diabetic neuropathy. With diabulimia there is an increased chance of fatality. Diabetic ketoacidosis (DKA) is very common in persons with Type 1 diabetes that have diabulimia. This is due to the reduction in the amount of insulin and an increase in blood sugars levels. DKA is a very serious condition that occurs without enough insulin and without treatment causes death.
Most commonly Diabulimia appears to start in adolescence and is more likely to occur in women than men. Diabulimia can be identified in a patient if there are unexplainable spikes in their Hemaglobin A1c, weight loss, lack of marks from finger sticks, lack of prescription refills for diabetes medications, and records that do not match the HbA1c.
# Symptoms
## Short term
These are the short term symptoms of patients with diabulimia
- Constant urination
- Constant thirst
- Excessive appetite
- High blood glucose levels (often over 600)
- Weakness
- Fatigue
- Large amounts of glucose in the urine
- Inability to concentrate
- Electrolyte disturbance
- Severe ketonuria, and, in DKA, severe ketonemia
- Low sodium levels
## Medium term
These are the medium term symptoms of patients with diabulimia. They are prevalent when diabulimia has not been treated and hence also includes the short term symptoms
- Muscle atrophy
- GERD
- Indigestion
- Severe weight loss
- Proteinuria
- Moderate to severe dehydration
- Edema with fluid replacement
- High cholesterol
- Death
## Long term
If a person with Type 1 diabetes with diabulimia is still alive after a medium term - which is usually due to phases where insulin is injected and phases of diabulimia (also known as a relapse) - then the following symptoms can also be expected:
- Severe kidney damage
- Blindness
- Severe neuropathy
- Extreme fatigue
- Edema (during blood sugars controlled phases)
- Heart problems
- High cholesterol
- Osteoporosis | Diabulimia
Editor(s)-in-Chief: C. Michael Gibson, M.S.,M.D. [1] Phone:617-632-7753; Mark Warren, M.D., M.P.H.; Fellow, Academy of Eating Disorders [2]
# Overview
Diabulimia (a portmanteau of diabetes and bulimia) refers to people with Type 1 diabetes who omit their insulin injections for the purpose of weight loss. Without the insulin injections, blood sugar levels rise as the cells cannot take in glucose. The body, in an attempt to lower the blood sugar, spills excess glucose into the urine.
Prior to a diagnosis of Type 1 diabetes there is a weight loss but, upon diagnosis, a person with Type 1 diabetes is put on insulin injections, a more controlled diet, and several blood sugar checks a day. The weight that was lost is quickly gained back. However, someone who realizes that omitting or severely reducing insulin dosages leads to weight loss may be tempted to do so, especially if the individual believes they are overweight. Omitting insulin injections does have the effect of losing weight, even though appetite and thirst increase, as well as urine volume.
Often, people with Type 1 diabetes who omit insulin injections will have already been diagnosed with an eating disorder such as anorexia nervosa, bulimia nervosa and/or compulsive eating. In cases where a person with Type 1 diabetes has another eating disorder, there is a tendency to discuss the other eating disorders more openly than they do about diabulimia as many people with diabetes are not happy that they have lost control of their diabetes. These individuals are often not aware that diabulimia is more common than what they think and is also very difficult to overcome. Unlike anorexia and bulimia, diabulimia only sometimes requires the afflicted individual to stop caring for a medical condition. Unlike vomiting or starving, there is sometimes no action or willpower involved. Diabulimia may be more appealing to individuals who want to lose weight and do not want to feel hungry, or to not engage in vomiting in order to purge. Often there is an obsessive compulsive urge to engage in this activity for the purpose of emotional disassociation or a need to satisfy feelings of 'control'.
This condition can be triggered or exacerbated by the need for constant vigilance in regard to food, weight and glycemic control. In adolescents "the need for parental control over the young Diabetic's life, and the increased weight gain that insulin treatment can cause, may all play roles in the increased risk for onset of Anorexia and/or Bulimia." (Something Fishy website) The frustration of hard to control blood sugars and their subsequent effects on weight and self perception (altered by dealing with a chronic illness) can also be damaging to self esteem and body image.
A person with diabulimia, especially if not caught and treated early, is likely to suffer the extent of diabetes earlier than a person with diabetes who is maintaining their diabetes in a healthy manner. The extent of diabetes include renal failure, blindness and diabetic neuropathy. With diabulimia there is an increased chance of fatality. Diabetic ketoacidosis (DKA) is very common in persons with Type 1 diabetes that have diabulimia. This is due to the reduction in the amount of insulin and an increase in blood sugars levels. DKA is a very serious condition that occurs without enough insulin and without treatment causes death.
Most commonly Diabulimia appears to start in adolescence and is more likely to occur in women than men. Diabulimia can be identified in a patient if there are unexplainable spikes in their Hemaglobin A1c, weight loss, lack of marks from finger sticks, lack of prescription refills for diabetes medications, and records that do not match the HbA1c.
# Symptoms
## Short term
These are the short term symptoms of patients with diabulimia
- Constant urination
- Constant thirst
- Excessive appetite
- High blood glucose levels (often over 600)
- Weakness
- Fatigue
- Large amounts of glucose in the urine
- Inability to concentrate
- Electrolyte disturbance
- Severe ketonuria, and, in DKA, severe ketonemia
- Low sodium levels
## Medium term
These are the medium term symptoms of patients with diabulimia. They are prevalent when diabulimia has not been treated and hence also includes the short term symptoms
- Muscle atrophy
- GERD
- Indigestion
- Severe weight loss
- Proteinuria
- Moderate to severe dehydration
- Edema with fluid replacement
- High cholesterol
- Death
## Long term
If a person with Type 1 diabetes with diabulimia is still alive after a medium term - which is usually due to phases where insulin is injected and phases of diabulimia (also known as a relapse) - then the following symptoms can also be expected:
- Severe kidney damage
- Blindness
- Severe neuropathy
- Extreme fatigue
- Edema (during blood sugars controlled phases)
- Heart problems
- High cholesterol
- Osteoporosis | https://www.wikidoc.org/index.php/Diabulimia | |
50871a5871fe098310bc26f53e4cb9bdb5b84066 | wikidoc | Loperamide | Loperamide
# 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
Loperamide is an antidiarrheal agent that is FDA approved for the treatment of acute nonspecific diarrhea, chronic diarrhea associated with inflammatory bowel disease, high output ileostomy, and traveler's diarrhea. Common adverse reactions include hyperglycemia, abdominal pain, nausea, vomiting, xerostomia, dizziness, and somnolence.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- 4 mg ORALLY followed by 2 mg after each loose stool up to a maximum of 16 mg/day.
- Initial; 4 mg ORALLY followed by 2 mg after each loose stool up to a maximum of 16 mg/day.
- Maintenance; titrate to individual's need, average daily dosage 4 mg to 8 mg ORALLY up to a maximum of 16 mg/day, may be taken as a single dose or in divided doses.
- 4 mg twice daily for 4 days, may then be increased to 12 mg daily for the remaining 3 days.
- 4 mg ORALLY followed by 2 mg after each loose stool up to a maximum of 8 mg/day.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Loperamide in adult patients.
### Non–Guideline-Supported Use
- Loperamide, dosed 12 to 24 milligrams/day (mg/day).
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- First day dosage
- (2 to 5 y, 13 to 20 kg) 1 mg orally 3 times daily.
- (6 to 8 y, 20 to 30 kg) 2 mg orally twice daily.
- (8 to 12 y, greater than 30 kg) 2 mg orally 3 times daily.
- Subsequent daily dosage
- (2 to 12 y) 1mg/10kg of body weight orally only after a loose stool, total daily dose should not exceed dosages for the first day.
- Dosing Information
- (2-5 yr, 24-47 lbs) 1 mg orally followed by 1 mg after each loose stool up to a maximum of 3 mg/day.
- (6-8 yr, 48-59 lbs) 2 mg orally followed by 1 mg after each loose stool up to a maximum of 4 mg/day.
- (9-11 yr, 60-95 lbs) 2 mg orally followed by 1 mg after each loose stool up to a maximum of 6 mg/day.
- (12 yr and older) 4 mg orally followed by 2 mg after each loose stool up to a maximum of 8 mg/day.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Loperamide in pediatric patients.
### Non–Guideline-Supported Use
- Doses of loperamide 0.08 to 0.24 milligram/kilogram/day in 2 to 3 divided doses.
# Contraindications
- Loperamide hydrochloride capsules are contraindicated in patients with a known hypersensitivity to loperamide hydrochloride or to any of the excipients.
- Loperamide hydrochloride is contraindicated in patients with abdominal pain in the absence of diarrhea.
- Loperamide hydrochloride is not recommended in infants below 24 months of age.
- Loperamide hydrochloride should not be used as the primary therapy:
- In patients with acute dysentery, which is characterized by blood in stools and high fever
- in patients with acute ulcerative colitis
- in patients with bacterial enterocolitis caused by invasive organisms including Salmonella, Shigella, and Campylobacter
- in patients with pseudomembranous colitis associated with the use of broad-spectrum antibiotics
# Warnings
- Fluid and electrolyte depletion often occur in patients who have diarrhea. In such cases, administration of appropriate fluid and electrolytes is very important. The use of loperamide hydrochloride does not preclude the need for appropriate fluid and electrolyte therapy.
- In general, loperamide hydrochloride should not be used when inhibition of peristalsis is to be avoided due to the possible risk of significant sequelae including ileus, megacolon and toxic megacolon. Loperamide hydrochloride must be discontinued promptly when constipation, abdominal distention or ileus develop.
- Treatment of diarrhea with loperamide hydrochloride is only symptomatic. Whenever an underlying etiology can be determined, specific treatment should be given when appropriate (or when indicated).
- Patients with AIDS treated with loperamide hydrochloride for diarrhea should have therapy stopped at the earliest signs of abdominal distention. There have been isolated reports of toxic megacolon in AIDS patients with infectious colitis from both viral and bacterial pathogens treated with loperamide hydrochloride.
- Loperamide hydrochloride should be used with special caution in young children because of the greater variability of response in this age group. Dehydration, particularly in younger children, may further influence the variability of response to loperamide hydrochloride.
### Precautions
- Extremely rare allergic reactions including anaphylaxis and anaphylactic shock have been reported. In acute diarrhea, if clinical improvement is not observed in 48 hours, the administration of loperamide hydrochloride should be discontinued and patients should be advised to consult their physician. Although no pharmacokinetic data are available in patients with hepatic impairment, loperamide hydrochloride should be used with caution in such patients because of reduced first pass metabolism. Patients with hepatic dysfunction should be monitored closely for signs of CNS toxicity. No pharmacokinetic data are available in patients with renal impairment. Since it has been reported that the majority of the drug is metabolized and metabolites or the unchanged drug is excreted mainly in the feces, dosage adjustments in patients with renal impairment are not required. No formal studies have been conducted to evaluate the pharmacokinetics of loperamide in elderly subjects. However, in two studies that enrolled elderly patients, there were no major differences in the drug disposition in elderly patients with diarrhea relative to young patients.
# Adverse Reactions
## Clinical Trials Experience
- The adverse effects reported during clinical investigations of loperamide hydrochloride are difficult to distinguish from symptoms associated with the diarrheal syndrome. Adverse experiences recorded during clinical studies with loperamide hydrochloride were generally of a minor and self-limiting nature. They were more commonly observed during the treatment of chronic diarrhea.
- The adverse events with an incidence of 1.0% or greater, which were more frequently reported in patients on placebo than on loperamide hydrochloride were: dry mouth, flatulence, abdominal cramp and colic.
## Postmarketing Experience
- The following adverse events have been reported:
Rash, pruritus, urticaria, angioedema, and extremely rare cases of bullous eruption including erythema multiforme, Stevens-Johnson syndrome and Toxic Epidermal Necrolysis have been reported with use of loperamide hydrochloride.
Isolated occurrences of allergic reactions and in some cases severe hypersensitivity reactions including anaphylactic shock and anaphylactoid reactions have been reported with the use of loperamide hydrochloride.
Dry mouth, abdominal pain, abdominal distention, nausea, vomiting, flatulence, dyspepsia, constipation, paralytic ileus, megacolon, including toxic megacolon.
Urinary retention.
Drowsiness, dizziness.
Tiredness.
- A number of the adverse events reported during the clinical investigations and postmarketing experience with loperamide are frequent symptoms of the underlying diarrheal syndrome (abdominal pain/discomfort, nausea, vomiting, dry mouth, tiredness, drowsiness, dizziness, constipation, and flatulence). These symptoms are often difficult to distinguish from undesirable drug effects.
# Drug Interactions
- Nonclinical data have shown that loperamide is a P-glycoprotein substrate. Concomitant administration of loperamide (16 mg single dose) with a 600 mg single dose of either quinidine or ritonavir, both of which are P-glycoprotein inhibitors, resulted in a 2 to 3 fold increase in loperamide plasma levels. Due to the potential for enhanced central effects when loperamide is coadministered with quinidine and with ritonavir, caution should be exercised when loperamide is administered at the recommended dosages (2 mg, up to 16 mg maximum daily dose) with P-glycoprotein inhibitors.
- When a single 16 mg dose of loperamide is coadministered with a 600 mg single dose of saquinavir, loperamide decreased saquinavir exposure by 54%, which may be of clinical relevance due to reduction of therapeutic efficacy of saquinavir. The effect of saquinavir on loperamide is of less clinical significance. Therefore, when loperamide is given with saquinavir, the therapeutic efficacy of saquinavir should be closely monitored.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- Teratology studies have been performed in rats using oral doses of 2.5, 10, and 40 mg/kg/day, and in rabbits using oral doses of 5, 20, and 40 mg/kg/day. These studies have revealed no evidence of impaired fertility or harm to the fetus at doses up to 10 mg/kg/day in rats (5 times the human dose based on body surface area comparison) and 40 mg/kg/day in rabbits (43 times the human dose based on body surface area comparison). Treatment of rats with 40 mg/kg/day p.o. (21 times the human dose based on a body surface area comparison) produced marked impairment of fertility. The studies produced no evidence of teratogenic activity. There are no adequate and well-controlled studies in pregnant women. Loperamide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Non-teratogenic Effects
- In a peri- and post-natal reproduction study in rats, oral administration of 40 mg/kg/day produced impairment of growth and survival of offspring.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Loperamide in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Loperamide during labor and delivery.
### Nursing Mothers
- Small amounts of loperamide may appear in human breast milk. Therefore, loperamide hydrochloride is not recommended during breast-feeding.
### Pediatric Use
There is no FDA guidance on the use of Loperamide with respect to pediatric patients.
### Geriatic Use
There is no FDA guidance on the use of Loperamide with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Loperamide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Loperamide with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Loperamide in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Loperamide in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Loperamide in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Loperamide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Loperamide in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Loperamide in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- In clinical trials an adult who took three 20 mg doses within a 24 hour period was nauseated after the second dose and vomited after the third dose. In studies designed to examine the potential for side effects, intentional ingestion of up to 60 mg of loperamide hydrochloride in a single dose to healthy subjects resulted in no significant adverse effects.
### Management
- In cases of overdosage, (including relative overdose due to hepatic dysfunction), urinary retention, paralytic ileus and CNS depression may occur. Children may be more sensitive to CNS effects than adults. Clinical trials have demonstrated that a slurry of activated charcoal administered promptly after ingestion of loperamide hydrochloride can reduce the amount of drug which is absorbed into the systemic circulation by as much as ninefold. If vomiting occurs spontaneously upon ingestion, a slurry of 100 grams of activated charcoal should be administered orally as soon as fluids can be retained.
- In cases of overdosage, (including relative overdose due to hepatic dysfunction), urinary retention, paralytic ileus and CNS depression may occur. Children may be more sensitive to CNS effects than adults. Clinical trials have demonstrated that a slurry of activated charcoal administered promptly after ingestion of loperamide hydrochloride can reduce the amount of drug which is absorbed into the systemic circulation by as much as ninefold. If vomiting occurs spontaneously upon ingestion, a slurry of 100 grams of activated charcoal should be administered orally as soon as fluids can be retained.
- If vomiting has not occurred, gastric lavage should be performed followed by administration of 100 grams of the activated charcoal slurry through the gastric tube. In the event of overdosage, patients should be monitored for signs of CNS depression for at least 24 hours.
- If symptoms of overdose occur, naloxone can be given as an antidote. If responsive to naloxone, vital signs must be monitored carefully for recurrence of symptoms of drug overdose for at least 24 hours after the last dose of naloxone.
- In view of the prolonged action of loperamide and the short duration (one to three hours) of naloxone, the patient must be monitored closely and treated repeatedly with naloxone as indicated. Since relatively little drug is excreted in the urine, forced diuresis is not expected to be effective for loperamide hydrochloride overdosage.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Loperamide in the drug label.
# Pharmacology
## Mechanism of Action
- In vitro and animal studies show that loperamide hydrochloride acts by slowing intestinal motility and by affecting water and electrolyte movement through the bowel. Loperamide binds to the opiate receptor in the gut wall. Consequently, it inhibits the release of acetylcholine and prostaglandins, thereby reducing peristalsis, and increasing intestinal transit time. Loperamide increases the tone of the anal sphincter, thereby reducing fecal incontinence and urgency.
## Structure
- Loperamide hydrochloride is a white to slightly yellow powder and is freely soluble in methanol, isopropyl alcohol, chloroform and slightly soluble in water.
- Loperamide hydrochloride, 4-(p-chlorophenyl)-4-hydroxy-N,N-dimethyl-α,α-diphenyl-1-piperidinebutyramide monohydrochloride, is a synthetic antidiarrheal for oral use.
- C29H33ClN2O2HCl M.W. 513.51
- Loperamide hydrochloride is available in 2 mg capsules.
- Each capsule, for oral administration, contains 2 mg loperamide hydrochloride. Loperamide hydrochloride capsules USP also contain the inactive ingredients: dimethylpolysiloxane, gelatin, iron oxide black, iron oxide red, iron oxide yellow, lactose monohydrate, pregelatinized corn starch, magnesium stearate, shellac, and titanium dioxide.
## Pharmacodynamics
- In man, loperamide hydrochloride prolongs the transit time of the intestinal contents. It reduces the daily fecal volume, increases the viscosity and bulk density, and diminishes the loss of fluid and electrolytes. Tolerance to the antidiarrheal effect has not been observed.
## Pharmacokinetics
- Clinical studies have indicated that the apparent elimination half-life of loperamide hydrochloride in man is 10.8 hours with a range of 9.1 to 14.4 hours. Plasma levels of unchanged drug remain below 2 nanograms per mL after the intake of a 2 mg loperamide hydrochloride capsule. Plasma levels are highest approximately five hours after administration of the capsule and 2.5 hours after the liquid. The peak plasma levels of loperamide were similar for both formulations. Elimination of loperamide mainly occurs by oxidative N-demethylation. Cytochrome P450 (CYP450) isozymes, CYP2C8 and CYP3A4, are thought to play an important role in loperamide N-demethylation process since quercetin (CYP2C8 inhibitor) and ketoconazole (CYP3A4 inhibitor) significantly inhibited the N-demethylation process in vitro by 40% and 90%, respectively. In addition, CYP2B6 and CYP2D6 appear to play a minor role in loperamide N-demethylation. Excretion of the unchanged loperamide and its metabolites mainly occurs through the feces. In those patients in whom biochemical and hematological parameters were monitored during clinical trials, no trends toward abnormality during loperamide hydrochloride therapy were noted. Similarly, urinalyses, EKG and clinical ophthalmological examinations did not show trends toward abnormality.
## Nonclinical Toxicology
- In an 18 month rat study with oral doses up to 40 mg/kg/day (21 times the maximum human dose of 16 mg/day, based on a body surface area comparison), there was no evidence of carcinogenesis.
- Loperamide was not genotoxic in the Ames test, the SOS chromotest in E. coli, the dominant lethal test in female mice, or the mouse embryo cell transformation assay.
- Fertility and reproductive performance was evaluated in rats using oral doses of 2.5, 10, and 40 mg/kg/day in one study, and 1, 5, 10, 20, and 40 mg/kg/day (females only) in a second study. Oral administration of 20 mg/kg/day (approximately 11 times the human dose based on a body surface area comparison) and higher produced strong impairment of female fertility. Treatment of female rats with up to 10 mg/kg/day p.o. (approximately 5 times the human dose based on a body surface area comparison) had no effect on fertility. Treatment of male rats with 40 mg/kg/day p.o. (approximately 21 times the human dose based on a body surface area comparison) produced impairment of male fertility, whereas administration of up to 10 mg/kg/day (approximately 5 times the human dose based on a body surface area comparison) had no effect.
# Clinical Studies
There is limited information regarding Clinical Studies of Loperamide in the drug label.
# How Supplied
There is limited information regarding Loperamide How Supplied in the drug label.
## Storage
There is limited information regarding Loperamide Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Loperamide in the drug label.
# Precautions with Alcohol
- Alcohol-Loperamide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- LOPERAMIDE HYDROCHLORIDE®
# Look-Alike Drug Names
There is limited information regarding Loperamide Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Loperamide
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Loperamide is an antidiarrheal agent that is FDA approved for the treatment of acute nonspecific diarrhea, chronic diarrhea associated with inflammatory bowel disease, high output ileostomy, and traveler's diarrhea. Common adverse reactions include hyperglycemia, abdominal pain, nausea, vomiting, xerostomia, dizziness, and somnolence.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- 4 mg ORALLY followed by 2 mg after each loose stool up to a maximum of 16 mg/day.
- Initial; 4 mg ORALLY followed by 2 mg after each loose stool up to a maximum of 16 mg/day.
- Maintenance; titrate to individual's need, average daily dosage 4 mg to 8 mg ORALLY up to a maximum of 16 mg/day, may be taken as a single dose or in divided doses.
- 4 mg twice daily for 4 days, may then be increased to 12 mg daily for the remaining 3 days.
- 4 mg ORALLY followed by 2 mg after each loose stool up to a maximum of 8 mg/day.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Loperamide in adult patients.
### Non–Guideline-Supported Use
- Loperamide, dosed 12 to 24 milligrams/day (mg/day).[1]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- First day dosage
- (2 to 5 y, 13 to 20 kg) 1 mg orally 3 times daily.
- (6 to 8 y, 20 to 30 kg) 2 mg orally twice daily.
- (8 to 12 y, greater than 30 kg) 2 mg orally 3 times daily.
- Subsequent daily dosage
- (2 to 12 y) 1mg/10kg of body weight orally only after a loose stool, total daily dose should not exceed dosages for the first day.
- Dosing Information
- (2-5 yr, 24-47 lbs) 1 mg orally followed by 1 mg after each loose stool up to a maximum of 3 mg/day.
- (6-8 yr, 48-59 lbs) 2 mg orally followed by 1 mg after each loose stool up to a maximum of 4 mg/day.
- (9-11 yr, 60-95 lbs) 2 mg orally followed by 1 mg after each loose stool up to a maximum of 6 mg/day.
- (12 yr and older) 4 mg orally followed by 2 mg after each loose stool up to a maximum of 8 mg/day.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Loperamide in pediatric patients.
### Non–Guideline-Supported Use
- Doses of loperamide 0.08 to 0.24 milligram/kilogram/day in 2 to 3 divided doses.[2]
# Contraindications
- Loperamide hydrochloride capsules are contraindicated in patients with a known hypersensitivity to loperamide hydrochloride or to any of the excipients.
- Loperamide hydrochloride is contraindicated in patients with abdominal pain in the absence of diarrhea.
- Loperamide hydrochloride is not recommended in infants below 24 months of age.
- Loperamide hydrochloride should not be used as the primary therapy:
- In patients with acute dysentery, which is characterized by blood in stools and high fever
- in patients with acute ulcerative colitis
- in patients with bacterial enterocolitis caused by invasive organisms including Salmonella, Shigella, and Campylobacter
- in patients with pseudomembranous colitis associated with the use of broad-spectrum antibiotics
# Warnings
- Fluid and electrolyte depletion often occur in patients who have diarrhea. In such cases, administration of appropriate fluid and electrolytes is very important. The use of loperamide hydrochloride does not preclude the need for appropriate fluid and electrolyte therapy.
- In general, loperamide hydrochloride should not be used when inhibition of peristalsis is to be avoided due to the possible risk of significant sequelae including ileus, megacolon and toxic megacolon. Loperamide hydrochloride must be discontinued promptly when constipation, abdominal distention or ileus develop.
- Treatment of diarrhea with loperamide hydrochloride is only symptomatic. Whenever an underlying etiology can be determined, specific treatment should be given when appropriate (or when indicated).
- Patients with AIDS treated with loperamide hydrochloride for diarrhea should have therapy stopped at the earliest signs of abdominal distention. There have been isolated reports of toxic megacolon in AIDS patients with infectious colitis from both viral and bacterial pathogens treated with loperamide hydrochloride.
- Loperamide hydrochloride should be used with special caution in young children because of the greater variability of response in this age group. Dehydration, particularly in younger children, may further influence the variability of response to loperamide hydrochloride.
### Precautions
- Extremely rare allergic reactions including anaphylaxis and anaphylactic shock have been reported. In acute diarrhea, if clinical improvement is not observed in 48 hours, the administration of loperamide hydrochloride should be discontinued and patients should be advised to consult their physician. Although no pharmacokinetic data are available in patients with hepatic impairment, loperamide hydrochloride should be used with caution in such patients because of reduced first pass metabolism. Patients with hepatic dysfunction should be monitored closely for signs of CNS toxicity. No pharmacokinetic data are available in patients with renal impairment. Since it has been reported that the majority of the drug is metabolized and metabolites or the unchanged drug is excreted mainly in the feces, dosage adjustments in patients with renal impairment are not required. No formal studies have been conducted to evaluate the pharmacokinetics of loperamide in elderly subjects. However, in two studies that enrolled elderly patients, there were no major differences in the drug disposition in elderly patients with diarrhea relative to young patients.
# Adverse Reactions
## Clinical Trials Experience
- The adverse effects reported during clinical investigations of loperamide hydrochloride are difficult to distinguish from symptoms associated with the diarrheal syndrome. Adverse experiences recorded during clinical studies with loperamide hydrochloride were generally of a minor and self-limiting nature. They were more commonly observed during the treatment of chronic diarrhea.
- The adverse events with an incidence of 1.0% or greater, which were more frequently reported in patients on placebo than on loperamide hydrochloride were: dry mouth, flatulence, abdominal cramp and colic.
## Postmarketing Experience
- The following adverse events have been reported:
Rash, pruritus, urticaria, angioedema, and extremely rare cases of bullous eruption including erythema multiforme, Stevens-Johnson syndrome and Toxic Epidermal Necrolysis have been reported with use of loperamide hydrochloride.
Isolated occurrences of allergic reactions and in some cases severe hypersensitivity reactions including anaphylactic shock and anaphylactoid reactions have been reported with the use of loperamide hydrochloride.
Dry mouth, abdominal pain, abdominal distention, nausea, vomiting, flatulence, dyspepsia, constipation, paralytic ileus, megacolon, including toxic megacolon.
Urinary retention.
Drowsiness, dizziness.
Tiredness.
- A number of the adverse events reported during the clinical investigations and postmarketing experience with loperamide are frequent symptoms of the underlying diarrheal syndrome (abdominal pain/discomfort, nausea, vomiting, dry mouth, tiredness, drowsiness, dizziness, constipation, and flatulence). These symptoms are often difficult to distinguish from undesirable drug effects.
# Drug Interactions
- Nonclinical data have shown that loperamide is a P-glycoprotein substrate. Concomitant administration of loperamide (16 mg single dose) with a 600 mg single dose of either quinidine or ritonavir, both of which are P-glycoprotein inhibitors, resulted in a 2 to 3 fold increase in loperamide plasma levels. Due to the potential for enhanced central effects when loperamide is coadministered with quinidine and with ritonavir, caution should be exercised when loperamide is administered at the recommended dosages (2 mg, up to 16 mg maximum daily dose) with P-glycoprotein inhibitors.
- When a single 16 mg dose of loperamide is coadministered with a 600 mg single dose of saquinavir, loperamide decreased saquinavir exposure by 54%, which may be of clinical relevance due to reduction of therapeutic efficacy of saquinavir. The effect of saquinavir on loperamide is of less clinical significance. Therefore, when loperamide is given with saquinavir, the therapeutic efficacy of saquinavir should be closely monitored.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- Teratology studies have been performed in rats using oral doses of 2.5, 10, and 40 mg/kg/day, and in rabbits using oral doses of 5, 20, and 40 mg/kg/day. These studies have revealed no evidence of impaired fertility or harm to the fetus at doses up to 10 mg/kg/day in rats (5 times the human dose based on body surface area comparison) and 40 mg/kg/day in rabbits (43 times the human dose based on body surface area comparison). Treatment of rats with 40 mg/kg/day p.o. (21 times the human dose based on a body surface area comparison) produced marked impairment of fertility. The studies produced no evidence of teratogenic activity. There are no adequate and well-controlled studies in pregnant women. Loperamide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Non-teratogenic Effects
- In a peri- and post-natal reproduction study in rats, oral administration of 40 mg/kg/day produced impairment of growth and survival of offspring.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Loperamide in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Loperamide during labor and delivery.
### Nursing Mothers
- Small amounts of loperamide may appear in human breast milk. Therefore, loperamide hydrochloride is not recommended during breast-feeding.
### Pediatric Use
There is no FDA guidance on the use of Loperamide with respect to pediatric patients.
### Geriatic Use
There is no FDA guidance on the use of Loperamide with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Loperamide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Loperamide with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Loperamide in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Loperamide in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Loperamide in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Loperamide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Loperamide in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Loperamide in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- In clinical trials an adult who took three 20 mg doses within a 24 hour period was nauseated after the second dose and vomited after the third dose. In studies designed to examine the potential for side effects, intentional ingestion of up to 60 mg of loperamide hydrochloride in a single dose to healthy subjects resulted in no significant adverse effects.
### Management
- In cases of overdosage, (including relative overdose due to hepatic dysfunction), urinary retention, paralytic ileus and CNS depression may occur. Children may be more sensitive to CNS effects than adults. Clinical trials have demonstrated that a slurry of activated charcoal administered promptly after ingestion of loperamide hydrochloride can reduce the amount of drug which is absorbed into the systemic circulation by as much as ninefold. If vomiting occurs spontaneously upon ingestion, a slurry of 100 grams of activated charcoal should be administered orally as soon as fluids can be retained.
- In cases of overdosage, (including relative overdose due to hepatic dysfunction), urinary retention, paralytic ileus and CNS depression may occur. Children may be more sensitive to CNS effects than adults. Clinical trials have demonstrated that a slurry of activated charcoal administered promptly after ingestion of loperamide hydrochloride can reduce the amount of drug which is absorbed into the systemic circulation by as much as ninefold. If vomiting occurs spontaneously upon ingestion, a slurry of 100 grams of activated charcoal should be administered orally as soon as fluids can be retained.
- If vomiting has not occurred, gastric lavage should be performed followed by administration of 100 grams of the activated charcoal slurry through the gastric tube. In the event of overdosage, patients should be monitored for signs of CNS depression for at least 24 hours.
- If symptoms of overdose occur, naloxone can be given as an antidote. If responsive to naloxone, vital signs must be monitored carefully for recurrence of symptoms of drug overdose for at least 24 hours after the last dose of naloxone.
- In view of the prolonged action of loperamide and the short duration (one to three hours) of naloxone, the patient must be monitored closely and treated repeatedly with naloxone as indicated. Since relatively little drug is excreted in the urine, forced diuresis is not expected to be effective for loperamide hydrochloride overdosage.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Loperamide in the drug label.
# Pharmacology
## Mechanism of Action
- In vitro and animal studies show that loperamide hydrochloride acts by slowing intestinal motility and by affecting water and electrolyte movement through the bowel. Loperamide binds to the opiate receptor in the gut wall. Consequently, it inhibits the release of acetylcholine and prostaglandins, thereby reducing peristalsis, and increasing intestinal transit time. Loperamide increases the tone of the anal sphincter, thereby reducing fecal incontinence and urgency.
## Structure
- Loperamide hydrochloride is a white to slightly yellow powder and is freely soluble in methanol, isopropyl alcohol, chloroform and slightly soluble in water.
- Loperamide hydrochloride, 4-(p-chlorophenyl)-4-hydroxy-N,N-dimethyl-α,α-diphenyl-1-piperidinebutyramide monohydrochloride, is a synthetic antidiarrheal for oral use.
- C29H33ClN2O2•HCl M.W. 513.51
- Loperamide hydrochloride is available in 2 mg capsules.
- Each capsule, for oral administration, contains 2 mg loperamide hydrochloride. Loperamide hydrochloride capsules USP also contain the inactive ingredients: dimethylpolysiloxane, gelatin, iron oxide black, iron oxide red, iron oxide yellow, lactose monohydrate, pregelatinized corn starch, magnesium stearate, shellac, and titanium dioxide.
## Pharmacodynamics
- In man, loperamide hydrochloride prolongs the transit time of the intestinal contents. It reduces the daily fecal volume, increases the viscosity and bulk density, and diminishes the loss of fluid and electrolytes. Tolerance to the antidiarrheal effect has not been observed.
## Pharmacokinetics
- Clinical studies have indicated that the apparent elimination half-life of loperamide hydrochloride in man is 10.8 hours with a range of 9.1 to 14.4 hours. Plasma levels of unchanged drug remain below 2 nanograms per mL after the intake of a 2 mg loperamide hydrochloride capsule. Plasma levels are highest approximately five hours after administration of the capsule and 2.5 hours after the liquid. The peak plasma levels of loperamide were similar for both formulations. Elimination of loperamide mainly occurs by oxidative N-demethylation. Cytochrome P450 (CYP450) isozymes, CYP2C8 and CYP3A4, are thought to play an important role in loperamide N-demethylation process since quercetin (CYP2C8 inhibitor) and ketoconazole (CYP3A4 inhibitor) significantly inhibited the N-demethylation process in vitro by 40% and 90%, respectively. In addition, CYP2B6 and CYP2D6 appear to play a minor role in loperamide N-demethylation. Excretion of the unchanged loperamide and its metabolites mainly occurs through the feces. In those patients in whom biochemical and hematological parameters were monitored during clinical trials, no trends toward abnormality during loperamide hydrochloride therapy were noted. Similarly, urinalyses, EKG and clinical ophthalmological examinations did not show trends toward abnormality.
## Nonclinical Toxicology
- In an 18 month rat study with oral doses up to 40 mg/kg/day (21 times the maximum human dose of 16 mg/day, based on a body surface area comparison), there was no evidence of carcinogenesis.
- Loperamide was not genotoxic in the Ames test, the SOS chromotest in E. coli, the dominant lethal test in female mice, or the mouse embryo cell transformation assay.
- Fertility and reproductive performance was evaluated in rats using oral doses of 2.5, 10, and 40 mg/kg/day in one study, and 1, 5, 10, 20, and 40 mg/kg/day (females only) in a second study. Oral administration of 20 mg/kg/day (approximately 11 times the human dose based on a body surface area comparison) and higher produced strong impairment of female fertility. Treatment of female rats with up to 10 mg/kg/day p.o. (approximately 5 times the human dose based on a body surface area comparison) had no effect on fertility. Treatment of male rats with 40 mg/kg/day p.o. (approximately 21 times the human dose based on a body surface area comparison) produced impairment of male fertility, whereas administration of up to 10 mg/kg/day (approximately 5 times the human dose based on a body surface area comparison) had no effect.
# Clinical Studies
There is limited information regarding Clinical Studies of Loperamide in the drug label.
# How Supplied
There is limited information regarding Loperamide How Supplied in the drug label.
## Storage
There is limited information regarding Loperamide Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Loperamide in the drug label.
# Precautions with Alcohol
- Alcohol-Loperamide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- LOPERAMIDE HYDROCHLORIDE®[3]
# Look-Alike Drug Names
There is limited information regarding Loperamide Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Diamode | |
c151e2ee0f6ba8a2ced5c78477760be840460bde | wikidoc | Dibenzepin | Dibenzepin
# Overview
Dibenzepin (Noveril, Anslopax, Deprex, Ecatril, Neodit, Victoril) is a tricyclic antidepressant (TCA) used widely throughout Europe for the treatment of depression. It has similar efficacy and effects relative to other TCAs like imipramine but with fewer side effects. Dibenzepin acts as a norepinephrine reuptake inhibitor, potent antihistamine, and weak anticholinergic. It lacks any 5-HT2 antagonistic properties.
# Chronic Pain
Like other tricyclic antidepressants, dibenzepin may have potential use in the treatment of chronic neuropathic pain.
# Overdose
As tricyclic antidepressants have a relatively narrow therapeutic index, the likelihood of overdose (both accidental and intentional) is fairly high and should be considered carefully by the prescribing physician prior to patient use. Symptoms of overdose are similar to those of other tricyclic antidepressants, with cardiac toxicity (due to inhibition of sodium and calcium channels) generally occurring before the threshold for serotonin syndrome is reached. Due to this risk, tricyclic antidepressants are rarely selected as the first line treatment for depression.
# Synthesis
The Ullmann reaction provides the key for preparing the diaryl-amine or -ether starting materials in this series.
Copper catalyzed coupling of methyl N-methylanthranilate () with nitrobromobenzene () leads to the arylaniline (). The ester is then saponified () and the nitro group reduced to the corresponding amine (). That product cyclizes to the lactam () on heating. A strong base preferentially removes the proton on the lactam nitrogen to form an anion. Alkylation with 2-chloroethyldimethylamine then affords dibenzepin (), a compound that shows antidepressant activity. | Dibenzepin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Dibenzepin (Noveril, Anslopax, Deprex, Ecatril, Neodit, Victoril) is a tricyclic antidepressant (TCA) used widely throughout Europe for the treatment of depression.[1][2][3] It has similar efficacy and effects relative to other TCAs like imipramine but with fewer side effects.[4][5][6][7] Dibenzepin acts as a norepinephrine reuptake inhibitor, potent antihistamine, and weak anticholinergic.[4][5][8] It lacks any 5-HT2 antagonistic properties.[9]
# Chronic Pain
Like other tricyclic antidepressants, dibenzepin may have potential use in the treatment of chronic neuropathic pain.
# Overdose
As tricyclic antidepressants have a relatively narrow therapeutic index, the likelihood of overdose (both accidental and intentional) is fairly high and should be considered carefully by the prescribing physician prior to patient use. Symptoms of overdose are similar to those of other tricyclic antidepressants, with cardiac toxicity (due to inhibition of sodium and calcium channels) generally occurring before the threshold for serotonin syndrome is reached. Due to this risk, tricyclic antidepressants are rarely selected as the first line treatment for depression.
# Synthesis
The Ullmann reaction provides the key for preparing the diaryl-amine or -ether starting materials in this series.
Copper catalyzed coupling of methyl N-methylanthranilate () with nitrobromobenzene () leads to the arylaniline (). The ester is then saponified () and the nitro group reduced to the corresponding amine (). That product cyclizes to the lactam () on heating. A strong base preferentially removes the proton on the lactam nitrogen to form an anion. Alkylation with 2-chloroethyldimethylamine then affords dibenzepin (), a compound that shows antidepressant activity.[11] | https://www.wikidoc.org/index.php/Dibenzepin | |
381511e48d94e8a63fc6a87fbe150143b7b6bbcc | wikidoc | Dichromacy | Dichromacy
Dichromacy in humans is a moderately severe color vision defect in which one of the three basic color mechanisms is absent or not functioning. It is hereditary and sex-linked, predominantly affecting males. Dichromacy occurs when one of the cone pigments is missing and color is reduced to two dimensions.
Organisms with dichromacy are called dichromats. Dichromats can match any color they see with a mixture of no more than two pure spectral lights. By comparison, a trichromat requires three pure spectral lights to match all colors in their visual spectrum.
There are various kinds of color blindness. Protanopia is a severe form of red-green color-blindness, where there is impairment in perception of very long wavelengths, such as reds. To these sufferers, reds are perceived as beige and greens tend to look like reds. Protanomaly is a less severe version. Deuteranopia consists of an impairment in perceiving medium wavelengths, such as greens. Deuteranomaly is a less severe form of deuteranopia. Those living with deuteranomaly cannot see reds and greens like normal people, however they can still distinguish them in most cases. A more rare form of color blindness is tritanopia, where there exists an inability to perceive short wavelengths, such as blues. Sufferers have trouble distinguishing between yellow and blue and tend to mistake greens for blues and yellows for reds.
# Dichromacy in mammals
It is currently believed that most mammals are dichromats. The straightforward exceptions are primates closely related to humans, which are usually trichromats, and sea mammals (both pinnipeds and cetaceans) which are monochromats. New World Monkeys are a partial exception: in most species, males are dichromats, and about 60% of females are trichromats, but the owl monkeys are monochromats, and both sexes of howler monkeys are trichromats. Recent research (e.g. Arrese et al, 2005) suggests that trichromacy may be widespread among marsupials.
# Notes
- ↑ Cassin, B. and Solomon, S. Dictionary of Eye Terminology. Gainsville, Florida: Triad Publishing Company, 1990.
- ↑ "Guidelines: Color Blindness." Tiresias.org. Accessed September 29, 2006. | Dichromacy
Dichromacy in humans is a moderately severe color vision defect in which one of the three basic color mechanisms is absent or not functioning. It is hereditary and sex-linked, predominantly affecting males.[1] Dichromacy occurs when one of the cone pigments is missing and color is reduced to two dimensions.[2]
Organisms with dichromacy are called dichromats. Dichromats can match any color they see with a mixture of no more than two pure spectral lights. By comparison, a trichromat requires three pure spectral lights to match all colors in their visual spectrum.
There are various kinds of color blindness. Protanopia is a severe form of red-green color-blindness, where there is impairment in perception of very long wavelengths, such as reds. To these sufferers, reds are perceived as beige and greens tend to look like reds. Protanomaly is a less severe version. Deuteranopia consists of an impairment in perceiving medium wavelengths, such as greens. Deuteranomaly is a less severe form of deuteranopia. Those living with deuteranomaly cannot see reds and greens like normal people, however they can still distinguish them in most cases. A more rare form of color blindness is tritanopia, where there exists an inability to perceive short wavelengths, such as blues. Sufferers have trouble distinguishing between yellow and blue and tend to mistake greens for blues and yellows for reds.
# Dichromacy in mammals
It is currently believed that most mammals are dichromats. The straightforward exceptions are primates closely related to humans, which are usually trichromats, and sea mammals (both pinnipeds and cetaceans) which are monochromats. New World Monkeys are a partial exception: in most species, males are dichromats, and about 60% of females are trichromats, but the owl monkeys are monochromats, and both sexes of howler monkeys are trichromats. Recent research (e.g. Arrese et al, 2005) suggests that trichromacy may be widespread among marsupials.
# Notes
- ↑ Cassin, B. and Solomon, S. Dictionary of Eye Terminology. Gainsville, Florida: Triad Publishing Company, 1990.
- ↑ "Guidelines: Color Blindness." Tiresias.org. Accessed September 29, 2006. | https://www.wikidoc.org/index.php/Dichromacy | |
952c97d445ce5ff70308b6dfdd09819dd8478f77 | wikidoc | Didanosine | Didanosine
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# Black Box Warning
# Overview
Didanosine is a nucleoside reverse transcriptase inhibitor that is FDA approved for the treatment of human immunodeficiency virus (HIV)-1 infection.. There is a Black Box Warning for this drug as shown here. Common adverse reactions include rash, abdominal pain, diarrhea, nausea, vomiting and headache.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Didanosine in combination with other antiretroviral agents is indicated for the treatment of human immunodeficiency virus (HIV)-1 infection.
- Should be administered on an empty stomach
- Total daily dose is based on body weight
- 20 kg to less than 25 kg: 200 mg once daily
- 25 kg to less than 60 kg: 250 mg once daily
- At least 60 kg: 400 mg once daily
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Didanosine in adult patients.
### Non–Guideline-Supported Use
- Prophylaxis of occupational exposure to HIV
- Didanosine: 400 mg (if body weight is less than 60 kg, 125 mg twice daily or 250 mg once daily) daily, on an empty stomach, AND
- Lamivudine: 300 mg once daily or 150 mg twice daily for 4 weeks.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Didanosine in combination with other antiretroviral agents is indicated for the treatment of human immunodeficiency virus (HIV)-1 infection.
- Should be administered on an empty stomach
- Total daily dose is based on body weight
- 20 kg to less than 25 kg: 200 mg once daily
- 25 kg to less than 60 kg: 250 mg once daily
- At least 60 kg: 400 mg once daily
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Didanosine in pediatric patients.
### Non–Guideline-Supported Use
- Prophylaxis of occupational exposure to HIV
- Didanosine: 400 mg (if body weight is less than 60 kg, 125 mg twice daily or 250 mg once daily) daily, on an empty stomach, AND
- Lamivudine: 300 mg once daily or 150 mg twice daily for 4 weeks.
# Contraindications
These recommendations are based on either drug interaction studies or observed clinical toxicities.
- Coadministration of didanosine and allopurinol is contraindicated because systemic exposures of didanosine are increased, which may increase didanosine-associated toxicity.
- Coadministration of didanosine and ribavirin is contraindicated because exposures of the active metabolite of didanosine (dideoxyadenosine 5’-triphosphate) are increased. Fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis have been reported in patients receiving both didanosine and ribavirin.
# Warnings
Fatal and nonfatal pancreatitis has occurred during therapy with didanosine used alone or in combination regimens in both treatment-naive and treatment-experienced patients, regardless of degree of immunosuppression. Didanosine delayed-release capsules should be suspended in patients with signs or symptoms of pancreatitis and discontinued in patients with confirmed pancreatitis. Patients treated with didanosine delayed-release capsules in combination with stavudine may be at increased risk for pancreatitis.
When treatment with life-sustaining drugs known to cause pancreatic toxicity is required, suspension of didanosine delayed-release capsules therapy is recommended. In patients with risk factors for pancreatitis, didanosine delayed-release capsules should be used with extreme caution and only if clearly indicated. Patients with advanced HIV-1 infection, especially the elderly, are at increased risk of pancreatitis and should be followed closely. Patients with renal impairment may be at greater risk for pancreatitis if treated without dose adjustment. The frequency of pancreatitis is dose related.
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including didanosine and other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Fatal lactic acidosis has been reported in pregnant women who received the combination of didanosine and stavudine with other antiretroviral agents. The combination of didanosine and stavudine should be used with caution during pregnancy and is recommended only if the potential benefit clearly outweighs the potential risk. Particular caution should be exercised when administering didanosine delayed-release capsules to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with didanosine delayed-release capsules should be suspended in any patient who develops clinical signs or symptoms with or without laboratory findings consistent with symptomatic hyperlactatemia, lactic acidosis, or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).
The safety and efficacy of didanosine delayed-release capsules have not been established in HIV-infected patients with significant underlying liver disease. During combination antiretroviral therapy, patients with preexisting liver dysfunction, including chronic active hepatitis, have an increased frequency of liver function abnormalities, including severe and potentially fatal hepatic adverse events, and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment must be considered.
Hepatotoxicity and hepatic failure resulting in death were reported during postmarketing surveillance in HIV-infected patients treated with hydroxyurea and other antiretroviral agents. Fatal hepatic events were reported most often in patients treated with the combination of hydroxyurea, didanosine, and stavudine. This combination should be avoided.
Postmarketing cases of non-cirrhotic portal hypertension have been reported, including cases leading to liver transplantation or death. Cases of didanosine-associated non-cirrhotic portal hypertension were confirmed by liver biopsy in patients with no evidence of viral hepatitis. Onset of signs and symptoms ranged from months to years after start of didanosine therapy. Common presenting features included elevated liver enzymes, esophageal varices, hematemesis, ascites, and splenomegaly.
Patients receiving didanosine delayed-release capsules should be monitored for early signs of portal hypertension (e.g., thrombocytopenia and splenomegaly) during routine medical visits. Appropriate laboratory testing including liver enzymes, serum bilirubin, albumin, complete blood count, and international normalized ratio (INR) and ultrasonography should be considered. Didanosine delayed-release capsules should be discontinued in patients with evidence of non-cirrhotic portal hypertension.
Peripheral neuropathy, manifested by numbness, tingling, or pain in the hands or feet, has been reported in patients receiving didanosine therapy. Peripheral neuropathy has occurred more frequently in patients with advanced HIV disease, in patients with a history of neuropathy, or in patients being treated with neurotoxic drug therapy, including stavudine. Discontinuation of didanosine delayed-release capsules should be considered in patients who develop peripheral neuropathy.
Retinal changes and optic neuritis have been reported in patients taking didanosine. Periodic retinal examinations should be considered for patients receiving didanosine delayed-release capsules.
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including didanosine delayed-release capsules. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia , or tuberculosis), which may necessitate further evaluation and treatment.
Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.
Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.
# 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.
Study AI454-152 was a 48-week, randomized, open-label study comparing didanosine delayed-release capsules (400 mg once daily) plus stavudine (40 mg twice daily) plus nelfinavir (750 mg three times daily) to zidovudine (300 mg) plus lamivudine (150 mg) combination tablets twice daily plus nelfinavir (750 mg three times daily) in 511 treatment-naive patients. Selected clinical adverse reactions that occurred in combination with other antiretroviral agents are provided in TABLE 3.
In clinical trials using a buffered formulation of didanosine, pancreatitis resulting in death was observed in one patient who received didanosine plus stavudine plus nelfinavir, one patient who received didanosine plus stavudine plus indinavir, and 2 of 68 patients who received didanosine plus stavudine plus indinavir plus hydroxyurea. In an early access program, pancreatitis resulting in death was observed in one patient who received didanosine delayed-release capsules plus stavudine plus hydroxyurea plus ritonavir plus indinavir plus efavirenz.
The frequency of pancreatitis is dose related. In phase 3 studies with buffered formulations of didanosine, incidence ranged from 1% to 10% with doses higher than are currently recommended and 1% to 7% with recommended dose.
Selected laboratory abnormalities that occurred in a study of didanosine delayed-release capsules in combination with other antiretroviral agents are shown in TABLE 4.
In clinical trials, 743 pediatric patients between 2 weeks and 18 years of age have been treated with didanosine. Adverse reactions and laboratory abnormalities reported to occur in these patients were generally consistent with the safety profile of didanosine in adults.
In pediatric phase 1 studies, pancreatitis occurred in 2 of 60 (3%) patients treated at entry doses below 300 mg/m2/day and in 5 of 38 (13%) patients treated at higher doses. In study ACTG 152, pancreatitis occurred in none of the 281 pediatric patients who received didanosine 120 mg/m2 every 12 hours and in less than 1% of the 274 pediatric patients who received didanosine 90 mg/m2 every 12 hours in combination with zidovudine.
Retinal changes and optic neuritis have been reported in pediatric patients.
## Postmarketing Experience
The following adverse reactions have been identified during postapproval use of didanosine. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These reactions have been chosen for inclusion due to their seriousness, frequency of reporting, causal connection to didanosine, or a combination of these factors.
- Blood and Lymphatic System Disorders - anemia, leukopenia, and thrombocytopenia.
- Body as a Whole - abdominal pain, alopecia, anaphylactoid reaction, asthenia, chills/fever, pain, and redistribution/accumulation of body fat.
- Digestive Disorders - anorexia, dyspepsia, and flatulence.
- Exocrine Gland Disorders - pancreatitis (including fatal cases), sialoadenitis, parotid gland enlargement, dry mouth, and dry eyes.
- Hepatobiliary Disorders - symptomatic hyperlactatemia/lactic acidosis and hepatic steatosis; non-cirrhotic portal hypertension; hepatitis and liver failure.
- Metabolic Disorders - diabetes mellitus, elevated serum alkaline phosphatase level, elevated serum amylase level, elevated serum gamma-glutamyltransferase level, elevated serum uric acid level, hypoglycemia, and hyperglycemia.
- Musculoskeletal Disorders - myalgia (with or without increases in creatine kinase), rhabdomyolysis including acute renal failure and hemodialysis, arthralgia, and myopathy.
- Ophthalmologic Disorders - retinal depigmentation and optic neuritis.
When didanosine is used in combination with other agents with similar toxicities, the incidence of these toxicities may be higher than when didanosine is used alone. Thus, patients treated with didanosine delayed-release capsules in combination with stavudine, with or without hydroxyurea, may be at increased risk for pancreatitis and hepatotoxicity, which may be fatal, and severe peripheral neuropathy. The combination of didanosine delayed-release capsules and hydroxyurea, with or without stavudine, should be avoided.
# Drug Interactions
Exposure to didanosine is increased when coadministered with tenofovir disoproxil fumarate. Increased exposure may cause or worsen didanosine-related clinical toxicities, including pancreatitis, symptomatic hyperlactatemia/lactic acidosis, and peripheral neuropathy. Coadministration of tenofovir disoproxil fumarate with didanosine delayed-release capsules should be undertaken with caution, and patients should be monitored closely for didanosine-related toxicities and clinical response. Didanosine delayed-release capsules should be suspended if signs or symptoms of pancreatitis, symptomatic hyperlactatemia, or lactic acidosis develop. Suppression of CD4 cell counts has been observed in patients receiving tenofovir disoproxil fumarate with didanosine at a dose of 400 mg daily.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
Reproduction studies have been performed in rats and rabbits at doses up to 12 and 14.2 times the estimated human exposure (based upon plasma levels), respectively, and have revealed no evidence of impaired fertility or harm to the fetus due to didanosine. At approximately 12 times the estimated human exposure, didanosine was slightly toxic to female rats and their pups during mid and late lactation. These rats showed reduced food intake and body weight gains but the physical and functional development of the offspring was not impaired and there were no major changes in the F2 generation. A study in rats showed that didanosine and/or its metabolites are transferred to the fetus through the placenta. Animal reproduction studies are not always predictive of human response.
There are no adequate and well-controlled studies of didanosine in pregnant women. Didanosine should be used during pregnancy only if the potential benefit justifies the potential risk.
Fatal lactic acidosis has been reported in pregnant women who received the combination of didanosine and stavudine with other antiretroviral agents. It is unclear if pregnancy augments the risk of lactic acidosis/hepatic steatosis syndrome reported in nonpregnant individuals receiving nucleoside analogues. The combination of didanosine and stavudine should be used with caution during pregnancy and is recommended only if the potential benefit clearly outweighs the potential risk. Healthcare providers caring for HIV-infected pregnant women receiving didanosine should be alert for early diagnosis of lactic acidosis/hepatic steatosis syndrome.
Pregnancy Category (AUS): B2
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Didanosine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Didanosine during labor and delivery.
### Nursing Mothers
The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. A study in rats showed that following oral administration, didanosine and/or its metabolites were excreted into the milk of lactating rats. It is not known if didanosine is excreted in human milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving didanosine.
### Pediatric Use
Use of didanosine in pediatric patients from 2 weeks of age through adolescence is supported by evidence from adequate and well-controlled studies of didanosine in adult and pediatric patients. Additional pharmacokinetic studies in pediatric patients support use of didanosine delayed-release capsules in pediatric patients who weigh at least 20 kg.
### Geriatic Use
In an Expanded Access Program using a buffered formulation of didanosine for the treatment of advanced HIV infection, patients aged 65 years and older had a higher frequency of pancreatitis (10%) than younger patients (5%). Clinical studies of didanosine, including those for didanosine delayed-release capsules, did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently than younger subjects. Didanosine 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. In addition, renal function should be monitored and dosage adjustments should be made accordingly.
### Gender
The effects of gender on didanosine pharmacokinetics have not been studied.
### Race
There is no FDA guidance on the use of Didanosine with respect to specific racial populations.
### Renal Impairment
Patients with renal impairment (creatinine clearance of less than 60 mL/min) may be at greater risk of toxicity from didanosine due to decreased drug clearance. A dose reduction is recommended for these patients.
### Hepatic Impairment
The pharmacokinetics of didanosine have been studied in 12 non-HIV-infected subjects with moderate (n = 8) to severe (n = 4) hepatic impairment (Child-Pugh Class B or C). Mean AUC and Cmax values following a single 400 mg dose of didanosine were approximately 13% and 19% higher, respectively, in patients with hepatic impairment compared to matched healthy subjects. No dose adjustment is needed, because a similar range and distribution of AUC and Cmax values was observed for subjects with hepatic impairment and matched healthy controls.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Didanosine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Didanosine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Oral
### Monitoring
There is limited information regarding Didanosine Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Didanosine and IV administrations.
# Overdosage
There is no known antidote for didanosine overdosage. In phase 1 studies, in which buffered formulations of didanosine were initially administered at doses ten times the currently recommended dose, toxicities included: pancreatitis, peripheral neuropathy, diarrhea, hyperuricemia, and hepatic dysfunction. Didanosine is not dialyzable by peritoneal dialysis, although there is some clearance by hemodialysis.
# Pharmacology
## Mechanism of Action
Didanosine is a synthetic nucleoside analogue of the naturally occurring nucleoside deoxyadenosine in which the 3’-hydroxyl group is replaced by hydrogen. Intracellularly, didanosine is converted by cellular enzymes to the active metabolite, dideoxyadenosine 5’-triphosphate. Dideoxyadenosine 5’-triphosphate inhibits the activity of HIV-1 reverse transcriptase both by competing with the natural substrate, deoxyadenosine 5’-triphosphate, and by its incorporation into viral DNA causing termination of viral DNA chain elongation.
## Structure
The chemical name for didanosine is 2' ,3' -dideoxyinosine. The structural formula is:
## Pharmacodynamics
There is limited information regarding Didanosine Pharmacodynamics in the drug label.
## Pharmacokinetics
The pharmacokinetic parameters of didanosine in HIV-infected adult and pediatric patients are summarized in TABLE 7, by weight ranges that correspond to recommended doses. Didanosine is rapidly absorbed, with peak plasma concentrations generally observed from 0.25 to 1.50 hours following oral dosing with a buffered formulation. Increases in plasma didanosine concentrations were dose proportional over the range of 50 to 400 mg. In adults, the mean (± standard deviation) oral bioavailability following single oral dosing with a buffered formulation is 42 (± 12)%. After oral administration, the urinary recovery of didanosine is approximately 18 (± 8)% of the dose. The CSF-plasma ratio following IV administration is 21 (± 0.03)%. Steady-state pharmacokinetic parameters did not differ significantly from values obtained after a single dose. Binding of didanosine to plasma proteins in vitro was low (less than 5%). Based on data from in vitro and animal studies, it is presumed that the metabolism of didanosine in man occurs by the same pathways responsible for the elimination of endogenous purines.
In didanosine delayed-release capsules, the active ingredient, didanosine, is protected against degradation by stomach acid by the use of an enteric coating on the pellets in the capsule. The enteric coating dissolves when the pellets empty into the small intestine, the site of drug absorption. With buffered formulations of didanosine, administration with antacid provides protection from degradation by stomach acid.
In healthy volunteers, as well as subjects infected with HIV-1, the AUC is equivalent for didanosine administered as the didanosine delayed-release capsules formulation relative to a buffered tablet formulation. The peak plasma concentration (Cmax) of didanosine, administered as didanosine delayed-release capsules, is reduced approximately 40% relative to didanosine buffered tablets. The time to the peak concentration (Tmax) increases from approximately 0.67 hours for didanosine buffered tablets to 2 hours for didanosine delayed-release capsules.
In the presence of food, the Cmax and AUC for didanosine delayed-release capsules were reduced by approximately 46% and 19%, respectively, compared to the fasting state. Didanosine delayed-release capsules should be taken on an empty stomach.
## Nonclinical Toxicology
The anti-HIV-1 activity of didanosine was evaluated in a variety of HIV-1 infected lymphoblastic cell lines and monocyte/macrophage cell cultures. The concentration of drug necessary to inhibit viral replication by 50% (EC50) ranged from 2.5 to 10 μM
(1 μM = 0.24 mcg/mL) in lymphoblastic cell lines and 0.01 to 0.1 μM in monocyte/macrophage cell cultures.
HIV-1 isolates with reduced sensitivity to didanosine have been selected in cell culture and were also obtained from patients treated with didanosine. Genetic analysis of isolates from didanosine-treated patients showed mutations in the reverse transcriptase gene that resulted in the amino acid substitutions K65R, L74V, and M184V. The L74V substitution was most frequently observed in clinical isolates. Phenotypic analysis of HIV-1 isolates from 60 patients (some with prior zidovudine treatment) receiving 6 to 24 months of didanosine monotherapy showed that isolates from 10 of 60 patients exhibited an average of a 10-fold decrease in susceptibility to didanosine in cell culture compared to baseline isolates. Clinical isolates that exhibited a decrease in didanosine susceptibility harbored one or more didanosine resistance-associated substitutions.
HIV-1 isolates from 2 of 39 patients receiving combination therapy for up to 2 years with didanosine and zidovudine exhibited decreased susceptibility to didanosine, lamivudine, stavudine, zalcitabine, and zidovudine in cell culture. These isolates harbored five substitutions (A62V, V75I, F77L, F116Y, and Q151M) in the reverse transcriptase gene. In data from clinical studies, the presence of thymidine analogue mutations (M41L, D67N, L210W, T215Y, K219Q) has been shown to decrease the response to didanosine.
Lifetime carcinogenicity studies were conducted in mice and rats for 22 and 24 months, respectively. In the mouse study, initial doses of 120, 800, and 1200 mg/kg/day for each sex were lowered after 8 months to 120, 210, and 210 mg/kg/day for females and 120, 300, and 600 mg/kg/day for males. The two higher doses exceeded the maximally tolerated dose in females and the high dose exceeded the maximally tolerated dose in males. The low dose in females represented 0.68-fold maximum human exposure and the intermediate dose in males represented 1.7-fold maximum human exposure based on relative AUC comparisons. In the rat study, initial doses were 100, 250, and 1000 mg/kg/day, and the high dose was lowered to 500 mg/kg/day after 18 months. The upper dose in male and female rats represented 3-fold maximum human exposure.
Didanosine induced no significant increase in neoplastic lesions in mice or rats at maximally tolerated doses.
Didanosine was positive in the following genetic toxicology assays: 1) the Escherichia coli tester strain WP2 uvrA bacterial mutagenicity assay; 2) the L5178Y/TK+/- mouse lymphoma mammalian cell gene mutation assay; 3) the in vitro chromosomal aberrations assay in cultured human peripheral lymphocytes; 4) the in vitro chromosomal aberrations assay in Chinese Hamster Lung cells; and 5) the BALB/c 3T3 in vitro transformation assay. No evidence of mutagenicity was observed in an Ames Salmonella bacterial mutagenicity assay or in rat and mouse in vivo micronucleus assays.
Evidence of a dose-limiting skeletal muscle toxicity has been observed in mice and rats (but not in dogs) following long-term (greater than 90 days) dosing with didanosine at doses that were approximately 1.2 to 12 times the estimated human exposure. The relationship of this finding to the potential of didanosine to cause myopathy in humans is unclear. However, human myopathy has been associated with administration of didanosine and other nucleoside analogues.
# Clinical Studies
Study AI454-152 was a 48-week, randomized, open-label study comparing didanosine delayed-release capsules (400 mg once daily) plus stavudine (40 mg twice daily) plus nelfinavir (750 mg three times daily) to zidovudine (300 mg) plus lamivudine (150 mg) combination tablets twice daily plus nelfinavir (750 mg three times daily) in 511 treatment-naive patients, with a mean CD4 cell count of 411 cells/mm3 (range 39 to 1105 cells/mm3) and a mean plasma HIV-1 RNA of 4.71 log10 copies/mL (range 2.8 to 5.9 log10 copies/mL) at baseline. Patients were primarily males (72%) and Caucasian (53%) with a mean age of 35 years (range 18 to 73 years). The percentages of patients with HIV-1 RNA less than 400 and less than 50 copies/mL and outcomes of patients through 48 weeks are summarized in FIGURE 1 and TABLE 13, respectively.
Efficacy in pediatric patients was demonstrated in a randomized, double-blind, controlled study (ACTG 152, conducted 1991-1995) involving 831 patients 3 months to 18 years of age treated for more than 1.5 years with zidovudine (180 mg/m2 every 6 hours), didanosine (120 mg/m2 every 12 hours), or zidovudine (120 mg/m2 every 6 hours) plus didanosine (90 mg/m2 every 12 hours). Patients treated with didanosine or didanosine plus zidovudine had lower rates of HIV-1 disease progression or death compared with those treated with zidovudine alone.
# How Supplied
- Didanosine 200 mg: Bottles of 30 capsules.
- Didanosine 250 mg: Bottles of 30 capsules.
- Didanosine 400 mg: Bottles of 30 capsules.
## Storage
Store at 20° to 25°C (68° to 77°F)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Patients should be informed that a serious toxicity of didanosine, used alone and in combination regimens, is pancreatitis, which may be fatal.
Patients should be informed that peripheral neuropathy, manifested by numbness, tingling, or pain in hands or feet, may develop during therapy with didanosine delayed-release capsules. Patients should be counseled that peripheral neuropathy occurs with greatest frequency in patients with advanced HIV-1 disease or a history of peripheral neuropathy, and discontinuation of didanosine delayed-release capsules may be required if toxicity develops.
Patients should be informed that lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including didanosine and other antiretrovirals.
Patients should be informed that hepatotoxicity including fatal hepatic adverse events were reported in patients with preexisting liver dysfunction. The safety and efficacy of didanosine delayed-release capsules has not been established in HIV-infected patients with significant underlying liver disease.
Patients should be informed that non-cirrhotic portal hypertension has been reported in patients taking didanosine delayed-release capsules, including cases leading to liver transplantation or death.
Patients should be informed that retinal changes and optic neuritis have been reported in adult and pediatric patients.
Patients should be informed that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known at this time.
Patients should be informed that when didanosine is used in combination with other agents with similar toxicities, the incidence of adverse events may be higher than when didanosine is used alone. These patients should be followed closely.
Patients should be cautioned about the use of medications or other substances, including alcohol, which may exacerbate didanosine delayed-release capsules toxicities.
Didanosine delayed-release capsules are not a cure for HIV-1 infection, and patients may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. Therefore, patients should remain under the care of a physician when using didanosine delayed-release capsules.
Patients should be advised to avoid doing things that can spread HIV-1 infection to others.
- Do not share needles or other injection equipment.
- Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.
- Do not have any kind of sex without protection. Always practice safe sex by using a latex or polyurethane condom or other barrier method to lower the chance of sexual contact with semen, vaginal secretions, or blood.
- Do not breastfeed. It is not known if didanosine can be passed to your baby in your breast milk and whether it could harm your baby. Also, mothers with HIV-1 should not breast-feed because HIV-1 can be passed to the baby in breast milk.
Patients should be instructed to swallow the capsule as a whole and to not open the capsule.
Patients should be instructed to not miss a dose but if they do, patients should take didanosine as soon as possible. Patients should be told that if it is almost time for the next dose, they should skip the missed dose and continue with the regular dosing schedule.
Patients should be instructed to contact a poison control center or emergency room right away in case of an overdose.
# Precautions with Alcohol
Alcohol-Didanosine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Videx
- Videx EC
- Videx Pediatric
# Look-Alike Drug Names
There is limited information regarding Didanosine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Didanosine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gloria Picoy [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
Didanosine is a nucleoside reverse transcriptase inhibitor that is FDA approved for the treatment of human immunodeficiency virus (HIV)-1 infection.. There is a Black Box Warning for this drug as shown here. Common adverse reactions include rash, abdominal pain, diarrhea, nausea, vomiting and headache.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Didanosine in combination with other antiretroviral agents is indicated for the treatment of human immunodeficiency virus (HIV)-1 infection.
- Should be administered on an empty stomach
- Total daily dose is based on body weight
- 20 kg to less than 25 kg: 200 mg once daily
- 25 kg to less than 60 kg: 250 mg once daily
- At least 60 kg: 400 mg once daily
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Didanosine in adult patients.
### Non–Guideline-Supported Use
- Prophylaxis of occupational exposure to HIV
- Didanosine: 400 mg (if body weight is less than 60 kg, 125 mg twice daily or 250 mg once daily) daily, on an empty stomach, AND
- Lamivudine: 300 mg once daily or 150 mg twice daily for 4 weeks.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Didanosine in combination with other antiretroviral agents is indicated for the treatment of human immunodeficiency virus (HIV)-1 infection.
- Should be administered on an empty stomach
- Total daily dose is based on body weight
- 20 kg to less than 25 kg: 200 mg once daily
- 25 kg to less than 60 kg: 250 mg once daily
- At least 60 kg: 400 mg once daily
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Didanosine in pediatric patients.
### Non–Guideline-Supported Use
- Prophylaxis of occupational exposure to HIV
- Didanosine: 400 mg (if body weight is less than 60 kg, 125 mg twice daily or 250 mg once daily) daily, on an empty stomach, AND
- Lamivudine: 300 mg once daily or 150 mg twice daily for 4 weeks.
# Contraindications
These recommendations are based on either drug interaction studies or observed clinical toxicities.
- Coadministration of didanosine and allopurinol is contraindicated because systemic exposures of didanosine are increased, which may increase didanosine-associated toxicity.
- Coadministration of didanosine and ribavirin is contraindicated because exposures of the active metabolite of didanosine (dideoxyadenosine 5’-triphosphate) are increased. Fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis have been reported in patients receiving both didanosine and ribavirin.
# Warnings
Fatal and nonfatal pancreatitis has occurred during therapy with didanosine used alone or in combination regimens in both treatment-naive and treatment-experienced patients, regardless of degree of immunosuppression. Didanosine delayed-release capsules should be suspended in patients with signs or symptoms of pancreatitis and discontinued in patients with confirmed pancreatitis. Patients treated with didanosine delayed-release capsules in combination with stavudine may be at increased risk for pancreatitis.
When treatment with life-sustaining drugs known to cause pancreatic toxicity is required, suspension of didanosine delayed-release capsules therapy is recommended. In patients with risk factors for pancreatitis, didanosine delayed-release capsules should be used with extreme caution and only if clearly indicated. Patients with advanced HIV-1 infection, especially the elderly, are at increased risk of pancreatitis and should be followed closely. Patients with renal impairment may be at greater risk for pancreatitis if treated without dose adjustment. The frequency of pancreatitis is dose related.
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including didanosine and other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Fatal lactic acidosis has been reported in pregnant women who received the combination of didanosine and stavudine with other antiretroviral agents. The combination of didanosine and stavudine should be used with caution during pregnancy and is recommended only if the potential benefit clearly outweighs the potential risk. Particular caution should be exercised when administering didanosine delayed-release capsules to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with didanosine delayed-release capsules should be suspended in any patient who develops clinical signs or symptoms with or without laboratory findings consistent with symptomatic hyperlactatemia, lactic acidosis, or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).
The safety and efficacy of didanosine delayed-release capsules have not been established in HIV-infected patients with significant underlying liver disease. During combination antiretroviral therapy, patients with preexisting liver dysfunction, including chronic active hepatitis, have an increased frequency of liver function abnormalities, including severe and potentially fatal hepatic adverse events, and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment must be considered.
Hepatotoxicity and hepatic failure resulting in death were reported during postmarketing surveillance in HIV-infected patients treated with hydroxyurea and other antiretroviral agents. Fatal hepatic events were reported most often in patients treated with the combination of hydroxyurea, didanosine, and stavudine. This combination should be avoided.
Postmarketing cases of non-cirrhotic portal hypertension have been reported, including cases leading to liver transplantation or death. Cases of didanosine-associated non-cirrhotic portal hypertension were confirmed by liver biopsy in patients with no evidence of viral hepatitis. Onset of signs and symptoms ranged from months to years after start of didanosine therapy. Common presenting features included elevated liver enzymes, esophageal varices, hematemesis, ascites, and splenomegaly.
Patients receiving didanosine delayed-release capsules should be monitored for early signs of portal hypertension (e.g., thrombocytopenia and splenomegaly) during routine medical visits. Appropriate laboratory testing including liver enzymes, serum bilirubin, albumin, complete blood count, and international normalized ratio (INR) and ultrasonography should be considered. Didanosine delayed-release capsules should be discontinued in patients with evidence of non-cirrhotic portal hypertension.
Peripheral neuropathy, manifested by numbness, tingling, or pain in the hands or feet, has been reported in patients receiving didanosine therapy. Peripheral neuropathy has occurred more frequently in patients with advanced HIV disease, in patients with a history of neuropathy, or in patients being treated with neurotoxic drug therapy, including stavudine. Discontinuation of didanosine delayed-release capsules should be considered in patients who develop peripheral neuropathy.
Retinal changes and optic neuritis have been reported in patients taking didanosine. Periodic retinal examinations should be considered for patients receiving didanosine delayed-release capsules.
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including didanosine delayed-release capsules. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.
Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.
Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.
# 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.
Study AI454-152 was a 48-week, randomized, open-label study comparing didanosine delayed-release capsules (400 mg once daily) plus stavudine (40 mg twice daily) plus nelfinavir (750 mg three times daily) to zidovudine (300 mg) plus lamivudine (150 mg) combination tablets twice daily plus nelfinavir (750 mg three times daily) in 511 treatment-naive patients. Selected clinical adverse reactions that occurred in combination with other antiretroviral agents are provided in TABLE 3.
In clinical trials using a buffered formulation of didanosine, pancreatitis resulting in death was observed in one patient who received didanosine plus stavudine plus nelfinavir, one patient who received didanosine plus stavudine plus indinavir, and 2 of 68 patients who received didanosine plus stavudine plus indinavir plus hydroxyurea. In an early access program, pancreatitis resulting in death was observed in one patient who received didanosine delayed-release capsules plus stavudine plus hydroxyurea plus ritonavir plus indinavir plus efavirenz.
The frequency of pancreatitis is dose related. In phase 3 studies with buffered formulations of didanosine, incidence ranged from 1% to 10% with doses higher than are currently recommended and 1% to 7% with recommended dose.
Selected laboratory abnormalities that occurred in a study of didanosine delayed-release capsules in combination with other antiretroviral agents are shown in TABLE 4.
In clinical trials, 743 pediatric patients between 2 weeks and 18 years of age have been treated with didanosine. Adverse reactions and laboratory abnormalities reported to occur in these patients were generally consistent with the safety profile of didanosine in adults.
In pediatric phase 1 studies, pancreatitis occurred in 2 of 60 (3%) patients treated at entry doses below 300 mg/m2/day and in 5 of 38 (13%) patients treated at higher doses. In study ACTG 152, pancreatitis occurred in none of the 281 pediatric patients who received didanosine 120 mg/m2 every 12 hours and in less than 1% of the 274 pediatric patients who received didanosine 90 mg/m2 every 12 hours in combination with zidovudine.
Retinal changes and optic neuritis have been reported in pediatric patients.
## Postmarketing Experience
The following adverse reactions have been identified during postapproval use of didanosine. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These reactions have been chosen for inclusion due to their seriousness, frequency of reporting, causal connection to didanosine, or a combination of these factors.
- Blood and Lymphatic System Disorders - anemia, leukopenia, and thrombocytopenia.
- Body as a Whole - abdominal pain, alopecia, anaphylactoid reaction, asthenia, chills/fever, pain, and redistribution/accumulation of body fat.
- Digestive Disorders - anorexia, dyspepsia, and flatulence.
- Exocrine Gland Disorders - pancreatitis (including fatal cases), sialoadenitis, parotid gland enlargement, dry mouth, and dry eyes.
- Hepatobiliary Disorders - symptomatic hyperlactatemia/lactic acidosis and hepatic steatosis; non-cirrhotic portal hypertension; hepatitis and liver failure.
- Metabolic Disorders - diabetes mellitus, elevated serum alkaline phosphatase level, elevated serum amylase level, elevated serum gamma-glutamyltransferase level, elevated serum uric acid level, hypoglycemia, and hyperglycemia.
- Musculoskeletal Disorders - myalgia (with or without increases in creatine kinase), rhabdomyolysis including acute renal failure and hemodialysis, arthralgia, and myopathy.
- Ophthalmologic Disorders - retinal depigmentation and optic neuritis.
When didanosine is used in combination with other agents with similar toxicities, the incidence of these toxicities may be higher than when didanosine is used alone. Thus, patients treated with didanosine delayed-release capsules in combination with stavudine, with or without hydroxyurea, may be at increased risk for pancreatitis and hepatotoxicity, which may be fatal, and severe peripheral neuropathy. The combination of didanosine delayed-release capsules and hydroxyurea, with or without stavudine, should be avoided.
# Drug Interactions
Exposure to didanosine is increased when coadministered with tenofovir disoproxil fumarate. Increased exposure may cause or worsen didanosine-related clinical toxicities, including pancreatitis, symptomatic hyperlactatemia/lactic acidosis, and peripheral neuropathy. Coadministration of tenofovir disoproxil fumarate with didanosine delayed-release capsules should be undertaken with caution, and patients should be monitored closely for didanosine-related toxicities and clinical response. Didanosine delayed-release capsules should be suspended if signs or symptoms of pancreatitis, symptomatic hyperlactatemia, or lactic acidosis develop. Suppression of CD4 cell counts has been observed in patients receiving tenofovir disoproxil fumarate with didanosine at a dose of 400 mg daily.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
Reproduction studies have been performed in rats and rabbits at doses up to 12 and 14.2 times the estimated human exposure (based upon plasma levels), respectively, and have revealed no evidence of impaired fertility or harm to the fetus due to didanosine. At approximately 12 times the estimated human exposure, didanosine was slightly toxic to female rats and their pups during mid and late lactation. These rats showed reduced food intake and body weight gains but the physical and functional development of the offspring was not impaired and there were no major changes in the F2 generation. A study in rats showed that didanosine and/or its metabolites are transferred to the fetus through the placenta. Animal reproduction studies are not always predictive of human response.
There are no adequate and well-controlled studies of didanosine in pregnant women. Didanosine should be used during pregnancy only if the potential benefit justifies the potential risk.
Fatal lactic acidosis has been reported in pregnant women who received the combination of didanosine and stavudine with other antiretroviral agents. It is unclear if pregnancy augments the risk of lactic acidosis/hepatic steatosis syndrome reported in nonpregnant individuals receiving nucleoside analogues. The combination of didanosine and stavudine should be used with caution during pregnancy and is recommended only if the potential benefit clearly outweighs the potential risk. Healthcare providers caring for HIV-infected pregnant women receiving didanosine should be alert for early diagnosis of lactic acidosis/hepatic steatosis syndrome.
Pregnancy Category (AUS): B2
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Didanosine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Didanosine during labor and delivery.
### Nursing Mothers
The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. A study in rats showed that following oral administration, didanosine and/or its metabolites were excreted into the milk of lactating rats. It is not known if didanosine is excreted in human milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving didanosine.
### Pediatric Use
Use of didanosine in pediatric patients from 2 weeks of age through adolescence is supported by evidence from adequate and well-controlled studies of didanosine in adult and pediatric patients. Additional pharmacokinetic studies in pediatric patients support use of didanosine delayed-release capsules in pediatric patients who weigh at least 20 kg.
### Geriatic Use
In an Expanded Access Program using a buffered formulation of didanosine for the treatment of advanced HIV infection, patients aged 65 years and older had a higher frequency of pancreatitis (10%) than younger patients (5%). Clinical studies of didanosine, including those for didanosine delayed-release capsules, did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently than younger subjects. Didanosine 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. In addition, renal function should be monitored and dosage adjustments should be made accordingly.
### Gender
The effects of gender on didanosine pharmacokinetics have not been studied.
### Race
There is no FDA guidance on the use of Didanosine with respect to specific racial populations.
### Renal Impairment
Patients with renal impairment (creatinine clearance of less than 60 mL/min) may be at greater risk of toxicity from didanosine due to decreased drug clearance. A dose reduction is recommended for these patients.
### Hepatic Impairment
The pharmacokinetics of didanosine have been studied in 12 non-HIV-infected subjects with moderate (n = 8) to severe (n = 4) hepatic impairment (Child-Pugh Class B or C). Mean AUC and Cmax values following a single 400 mg dose of didanosine were approximately 13% and 19% higher, respectively, in patients with hepatic impairment compared to matched healthy subjects. No dose adjustment is needed, because a similar range and distribution of AUC and Cmax values was observed for subjects with hepatic impairment and matched healthy controls.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Didanosine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Didanosine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Oral
### Monitoring
There is limited information regarding Didanosine Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Didanosine and IV administrations.
# Overdosage
There is no known antidote for didanosine overdosage. In phase 1 studies, in which buffered formulations of didanosine were initially administered at doses ten times the currently recommended dose, toxicities included: pancreatitis, peripheral neuropathy, diarrhea, hyperuricemia, and hepatic dysfunction. Didanosine is not dialyzable by peritoneal dialysis, although there is some clearance by hemodialysis.
# Pharmacology
## Mechanism of Action
Didanosine is a synthetic nucleoside analogue of the naturally occurring nucleoside deoxyadenosine in which the 3’-hydroxyl group is replaced by hydrogen. Intracellularly, didanosine is converted by cellular enzymes to the active metabolite, dideoxyadenosine 5’-triphosphate. Dideoxyadenosine 5’-triphosphate inhibits the activity of HIV-1 reverse transcriptase both by competing with the natural substrate, deoxyadenosine 5’-triphosphate, and by its incorporation into viral DNA causing termination of viral DNA chain elongation.
## Structure
The chemical name for didanosine is 2' ,3' -dideoxyinosine. The structural formula is:
## Pharmacodynamics
There is limited information regarding Didanosine Pharmacodynamics in the drug label.
## Pharmacokinetics
The pharmacokinetic parameters of didanosine in HIV-infected adult and pediatric patients are summarized in TABLE 7, by weight ranges that correspond to recommended doses. Didanosine is rapidly absorbed, with peak plasma concentrations generally observed from 0.25 to 1.50 hours following oral dosing with a buffered formulation. Increases in plasma didanosine concentrations were dose proportional over the range of 50 to 400 mg. In adults, the mean (± standard deviation) oral bioavailability following single oral dosing with a buffered formulation is 42 (± 12)%. After oral administration, the urinary recovery of didanosine is approximately 18 (± 8)% of the dose. The CSF-plasma ratio following IV administration is 21 (± 0.03)%. Steady-state pharmacokinetic parameters did not differ significantly from values obtained after a single dose. Binding of didanosine to plasma proteins in vitro was low (less than 5%). Based on data from in vitro and animal studies, it is presumed that the metabolism of didanosine in man occurs by the same pathways responsible for the elimination of endogenous purines.
In didanosine delayed-release capsules, the active ingredient, didanosine, is protected against degradation by stomach acid by the use of an enteric coating on the pellets in the capsule. The enteric coating dissolves when the pellets empty into the small intestine, the site of drug absorption. With buffered formulations of didanosine, administration with antacid provides protection from degradation by stomach acid.
In healthy volunteers, as well as subjects infected with HIV-1, the AUC is equivalent for didanosine administered as the didanosine delayed-release capsules formulation relative to a buffered tablet formulation. The peak plasma concentration (Cmax) of didanosine, administered as didanosine delayed-release capsules, is reduced approximately 40% relative to didanosine buffered tablets. The time to the peak concentration (Tmax) increases from approximately 0.67 hours for didanosine buffered tablets to 2 hours for didanosine delayed-release capsules.
In the presence of food, the Cmax and AUC for didanosine delayed-release capsules were reduced by approximately 46% and 19%, respectively, compared to the fasting state. Didanosine delayed-release capsules should be taken on an empty stomach.
## Nonclinical Toxicology
The anti-HIV-1 activity of didanosine was evaluated in a variety of HIV-1 infected lymphoblastic cell lines and monocyte/macrophage cell cultures. The concentration of drug necessary to inhibit viral replication by 50% (EC50) ranged from 2.5 to 10 μM
(1 μM = 0.24 mcg/mL) in lymphoblastic cell lines and 0.01 to 0.1 μM in monocyte/macrophage cell cultures.
HIV-1 isolates with reduced sensitivity to didanosine have been selected in cell culture and were also obtained from patients treated with didanosine. Genetic analysis of isolates from didanosine-treated patients showed mutations in the reverse transcriptase gene that resulted in the amino acid substitutions K65R, L74V, and M184V. The L74V substitution was most frequently observed in clinical isolates. Phenotypic analysis of HIV-1 isolates from 60 patients (some with prior zidovudine treatment) receiving 6 to 24 months of didanosine monotherapy showed that isolates from 10 of 60 patients exhibited an average of a 10-fold decrease in susceptibility to didanosine in cell culture compared to baseline isolates. Clinical isolates that exhibited a decrease in didanosine susceptibility harbored one or more didanosine resistance-associated substitutions.
HIV-1 isolates from 2 of 39 patients receiving combination therapy for up to 2 years with didanosine and zidovudine exhibited decreased susceptibility to didanosine, lamivudine, stavudine, zalcitabine, and zidovudine in cell culture. These isolates harbored five substitutions (A62V, V75I, F77L, F116Y, and Q151M) in the reverse transcriptase gene. In data from clinical studies, the presence of thymidine analogue mutations (M41L, D67N, L210W, T215Y, K219Q) has been shown to decrease the response to didanosine.
Lifetime carcinogenicity studies were conducted in mice and rats for 22 and 24 months, respectively. In the mouse study, initial doses of 120, 800, and 1200 mg/kg/day for each sex were lowered after 8 months to 120, 210, and 210 mg/kg/day for females and 120, 300, and 600 mg/kg/day for males. The two higher doses exceeded the maximally tolerated dose in females and the high dose exceeded the maximally tolerated dose in males. The low dose in females represented 0.68-fold maximum human exposure and the intermediate dose in males represented 1.7-fold maximum human exposure based on relative AUC comparisons. In the rat study, initial doses were 100, 250, and 1000 mg/kg/day, and the high dose was lowered to 500 mg/kg/day after 18 months. The upper dose in male and female rats represented 3-fold maximum human exposure.
Didanosine induced no significant increase in neoplastic lesions in mice or rats at maximally tolerated doses.
Didanosine was positive in the following genetic toxicology assays: 1) the Escherichia coli tester strain WP2 uvrA bacterial mutagenicity assay; 2) the L5178Y/TK+/- mouse lymphoma mammalian cell gene mutation assay; 3) the in vitro chromosomal aberrations assay in cultured human peripheral lymphocytes; 4) the in vitro chromosomal aberrations assay in Chinese Hamster Lung cells; and 5) the BALB/c 3T3 in vitro transformation assay. No evidence of mutagenicity was observed in an Ames Salmonella bacterial mutagenicity assay or in rat and mouse in vivo micronucleus assays.
Evidence of a dose-limiting skeletal muscle toxicity has been observed in mice and rats (but not in dogs) following long-term (greater than 90 days) dosing with didanosine at doses that were approximately 1.2 to 12 times the estimated human exposure. The relationship of this finding to the potential of didanosine to cause myopathy in humans is unclear. However, human myopathy has been associated with administration of didanosine and other nucleoside analogues.
# Clinical Studies
Study AI454-152 was a 48-week, randomized, open-label study comparing didanosine delayed-release capsules (400 mg once daily) plus stavudine (40 mg twice daily) plus nelfinavir (750 mg three times daily) to zidovudine (300 mg) plus lamivudine (150 mg) combination tablets twice daily plus nelfinavir (750 mg three times daily) in 511 treatment-naive patients, with a mean CD4 cell count of 411 cells/mm3 (range 39 to 1105 cells/mm3) and a mean plasma HIV-1 RNA of 4.71 log10 copies/mL (range 2.8 to 5.9 log10 copies/mL) at baseline. Patients were primarily males (72%) and Caucasian (53%) with a mean age of 35 years (range 18 to 73 years). The percentages of patients with HIV-1 RNA less than 400 and less than 50 copies/mL and outcomes of patients through 48 weeks are summarized in FIGURE 1 and TABLE 13, respectively.
Efficacy in pediatric patients was demonstrated in a randomized, double-blind, controlled study (ACTG 152, conducted 1991-1995) involving 831 patients 3 months to 18 years of age treated for more than 1.5 years with zidovudine (180 mg/m2 every 6 hours), didanosine (120 mg/m2 every 12 hours), or zidovudine (120 mg/m2 every 6 hours) plus didanosine (90 mg/m2 every 12 hours). Patients treated with didanosine or didanosine plus zidovudine had lower rates of HIV-1 disease progression or death compared with those treated with zidovudine alone.
# How Supplied
- Didanosine 200 mg: Bottles of 30 capsules.
- Didanosine 250 mg: Bottles of 30 capsules.
- Didanosine 400 mg: Bottles of 30 capsules.
## Storage
Store at 20° to 25°C (68° to 77°F)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Patients should be informed that a serious toxicity of didanosine, used alone and in combination regimens, is pancreatitis, which may be fatal.
Patients should be informed that peripheral neuropathy, manifested by numbness, tingling, or pain in hands or feet, may develop during therapy with didanosine delayed-release capsules. Patients should be counseled that peripheral neuropathy occurs with greatest frequency in patients with advanced HIV-1 disease or a history of peripheral neuropathy, and discontinuation of didanosine delayed-release capsules may be required if toxicity develops.
Patients should be informed that lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including didanosine and other antiretrovirals.
Patients should be informed that hepatotoxicity including fatal hepatic adverse events were reported in patients with preexisting liver dysfunction. The safety and efficacy of didanosine delayed-release capsules has not been established in HIV-infected patients with significant underlying liver disease.
Patients should be informed that non-cirrhotic portal hypertension has been reported in patients taking didanosine delayed-release capsules, including cases leading to liver transplantation or death.
Patients should be informed that retinal changes and optic neuritis have been reported in adult and pediatric patients.
Patients should be informed that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known at this time.
Patients should be informed that when didanosine is used in combination with other agents with similar toxicities, the incidence of adverse events may be higher than when didanosine is used alone. These patients should be followed closely.
Patients should be cautioned about the use of medications or other substances, including alcohol, which may exacerbate didanosine delayed-release capsules toxicities.
Didanosine delayed-release capsules are not a cure for HIV-1 infection, and patients may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. Therefore, patients should remain under the care of a physician when using didanosine delayed-release capsules.
Patients should be advised to avoid doing things that can spread HIV-1 infection to others.
- Do not share needles or other injection equipment.
- Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.
- Do not have any kind of sex without protection. Always practice safe sex by using a latex or polyurethane condom or other barrier method to lower the chance of sexual contact with semen, vaginal secretions, or blood.
- Do not breastfeed. It is not known if didanosine can be passed to your baby in your breast milk and whether it could harm your baby. Also, mothers with HIV-1 should not breast-feed because HIV-1 can be passed to the baby in breast milk.
Patients should be instructed to swallow the capsule as a whole and to not open the capsule.
Patients should be instructed to not miss a dose but if they do, patients should take didanosine as soon as possible. Patients should be told that if it is almost time for the next dose, they should skip the missed dose and continue with the regular dosing schedule.
Patients should be instructed to contact a poison control center or emergency room right away in case of an overdose.
# Precautions with Alcohol
Alcohol-Didanosine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Videx [1]
- Videx EC
- Videx Pediatric
# Look-Alike Drug Names
There is limited information regarding Didanosine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Didanosine | |
d583f10c86b3e2db259daaaa48f5466c73a7e478 | wikidoc | Diflunisal | Diflunisal
# 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
Diflunisal is an NSAID that is FDA approved for the treatment of mild to moderate pain, osteoarthritis, and rheumatoid arthritis. There is a Black Box Warning for this drug as shown here. Common adverse reactions include edema, rash, abdominal pain, constipation, diarrhea, flatulence, dyspepsia, nausea, vomiting, dizziness, headache, insomnia, and somnolence.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Initial dose of 1000 mg followed by 500 mg every 12 hours is recommended for most patients. Following the initial dose, some patients may require 500 mg every 8 hours.
- 500 mg to 1000 mg daily in two divided doses. The dosage of diflunisal may be increased or decreased according to patient response.
- 500 mg to 1000 mg daily in two divided doses. The dosage of diflunisal may be increased or decreased according to patient response.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Diflunisal in adult patients.
### Non–Guideline-Supported Use
- Diflunisal 1000 milligrams/day.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Diflunisal in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Diflunisal in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Diflunisal in pediatric patients.
# Contraindications
- Diflunisal tablets are contraindicated in patients with known hypersensitivity to diflunisal or the excipients.
- Diflunisal tablets should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic/analphylactoid reactions to NSAIDs have been reported in such patients.
- Diflunisal tablets are contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery.
# Warnings
- Cardiovascular Thrombotic Events
- Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV events and the steps to take if they occur.
- There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID does increase the risk of serious GI events.
- Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke.
- Hypertension
- NSAIDs, including diflunisal tablets, can lead to onset of new hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including diflunisal tablets, should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy.
- Congestive Heart Failure and Edema
- Fluid retention and edema have been observed in some patients taking NSAIDs. Diflunisal tablets should be used with caution in patients with fluid retention or heart failure.
- NSAIDs, including diflunisal tablets, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients, who develop a serious upper GI adverse event on NSAID therapy, is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3 to 6 months, and in about 2 to 4% of patients treated for one year. These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk.
- NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10 fold increased risk for developing a GI bleed compared to patients with neither of these risk factors. Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore, special care should be taken in treating this population.
- To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high risk patients, alternate therapies that do not involve NSAIDs should be considered.
- Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a non-steroidal anti-inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, patients who are volume depleted, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.
- Advanced Renal Disease
- No information is available from controlled clinical studies regarding the use of diflunisal tablets in patients with advanced renal disease. Therefore, treatment with diflunisal tablets is not recommended in these patients with advanced renal disease. If diflunisal tablet therapy must be initiated, close monitoring of the patient's renal function is advisable.
- As with other NSAIDs, anaphylactic/anaphylactoid reactions may occur in patients without known prior exposure to diflunisal tablets. Diflunisal tablets should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs. Emergency help should be sought in cases where an anaphylactic/ anaphylactoid reaction occurs.
- Skin Reactions
- NSAIDs, including diflunisal tablets, can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.
- Hypersensitivity Syndrome
- A potentially life-threatening, apparent hypersensitivity syndrome has been reported. This multisystem syndrome includes constitutional symptoms (fever, chills), and cutaneous findings. It may also include involvement of major organs (changes in liver function, jaundice, leukopenia, thrombocytopenia, eosinophilia, disseminated intravascular coagulation, renal impairment, including renal failure), and less specific findings (adenitis, arthralgia, myalgia, arthritis, malaise, anorexia, disorientation). If evidence of hypersensitivity occurs, therapy with diflunisal tablets should be discontinued.
- In late pregnancy, as with other NSAIDs, diflunisal tablets should be avoided because they may cause premature closure of the ductus arteriosus.
### Precautions
- General
- Diflunisal tablets cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids.
- The pharmacological activity of diflunisal tablets in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.
- Hepatic Effects
- Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs including diflunisal tablets. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been reported.
- A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with diflunisal tablets. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), diflunisal tablets should be discontinued.
- Hematological Effects
- Anemia is sometimes seen in patients receiving NSAIDs, including diflunisal tablets. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including diflunisal tablets, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia.
- NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving diflunisal tablets who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored.
- Preexisting Asthma
- Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other non-steroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, diflunisal tablets should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma.
- Ocular Effects
- Because of reports of adverse eye findings with agents of this class, it is recommended that patients who develop eye complaints during treatment with diflunisal tablets have ophthalmologic studies.
- Reye’s Syndrome
- Acetylsalicylic acid has been associated with Reye’s syndrome. Because diflunisal is a derivative of salicylic acid, the possibility of its association with Reye’s syndrome cannot be excluded.
# Adverse Reactions
## Clinical Trials Experience
- The adverse reactions observed in controlled clinical trials encompass observations in 2,427 patients.
- Listed below are the adverse reactions reported in the 1,314 of these patients who received treatment in studies of two weeks or longer. Five hundred thirteen patients were treated for at least 24 weeks, 255 patients were treated for at least 48 weeks, and 46 patients were treated for 96 weeks. In general, the adverse reactions listed below were 2 to 14 times less frequent in the 1,113 patients who received short-term treatment for mild to moderate pain.
- Incidence Greater Than 1%
The most frequent types of adverse reactions occurring with diflunisal are gastrointestinal: these include nausea*, vomiting, dyspepsia*, gastrointestinal pain*, diarrhea*, constipation, and flatulence.
Somnolence, insomnia.
Dizziness.
Tinnitus.
Rash*.
Headache*, fatigue/tiredness.
.- Incidence between 3% and 9%. Those reactions occurring in 1% to 3% are not marked with an asterisk.
- Incidence Less Than 1 in 100
- The following adverse reactions, occurring less frequently than 1 in 100, were reported in clinical trials or since the drug was marketed. The probability exists of a causal relationship between diflunisal and these adverse reactions.
Erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria, pruritus, sweating, dry mucous membranes, stomatitis, photosensitivity.
Peptic ulcer, gastrointestinal bleeding, anorexia, eructation, gastrointestinal perforation, gastritis. Liver function abnormalities; jaundice, sometimes with fever; cholestasis; hepatitis.
Thrombocytopenia; agranulocytosis; hemolytic anemia.
Dysuria; renal impairment, including renal failure; interstitial nephritis; hematuria; proteinuria.
Nervousness, depression, hallucinations, confusion, disorientation.
Vertigo; light-headedness; paresthesias.
Transient visual disturbances including blurred vision.
Acute anaphylactic reaction with bronchospasm; angioedema; flushing. Hypersensitivity vasculitis. Hypersensitivity syndrome.
Asthenia, edema.
## Postmarketing Experience
- Other reactions have been reported in clinical trials or since the drug was marketed, but occurred under circumstances where a causal relationship could not be established. However, in these rarely reported events, that possibility cannot be excluded. Therefore, these observations are listed to serve as alerting information to physicians.
Dyspnea.
Palpitation, syncope.
Muscle cramps.
Nephrotic syndrome.
Hearing loss.
Chest pain.
- A rare occurrence of fulminant necrotizing fasciitis, particularly in association with Group A β-hemolytic streptococcus, has been described in persons treated with non-steroidal anti-inflammatory agents, including diflunisal, sometimes with fatal outcome.
# Drug Interactions
- ACE-inhibitors and Angiotensin II Anagonists
- Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors and angiotensin II antagonists. These interactions should be given consideration in patients taking NSAIDs concomitantly with ACE-inhibitors or angiotensin II antagonists. In some patients with compromised renal function, the coadministration of an NSAID and an ACE-inhibitor or an angiotensin II antagonist may result in further deterioration of renal function, including possible acute renal failure, which is usually reversible.
- Acetaminophen
- In normal volunteers, concomitant administration of diflunisal and acetaminophen resulted in an approximate 50% increase in plasma levels of acetaminophen. Acetaminophen had no effect on plasma levels of diflunisal. Since acetaminophen in high doses has been associated with hepatotoxicity, concomitant administration of diflunisal tablets and acetaminophen should be used cautiously, with careful monitoring of patients.
- Concomitant administration of diflunisal and acetaminophen in dogs, but not in rats, at approximately 2 times the recommended maximum human therapeutic dose of each (40 to 52 mg/kg/day of diflunisal/acetaminophen), resulted in greater gastrointestinal toxicity than when either drug was administered alone. The clinical significance of these findings has not been established.
- Antacids
- Concomitant administration of antacids may reduce plasma levels of diflunisal. This effect is small with occasional doses of antacids, but may be clinically significant when antacids are used on a continuous schedule.
- Aspirin
- When diflunisal is administered with aspirin, its protein binding is reduced, although the clearance of free diflunisal is not altered. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of diflunisal tablets and aspirin is not generally recommended because of the potential of increased adverse effects.
- In normal volunteers, a small decrease in diflunisal levels was observed when multiple doses of diflunisal and aspirin were administered concomitantly.
- Cyclosporine
- Administration of non-steroidal anti-inflammatory drugs concomitantly with cyclosporine has been associated with an increase in cyclosporine-induced toxicity, possibly due to decreased synthesis of renal prostacyclin. NSAIDs should be used with caution in patients taking cyclosporine, and renal function should be carefully monitored.
- Diuretics
- Clinical studies, as well as postmarketing observations, have shown that diflunisal can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis.
- In normal volunteers, concomitant administration of diflunisal and hydrochlorothiazide resulted in significantly increased plasma levels of hydrochlorothiazide. Diflunisal decreased the hyperuricemic effect of hydrochlorothiazide. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure, as well as to assure diuretic efficacy.
- Lithium
- NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity.
- Methotrexate
- NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate.
- NSAIDs
- The administration of diflunisal to normal volunteers receiving indomethacin decreased the renal clearance and significantly increased the plasma levels of indomethacin. In some patients the combined use of indomethacin and diflunisal has been associated with fatal gastrointestinal hemorrhage. Therefore, indomethacin and diflunisal tablets should not be used concomitantly.
- The concomitant use of diflunisal tablets and other NSAIDs is not recommended due to the increased possibility of gastrointestinal toxicity, with little or no increase in efficacy. The following information was obtained from studies in normal volunteers.
- Sulindac
- The concomitant administration of diflunisal and sulindac in normal volunteers resulted in lowering of the plasma levels of the active sulindac sulfide metabolite by approximately one-third.
- Naproxen
- The concomitant administration of diflunisal and naproxen in normal volunteers had no effect on the plasma levels of naproxen, but significantly decreased the urinary excretion of naproxen and its glucuronide metabolite. Naproxen had no effect on plasma levels of diflunisal.
- Oral Anticoagulants
- In some normal volunteers, the concomitant administration of diflunisal and warfarin, acenocoumarol, or phenprocoumon resulted in prolongation of prothrombin time. This may occur because diflunisal competitively displaces coumarins from protein binding sites. Accordingly, when diflunisal tablets are administered with oral anticoagulants, the prothrombin time should be closely monitored during and for several days after concomitant drug administration. Adjustment of dosage of oral anticoagulants may be required. The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone.
- Tolbutamide
- In diabetic patients receiving diflunisal and tolbutamide, no significant effects were seen on tolbutamide plasma levels or fasting blood glucose.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- A dose of 60 mg/kg/day of diflunisal (equivalent to two times the maximum human dose) was maternotoxic, embryotoxic, and teratogenic in rabbits. In three of six studies in rabbits, evidence of teratogenicity was observed at doses ranging from 40 to 50 mg/kg/day. Teratology studies in mice, at doses up to 45 mg/kg/day, and in rats at doses up to 100 mg/kg/day, revealed no harm to the fetus due to diflunisal. Aspirin and other salicylates have been shown to be teratogenic in a wide variety of species, including the rat and rabbit, at doses ranging from 50 to 400 mg/kg/day (approximately one to eight times the human dose). Animal reproduction studies are not always predictive of human response. There are no adequate and well controlled studies with diflunisal in pregnant women. Diflunisal tablets should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Nonteratogenic Effects
- Because of the known effects of non-steroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be avoided.
- The known effects of drugs of this class on the human fetus during the third trimester of pregnancy include: constriction of the ductus arteriosus prenatally, tricuspid incompetence, and pulmonary hypertension; non-closure of the ductus arteriosus postnatally which may be resistant to medical management; myocardial degenerative changes, platelet dysfunction with resultant bleeding, intracranial bleeding, renal dysfunction or failure, renal injury/dysgenesis which may result in prolonged or permanent renal failure, oligohydramnios, gastrointestinal bleeding or perforation, and increased risk of necrotizing enterocolitis.
- In rats at a dose of one and one-half times the maximum human dose, there was an increase in the average length of gestation. Similar increases in the length of gestation have been observed with aspirin, indomethacin, and phenylbutazone, and may be related to inhibition of prostaglandin synthetase.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Diflunisal in women who are pregnant.
### Labor and Delivery
- In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. The effects of diflunisal tablets on labor and delivery in pregnant women are unknown.
### Nursing Mothers
- Diflunisal is excreted in human milk in concentrations of 2 to 7% of those in plasma. Because of the potential for serious adverse reactions in nursing infants from diflunisal, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
- Safety and effectiveness of diflunisal in pediatric patients below the age of 12 have not been established. Use of diflunisal tablets in pediatric patients below the age of 12 is not recommended.
- The adverse effects observed following diflunisal administration to neonatal animals appear to be species, age, and dose-dependent. At dose levels approximately 3 times the usual human therapeutic dose, both aspirin (200 to 400 mg/kg/day) and diflunisal (80 mg/kg/day) resulted in death, leukocytosis, weight loss, and bilateral cataracts in neonatal (4 to 5-day-old) beagle puppies after 2 to 10 doses. Administration of an 80 mg/kg/day dose of diflunisal to 25-day-old puppies resulted in lower mortality, and did not produce cataracts. In newborn rats, a 400 mg/kg/day dose of aspirin resulted in increased mortality and some cataracts, whereas the effects of diflunisal administration at doses up to 140 mg/kg/day were limited to a decrease in average body weight gain.
### Geriatic Use
- As with any NSAID, caution should be exercised in treating the elderly (65 years and older) since advancing age appears to increase the possibility of adverse reactions. Elderly patients seem to tolerate ulceration or bleeding less well than other individuals and many spontaneous reports of fatal GI events are in this population.
- 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 Diflunisal with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Diflunisal with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Diflunisal in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Diflunisal in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Diflunisal in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Diflunisal in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Diflunisal in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Diflunisal in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Cases of overdosage have occurred and deaths have been reported. Most patients recovered without evidence of permanent sequelae. The most common signs and symptoms observed with overdosage were drowsiness, vomiting, nausea, diarrhea, hyperventilation, tachycardia, sweating, tinnitus, disorientation, stupor, and coma. Diminished urine output and cardiorespiratory arrest have also been reported. The lowest dosage of diflunisal at which a death has been reported was 15 grams without the presence of other drugs. In a mixed drug overdose, ingestion of 7.5 grams of diflunisal resulted in death.
### Management
- In the event of overdosage, the stomach should be emptied by inducing vomiting or by gastric lavage, and the patient carefully observed and given symptomatic and supportive treatment. Because of the high degree of protein binding, hemodialysis may not be effective.
- The oral LD50 of the drug is 500 mg/kg and 826 mg/kg in female mice and female rats, respectively.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Diflunisal in the drug label.
# Pharmacology
## Mechanism of Action
- Diflunisal is a non-steroidal drug with analgesic, anti-inflammatory and antipyretic properties. It is a peripherally-acting non-narcotic analgesic drug. Habituation, tolerance, and addiction have not been reported.
- Diflunisal is a difluorophenyl derivative of salicylic acid. Chemically, diflunisal differs from aspirin (acetylsalicylic acid) in two respects. The first of these two is the presence of a difluorophenyl substituent at carbon 1. The second difference is the removal of the O-acetyl group from the carbon 4 position. Diflunisal is not metabolized to salicylic acid, and the fluorine atoms are not displaced from the difluorophenyl ring structure.
- The precise mechanism of the analgesic and anti-inflammatory actions of diflunisal is not known. Diflunisal is a prostaglandin synthetase inhibitor. In animals, prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain. Since prostaglandins are known to be among the mediators of pain and inflammation, the mode of action of diflunisal may be due to a decrease of prostaglandins in peripheral tissues.
## Structure
- Diflunisal is 2',4'-difluoro-4-hydroxy-3-biphenylcarboxylic acid. Its structural formula is:
- Chemical structure for diflunisal
- C13H8F2O3 M.W. 250.20
- Diflunisal is a stable, white, crystalline compound with a melting point of 211° to 213°C. It is practically insoluble in water at neutral or acidic pH. Because it is an organic acid, it dissolves readily in dilute alkali to give a moderately stable solution at room temperature. It is soluble in most organic solvents including ethanol, methanol, and acetone.
- Each tablet, for oral administration, contains 500 mg diflunisal. In addition, each tablet contains the following inactive ingredients: croscarmellose sodium, FD&C Blue #2 aluminum lake, hypromellose, microcrystalline cellulose, pregelatinized starch, propylene glycol, sodium stearyl fumarate, and titanium dioxide.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Diflunisal in the drug label.
## Pharmacokinetics
- Diflunisal is rapidly and completely absorbed following oral administration with peak plasma concentrations occurring between 2 to 3 hours. The drug is excreted in the urine as two soluble glucuronide conjugates accounting for about 90% of the administered dose. Little or no diflunisal is excreted in the feces. Diflunisal appears in human milk in concentrations of 2 to 7% of those in plasma. More than 99% of diflunisal in plasma is bound to proteins.
- As is the case with salicylic acid, concentration-dependent pharmacokinetics prevail when diflunisal is administered; a doubling of dosage produces a greater than doubling of drug accumulation. The effect becomes more apparent with repetitive doses. Following single doses, peak plasma concentrations of 41 ± 11 mcg/mL (mean ± S.D.) were observed following 250 mg doses, 87 ± 17 mcg/mL were observed following 500 mg and 124 ± 11 mcg/mL following single 1000 mg doses. However, following administration of 250 mg b.i.d., a mean peak level of 56 ± 14 mcg/mL was observed on day 8, while the mean peak level after 500 mg b.i.d. for 11 days was 190 ± 33 mcg/mL. In contrast to salicylic acid which has a plasma half-life of 2 1/2 hours, the plasma half-life of diflunisal is 3 to 4 times longer (8 to 12 hours), because of a difluorophenyl substituent at carbon 1. Because of its long half-life and nonlinear pharmacokinetics, several days are required for diflunisal plasma levels to reach steady state following multiple doses. For this reason, an initial loading dose is necessary to shorten the time to reach steady-state levels, and 2 to 3 days of observation are necessary for evaluating changes in treatment regimens if a loading dose is not used.
- Studies in baboons to determine passage across the blood-brain barrier have shown that only small quantities of diflunisal, under normal or acidotic conditions are transported into the cerebrospinal fluid (CSF). The ratio of blood/CSF concentrations after intravenous doses of 50 mg/kg or oral doses of 100 mg/kg of diflunisal was 100:1. In contrast, oral doses of 500 mg/kg of aspirin resulted in a blood/CSF ratio of 5:1.
## Nonclinical Toxicology
- Diflunisal did not affect the type or incidence of neoplasia in a 105 week study in the rat given doses up to 40 mg/kg/day (equivalent to approximately 1.3 times the maximum recommended human dose), or in long-term carcinogenic studies in mice given diflunisal at doses up to 80 mg/kg/day (equivalent to approximately 2.7 times the maximum recommended human dose). It was concluded that there was no carcinogenic potential for diflunisal.
- Diflunisal passes the placental barrier to a minor degree in the rat. Diflunisal had no mutagenic activity after oral administration in the dominant lethal assay, in the Ames microbial mutagen test or in the V-79 Chinese hamster lung cell assay.
- No evidence of impaired fertility was found in reproduction studies in rats at doses up to 50 mg/kg/day.
# Clinical Studies
There is limited information regarding Clinical Studies of Diflunisal in the drug label.
# How Supplied
- Diflunisal tablets USP are supplied as follows:
- 500 mg tablets: blue, unscored, oblong, film-coated tablets, debossed "755"-"93". Packaged in bottles of 100, 500 and unit of use 60's.
- Dispense in a well-closed container as defined in the USP, with a child-resistant closure (as required).
- Keep tightly closed.
- Store at 20° to 25°C (68° to 77°F).
## Storage
There is limited information regarding Diflunisal Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed.
- Diflunisal tablets, like other NSAIDs, may cause serious CV side effects, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be apprised of the importance of this follow-up.
- Diflunisal tablets, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative signs or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up.
- Diflunisal tablets, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalization and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible.
- Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians.
- Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical therapy.
- Patients should be informed of the signs of an anaphylactic/anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help.
- In late pregnancy, as with other NSAIDs, diflunisal tablets should be avoided because they may cause premature closure of the ductus arteriosus.
# Precautions with Alcohol
- Alcohol-Diflunisal interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- DIFLUNISAL®
# Look-Alike Drug Names
There is limited information regarding Diflunisal Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Diflunisal
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
Diflunisal is an NSAID that is FDA approved for the treatment of mild to moderate pain, osteoarthritis, and rheumatoid arthritis. There is a Black Box Warning for this drug as shown here. Common adverse reactions include edema, rash, abdominal pain, constipation, diarrhea, flatulence, dyspepsia, nausea, vomiting, dizziness, headache, insomnia, and somnolence.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Initial dose of 1000 mg followed by 500 mg every 12 hours is recommended for most patients. Following the initial dose, some patients may require 500 mg every 8 hours.
- 500 mg to 1000 mg daily in two divided doses. The dosage of diflunisal may be increased or decreased according to patient response.
- 500 mg to 1000 mg daily in two divided doses. The dosage of diflunisal may be increased or decreased according to patient response.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Diflunisal in adult patients.
### Non–Guideline-Supported Use
- Diflunisal 1000 milligrams/day.[1]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Diflunisal in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Diflunisal in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Diflunisal in pediatric patients.
# Contraindications
- Diflunisal tablets are contraindicated in patients with known hypersensitivity to diflunisal or the excipients.
- Diflunisal tablets should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic/analphylactoid reactions to NSAIDs have been reported in such patients.
- Diflunisal tablets are contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery.
# Warnings
- Cardiovascular Thrombotic Events
- Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV events and the steps to take if they occur.
- There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID does increase the risk of serious GI events.
- Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke.
- Hypertension
- NSAIDs, including diflunisal tablets, can lead to onset of new hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including diflunisal tablets, should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy.
- Congestive Heart Failure and Edema
- Fluid retention and edema have been observed in some patients taking NSAIDs. Diflunisal tablets should be used with caution in patients with fluid retention or heart failure.
- NSAIDs, including diflunisal tablets, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients, who develop a serious upper GI adverse event on NSAID therapy, is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3 to 6 months, and in about 2 to 4% of patients treated for one year. These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk.
- NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10 fold increased risk for developing a GI bleed compared to patients with neither of these risk factors. Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore, special care should be taken in treating this population.
- To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high risk patients, alternate therapies that do not involve NSAIDs should be considered.
- Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a non-steroidal anti-inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, patients who are volume depleted, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.
- Advanced Renal Disease
- No information is available from controlled clinical studies regarding the use of diflunisal tablets in patients with advanced renal disease. Therefore, treatment with diflunisal tablets is not recommended in these patients with advanced renal disease. If diflunisal tablet therapy must be initiated, close monitoring of the patient's renal function is advisable.
- As with other NSAIDs, anaphylactic/anaphylactoid reactions may occur in patients without known prior exposure to diflunisal tablets. Diflunisal tablets should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs. Emergency help should be sought in cases where an anaphylactic/ anaphylactoid reaction occurs.
- Skin Reactions
- NSAIDs, including diflunisal tablets, can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.
- Hypersensitivity Syndrome
- A potentially life-threatening, apparent hypersensitivity syndrome has been reported. This multisystem syndrome includes constitutional symptoms (fever, chills), and cutaneous findings. It may also include involvement of major organs (changes in liver function, jaundice, leukopenia, thrombocytopenia, eosinophilia, disseminated intravascular coagulation, renal impairment, including renal failure), and less specific findings (adenitis, arthralgia, myalgia, arthritis, malaise, anorexia, disorientation). If evidence of hypersensitivity occurs, therapy with diflunisal tablets should be discontinued.
- In late pregnancy, as with other NSAIDs, diflunisal tablets should be avoided because they may cause premature closure of the ductus arteriosus.
### Precautions
- General
- Diflunisal tablets cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids.
- The pharmacological activity of diflunisal tablets in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.
- Hepatic Effects
- Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs including diflunisal tablets. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been reported.
- A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with diflunisal tablets. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), diflunisal tablets should be discontinued.
- Hematological Effects
- Anemia is sometimes seen in patients receiving NSAIDs, including diflunisal tablets. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including diflunisal tablets, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia.
- NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving diflunisal tablets who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored.
- Preexisting Asthma
- Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other non-steroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, diflunisal tablets should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma.
- Ocular Effects
- Because of reports of adverse eye findings with agents of this class, it is recommended that patients who develop eye complaints during treatment with diflunisal tablets have ophthalmologic studies.
- Reye’s Syndrome
- Acetylsalicylic acid has been associated with Reye’s syndrome. Because diflunisal is a derivative of salicylic acid, the possibility of its association with Reye’s syndrome cannot be excluded.
# Adverse Reactions
## Clinical Trials Experience
- The adverse reactions observed in controlled clinical trials encompass observations in 2,427 patients.
- Listed below are the adverse reactions reported in the 1,314 of these patients who received treatment in studies of two weeks or longer. Five hundred thirteen patients were treated for at least 24 weeks, 255 patients were treated for at least 48 weeks, and 46 patients were treated for 96 weeks. In general, the adverse reactions listed below were 2 to 14 times less frequent in the 1,113 patients who received short-term treatment for mild to moderate pain.
- Incidence Greater Than 1%
The most frequent types of adverse reactions occurring with diflunisal are gastrointestinal: these include nausea*, vomiting, dyspepsia*, gastrointestinal pain*, diarrhea*, constipation, and flatulence.
Somnolence, insomnia.
Dizziness.
Tinnitus.
Rash*.
Headache*, fatigue/tiredness.
.* Incidence between 3% and 9%. Those reactions occurring in 1% to 3% are not marked with an asterisk.
- Incidence Less Than 1 in 100
- The following adverse reactions, occurring less frequently than 1 in 100, were reported in clinical trials or since the drug was marketed. The probability exists of a causal relationship between diflunisal and these adverse reactions.
Erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria, pruritus, sweating, dry mucous membranes, stomatitis, photosensitivity.
Peptic ulcer, gastrointestinal bleeding, anorexia, eructation, gastrointestinal perforation, gastritis. Liver function abnormalities; jaundice, sometimes with fever; cholestasis; hepatitis.
Thrombocytopenia; agranulocytosis; hemolytic anemia.
Dysuria; renal impairment, including renal failure; interstitial nephritis; hematuria; proteinuria.
Nervousness, depression, hallucinations, confusion, disorientation.
Vertigo; light-headedness; paresthesias.
Transient visual disturbances including blurred vision.
Acute anaphylactic reaction with bronchospasm; angioedema; flushing. Hypersensitivity vasculitis. Hypersensitivity syndrome.
Asthenia, edema.
## Postmarketing Experience
- Other reactions have been reported in clinical trials or since the drug was marketed, but occurred under circumstances where a causal relationship could not be established. However, in these rarely reported events, that possibility cannot be excluded. Therefore, these observations are listed to serve as alerting information to physicians.
Dyspnea.
Palpitation, syncope.
Muscle cramps.
Nephrotic syndrome.
Hearing loss.
Chest pain.
- A rare occurrence of fulminant necrotizing fasciitis, particularly in association with Group A β-hemolytic streptococcus, has been described in persons treated with non-steroidal anti-inflammatory agents, including diflunisal, sometimes with fatal outcome.
# Drug Interactions
- ACE-inhibitors and Angiotensin II Anagonists
- Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors and angiotensin II antagonists. These interactions should be given consideration in patients taking NSAIDs concomitantly with ACE-inhibitors or angiotensin II antagonists. In some patients with compromised renal function, the coadministration of an NSAID and an ACE-inhibitor or an angiotensin II antagonist may result in further deterioration of renal function, including possible acute renal failure, which is usually reversible.
- Acetaminophen
- In normal volunteers, concomitant administration of diflunisal and acetaminophen resulted in an approximate 50% increase in plasma levels of acetaminophen. Acetaminophen had no effect on plasma levels of diflunisal. Since acetaminophen in high doses has been associated with hepatotoxicity, concomitant administration of diflunisal tablets and acetaminophen should be used cautiously, with careful monitoring of patients.
- Concomitant administration of diflunisal and acetaminophen in dogs, but not in rats, at approximately 2 times the recommended maximum human therapeutic dose of each (40 to 52 mg/kg/day of diflunisal/acetaminophen), resulted in greater gastrointestinal toxicity than when either drug was administered alone. The clinical significance of these findings has not been established.
- Antacids
- Concomitant administration of antacids may reduce plasma levels of diflunisal. This effect is small with occasional doses of antacids, but may be clinically significant when antacids are used on a continuous schedule.
- Aspirin
- When diflunisal is administered with aspirin, its protein binding is reduced, although the clearance of free diflunisal is not altered. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of diflunisal tablets and aspirin is not generally recommended because of the potential of increased adverse effects.
- In normal volunteers, a small decrease in diflunisal levels was observed when multiple doses of diflunisal and aspirin were administered concomitantly.
- Cyclosporine
- Administration of non-steroidal anti-inflammatory drugs concomitantly with cyclosporine has been associated with an increase in cyclosporine-induced toxicity, possibly due to decreased synthesis of renal prostacyclin. NSAIDs should be used with caution in patients taking cyclosporine, and renal function should be carefully monitored.
- Diuretics
- Clinical studies, as well as postmarketing observations, have shown that diflunisal can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis.
- In normal volunteers, concomitant administration of diflunisal and hydrochlorothiazide resulted in significantly increased plasma levels of hydrochlorothiazide. Diflunisal decreased the hyperuricemic effect of hydrochlorothiazide. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure, as well as to assure diuretic efficacy.
- Lithium
- NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity.
- Methotrexate
- NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate.
- NSAIDs
- The administration of diflunisal to normal volunteers receiving indomethacin decreased the renal clearance and significantly increased the plasma levels of indomethacin. In some patients the combined use of indomethacin and diflunisal has been associated with fatal gastrointestinal hemorrhage. Therefore, indomethacin and diflunisal tablets should not be used concomitantly.
- The concomitant use of diflunisal tablets and other NSAIDs is not recommended due to the increased possibility of gastrointestinal toxicity, with little or no increase in efficacy. The following information was obtained from studies in normal volunteers.
- Sulindac
- The concomitant administration of diflunisal and sulindac in normal volunteers resulted in lowering of the plasma levels of the active sulindac sulfide metabolite by approximately one-third.
- Naproxen
- The concomitant administration of diflunisal and naproxen in normal volunteers had no effect on the plasma levels of naproxen, but significantly decreased the urinary excretion of naproxen and its glucuronide metabolite. Naproxen had no effect on plasma levels of diflunisal.
- Oral Anticoagulants
- In some normal volunteers, the concomitant administration of diflunisal and warfarin, acenocoumarol, or phenprocoumon resulted in prolongation of prothrombin time. This may occur because diflunisal competitively displaces coumarins from protein binding sites. Accordingly, when diflunisal tablets are administered with oral anticoagulants, the prothrombin time should be closely monitored during and for several days after concomitant drug administration. Adjustment of dosage of oral anticoagulants may be required. The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone.
- Tolbutamide
- In diabetic patients receiving diflunisal and tolbutamide, no significant effects were seen on tolbutamide plasma levels or fasting blood glucose.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- A dose of 60 mg/kg/day of diflunisal (equivalent to two times the maximum human dose) was maternotoxic, embryotoxic, and teratogenic in rabbits. In three of six studies in rabbits, evidence of teratogenicity was observed at doses ranging from 40 to 50 mg/kg/day. Teratology studies in mice, at doses up to 45 mg/kg/day, and in rats at doses up to 100 mg/kg/day, revealed no harm to the fetus due to diflunisal. Aspirin and other salicylates have been shown to be teratogenic in a wide variety of species, including the rat and rabbit, at doses ranging from 50 to 400 mg/kg/day (approximately one to eight times the human dose). Animal reproduction studies are not always predictive of human response. There are no adequate and well controlled studies with diflunisal in pregnant women. Diflunisal tablets should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Nonteratogenic Effects
- Because of the known effects of non-steroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be avoided.
- The known effects of drugs of this class on the human fetus during the third trimester of pregnancy include: constriction of the ductus arteriosus prenatally, tricuspid incompetence, and pulmonary hypertension; non-closure of the ductus arteriosus postnatally which may be resistant to medical management; myocardial degenerative changes, platelet dysfunction with resultant bleeding, intracranial bleeding, renal dysfunction or failure, renal injury/dysgenesis which may result in prolonged or permanent renal failure, oligohydramnios, gastrointestinal bleeding or perforation, and increased risk of necrotizing enterocolitis.
- In rats at a dose of one and one-half times the maximum human dose, there was an increase in the average length of gestation. Similar increases in the length of gestation have been observed with aspirin, indomethacin, and phenylbutazone, and may be related to inhibition of prostaglandin synthetase.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Diflunisal in women who are pregnant.
### Labor and Delivery
- In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. The effects of diflunisal tablets on labor and delivery in pregnant women are unknown.
### Nursing Mothers
- Diflunisal is excreted in human milk in concentrations of 2 to 7% of those in plasma. Because of the potential for serious adverse reactions in nursing infants from diflunisal, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
- Safety and effectiveness of diflunisal in pediatric patients below the age of 12 have not been established. Use of diflunisal tablets in pediatric patients below the age of 12 is not recommended.
- The adverse effects observed following diflunisal administration to neonatal animals appear to be species, age, and dose-dependent. At dose levels approximately 3 times the usual human therapeutic dose, both aspirin (200 to 400 mg/kg/day) and diflunisal (80 mg/kg/day) resulted in death, leukocytosis, weight loss, and bilateral cataracts in neonatal (4 to 5-day-old) beagle puppies after 2 to 10 doses. Administration of an 80 mg/kg/day dose of diflunisal to 25-day-old puppies resulted in lower mortality, and did not produce cataracts. In newborn rats, a 400 mg/kg/day dose of aspirin resulted in increased mortality and some cataracts, whereas the effects of diflunisal administration at doses up to 140 mg/kg/day were limited to a decrease in average body weight gain.
### Geriatic Use
- As with any NSAID, caution should be exercised in treating the elderly (65 years and older) since advancing age appears to increase the possibility of adverse reactions. Elderly patients seem to tolerate ulceration or bleeding less well than other individuals and many spontaneous reports of fatal GI events are in this population.
- 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 Diflunisal with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Diflunisal with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Diflunisal in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Diflunisal in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Diflunisal in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Diflunisal in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Diflunisal in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Diflunisal in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Cases of overdosage have occurred and deaths have been reported. Most patients recovered without evidence of permanent sequelae. The most common signs and symptoms observed with overdosage were drowsiness, vomiting, nausea, diarrhea, hyperventilation, tachycardia, sweating, tinnitus, disorientation, stupor, and coma. Diminished urine output and cardiorespiratory arrest have also been reported. The lowest dosage of diflunisal at which a death has been reported was 15 grams without the presence of other drugs. In a mixed drug overdose, ingestion of 7.5 grams of diflunisal resulted in death.
### Management
- In the event of overdosage, the stomach should be emptied by inducing vomiting or by gastric lavage, and the patient carefully observed and given symptomatic and supportive treatment. Because of the high degree of protein binding, hemodialysis may not be effective.
- The oral LD50 of the drug is 500 mg/kg and 826 mg/kg in female mice and female rats, respectively.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Diflunisal in the drug label.
# Pharmacology
## Mechanism of Action
- Diflunisal is a non-steroidal drug with analgesic, anti-inflammatory and antipyretic properties. It is a peripherally-acting non-narcotic analgesic drug. Habituation, tolerance, and addiction have not been reported.
- Diflunisal is a difluorophenyl derivative of salicylic acid. Chemically, diflunisal differs from aspirin (acetylsalicylic acid) in two respects. The first of these two is the presence of a difluorophenyl substituent at carbon 1. The second difference is the removal of the O-acetyl group from the carbon 4 position. Diflunisal is not metabolized to salicylic acid, and the fluorine atoms are not displaced from the difluorophenyl ring structure.
- The precise mechanism of the analgesic and anti-inflammatory actions of diflunisal is not known. Diflunisal is a prostaglandin synthetase inhibitor. In animals, prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain. Since prostaglandins are known to be among the mediators of pain and inflammation, the mode of action of diflunisal may be due to a decrease of prostaglandins in peripheral tissues.
## Structure
- Diflunisal is 2',4'-difluoro-4-hydroxy-3-biphenylcarboxylic acid. Its structural formula is:
- Chemical structure for diflunisal
- C13H8F2O3 M.W. 250.20
- Diflunisal is a stable, white, crystalline compound with a melting point of 211° to 213°C. It is practically insoluble in water at neutral or acidic pH. Because it is an organic acid, it dissolves readily in dilute alkali to give a moderately stable solution at room temperature. It is soluble in most organic solvents including ethanol, methanol, and acetone.
- Each tablet, for oral administration, contains 500 mg diflunisal. In addition, each tablet contains the following inactive ingredients: croscarmellose sodium, FD&C Blue #2 aluminum lake, hypromellose, microcrystalline cellulose, pregelatinized starch, propylene glycol, sodium stearyl fumarate, and titanium dioxide.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Diflunisal in the drug label.
## Pharmacokinetics
- Diflunisal is rapidly and completely absorbed following oral administration with peak plasma concentrations occurring between 2 to 3 hours. The drug is excreted in the urine as two soluble glucuronide conjugates accounting for about 90% of the administered dose. Little or no diflunisal is excreted in the feces. Diflunisal appears in human milk in concentrations of 2 to 7% of those in plasma. More than 99% of diflunisal in plasma is bound to proteins.
- As is the case with salicylic acid, concentration-dependent pharmacokinetics prevail when diflunisal is administered; a doubling of dosage produces a greater than doubling of drug accumulation. The effect becomes more apparent with repetitive doses. Following single doses, peak plasma concentrations of 41 ± 11 mcg/mL (mean ± S.D.) were observed following 250 mg doses, 87 ± 17 mcg/mL were observed following 500 mg and 124 ± 11 mcg/mL following single 1000 mg doses. However, following administration of 250 mg b.i.d., a mean peak level of 56 ± 14 mcg/mL was observed on day 8, while the mean peak level after 500 mg b.i.d. for 11 days was 190 ± 33 mcg/mL. In contrast to salicylic acid which has a plasma half-life of 2 1/2 hours, the plasma half-life of diflunisal is 3 to 4 times longer (8 to 12 hours), because of a difluorophenyl substituent at carbon 1. Because of its long half-life and nonlinear pharmacokinetics, several days are required for diflunisal plasma levels to reach steady state following multiple doses. For this reason, an initial loading dose is necessary to shorten the time to reach steady-state levels, and 2 to 3 days of observation are necessary for evaluating changes in treatment regimens if a loading dose is not used.
- Studies in baboons to determine passage across the blood-brain barrier have shown that only small quantities of diflunisal, under normal or acidotic conditions are transported into the cerebrospinal fluid (CSF). The ratio of blood/CSF concentrations after intravenous doses of 50 mg/kg or oral doses of 100 mg/kg of diflunisal was 100:1. In contrast, oral doses of 500 mg/kg of aspirin resulted in a blood/CSF ratio of 5:1.
## Nonclinical Toxicology
- Diflunisal did not affect the type or incidence of neoplasia in a 105 week study in the rat given doses up to 40 mg/kg/day (equivalent to approximately 1.3 times the maximum recommended human dose), or in long-term carcinogenic studies in mice given diflunisal at doses up to 80 mg/kg/day (equivalent to approximately 2.7 times the maximum recommended human dose). It was concluded that there was no carcinogenic potential for diflunisal.
- Diflunisal passes the placental barrier to a minor degree in the rat. Diflunisal had no mutagenic activity after oral administration in the dominant lethal assay, in the Ames microbial mutagen test or in the V-79 Chinese hamster lung cell assay.
- No evidence of impaired fertility was found in reproduction studies in rats at doses up to 50 mg/kg/day.
# Clinical Studies
There is limited information regarding Clinical Studies of Diflunisal in the drug label.
# How Supplied
- Diflunisal tablets USP are supplied as follows:
- 500 mg tablets: blue, unscored, oblong, film-coated tablets, debossed "755"-"93". Packaged in bottles of 100, 500 and unit of use 60's.
- Dispense in a well-closed container as defined in the USP, with a child-resistant closure (as required).
- Keep tightly closed.
- Store at 20° to 25°C (68° to 77°F).
## Storage
There is limited information regarding Diflunisal Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed.
- Diflunisal tablets, like other NSAIDs, may cause serious CV side effects, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be apprised of the importance of this follow-up.
- Diflunisal tablets, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative signs or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up.
- Diflunisal tablets, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalization and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible.
- Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians.
- Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical therapy.
- Patients should be informed of the signs of an anaphylactic/anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help.
- In late pregnancy, as with other NSAIDs, diflunisal tablets should be avoided because they may cause premature closure of the ductus arteriosus.
# Precautions with Alcohol
- Alcohol-Diflunisal interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- DIFLUNISAL®[2]
# Look-Alike Drug Names
There is limited information regarding Diflunisal Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Diflunisal | |
2812ac3429010c327dc6dfbd4c2cb36b9203ce2b | wikidoc | Dioxygenyl | Dioxygenyl
The dioxygenyl ion, O2+, is a rarely-encountered oxycation in which both oxygen atoms have an oxidation state of +½. It is formally derived from oxygen by the removal of an electron:
The energy change for this process is called the ionization energy of the oxygen molecule. Relative to most molecules, this ionization energy is very high at 1165 kJ/mol.
# Structure and molecular properties
O2+ has a bond order of 2.5, and a bond length of 112.3 pm. It has the same number of valence electrons as nitric oxide. The bond energy is 625.1 kJ mol−1 and stretching frequency of 1858 cm−1, both of which are high relative to most molecules.
# Compounds
## Dioxygenyl hexafluoroplatinate
The reaction of dioxygen, O2, with platinum hexafluoride, PtF6, yields dioxygenyl hexafluoroplatinate, O2:
PtF6 is one of the few oxidising agents sufficiently powerful to oxidise O2.
Dioxygenyl hexafluoroplatinate played a pivotal role in the discovery of noble gas compounds. After Neil Bartlett found that PtF6 could oxidise O2 to O2+, he investigated its reaction with noble gases and discovered "xenon hexafluoroplatinate. "
## Other compounds
O2+ is also found in the similar compound O2, dioxygenyl hexafluoroarsenate. | Dioxygenyl
The dioxygenyl ion, O2+, is a rarely-encountered oxycation in which both oxygen atoms have an oxidation state of +½. It is formally derived from oxygen by the removal of an electron:
The energy change for this process is called the ionization energy of the oxygen molecule. Relative to most molecules, this ionization energy is very high at 1165 kJ/mol.
# Structure and molecular properties
O2+ has a bond order of 2.5, and a bond length of 112.3 pm. It has the same number of valence electrons as nitric oxide. The bond energy is 625.1 kJ mol−1 and stretching frequency of 1858 cm−1, both of which are high relative to most molecules.
# Compounds
## Dioxygenyl hexafluoroplatinate
The reaction of dioxygen, O2, with platinum hexafluoride, PtF6, yields dioxygenyl hexafluoroplatinate, O2[PtF6]:
PtF6 is one of the few oxidising agents sufficiently powerful to oxidise O2.
Dioxygenyl hexafluoroplatinate played a pivotal role in the discovery of noble gas compounds. After Neil Bartlett found that PtF6 could oxidise O2 to O2+, he investigated its reaction with noble gases and discovered "xenon hexafluoroplatinate. "
## Other compounds
O2+ is also found in the similar compound O2[AsF6], dioxygenyl hexafluoroarsenate.
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Dioxygenyl | |
6bd4e0434a7069e093548a8428d4d82f62bd76c6 | wikidoc | Dipipanone | Dipipanone
Dipipanone hydrochloride is an opioid painkiller. In combination with cyclizine hydrochloride, it is marketed as Diconal, indicated for relief of moderate to severe pain.
Chemically, dipipanone belongs to the class of opiates called the 3-diphenyl heptanones. It closely resembles methadone, the only structural difference being the N,N-dimethyl moiety of methadone being replaced with a piperidine ring. It's usage is now officially discouraged because of the abuse risk. The combination with cyclizine lends a very strong rush if the drug is injected. During the late 1970s to early 1980s in the UK, a whole spate of deaths were blamed on this preparation.
As supplies became unavailable, opiate users would mix crushed methadone tablets with crushed Valoid (a cyclizine containing antihistamine) tablets in an attempt to replecate the affect of dipipanone.
See P. A. J. Janssen, Synthetic Analgesics. Part 1. Diphenylpropylamines, Pergamon Press, NY. for details on the synthesis of methadone and its cogeners before 1960. The general procedure for synthesis is illustrated by nucleophillic attack of diphenylacetonitrile on 2-chloro--1-dimethylaminoethane. The resulting aminonitrile is then converted to the ethyl ketone with ethyl magnesium bromide by way of the kitimine which is hydrolized by cold aqueous acid (Casey & Parfitt, Opioid Analgesics, Plenum Press, NY, london). | Dipipanone
Dipipanone hydrochloride is an opioid painkiller. In combination with cyclizine hydrochloride, it is marketed as Diconal, indicated for relief of moderate to severe pain.
Chemically, dipipanone belongs to the class of opiates called the 3-diphenyl heptanones. It closely resembles methadone, the only structural difference being the N,N-dimethyl moiety of methadone being replaced with a piperidine ring. It's usage is now officially discouraged because of the abuse risk. The combination with cyclizine lends a very strong rush if the drug is injected. During the late 1970s to early 1980s in the UK, a whole spate of deaths were blamed on this preparation.
As supplies became unavailable, opiate users would mix crushed methadone tablets with crushed Valoid (a cyclizine containing antihistamine) tablets in an attempt to replecate the affect of dipipanone.
See P. A. J. Janssen, Synthetic Analgesics. Part 1. Diphenylpropylamines, Pergamon Press, NY. for details on the synthesis of methadone and its cogeners before 1960. The general procedure for synthesis is illustrated by nucleophillic attack of diphenylacetonitrile on 2-chloro--1-dimethylaminoethane. The resulting aminonitrile is then converted to the ethyl ketone with ethyl magnesium bromide by way of the kitimine which is hydrolized by cold aqueous acid (Casey & Parfitt, Opioid Analgesics, Plenum Press, NY, london).
# External links
Template:Psychoactive-stub
Template:Opioids | https://www.wikidoc.org/index.php/Dipipanone | |
10c028d45b89222942b6c418a815c370a14a6206 | wikidoc | Dyphylline | Dyphylline
# 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
Dyphylline is a bronchodilator that is FDA approved for the treatment of acute bronchial asthma and for reversible bronchospasm associated with chronic bronchitis and emphysema. Common adverse reactions include diarrhea, nausea, vomiting, headache, agitation, feeling excited, irritability.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
## Indications
- For relief of acute bronchial asthma and for reversible bronchospasm associated with chronic bronchitis and emphysema.
## Dosage
- Dosage should be individually titrated according to the severity of the condition and the response of the patient.
- Usual adult dosage: Up to 15 mg/kg every six hours.
- Appropriate dosage adjustments should be made in patients with impaired renal function
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Dyphylline in adult patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Dyphylline in adult patients.
# 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
- There is limited information regarding Off-Label Guideline-Supported Use of Dyphylline in pediatric patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Dyphylline in pediatric patients.
# Contraindications
- Hypersensitivity to dyphylline or related xanthine compounds.
# Warnings
- Dyphylline is not indicated in the management of status asthmaticus, which is a serious medical emergency.
- Although the relationship between plasma levels of dyphylline and appearance of toxicity is unknown, excessive doses may be expected to be associated with an increased risk of adverse effects.
### Precautions
- General: Use dyphylline with caution in patients with severe cardiac disease, hypertension, hyperthyroidism, acute myocardial injury, or peptic ulcer.
- Concurrent administration of dyphylline and probenecid, which competes for tubular secretion, has been shown to increase the plasma half-life of dyphylline.
# Adverse Reactions
## Clinical Trials Experience
- Adverse reactions with the use of dyphylline have been infrequent, relatively mild, and rarely required reduction in dosage or withdrawal of therapy.
- The following adverse reactions which have been reported with other xanthine bronchodilators, and which have most often been related to excessive drug plasma levels, should be considered as potential adverse effects when dyphylline is administered:
- Gastrointestinal: nausea, vomiting, epigastric pain, hematemesis, diarrhea.
- Central nervous system: headache, irritability, restlessness, insomnia, hyperexcitability, agitation, muscle twitching, generalized clonic and tonic convulsions.
- Cardiovascular: palpitation, tachycardia, extrasystoles, flushing, hypotension, circulatory failure, ventricular arrhythmias.
- Respiratory: tachypnea.
- Renal: albuminuria, gross and microscopic hematuria, diuresis.
- Other: hyperglycemia, inappropriate ADH syndrome.
## Postmarketing Experience
- There is limited information regarding Postmarketing experience of Dyphylline.
# Drug Interactions
- Synergism between xanthine bronchodilators (e.g., theophylline), ephedrine, and other sympathomimetic bronchodilators has been reported. This should be considered whenever these agents are prescribed concomitantly.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Animal reproduction studies have not been conducted with dyphylline. It is also not known if dyphylline can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Dyphylline 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 Dyphylline in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Dyphylline during labor and delivery.
### Nursing Mothers
- Dyphylline is present in human milk at approximately twice the maternal plasma concentration. Caution should be exercised when dyphylline is administered to a nursing woman.
### Pediatric Use
- Safety and effectiveness in children have not been established.
### Geriatic Use
- Clinical studies of dyphylline 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 responses 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.
### Gender
There is no FDA guidance on the use of Dyphylline with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Dyphylline with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Dyphylline in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Dyphylline in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Dyphylline in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Dyphylline in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- Monitoring and maintenance of vital signs, fluids, and electrolytes in overdosage.
# IV Compatibility
- There is limited information regarding IV Compatibility.
# Overdosage
- There have been no reports, in the literature, of overdosage with dyphylline. However, the following information based on reports of theophylline overdosage are considered typical of the xanthine class of drugs and should be kept in mind.
- Signs and symptoms: Restlessness, anorexia, nausea, vomiting, diarrhea, insomnia, irritability, and headache. Marked overdosage with resulting severe toxicity has produced agitation, severe vomiting, dehydration, excessive thirst, tinnitus, cardiac arrhythmias, hyperthermia, diaphoresis, and generalized clonic and tonic convulsions. Cardiovascular collapse has also occurred, with some fatalities. Seizures have occurred in some cases associated with very high theophylline plasma concentrations, without any premonitory symptoms of toxicity.
- Treatment: There is no specific antidote for overdosage with drugs of the xanthine class. Symptomatic treatment and general supportive measures should be instituted with careful monitoring and maintenance of vital signs, fluids, and electrolytes. The stomach should be emptied by inducing emesis if the patient is conscious and responsive, or by gastric lavage, taking care to protect against aspiration, especially in stuporous or comatose patients. Maintenance of an adequate airway is essential in case oxygen or assisted respiration is needed. Sympathomimetic agents should be avoided but sedatives such as short-acting barbiturates may be useful.
- Dyphylline is dialyzable and, although not recommended as a routine procedure in overdosage cases, hemodialysis may be of some benefit when severe intoxication is present or when the patient has not responded to general supportive and symptomatic treatment.
# Pharmacology
## Mechanism of Action
Dyphylline is a xanthine derivative with pharmacologic actions similar to theophylline and other members of this class of drugs. Its primary action is that of bronchodilation, but it also exhibits peripheral vasodilatory and other smooth muscle relaxant activity to a lesser degree. The bronchodilatory action of dyphylline, as with other xanthines, is thought to be mediated through competitive inhibition of phosphodiesterase with a resulting increase in cyclic AMP producing relaxation of bronchial smooth muscle.
## Structure
Dyphylline, a xanthine derivative, is a bronchodilator available for oral administration as tablets containing 200 mg and 400 mg of dyphylline. Other ingredients: magnesium stearate, microcrystalline cellulose.
Chemically, dyphylline is 7-(2,3-dihydroxypropyl)-theophylline, a white, extremely bitter, amorphous powder that is freely soluble in water and soluble in alcohol to the extent of 2 g/100 mL. Dyphylline forms a neutral solution that is stable in gastrointestinal fluids over a wide range of pH.
The molecular formula for dyphylline is C10H14N4O4 with a molecular weight of 254.25. Its structural formula is:
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Dyphylline.
## Pharmacokinetics
- Dyphylline is well tolerated and produces less nausea than aminophylline and other alkaline theophylline compounds when administered orally. Unlike the hydrolyzable salts of theophylline, dyphylline is not converted to free theophylline in vivo. It is absorbed rapidly in therapeutically active form and in healthy volunteers reaches a mean peak plasma concentration of 17.1 mcg/mL in approximately 45 minutes following a single oral dose of 1000 mg of dyphylline.
- Dyphylline exerts its bronchodilatory effects directly and, unlike theophylline, is excreted unchanged by the kidneys without being metabolized by the liver. Because of this, dyphylline pharmacokinetics and plasma levels are not influenced by various factors that affect liver function and hepatic enzyme activity, such as smoking, age, congestive heart failure, or concomitant use of drugs which affect liver function.
- The elimination half-life of dyphylline is approximately two hours (1.8-2.1 hr) and approximately 88% of a single oral dose can be recovered from the urine unchanged. The renal clearance would be correspondingly reduced in patients with impaired renal function. In anuric patients, the half-life may be increased 3 to 4 times normal.
- Dyphylline plasma levels are dose-related and generally predictable. The range of plasma levels within which dyphylline can be expected to produce effective bronchodilation has not been determined.
## Nonclinical Toxicology
- Carcinogenesis, mutagenesis, impairment of fertility: No long-term animal studies have been performed with dyphylline.
# Clinical Studies
- There is limited information regarding Clinical Studies of Dyphylline.
# How Supplied
- LUFYLLIN Tablets contain 200 mg dyphylline and are white, rectangular, scored on one side and imprinted WALLACE 521 on the other side. The tablets are available in bottles of 100 (NDC 0037-0521-92).
- LUFYLLIN-400 Tablets contain 400 mg dyphylline and are white, capsule-shaped, scored on one side and imprinted WALLACE 731 on the other side. The tablets are available in bottles of 100 (NDC 0037-0731-92).
## Storage
- Store at controlled room temperature 20°-25°C (68°-77°F).
- Dispense in a tight container.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Dyphylline Patient Counseling Information in the drug label.
# Precautions with Alcohol
- Alcohol-Dyphylline interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- LUFYLLIN ®
# Look-Alike Drug Names
- There is limited information regarding Look-Alike Drug Names.
# Drug Shortage Status
# Price | Dyphylline
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Turky Alkathery, 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
Dyphylline is a bronchodilator that is FDA approved for the treatment of acute bronchial asthma and for reversible bronchospasm associated with chronic bronchitis and emphysema. Common adverse reactions include diarrhea, nausea, vomiting, headache, agitation, feeling excited, irritability.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
## Indications
- For relief of acute bronchial asthma and for reversible bronchospasm associated with chronic bronchitis and emphysema.
## Dosage
- Dosage should be individually titrated according to the severity of the condition and the response of the patient.
- Usual adult dosage: Up to 15 mg/kg every six hours.
- Appropriate dosage adjustments should be made in patients with impaired renal function
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Dyphylline in adult patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Dyphylline in adult patients.
# 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
- There is limited information regarding Off-Label Guideline-Supported Use of Dyphylline in pediatric patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Dyphylline in pediatric patients.
# Contraindications
- Hypersensitivity to dyphylline or related xanthine compounds.
# Warnings
- Dyphylline is not indicated in the management of status asthmaticus, which is a serious medical emergency.
- Although the relationship between plasma levels of dyphylline and appearance of toxicity is unknown, excessive doses may be expected to be associated with an increased risk of adverse effects.
### Precautions
- General: Use dyphylline with caution in patients with severe cardiac disease, hypertension, hyperthyroidism, acute myocardial injury, or peptic ulcer.
- Concurrent administration of dyphylline and probenecid, which competes for tubular secretion, has been shown to increase the plasma half-life of dyphylline.
# Adverse Reactions
## Clinical Trials Experience
- Adverse reactions with the use of dyphylline have been infrequent, relatively mild, and rarely required reduction in dosage or withdrawal of therapy.
- The following adverse reactions which have been reported with other xanthine bronchodilators, and which have most often been related to excessive drug plasma levels, should be considered as potential adverse effects when dyphylline is administered:
- Gastrointestinal: nausea, vomiting, epigastric pain, hematemesis, diarrhea.
- Central nervous system: headache, irritability, restlessness, insomnia, hyperexcitability, agitation, muscle twitching, generalized clonic and tonic convulsions.
- Cardiovascular: palpitation, tachycardia, extrasystoles, flushing, hypotension, circulatory failure, ventricular arrhythmias.
- Respiratory: tachypnea.
- Renal: albuminuria, gross and microscopic hematuria, diuresis.
- Other: hyperglycemia, inappropriate ADH syndrome.
## Postmarketing Experience
- There is limited information regarding Postmarketing experience of Dyphylline.
# Drug Interactions
- Synergism between xanthine bronchodilators (e.g., theophylline), ephedrine, and other sympathomimetic bronchodilators has been reported. This should be considered whenever these agents are prescribed concomitantly.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Animal reproduction studies have not been conducted with dyphylline. It is also not known if dyphylline can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Dyphylline 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 Dyphylline in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Dyphylline during labor and delivery.
### Nursing Mothers
- Dyphylline is present in human milk at approximately twice the maternal plasma concentration. Caution should be exercised when dyphylline is administered to a nursing woman.
### Pediatric Use
- Safety and effectiveness in children have not been established.
### Geriatic Use
- Clinical studies of dyphylline 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 responses 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.
### Gender
There is no FDA guidance on the use of Dyphylline with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Dyphylline with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Dyphylline in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Dyphylline in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Dyphylline in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Dyphylline in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- Monitoring and maintenance of vital signs, fluids, and electrolytes in overdosage.
# IV Compatibility
- There is limited information regarding IV Compatibility.
# Overdosage
- There have been no reports, in the literature, of overdosage with dyphylline. However, the following information based on reports of theophylline overdosage are considered typical of the xanthine class of drugs and should be kept in mind.
- Signs and symptoms: Restlessness, anorexia, nausea, vomiting, diarrhea, insomnia, irritability, and headache. Marked overdosage with resulting severe toxicity has produced agitation, severe vomiting, dehydration, excessive thirst, tinnitus, cardiac arrhythmias, hyperthermia, diaphoresis, and generalized clonic and tonic convulsions. Cardiovascular collapse has also occurred, with some fatalities. Seizures have occurred in some cases associated with very high theophylline plasma concentrations, without any premonitory symptoms of toxicity.
- Treatment: There is no specific antidote for overdosage with drugs of the xanthine class. Symptomatic treatment and general supportive measures should be instituted with careful monitoring and maintenance of vital signs, fluids, and electrolytes. The stomach should be emptied by inducing emesis if the patient is conscious and responsive, or by gastric lavage, taking care to protect against aspiration, especially in stuporous or comatose patients. Maintenance of an adequate airway is essential in case oxygen or assisted respiration is needed. Sympathomimetic agents should be avoided but sedatives such as short-acting barbiturates may be useful.
- Dyphylline is dialyzable and, although not recommended as a routine procedure in overdosage cases, hemodialysis may be of some benefit when severe intoxication is present or when the patient has not responded to general supportive and symptomatic treatment.
# Pharmacology
## Mechanism of Action
Dyphylline is a xanthine derivative with pharmacologic actions similar to theophylline and other members of this class of drugs. Its primary action is that of bronchodilation, but it also exhibits peripheral vasodilatory and other smooth muscle relaxant activity to a lesser degree. The bronchodilatory action of dyphylline, as with other xanthines, is thought to be mediated through competitive inhibition of phosphodiesterase with a resulting increase in cyclic AMP producing relaxation of bronchial smooth muscle.
## Structure
Dyphylline, a xanthine derivative, is a bronchodilator available for oral administration as tablets containing 200 mg and 400 mg of dyphylline. Other ingredients: magnesium stearate, microcrystalline cellulose.
Chemically, dyphylline is 7-(2,3-dihydroxypropyl)-theophylline, a white, extremely bitter, amorphous powder that is freely soluble in water and soluble in alcohol to the extent of 2 g/100 mL. Dyphylline forms a neutral solution that is stable in gastrointestinal fluids over a wide range of pH.
The molecular formula for dyphylline is C10H14N4O4 with a molecular weight of 254.25. Its structural formula is:
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Dyphylline.
## Pharmacokinetics
- Dyphylline is well tolerated and produces less nausea than aminophylline and other alkaline theophylline compounds when administered orally. Unlike the hydrolyzable salts of theophylline, dyphylline is not converted to free theophylline in vivo. It is absorbed rapidly in therapeutically active form and in healthy volunteers reaches a mean peak plasma concentration of 17.1 mcg/mL in approximately 45 minutes following a single oral dose of 1000 mg of dyphylline.
- Dyphylline exerts its bronchodilatory effects directly and, unlike theophylline, is excreted unchanged by the kidneys without being metabolized by the liver. Because of this, dyphylline pharmacokinetics and plasma levels are not influenced by various factors that affect liver function and hepatic enzyme activity, such as smoking, age, congestive heart failure, or concomitant use of drugs which affect liver function.
- The elimination half-life of dyphylline is approximately two hours (1.8-2.1 hr) and approximately 88% of a single oral dose can be recovered from the urine unchanged. The renal clearance would be correspondingly reduced in patients with impaired renal function. In anuric patients, the half-life may be increased 3 to 4 times normal.
- Dyphylline plasma levels are dose-related and generally predictable. The range of plasma levels within which dyphylline can be expected to produce effective bronchodilation has not been determined.
## Nonclinical Toxicology
- Carcinogenesis, mutagenesis, impairment of fertility: No long-term animal studies have been performed with dyphylline.
# Clinical Studies
- There is limited information regarding Clinical Studies of Dyphylline.
# How Supplied
- LUFYLLIN Tablets contain 200 mg dyphylline and are white, rectangular, scored on one side and imprinted WALLACE 521 on the other side. The tablets are available in bottles of 100 (NDC 0037-0521-92).
- LUFYLLIN-400 Tablets contain 400 mg dyphylline and are white, capsule-shaped, scored on one side and imprinted WALLACE 731 on the other side. The tablets are available in bottles of 100 (NDC 0037-0731-92).
## Storage
- Store at controlled room temperature 20°-25°C (68°-77°F).
- Dispense in a tight container.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Dyphylline Patient Counseling Information in the drug label.
# Precautions with Alcohol
- Alcohol-Dyphylline interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- LUFYLLIN ®[1]
# Look-Alike Drug Names
- There is limited information regarding Look-Alike Drug Names.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Diprophylline | |
47b67fd25bf0382deb2d40be84e945003f90e5a8 | wikidoc | Dipsacales | Dipsacales
The Dipsacales are an order of flowering plant, included within the asterid group of dicotyledons.
Under the Cronquist system, the order included Adoxaceae, Caprifoliaceae, Dipsacaceae, and Valerianaceae. Under the more recent Angiosperm Phylogeny Group (APG II) system, the circumscription of the order is much the same but the families are circumscribed differently. APG includes Adoxaceae and a broadly circumscribed Caprifoliaceae, the latter including the alternatively acceptable families Diervillaceae, Dipsacaceae, Linnaeaceae, Morinaceae, and Valerianaceae.
Under the APG II definition some well-known members of Dipsacales are honeysuckle, elder, viburnum, and valerian.
A few other families may also belong near this order. These include the Columelliaceae, Paracryphiaceae, and Sphenostemonaceae. | Dipsacales
The Dipsacales are an order of flowering plant, included within the asterid group of dicotyledons.
Under the Cronquist system, the order included Adoxaceae, Caprifoliaceae, Dipsacaceae, and Valerianaceae. Under the more recent Angiosperm Phylogeny Group (APG II) system, the circumscription of the order is much the same but the families are circumscribed differently. APG includes Adoxaceae and a broadly circumscribed Caprifoliaceae, the latter including the alternatively acceptable families Diervillaceae, Dipsacaceae, Linnaeaceae, Morinaceae, and Valerianaceae.
Under the APG II definition some well-known members of Dipsacales are honeysuckle, elder, viburnum, and valerian.
A few other families may also belong near this order. These include the Columelliaceae, Paracryphiaceae, and Sphenostemonaceae. | https://www.wikidoc.org/index.php/Dipsacales | |
b8c67ae5b203ee57bdc3e10e3cca4ac7b06b4dcb | wikidoc | Dipsomania | Dipsomania
# Overview
Dipsomania is a term related to an incontrollable craving for alcohol. It means "compulsive thirst" but the term when used, is reserved primarily related to the consumption of alcohol. As a result, a dipsomaniac is a person in which this condition appears, in the form of a physical and psychological craving for ethyl alcohol, especially liquor. However, the obsession is so compulsive that the dipsomanic will ingest whatever intoxifying liquid is at hand, whether it is fit for consumption or not.
Dipsomania differs from alcoholism in that it is an uncontrollable periodic lust for alcohol, with, in the interim, no desire for alcoholic beverages. However when dipsomania manifests, it usually results in multi-day or weekly episodes of excessive binge drinking and blackouts. It generally involves solitary alcohol abuse in combination with the loss of interest in any other usual activities. It is not known what causes dipsomania, it is thought that enzyme deficiencies may contribute to its root cause, in part contributing to depressive illness in many dipsomaniacs. There appears to be no cure for dipsomania, with the exception of abstinence from alcohol of any kind. Dipsomanics tend to be social, outgoing individuals, who find an unusual phenomenon overtakes any will not to drink, and the compulsion becomes so overwhelming that it cannot be stopped in many cases. The dipsomaniac will fall prey to this compulsion and eventually drink until blackouts, seizures or even reported deaths. Contrary to alcoholism, where the desire to drink predominates all thought processes, dipsomania will manifest itself suddenly, and in large part, "surprise" the dipsomaniac who then falls prey to the overconsumption of alcohol. Research is underway in many psychiatric circles to determine what if any psychological disorders may contribute to its cause.
# Remedies/Cures
In certain African countries it is believed that a cold infusion, made from the roots of the Buffalo Thorn, can curb this addiction. The irony is, however, that the same Buffalo Thorn produces berries, from which a very potent alcoholic drink called Katkasu can be home-brewed.
# Famous Dipsomaniacs
In 1921, John W. Robertson theorized that Dipsomania could have been the cause of the mysterious death of writer Edgar Allan Poe.
- The German composer Max Reger
- The Russian composer Modest Mussorgsky
- Another famed self-described "dipsomaniac" is New York writer Jonathan Ames.
- The character of Sebastian Flyte, from the novel Brideshead Revisited by Evelyn Waugh, memorably and sarcastically describes himself as a dipsomaniac, ("If they treat me like a dipsomaniac, they can bloody well have a dipsomaniac."). He is later called the same by his brother, and a "dipso" by one of the minor characters.
- William (Billy) Shusler, famed president of the original "Under the Sink Club", which was founded in 1987 and today, has over one thousand dipsomaniac members worldwide.
- Ernest Hemingway, American author
- Adrian "Ade" Edmondson, English comedian
- Dave Mohring, best selling author of "Dipsomania: Why It Drives Me To Drink", and Under The Sink Club Past President
- Marilyn Monroe, American Actress and Model
- Joseph Mullholland, former Canadian bodybuilder and self reported dipsomaniac, Under The Sink Club Member 1994-5
# Sources
"Poe's Life." The PoeMuseum.
hr:Dipsomanija
sr:Дипсоманија
fi:Dipsomania | Dipsomania
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Dipsomania is a term related to an incontrollable craving for alcohol. It means "compulsive thirst" but the term when used, is reserved primarily related to the consumption of alcohol. As a result, a dipsomaniac is a person in which this condition appears, in the form of a physical and psychological craving for ethyl alcohol, especially liquor. However, the obsession is so compulsive that the dipsomanic will ingest whatever intoxifying liquid is at hand, whether it is fit for consumption or not.
Dipsomania differs from alcoholism in that it is an uncontrollable periodic lust for alcohol, with, in the interim, no desire for alcoholic beverages. However when dipsomania manifests, it usually results in multi-day or weekly episodes of excessive binge drinking and blackouts. It generally involves solitary alcohol abuse in combination with the loss of interest in any other usual activities. It is not known what causes dipsomania, it is thought that enzyme deficiencies may contribute to its root cause, in part contributing to depressive illness in many dipsomaniacs. There appears to be no cure for dipsomania, with the exception of abstinence from alcohol of any kind. Dipsomanics tend to be social, outgoing individuals, who find an unusual phenomenon overtakes any will not to drink, and the compulsion becomes so overwhelming that it cannot be stopped in many cases. The dipsomaniac will fall prey to this compulsion and eventually drink until blackouts, seizures or even reported deaths. Contrary to alcoholism, where the desire to drink predominates all thought processes, dipsomania will manifest itself suddenly, and in large part, "surprise" the dipsomaniac who then falls prey to the overconsumption of alcohol. Research is underway in many psychiatric circles to determine what if any psychological disorders may contribute to its cause.
# Remedies/Cures
In certain African countries it is believed that a cold infusion, made from the roots of the Buffalo Thorn, can curb this addiction. The irony is, however, that the same Buffalo Thorn produces berries, from which a very potent alcoholic drink called Katkasu can be home-brewed.
# Famous Dipsomaniacs
In 1921, John W. Robertson theorized that Dipsomania could have been the cause of the mysterious death of writer Edgar Allan Poe.
- The German composer Max Reger
- The Russian composer Modest Mussorgsky
- Another famed self-described "dipsomaniac" is New York writer Jonathan Ames.
- The character of Sebastian Flyte, from the novel Brideshead Revisited by Evelyn Waugh, memorably and sarcastically describes himself as a dipsomaniac, ("If they treat me like a dipsomaniac, they can bloody well have a dipsomaniac."). He is later called the same by his brother, and a "dipso" by one of the minor characters.
- William (Billy) Shusler, famed president of the original "Under the Sink Club", which was founded in 1987 and today, has over one thousand dipsomaniac members worldwide.
- Ernest Hemingway, American author
- Adrian "Ade" Edmondson, English comedian
- Dave Mohring, best selling author of "Dipsomania: Why It Drives Me To Drink", and Under The Sink Club Past President
- Marilyn Monroe, American Actress and Model
- Joseph Mullholland, former Canadian bodybuilder and self reported dipsomaniac, Under The Sink Club Member 1994-5
# Sources
"Poe's Life." The PoeMuseum. http://www.poemuseum.org/poes_life/death_myths.html
hr:Dipsomanija
sr:Дипсоманија
fi:Dipsomania
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Dipsomania | |
b6a132c7ef0ccd0e6d2db9916a0a4fc07479acbf | wikidoc | Metamizole | Metamizole
Metamizole sodium is a non-steroidal anti-inflammatory drug (NSAID), commonly used in the past as a powerful painkiller and fever reducer. It is better known under the names Dipyrone, Analgin and Novalgin.
Metamizole was first synthesized by the German company Hoechst AG in 1920, and its mass production started in 1922. It remained freely available worldwide until the 1970s, when it was discovered that the drug carries a small risk of causing agranulocytosis - a very dangerous and potentially fatal condition. Controversy remains regarding the level of risk. Several national medical authorities have banned metamizole either totally or have restricted it to be available only on prescription.
# Risks of agranulocytosis
According to comments by Dr Anthony Wong of the University of São Paulo, Brazil in a WHO newsletter, recent studies estimate that the incidence rate of metamizole-induced agranulocytosis is between 0.2 and 2 cases per million person days of use, with approximately 7% of all cases fatal (provided that all patients have access to urgent medical care). In other words, one should expect 50 to 500 deaths annually due to metamizole in a country of 300 million, assuming that every citizen takes the drug once a month. This is not a very high rate compared to other drugs - for example, the prescription drug clozapine is known to be at least 50 times more likely to trigger agranulocytosis. However, at the time the risk was assumed to be much greater and, as such, excessive for an over-the-counter analgesic, especially considering the existence of safer alternatives (aspirin and ibuprofen).
A study in Northern Sweden published in 2002 estimated the total risk during metamizole therapy for patients in hospitals (inpatients) and outside of hospital (outpatients) about 3 to 100 times greater than that estimated by Dr Wong: "Given certain assumptions including the actual amounts prescribed the calculated risks of agranulocytosis would be approximately one out of every 31,000 metamizole-treated inpatients and one of every 1400 metamizole-treated outpatients."
# Availability around the world
Metamizole was banned in Sweden in 1974, in the United States in 1977; more than 30 countries, including Japan, Australia, Iran, and part of the European Union, have followed suit. In these countries metamizole is still occasionally used as a veterinary drug. In Germany it became a prescription drug. Some European pharmaceutical companies, notably Hoechst and Merck, continue to develop metamizole-containing drugs and market them in some countries. In Sweden, the ban was lifted in 1995 and re-introduced in 1999 only to be taken off the market again just a few years later.
In other parts of the world (notably in Spain, Mexico, India, Brazil, Russia, Bulgaria, Romania, Israel and Third World countries) metamizole is still freely available over-the-counter, remains one of the most popular analgesics, and plays an important role in self-medication. For example, metamizole and metamizole-containing drugs account for 80% of OTC analgesic market in Russia, whereas ibuprofen accounts for 2.5%. In Brazil, metamizole (Novalgina) products, although over-the-counter, carry warnings to avoid usage by those under 19 years old, and have several informations about early detection and treatment of agranulocytosis. Although the Brazilian government did not push for a ban on the drug, its use has seen a decline on the past years as pharmaceutical companies and doctors pushed aspirin, paracetamol and ibuprofen based products as replacement, specialy regarding child care. Amongst adults it is still widely used. Some of the most widely available metamizole-containing product still in use in Brazil are: Buscopan Plus (under the name of Buscopan Composto), Novalgina and Neosaldina. Generic Dipyrone is also available.
# Media attention
Metamizole received brief period of attention by American media in 2001, when a Latino immigrant boy was admitted into a Salt Lake City clinic with symptoms of agranulocytosis. It was discovered that the drug remained freely available in Latino shops and highly popular among Mexican immigrants, despite the ban. The ongoing "LATIN" Study, a multicenter international case-control study, is examining the incidence of agranulocytosis in Latin America and the role of metamizole.
# Brand names
- Brazil: Novalgina, Neosaldina, Sedalgina, Doridina, Migranette, Benegrip, Anador, Magnopyrol, Conmel, Difebril, Termopirona, Dipifarma, Termosil, Dorona, Hynalgin, Lisador, among others.
- Bulgaria: Proalgin, Analgin
- Croatia: Analgin
- Finland: Litalgin
- Germany: Novalgin, Analgin, Berlosin, Metalgin, Metamizol-Puren, Novaminsulfon.
- Hungary: Algopyrin
- India: Novalgin
- Israel: Optalgin
- Italy: Novalgina
- Macedonia: Analgin
- Mexico: Neo-Melubrina
- Poland: Pyralgina
- Romania: Algocalmin, Novocalmin, Algozone, Nevralgin
- Russia/Bulgaria: Tempalgin (combination drug; metamizole is one of its components)
- Slovenia: Analgin
- Serbia: Analgin
- Spain: Nolotil
- Switzerland: Novalgin
- Turkey: Novalgin
- Venezuela: Novalcina | Metamizole
Metamizole sodium is a non-steroidal anti-inflammatory drug (NSAID), commonly used in the past as a powerful painkiller and fever reducer. It is better known under the names Dipyrone, Analgin and Novalgin.
Metamizole was first synthesized by the German company Hoechst AG in 1920, and its mass production started in 1922. It remained freely available worldwide until the 1970s, when it was discovered that the drug carries a small risk of causing agranulocytosis - a very dangerous and potentially fatal condition. Controversy remains regarding the level of risk. Several national medical authorities have banned metamizole either totally or have restricted it to be available only on prescription.
# Risks of agranulocytosis
According to comments by Dr Anthony Wong of the University of São Paulo, Brazil in a WHO newsletter,[1] recent studies estimate that the incidence rate of metamizole-induced agranulocytosis is between 0.2 and 2 cases per million person days of use, with approximately 7% of all cases fatal (provided that all patients have access to urgent medical care). In other words, one should expect 50 to 500 deaths annually due to metamizole in a country of 300 million, assuming that every citizen takes the drug once a month. This is not a very high rate compared to other drugs - for example, the prescription drug clozapine is known to be at least 50 times more likely to trigger agranulocytosis. However, at the time the risk was assumed to be much greater and, as such, excessive for an over-the-counter analgesic, especially considering the existence of safer alternatives (aspirin and ibuprofen).
A study in Northern Sweden published in 2002 estimated the total risk during metamizole therapy for patients in hospitals (inpatients) and outside of hospital (outpatients) about 3 to 100 times greater than that estimated by Dr Wong: "Given certain assumptions including the actual amounts prescribed the calculated risks of agranulocytosis would be approximately one out of every 31,000 metamizole-treated inpatients and one of every 1400 metamizole-treated outpatients."[2]
# Availability around the world
Metamizole was banned in Sweden in 1974, in the United States in 1977; more than 30 countries, including Japan, Australia, Iran, and part of the European Union, have followed suit. In these countries metamizole is still occasionally used as a veterinary drug. In Germany it became a prescription drug. Some European pharmaceutical companies, notably Hoechst and Merck, continue to develop metamizole-containing drugs and market them in some countries. In Sweden, the ban was lifted in 1995 and re-introduced in 1999 only to be taken off the market again just a few years later.
In other parts of the world (notably in Spain, Mexico, India, Brazil, Russia, Bulgaria, Romania, Israel and Third World countries) metamizole is still freely available over-the-counter, remains one of the most popular analgesics, and plays an important role in self-medication. For example, metamizole and metamizole-containing drugs account for 80% of OTC analgesic market in Russia, whereas ibuprofen accounts for 2.5%. In Brazil, metamizole (Novalgina) products, although over-the-counter, carry warnings to avoid usage by those under 19 years old, and have several informations about early detection and treatment of agranulocytosis. Although the Brazilian government did not push for a ban on the drug, its use has seen a decline on the past years as pharmaceutical companies and doctors pushed aspirin, paracetamol and ibuprofen based products as replacement, specialy regarding child care. Amongst adults it is still widely used. Some of the most widely available metamizole-containing product still in use in Brazil are: Buscopan Plus (under the name of Buscopan Composto), Novalgina and Neosaldina. Generic Dipyrone is also available.
# Media attention
Metamizole received brief period of attention by American media in 2001[3], when a Latino immigrant boy was admitted into a Salt Lake City clinic with symptoms of agranulocytosis. It was discovered that the drug remained freely available in Latino shops and highly popular among Mexican immigrants, despite the ban. The ongoing "LATIN" Study, a multicenter international case-control study, is examining the incidence of agranulocytosis in Latin America and the role of metamizole.
# Brand names
- Brazil: Novalgina, Neosaldina, Sedalgina, Doridina, Migranette, Benegrip, Anador, Magnopyrol, Conmel, Difebril, Termopirona, Dipifarma, Termosil, Dorona, Hynalgin, Lisador, among others.
- Bulgaria: Proalgin, Analgin
- Croatia: Analgin
- Finland: Litalgin
- Germany: Novalgin, Analgin, Berlosin, Metalgin, Metamizol-Puren, Novaminsulfon.
- Hungary: Algopyrin
- India: Novalgin
- Israel: Optalgin
- Italy: Novalgina
- Macedonia: Analgin
- Mexico: Neo-Melubrina
- Poland: Pyralgina
- Romania: Algocalmin, Novocalmin, Algozone, Nevralgin
- Russia/Bulgaria: Tempalgin (combination drug; metamizole is one of its components)
- Slovenia: Analgin
- Serbia: Analgin
- Spain: Nolotil
- Switzerland: Novalgin
- Turkey: Novalgin
- Venezuela: Novalcina | https://www.wikidoc.org/index.php/Dipyrone | |
a57e785e38950fa1a31fe2961e8fa1e4fc1e1b20 | wikidoc | Optic disc | Optic disc
The optic disc or optic nerve head is the location where ganglion cell axons exit the eye to form the optic nerve. There are no light sensitive rods or cones to respond to a light stimulus at this point thus it is also known as "the blind spot" or "anatomical blind spot"; the break in the visual field created by the optic disc is also called "the blind spot" or "physiological blind spot". The optic nerve head in a normal human eye carries from 1 to 1.2 million neurons from the eye towards the brain.
# Clinical examination
The eye is unique due to the transparency of its optical medium. Almost all eye structures can be examined with appropriate optical equipment and lenses. Using a modern direct ophthalmoscope gives a view of the optic disc using the principle of reversibility of light. A slit lamp biomicroscopic examination along with an appropriate aspheric focusing lens (+66D, +78D or +90D) is required for a detailed stereoscopic view of the optic disc and structures inside the eye.
Inspection of the optic disc by ophthalmoscopy or biomicroscopy can give an indication of the health of the optic nerve. In particular, the eye care physician notes the colour, cupping size (as a cup-to-disc ratio), sharpness of edge, swelling, hemorrhages, notching in the optic disc and any other unusual anomalies. It is useful for finding evidence corroborating the diagnosis of glaucoma and other optic neuropathies, optic neuritis, anterior ischemic optic neuropathy or papilledema (i.e. optic disc swelling produced by raised intracranial pressure). Women in advanced stage of pregnancy with pre-eclampsia should be screened by an ophthalmoscopic examination of the optic disc for early evidence of rise in intracranial pressure.
# Imaging of the optic disc
Traditional colour-film camera images are the gold standard in imaging, requiring an expert ophthalmic photographer, ophthalmic technician, optometrist or an ophthalmologist for taking standardised pictures of the optic disc. Stereoscopic images offer an excellent investigative tool for serial follow-up of suspected changes in the hands of an expert optometrist or ophthalmologist. However, since not everybody can be trained so well, automated techniques have been devised to supplant or replace the human expertise. Heidelberg Retinal Tomography (HRT-II), GDx-VCC and optical coherence tomography (Stratus-OCT 3) are the currently available computerised techniques for imaging various structures of the eyes, including the optic disc. They quantitate the nerve fiber layer of disc and surrounding retina and statistically correlate the findings with a database of previously screened population of normals. They are useful for baseline and serial follow-up to monitor minute changes in optic disc morphology.
It should be noted that imaging won't provide conclusive evidence for clinical diagnosis however, and the evidence needs to be supplanted by serial physiological testing for functional changes. Such tests may include visual field charting, and final clinical interpretation of the complete eye examination by an eye care physician. Ophthalmologists and Optometrists are able to provide this service. | Optic disc
Template:Infobox Anatomy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
The optic disc or optic nerve head is the location where ganglion cell axons exit the eye to form the optic nerve. There are no light sensitive rods or cones to respond to a light stimulus at this point thus it is also known as "the blind spot" or "anatomical blind spot"; the break in the visual field created by the optic disc is also called "the blind spot" or "physiological blind spot". The optic nerve head in a normal human eye carries from 1 to 1.2 million neurons from the eye towards the brain.
# Clinical examination
The eye is unique due to the transparency of its optical medium. Almost all eye structures can be examined with appropriate optical equipment and lenses. Using a modern direct ophthalmoscope gives a view of the optic disc using the principle of reversibility of light. A slit lamp biomicroscopic examination along with an appropriate aspheric focusing lens (+66D, +78D or +90D) is required for a detailed stereoscopic view of the optic disc and structures inside the eye.
Inspection of the optic disc by ophthalmoscopy or biomicroscopy can give an indication of the health of the optic nerve. In particular, the eye care physician notes the colour, cupping size (as a cup-to-disc ratio), sharpness of edge, swelling, hemorrhages, notching in the optic disc and any other unusual anomalies. It is useful for finding evidence corroborating the diagnosis of glaucoma and other optic neuropathies, optic neuritis, anterior ischemic optic neuropathy or papilledema (i.e. optic disc swelling produced by raised intracranial pressure). Women in advanced stage of pregnancy with pre-eclampsia should be screened by an ophthalmoscopic examination of the optic disc for early evidence of rise in intracranial pressure.
# Imaging of the optic disc
Traditional colour-film camera images are the gold standard in imaging, requiring an expert ophthalmic photographer, ophthalmic technician, optometrist or an ophthalmologist for taking standardised pictures of the optic disc. Stereoscopic images offer an excellent investigative tool for serial follow-up of suspected changes in the hands of an expert optometrist or ophthalmologist. However, since not everybody can be trained so well, automated techniques have been devised to supplant or replace the human expertise. Heidelberg Retinal Tomography (HRT-II), GDx-VCC and optical coherence tomography (Stratus-OCT 3) are the currently available computerised techniques for imaging various structures of the eyes, including the optic disc. They quantitate the nerve fiber layer of disc and surrounding retina and statistically correlate the findings with a database of previously screened population of normals. They are useful for baseline and serial follow-up to monitor minute changes in optic disc morphology.
It should be noted that imaging won't provide conclusive evidence for clinical diagnosis however, and the evidence needs to be supplanted by serial physiological testing for functional changes. Such tests may include visual field charting, and final clinical interpretation of the complete eye examination by an eye care physician. Ophthalmologists and Optometrists are able to provide this service.
# External links
- Diagram at Moorfields Eye Hospital
- Diagram at Ballard Optical
Template:Eye
de:Blinder Fleck (Auge)
nl:Blinde vlek
no:Den blinde flekk
sk:Slepá škvrna (oko)
sv:Blinda fläcken
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Disc_margins | |
4006788d95d0566593f14beb9e926da069d311dd | wikidoc | Disulphide | Disulphide
In chemistry, a disulfide usually refers to the structural unit composed of a linked pair of sulfur atoms. The disulfide anion is S22−. The term disulfide can also refer to a chemical compound that contains a disulfide center, such as diphenyl disulfide, C6H5S-SC6H5.
Sulfur is usually assigned to the reduced oxidation number −2, described as S2− and called sulfide. It has the electron configuration of a noble gas (argon).
In disulfides, sulfur is only reduced to a state with oxidation number −1. Its configuration then resembles that of chlorine and, like it, has the tendency to form a covalent bond with another S− ion to form a disulfide (S2)2− group. Oxygen can also do this; e.g. in peroxides such as H2O2. In many cases, each of the two sulfur atoms in a disulfide group is covalently bonded to a carbon atom in an organic compound, forming a disulfide bond, sometimes called a disulfide linkage or a disulfide bridge.
The tendency is a bit more elaborate in the case of sulfur, which can form polysulfides.
# Some examples
- Iron disulfide (FeS2), known as the mineral pyrite.
- Disulfur dichloride (S2Cl2), a distillable liquid.
- The amino acid cystine
- The vitamin lipoic acid
- Diphenyl disulfide (Ph2S2).
# Misnomers
Disulfide is also used to refer to compounds that contain two sulfide (S2−) centers. The compound carbon disulfide, CS2 is described with the structural formula i.e. S=C=S. This molecule is not a disulfide in the sense that it lacks a S-S bond. Similarly, molybdenum disulfide, MoS2, is not a disulfide in the sense again that its sulfur atoms are not linked. | Disulphide
In chemistry, a disulfide usually refers to the structural unit composed of a linked pair of sulfur atoms. The disulfide anion is S22−. The term disulfide can also refer to a chemical compound that contains a disulfide center, such as diphenyl disulfide, C6H5S-SC6H5.
Sulfur is usually assigned to the reduced oxidation number −2, described as S2− and called sulfide. It has the electron configuration of a noble gas (argon).
In disulfides, sulfur is only reduced to a state with oxidation number −1. Its configuration then resembles that of chlorine and, like it, has the tendency to form a covalent bond with another S− ion to form a disulfide (S2)2− group. Oxygen can also do this; e.g. in peroxides such as H2O2. In many cases, each of the two sulfur atoms in a disulfide group is covalently bonded to a carbon atom in an organic compound, forming a disulfide bond, sometimes called a disulfide linkage or a disulfide bridge.
The tendency is a bit more elaborate in the case of sulfur, which can form polysulfides.
# Some examples
- Iron disulfide (FeS2), known as the mineral pyrite.
- Disulfur dichloride (S2Cl2), a distillable liquid.
- The amino acid cystine
- The vitamin lipoic acid
- Diphenyl disulfide (Ph2S2).
# Misnomers
Disulfide is also used to refer to compounds that contain two sulfide (S2−) centers. The compound carbon disulfide, CS2 is described with the structural formula i.e. S=C=S. This molecule is not a disulfide in the sense that it lacks a S-S bond. Similarly, molybdenum disulfide, MoS2, is not a disulfide in the sense again that its sulfur atoms are not linked. | https://www.wikidoc.org/index.php/Disulphide | |
70f30cbb183a2f90a9e22cca9812f9ba864be3d5 | wikidoc | Dithionate | Dithionate
The dithionate anion, S2O62−, is a sulfur oxoanion derived from dithionic acid, H2S2O6. Its chemical formula is sometimes written in a semistructural format, as 2−.
The sulfur atoms of the dithionate ion are in the +5 oxidation state due to the presence of the S-S bond. Generally dithionates form stable compounds that are not readily oxidised or reduced. Strong oxidants oxidise them to sulfates and strong reducing agents reduce them to sulfites and dithionites. Aqueous solutions of dithionates are quite stable and can be boiled without decomposition .
The γ irradiation of crystalline dithionates produces SO3− radical ions. The unpaired electron in the SO3− radical can be detected with electron paramagnetic resonance and barium dithionate has been proposed as the basis for a radiation dosimeter
The dithionate ion can act as a bidentate ligand .
The structure of the dithionate ion in the solid state is staggered in Na2S2O6.2H2O whereas in the anyhydrous potassium salt it is nearly eclipsed.
# Compounds
Compounds containing the dithionate ion include:
- sodium dithionate, Na2S2O6
- potassium dithionate, K2S2O6
- barium dithionate, BaS2O6 | Dithionate
The dithionate anion, S2O62−, is a sulfur oxoanion derived from dithionic acid, H2S2O6. Its chemical formula is sometimes written in a semistructural format, as [O3SSO3]2−.
The sulfur atoms of the dithionate ion are in the +5 oxidation state due to the presence of the S-S bond. Generally dithionates form stable compounds that are not readily oxidised or reduced. Strong oxidants oxidise them to sulfates and strong reducing agents reduce them to sulfites and dithionites[1]. Aqueous solutions of dithionates are quite stable and can be boiled without decomposition [2].
The γ irradiation of crystalline dithionates produces SO3− radical ions[3]. The unpaired electron in the SO3− radical can be detected with electron paramagnetic resonance and barium dithionate has been proposed as the basis for a radiation dosimeter[4]
The dithionate ion can act as a bidentate ligand [5].
The structure of the dithionate ion in the solid state is staggered in Na2S2O6.2H2O whereas in the anyhydrous potassium salt it is nearly eclipsed[1].
# Compounds
Compounds containing the dithionate ion include:
- sodium dithionate, Na2S2O6
- potassium dithionate, K2S2O6
- barium dithionate, BaS2O6 | https://www.wikidoc.org/index.php/Dithionate |
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