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805c0df601d50467d5810c15f0902fff58c6e1f0 | wikidoc | Ad libitum | Ad libitum
Ad libitum is Latin for "at one's pleasure"; often shortened to 'Ad lib' (as an adjective or adverb), or 'ad-lib' (as a verb or noun). There is a less commonly used synonym, a bene placito.
# Biology
Ad libitum is also used in psychology and biology to refer to the "free-feeding" weight of an animal, as opposed, for example, to the weight after a restricted diet. For example, "The rat's ad libitum weight was about 320 grams." In nutritional studies, this phrase denotes providing an animal free access to feed or water thereby allowing the animal to self-regulate intake according to its biological needs. For example, "Rats were given ad libitum access to food and water."
In biological field studies it can also mean that information or data was obtained spontaneously without a specific method.
Medical prescriptions may use the abbreviation ad lib. to indicate "freely" or that as much as one desires should be used.
ca:Ad líbitum
cs:Ad libitum
de:Ad libitum
et:Ad libitum
it:Ad libitum
no:Ad lib
sv:Ad libitum | Ad libitum
Ad libitum is Latin for "at one's pleasure"; often shortened to 'Ad lib' (as an adjective or adverb), or 'ad-lib' (as a verb or noun). There is a less commonly used synonym, a bene placito.
# Biology
Ad libitum is also used in psychology and biology to refer to the "free-feeding" weight of an animal, as opposed, for example, to the weight after a restricted diet. For example, "The rat's ad libitum weight was about 320 grams." In nutritional studies, this phrase denotes providing an animal free access to feed or water thereby allowing the animal to self-regulate intake according to its biological needs. For example, "Rats were given ad libitum access to food and water."
In biological field studies it can also mean that information or data was obtained spontaneously without a specific method.
Medical prescriptions may use the abbreviation ad lib. to indicate "freely" or that as much as one desires should be used.
ca:Ad líbitum
cs:Ad libitum
de:Ad libitum
et:Ad libitum
it:Ad libitum
no:Ad lib
sv:Ad libitum
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Ad_lib | |
a4537e13af0b41aac523d17ef73a5e10030b842f | wikidoc | Nifedipine | Nifedipine
# Disclaimer
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# Overview
Nifedipine is a calcium channel blocker, dihydropirydine calcium channel blocker that is FDA approved for the treatment of hypertension, vasospastic angina, stable angina. Common adverse reactions include hypotension, palpitations, peripheral edema, flushing, nausea, dizziness, headache, feeling nervous, cough, dyspnea.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- Dosage should be adjusted according to each patient’s needs. It is recommended that nifedipine extended-release tablets be administered orally once daily on an empty stomach. In general, titration should proceed over a 7 to 14 day period starting with 30 mg once daily. Upward titration should be based on therapeutic efficacy and safety. The usual maintenance dose is 30 mg to 60 mg once daily. Titration to doses above 90 mg daily is not recommended. If discontinuation of nifedipine is necessary, sound clinical practice suggests that the dosage should be decreased gradually with close physician supervision. Co-administration of nifedipine with grapefruit juice is to be avoided. Care should be taken when dispensing nifedipine to assure that the extended-release dosage form has been prescribed.
- Dosing Information
- Nifedipine is indicated for the management of vasospastic angina confirmed by any of the following criteria: 1) classical pattern of angina at rest accompanied by ST segment elevation, 2) angina or coronary artery spasm provoked by ergonovine, or 3) angiographically demonstrated coronary artery spasm. In those patients who have had angiography, the presence of significant fixed obstructive disease is not incompatible with the diagnosis of vasospastic angina, provided that the above criteria are satisfied. Nifedipine may also be used where the clinical presentation suggests a possible vasospastic component but where vasospasm has not been confirmed, e.g., where pain has a variable threshold on exertion or when angina is refractory to nitrates and/or adequate doses of beta-blockers.
- Dosing information
- Nifedipine is indicated for the management of chronic stable angina (effort-associated angina) without evidence of vasospasm in patients who remain symptomatic despite adequate doses of beta-blockers and/or organic nitrates or who cannot tolerate those agents. In chronic stable angina (effort-associated angina) nifedipine has been effective in controlled trials of up to eight weeks duration in reducing angina frequency and increasing exercise tolerance, but confirmation of sustained effectiveness and evaluation of long-term safety in these patients are incomplete. Controlled studies in small numbers of patients suggest concomitant use of nifedipine and beta-blocking agents may be beneficial in patients with chronic stable angina, but available information is not sufficient to predict with confidence the effects of concurrent treatment, especially in patients with compromised left ventricular function or cardiac conduction abnormalities. When introducing such concomitant therapy, care must be taken to monitor blood pressure closely since severe hypotension can occur from the combined effects of the drugs.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- Developed by: American College of Obstetritians and Gynecologists (ACOG)
- Class of Recommendation: Strong recommendation
- Strength of Evidence: Moderate
- Dosing Information/Recommendation
- 10 to 20 mg PO q30m if necessary, continue treatment with 10-20 mg q2-6h.
### Non–Guideline-Supported Use
- Dosing Information
- 10 mg PO/SL.
- Dosing Information
- IV infusion 10 mcg/kg/hour to a total of 24 hours, starting concomitantly with the extracorporeal circulation.
- Dosing Information
- 60-80 mg/day.
- Dosing Information
- 10 to 30 mg PO/SL q8h.
- Dosing Information
- Increased anal sphincter pressure: 20 mg.
- Acute anal fissures: 0.2% gel q12h.
- External thrombosed hemorroids: Nifedipine 0.3% + lidocaine 1.5% q12h.
- Dosing Information
- 10 mg PO q30m to total of 3 doses.
- Dosing Information
- 20 mg at bedtime 2 and 3 days prior to the ascent, followed by 20 mg q8h through the ascent.
- Dosing Information
- Renal transplant: 10-40 mg PO q12h.
- Liver transplant: 10 mg/day.
- Bone marrow transplant: 10 mg PO q8h.
- Dosing Information
- 20 mg SL q12h.
- Dosing Information
- 20 mg SL q12h.
- Dosing Information
- 10-20 mg PO q8h.
- Dosing Information
- 10 mg SL (administer immediately), followed by 30-40 mg/day (maintenance therapy).
- Dosing Information
- 20 mg/day.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Nifedipine 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 Nifedipine in pediatric patients.
### Non–Guideline-Supported Use
- Dosing Information
- 10 mg PO q8h 10 to 15 minutes before meals.
- Dosing Information
- 0.24 mg/kg SL.
# Contraindications
- Hypersensitivity to nifedipine
# Warnings
Although, in most patients, the hypotensive effect of nifedipine is modest and well tolerated, occasional patients have had excessive and poorly tolerated hypotension. These responses have usually occurred during initial titration or at the time of subsequent upward dosage adjustment. Although patients have rarely experienced excessive hypotension on nifedipine alone, this may be more common in patients on concomitant beta blocker therapy. Although not approved for this purpose, nifedipine capsules have been used (orally and sublingually) for acute reduction of blood pressure. Several well-documented reports describe cases of profound hypotension, myocardial infarction, and death when immediate-release nifedipine was used in this way. Nifedipine capsules should not be used for the acute reduction of blood pressure.
Severe hypotension and/or increased fluid volume requirements have been reported in patients receiving nifedipine together with a beta-blocking agent who underwent coronary artery bypass surgery using high dose fentanyl anesthesia. The interaction with high dose fentanyl appears to be due to the combination of nifedipine and a beta blocker, but the possibility that it may occur with nifedipine alone, with low doses of fentanyl, in other surgical procedures, or with other narcotic analgesics cannot be ruled out. In nifedipine treated patients where surgery using high dose fentanyl anesthesia is contemplated, the physician should be aware of these potential problems and, if the patient's condition permits, sufficient time (at least 36 hours) should be allowed for nifedipine to be washed out of the body prior to surgery.
Rarely, patients, particularly those who have severe obstructive coronary artery disease, have developed well documented increased frequency, duration, and/or severity of angina or acute myocardial infarction on starting nifedipine or at the time of dosage increase. The mechanism of this effect is not established.
Several well-controlled, randomized trials studied the use of immediate-release nifedipine in patients who had just sustained myocardial infarctions. In none of these trials did immediate-release nifedipine appear to provide any benefit. In some of the trials, patients who received immediate-release nifedipine had significantly worse outcomes than patients who received placebo. Nifedipine capsules should not be administered within the first week or two after myocardial infarction, and they should also be avoided in the setting of acute coronary syndrome (when infarction may be imminent).
Nifedipine and other immediate-release nifedipine capsules have also been used for the long-term control of essential hypertension, although nifedipine capsules have not been approved for this purpose and no properly controlled studies have been conducted to define an appropriate dose or dose interval for such treatment. Nifedipine capsules should not be used for the control of essential hypertension.
Patients recently withdrawn from beta-blockers may develop a withdrawal syndrome with increased angina, probably related to increased sensitivity to catecholamines. Initiation of nifedipine treatment will not prevent this occurrence and might be expected to exacerbate it by provoking reflex catecholamine release. There have been occasional reports of increased angina in a setting of beta blocker withdrawal and nifedipine initiation. It is important to taper beta blockers if possible, rather than stopping them abruptly before beginning nifedipine.
Rarely, patients, usually those receiving a beta blocker, have developed heart failure after beginning nifedipine. Patients with tight aortic stenosis may be at greater risk for such an event, as the unloading effect of nifedipine would be expected to be of less benefit to these patients, owing to their fixed impedance to flow across the aortic valve.
### Precausions
Because nifedipine decreases peripheral vascular resistance, careful monitoring of blood pressure during the initial administration and titration of nifedipine is suggested. Close observation is especially recommended for patients already taking medications that are known to lower blood pressure.
Mild to moderate peripheral edema occurs in a dose dependent manner with an incidence ranging from approximately 10% to about 30% at the highest dose studied (180 mg). It is a localized phenomenon thought to be associated with vasodilation of dependent arterioles and small blood vessels and not due to left ventricular dysfunction or generalized fluid retention. With patients whose angina or hypertension is complicated by congestive heart failure, care should be taken to differentiate this peripheral edema from the effects of increasing left ventricular dysfunction.
As with any other non-deformable material, caution should be used when administering nifedipine extended-release in patients with preexisting severe gastrointestinal narrowing (pathologic or iatrogenic). There have been rare reports of obstructive symptoms in patients with known strictures in association with the ingestion of nifedipine extended-release.
Rare, usually transient, but occasionally significant elevations of enzymes such as alkaline phosphatase, CPK, LDH, SGOT and SGPT have been noted. The relationship to nifedipine therapy is uncertain in most cases, but probable in some. These laboratory abnormalities have rarely been associated with clinical symptoms; however, cholestasis with or without jaundicehas been reported. A small (5.4%) increase in mean alkaline phosphatase was noted in patients treated with nifedipine extended-release. This was an isolated finding not associated with clinical symptoms and it rarely resulted in values which fell outside the normal range. Rare instances of allergic hepatitis have been reported. In controlled studies, nifedipine extended-release did not adversely affect serum uric acid, glucose, or cholesterol. Serum potassium was unchanged in patients receiving nifedipine extended-release in the absence of concomitant diuretic therapy, and slightly decreased in patients receiving concomitant diuretics.
Nifedipine, like other calcium channel blockers, decreases platelet aggregation in vitro. Limited clinical studies have demonstrated a moderate but statistically significant decrease in platelet aggregation and an increase in bleeding time in some nifedipine patients. This is thought to be a function of inhibition of calcium transport across the platelet membrane. No clinical significance for these findings has been demonstrated.
Positive direct Coombs test with/without hemolytic anemia has been reported but a causal relationship between nifedipine administration and positivity of this laboratory test, including hemolysis, could not be determined.
Although nifedipine has been used safely in patients with renal dysfunction and has been reported to exert a beneficial effect, in certain cases, rare, reversible elevations in BUN and serum creatinine have been reported in patients with pre-existing chronic renal insufficiency. The relationship to nifedipine therapy is uncertain in most cases but probable in some.
# Adverse Reactions
## Clinical Trials Experience
Over 1000 patients from both controlled and open trials with nifedipine extended-release tablets in hypertension and angina were included in the evaluation of adverse experiences. All side effects reported during nifedipine extended-release tablet therapy were tabulated independent of their causal relation to medication. The most common side effect reported with nifedipine extended-release was edema which was dose related and ranged in frequency from approximately 10% to about 30% at the highest dose studied (180 mg). Other common adverse experiences reported in placebo-controlled trials include:
Where the frequency of adverse events with nifedipine extended-release tablets and placebo is similar, causal relationship cannot be established.
The following adverse events were reported with an incidence of 3% or less in daily doses up to 90 mg:
- Body as a Whole/Systemic: Chest pain, leg pain.
- Central Nervous System: Paresthesia, vertigo.
- Dermatologic: Rash.
- Gastrointestinal: Constipation.
- Musculoskeletal: Leg cramps.
- Respiratory: Epistaxis, rhinitis.
- Urogenital: Impotence, urinary frequency
Other adverse events reported with an incidence of less than 1.0% were:
- Body as a Whole/Systemic: Allergic reaction, asthenia, cellulitis, substernal chest pain, chills, facial edema, lab test abnormal, malaise, neck pain, pelvic pain, pain, photosensitivity reaction.
- Cardiovascular: Atrial fibrillation, bradycardia, cardiac arrest, extrasystole, hypotension, migraine, palpitations, phlebitis, postural hypotension, tachycardia, cutaneous angiectases
- Central Nervous System: Anxiety, confusion, decreased libido, depression, hypertonia, hypesthesia, insomnia, somnolence.
- Dermatologic: Angioedema, petechial rash, pruritus, sweating.
- Gastrointestinal: Abdominal pain, diarrhea, dry mouth, dysphagia, dyspepsia, eructation, esophagitis, flatulence, gastrointestinal disorder, gastrointestinal hemorrhage, GGT increased, gum disorder, gum hemorrhage, vomiting.
- Hematologic: Eosinophilia, lymphadenopathy.
- Metabolic: Gout, weight loss.
- Musculoskeletal: Arthralgia, arthritis, joint disorder, myalgia, myasthenia.
- Respiratory: Dyspnea, increased cough, rales, pharyngitis, stridor.
- Special Senses: Abnormal vision, amblyopia, conjunctivitis, diplopia, eye disorder, eye hemorrhage, tinnitus.
- Urogenital/Reproductive: Dysuria, kidney calculus, nocturia, breast engorgement, polyuria, urogenital disorder
The following adverse events have been reported rarely in patients given nifedipine in coat core or other formulations: Allergenic hepatitis, alopecia, anaphylactic reaction, anemia, arthritis with ANA (+), depression, erythromelalgia, exfoliative dermatitis, fever, gingival hyperplasia, gynecomastia, hyperglycemia, jaundice, leukopenia, mood changes, muscle cramps, nervousness, paranoid syndrome, purpura, shakiness, sleep disturbances, Stevens-Johnson syndrome, syncope, taste perversion, thrombocytopenia, toxic epidermal necrolysis, transient blindness at the peak of plasma level, tremor and urticaria.
## Postmarketing Experience
There is limited information regarding Nifedipine Postmarketing Experience in the drug label.
# Drug Interactions
Nifedipine is mainly eliminated by metabolism and is a substrate of CYP3A. Inhibitors and inducers of CYP3A4 can impact the exposure to nifedipine and consequently its desirable and undesirable effects. In vitro and in vivo data indicate that nifedipine can inhibit the metabolism of drugs that are substrates of CYP3A, thereby increasing the exposure to other drugs. Nifedipine is a vasodilator, and co-administration of other drugs affecting blood pressure may result in pharmacodynamic interactions.
- Quinidine: Quinidine is a substrate of CYP3A and has been shown to inhibit CYP3A in vitro. Co-administration of multiple doses of quinidine sulfate, 200 mg t.i.d., and nifedipine, 20 mg t.i.d., increased Cmax and AUC of nifedipine in healthy volunteers by factors of 2.30 and 1.37, respectively. The heart rate in the initial interval after drug administration was increased by up to 17.9 beats/minute. The exposure to quinidine was not importantly changed in the presence of nifedipine. Monitoring of heart rate and adjustment of the nifedipine dose, if necessary, are recommended when quinidine is added to a treatment with nifedipine.
- Flecainide: There has been too little experience with the co-administration of flecainide with nifedipine to recommend concomitant use.
- Diltiazem: Pre-treatment of healthy volunteers with 30 mg or 90 mg t.i.d. diltiazem p.o. increased the AUC of nifedipine after a single dose of 20 mg nifedipine by factors of 2.2 and 3.1, respectively. The corresponding Cmax values of nifedipine increased by factors of 2.0 and 1.7, respectively. Caution should be exercised when co-administering diltiazem and nifedipine and a reduction of the dose of nifedipine should be considered.
- Verapamil: Verapamil, a CYP3A inhibitor, can inhibit the metabolism of nifedipine and increase the exposure to nifedipine during concomitant therapy. Blood pressure should be monitored and reduction of the dose of nifedipine considered.
- Benazepril: In healthy volunteers receiving single dose of 20 mg nifedipine ER and benazepril 20 mg, the plasma concentrations of benazeprilat and nifedipine in the presence and absence of each other were not statistically significantly different. A hypotensive effect was only seen after co-administration of the two drugs. The tachycardic effect of nifedipine was attenuated in the presence of benazepril.
- Irbesartan: In vitro studies show significant inhibition of the formation of oxidized irbesartan metabolites by nifedipine. However, in clinical studies, concomitant nifedipine had no effect on irbesartan pharmacokinetics.
- Candesartan: No significant drug interaction has been reported in studies with candesartan cilexitil given together with nifedipine. Because candesartan is not significantly metabolized by the cytochrome P450 system and at therapeutic concentrations has no effect on cytochrome P450 enzymes, interactions with drugs that inhibit or are metabolized by those enzymes would not be expected.
- Nifedipine was well tolerated when administered in combination with beta-blockers in 187 hypertensive patients in a placebo-controlled clinical trial. However, there have been occasional literature reports suggesting that the combination of nifedipine and beta-blocking drugs may increase the likelihood of congestive heart failure, severe hypotension or exacerbation of angina in patients with cardiovascular disease. Clinical monitoring is recommended and a dose adjustment of nifedipine should be considered.
- Timolol: Hypotension is more likely to occur if dihydropryridine calcium channel blockers such as nifedipine are co-administered with timolol.
- Doxazosin: Healthy volunteers participating in a multiple dose doxazosin-nifedipine interaction study received 2 mg doxazosin q.d. alone or combined with 20 mg nifedipine ER b.i.d. Co-administration of nifedipine resulted in a decrease in AUC and Cmax of doxazosin to 83% and 86% of the values in the absence of nifedipine, respectively. In the presence of doxazosin, AUC and Cmax of nifedipine were increased by factors of 1.13 and 1.23, respectively. Compared to nifedipine monotherapy, blood pressure was lower in the presence of doxazosin. Blood pressure should be monitored when doxazosin is co-administered with nifedipine, and dose reduction of nifedipine considered.
- Digoxin: Since there have been isolated reports of patients with elevated digoxin levels, and there is a possible interaction between digoxin and nifedipine, it is recommended that digoxin levels be monitored when initiating, adjusting and discontinuing nifedipine extended-release tablets to avoid possible over- or under-digitalization.
- Coumarins: There have been rare reports of increased prothrombin time in patients taking coumarin anticoagulants to whom nifedipine was administered. However, the relationship to nifedipine therapy is uncertain.
- Clopidogrel: No clinically significant pharmacodynamic interactions were observed when clopidrogrel was co-administered with nifedipine.
- Tirofiban: Co-administration of nifedipine did not alter the exposure to tirofiban importantly.
Ketoconazole, itraconazole and fluconazole are CYP3A inhibitors and can inhibit the metabolism of nifedipine and increase the exposure to nifedipine during concomitant therapy. Blood pressure should be monitored and a dose reduction of nifedipine considered.
- Omeprazole: In healthy volunteers receiving a single dose of 10 mg nifedipine, AUC and Cmax of nifedipine after pretreatment with omeprazole 20 mg q.d. for 8 days were 1.26 and 0.87 times those after pre-treatment with placebo. Pretreatment with or co-administration of omeprazole did not impact the effect of nifedipine on blood pressure or heart rate. The impact of omeprazole on nifedipine is not likely to be of clinical relevance.
- Pantoprazole: In healthy volunteers the exposure to neither drug was changed significantly in the presence of the other drug.
- Ranitidine: Five studies in healthy volunteers investigated the impact of multiple ranitidine doses on the single or multiple dose pharmacokinetics of nifedipine. Two studies investigated the impact of coadministered ranitidine on blood pressure in hypertensive subjects on nifedipine. Co-administration of ranitidine did not have relevant effects on the exposure to nifedipine that affected the blood pressure or heart rate in normotensive or hypertensive subjects.
- Cimetidine: Five studies in healthy volunteers investigated the impact of multiple cimetidine doses on the single or multiple dose pharmacokinetics of nifedipine. Two studies investigated the impact of coadministered cimetidine on blood pressure in hypertensive subjects on nifedipine. In normotensive subjects receiving single doses of 10 mg or multiple doses of up to 20 mg nifedipine t.i.d. alone or together with cimetidine up to 1000 mg/day, the AUC values of nifedipine in the presence of cimetidine were between 1.52 and 2.01 times those in the absence of cimetidine. The Cmax values of nifedipine in the presence of cimetidine were increased by factors ranging between 1.60 and 2.02. The increase in exposure to nifedipine by cimetidine was accompanied by relevant changes in blood pressure or heart rate in normotensive subjects. Hypertensive subjects receiving 10 mg q.d. nifedipine alone or in combination with cimetidine 1000 mg q.d. also experienced relevant changes in blood pressure when cimetidine was added to nifedipine. The interaction between cimetidine and nifedipine is of clinical relevance and blood pressure should be monitored and a reduction of the dose of nifedipine considered.
Quinupristin/Dalfopristin: In vitro drug interaction studies have demonstrated that quinupristin/dalfopristin significantly inhibits the CYP3A metabolism of nifedipine. Concomitant administration of quinupristin/dalfopristin and nifedipine (repeated oral dose) in healthy volunteers increased AUC and Cmax for nifedipine by factors of 1.44 and 1.18, respectively, compared to nifedipine monotherapy. Upon co-administration of quinupristin/dalfopristin with nifedipine, blood pressure should be monitored and a reduction of the dose of nifedipine considered.
Erythromycin: Erythromycin, a CYP3A inhibitor, can inhibit the metabolism of nifedipine and increase the exposure to nifedipine during concomitant therapy. Blood pressure should be monitored and reduction of the dose of nifedipine considered.
- Rifampin: Pretreatment of healthy volunteers with 600 mg/day rifampin p.o. decreased the exposure to oral nifedipine (20 μg/kg) to 13%. The exposure to intravenous nifedipine by the same rifampin treatment was decreased to 70%. Dose adjustment of nifedipine may be necessary if nifedipine is co-administered with rifampin.
- Rifapentine: Rifapentine, as an inducer of CYP3A4, can decrease the exposure to nifedipine. A dose adjustment of nifedipine when co-administered with rifapentine should be considered.
Amprenavir, atanazavir, delavirine, fosamprinavir, indinavir, nelfinavir and ritonavir, as CYP3A inhibitors, can inhibit the metabolism of nifedipine and increase the exposure to nifedipine. Caution is warranted and clinical monitoring of patients recommended.
- Nefazodone, a CYP3A inhibitor, can inhibit the metabolism of nifedipine and increase the exposure to nifedipine during concomitant therapy. Blood pressure should be monitored and a reduction of the dose of nifedipine considered.
- Valproic acid may increase the exposure to nifedipine during concomitant therapy. Blood pressure should be monitored and a dose reduction of nifedipine considered.
- Phenytoin: Nifedipine is metabolized by CYP3A4. Co-administration of nifedipine 10 mg capsule and 60 mg nifedipine coat-core tablet with phenytoin, an inducer of CYP3A4, lowered the AUC and Cmax of nifedipine by approximately 70%. When using nifedipine with phenytoin, the clinical response to nifedipine should be monitored and its dose adjusted if necessary.
- Phenobarbitone and carbamazepine as inducers of CYP3A can decrease the exposure to nifedipine. Dose adjustment of nifedipine may be necessary if phenobarbitone, carbamazepine or phenytoin is coadministered.
- Dolasetron: In patients taking dolasetron by the oral or intravenous route and nifedipine, no effect was shown on the clearance of hydrodolasetron.
- Tacrolimus: Nifedipine has been shown to inhibit the metabolism of tacrolimus in vitro. Transplant patients on tacrolimus and nifedipine required from 26% to 38% smaller doses than patients not receiving nifedipine. Nifedipine can increase the exposure to tacrolimus. When nifedipine is co-administered with tacrolimus the blood concentrations of tacrolimus should be monitored and a reduction of the dose of tacrolimus considered.
- Sirolimus: A single 60 mg dose of nifedipine and a single 10 mg dose of sirolimus oral solution were administered to 24 healthy volunteers. Clinically significant pharmacokinetic drug interactions were not observed.
- Pioglitazone: Co-administration of pioglitazone for 7 days with 30 mg nifedipine ER administered orally q.d. for 4 days to male and female volunteers resulted in least square mean (90% CI) values for unchanged nifedipine of 0.83 (0.73-0.95) for Cmax and 0.88 (0.80-0.96) for AUC relative to nifedipine monotherapy. In view of the high variability of nifedipine pharmacokinetics, the clinical significance of this finding is unknown.
- Rosiglitazone: Co-administration of rosiglitazone (4 mg b.i.d.) was shown to have no clinically relevant effect on the pharmacokinetics of nifedipine.
- Metformin: A single dose metformin-nifedipine interaction study in normal healthy volunteers demonstrated that co-administration of nifedipine increased plasma metformin Cmax and AUC by 20% and 9%, respectively, and increased the amount of metformin excreted in urine. Tmax and half-life were unaffected. Nifedipine appears to enhance the absorption of metformin.
- Miglitol: No effect of miglitol was observed on the pharmacokinetics and pharmacodynamics of nifedipine.
- Repaglinide: Co-administration of 10 mg nifedipine with a single dose of 2 mg repaglinide (after 4 days nifedipine 10 mg t.i.d. and repaglinide 2 mg t.i.d.) resulted in unchanged AUC and Cmax values for both drugs.
- Acarbose: Nifedipine tends to produce hyperglycemia and may lead to loss of glucose control. If nifedipine is co-administered with acarbose, blood glucose levels should be monitored carefully and a dose adjustment of nifedipine considered.
- Orlistat: In 17 normal-weight subjects receiving orlistat 120 mg t.i.d. for 6 days, orlistat did not alter the bioavailability of 60 mg nifedipine (extended-release tablets).
- Grapefruit Juice: In healthy volunteers, a single dose co-administration of 250 mL double strength grapefruit juice with 10 mg nifedipine increased AUC and Cmax by factors of 1.35 and 1.13, respectively. Ingestion of repeated doses of grapefruit juice (5 x 200 mL in 12 hours) after administration of 20 mg nifedipine ER increased AUC and Cmax of nifedipine by a factor of 2.0. Grapefruit juice should be avoided by patients on nifedipine. The intake of grapefruit juice should be stopped at least 3 days prior to initiating patients on nifedipine.
- Herbals
- St. John’s Wort: Is an inducer of CYP3A4 and may decrease the exposure to nifedipine. Dose adjustment of nifedipine may be necessary if St. John’s Wort is co-administered.
CYP2D6 Probe Drug
- Debrisoquine: In healthy volunteers, pretreatment with nifedipine 20 mg t.i.d. for 5 days did not change the metabolic ratio of hydroxydebrisoquine to debrisoquine measured in urine after a single dose of 10 mg debrisoquine. Thus, it is improbable that nifedipine inhibits in vivo the metabolism of other drugs that are substrates of CYP2D6.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
In rodents, rabbits and monkeys, nifedipine has been shown to have a variety of embryotoxic, placentotoxic and fetotoxic effects, including stunted fetuses (rats, mice and rabbits), digital anomalies (rats and rabbits), rib deformities (mice), cleft palate (mice), small placentas and underdeveloped chorionic villi (monkeys), embryonic and fetal deaths (rats, mice and rabbits), prolonged pregnancy (rats; not evaluated in other species), and decreased neonatal survival (rats; not evaluated in other species). On a mg/kg or mg/m2 basis, some of the doses associated with these various effects are higher than the maximum recommended human dose and some are lower, but all are within an order of magnitude of it.
The digital anomalies seen in nifedipine-exposed rabbit pups are strikingly similar to those seen in pups exposed to phenytoin, and these are in turn similar to the phalangeal deformities that are the most common malformation seen in human children with in utero exposure to phenytoin.
There are no adequate and well-controlled studies in pregnant women. Nifedipine should generally be avoided during pregnancy and used only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Nifedipine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Nifedipine during labor and delivery.
### Nursing Mothers
Nifedipine is excreted in human milk. Therefore, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
There is no FDA guidance on the use of Nifedipine in pediatric settings.
### Geriatic Use
Although small pharmacokinetic studies have identified an increased half-life and increased Cmax and AUC, clinical studies of nifedipine 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 Nifedipine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Nifedipine with respect to specific racial populations.
### Renal Impairment
No studies have been performed with nifedipine extended release tablets in patients with renal failure; however, significant alterations in the pharmacokinetics of nifedipine immediate release capsules have not been reported in patients undergoing hemodialysis or chronic ambulatory peritoneal dialysis. Since the absorption of nifedipine could be modified by renal disease, caution should be exercised in treating such patients.
### Hepatic Impairment
Because hepatic biotransformation is the predominant route for the disposition of nifedipine, its pharmacokinetics may be altered in patients with chronic liver disease. Nifedipine extended-release tablets have not been studied in patients with hepatic disease; however, in patients with hepatic impairment (liver cirrhosis) nifedipine has a longer elimination half-life and higher bioavailability than in healthy volunteers.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Nifedipine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Nifedipine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Oral
### Monitoring
Because nifedipine decreases peripheral vascular resistance, careful monitoring of blood pressure during the initial administration and titration of nifedipine is suggested. Close observation is especially recommended for patients already taking medications that are known to lower blood pressure.
# IV Compatibility
There is limited information regarding the compatibility of Nifedipine and IV administrations.
# Overdosage
Experience with nifedipine overdosage is limited. Symptoms associated with severe nifedipine overdosage include:
- Loss of consciousness.
- Drop in blood pressure.
- Heart rhythm disturbances.
- Metabolic acidosis.
- Hypoxia.
- Cardiogenic shock with pulmonary edema.
Generally, overdosage with nifedipine leading to pronounced hypotension calls for active cardiovascular support including monitoring of cardiovascular and respiratory function, elevation of extremities, judicious use of calcium infusion, pressor agents and fluids. Clearance of nifedipine would be expected to be prolonged in patients with impaired liver function. Since nifedipine is highly protein bound, dialysis is not likely to be of any benefit; however, plasmapheresis may be beneficial.
There has been one reported case of massive overdosage with tablets of another extended-release formulation of nifedipine. The main effects of ingestion of approximately 4800 mg of nifedipine in a young man attempting suicide as a result of cocaine-induced depression was initial dizziness, palpitations, flushing, and nervousness. Within several hours of ingestion, nausea, vomiting, and generalized edema developed. No significant hypotension was apparent at presentation, 18 hours post ingestion. Blood chemistry abnormalities consisted of a mild, transient elevation of serum creatinine, and modest elevations of LDH and CPK, but normal SGOT. Vital signs remained stable, no electrocardiographic abnormalities were noted and renal function returned to normal within 24 to 48 hours with routine supportive measures alone. No prolonged sequelae were observed.
The effect of a single 900 mg ingestion of nifedipine capsules in a depressed anginal patient on tricyclic antidepressants was loss of consciousness within 30 minutes of ingestion, and profound hypotension, which responded to calcium infusion, pressor agents, and fluid replacement. A variety of ECG abnormalities were seen in this patient with a history of bundle branch block, including sinus bradycardia and varying degrees of AV block. These dictated the prophylactic placement of a temporary ventricular pacemaker, but otherwise resolved spontaneously. Significant hyperglycemia was seen initially in this patient, but plasma glucose levels rapidly normalized without further treatment.
A young hypertensive patient with advanced renal failure ingested 280 mg of nifedipine capsules at one time, with resulting marked hypotension responding to calcium infusion and fluids. No AV conduction abnormalities, arrhythmias, or pronounced changes in heart rate were noted, nor was there any further deterioration in renal function.
# Pharmacology
## Mechanism of Action
The mechanism by which nifedipine reduces arterial blood pressure involves peripheral arterial vasodilatation and, consequently, a reduction in peripheral vascular resistance. The increased peripheral vascular resistance that is an underlying cause of hypertension results from an increase in active tension in the vascular smooth muscle. Studies have demonstrated that the increase in active tension reflects an increase in cytosolic free calcium.
Nifedipine is a peripheral arterial vasodilator which acts directly on vascular smooth muscle. The binding of nifedipine to voltage-dependent and possibly receptor-operated channels in vascular smooth muscle results in an inhibition of calcium influx through these channels. Stores of intracellular calcium in vascular smooth muscle are limited and thus dependent upon the influx of extracellular calcium for contraction to occur. The reduction in calcium influx by nifedipine causes arterial vasodilation and decreased peripheral vascular resistance which results in reduced arterial blood pressure.
## Structure
Nifedipine is an extended release tablet dosage form of the calcium channel blocker nifedipine. Nifedipine is 3,5-pyridinedicarboxylic acid, 1,4-dihydro-2,6-dimethyl-4-(2- nitrophenyl)-dimethyl ester, C17H18N2O6, and has the structural formula:
Nifedipine is a yellow crystalline substance, practically insoluble in water but soluble in ethanol. It has a molecular weight of 346.3.
Nifedipine tablets contain either 30 mg or 60 mg of nifedipine for once-a-day oral administration.
Each tablet also contains the following inactive ingredients: colloidal silicon dioxide, hypromellose, lactose monohydrate (60 mg), magnesium stearate, and microcrystalline cellulose (30 mg). The inert ingredients in the film coating are: hypromellose, iron oxide, polyethylene glycol, and titanium dioxide. The ingredients of the printing ink are: ammonium hydroxide, iron oxide black, isopropyl alcohol, n-butyl alcohol, propylene glycol and shellac.
## Pharmacodynamics
Nifedipine is a calcium ion influx inhibitor (slow-channel blocker or calcium ion antagonist) which inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. The contractile processes of vascular smooth muscle and cardiac muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. Nifedipine selectively inhibits calcium ion influx across the cell membrane of vascular smooth muscle and cardiac muscle without altering serum calcium concentrations.
## Pharmacokinetics
Nifedipine is completely absorbed after oral administration. The bioavailability of nifedipine as extended release relative to immediate release nifedipine is in the range of 84%-89%. After ingestion of nifedipine tablets under fasting conditions, plasma concentrations peak at about 2.5-5 hours with a second small peak or shoulder evident at approximately 6-12 hours post dose. The elimination half-life of nifedipine administered as nifedipine is approximately 7 hours in contrast to the known 2 hour elimination half-life of nifedipine administered as an immediate release capsule.
When nifedipine is administered as multiples of 30 mg tablets over a dose range of 30 mg to 90 mg, the area under the curve (AUC) is dose proportional: however, the peak plasma concentration for the 90 mg dose given as 3 x 30 mg is 29% greater than predicted from the 30 mg and 60 mg doses.
Two 30 mg nifedipine tablets may be interchanged with a 60 mg nifedipine CR tablet. Three 30 mg nifedipine tablets, however, result in substantially higher Cmax values than those after a single 90 mg nifedipine tablet. Three 30 mg tablets should, therefore, not be considered interchangeable with a 90 mg tablet.
Once daily dosing of nifedipine extended-release tablets under fasting conditions results in decreased fluctuations in the plasma concentration of nifedipine when compared to t.i.d. dosing with immediate-release nifedipine capsules. The mean peak plasma concentration of nifedipine following a 90 mg nifedipine extended-release tablets, administered under fasting conditions, is approximately 115 ng/mL. When nifedipine extended-release tablets is given immediately after a high fat meal in healthy volunteers, there is an average increase of 60% in the peak plasma nifedipine concentration, a prolongation in the time to peak concentration, but no significant change in the AUC. Plasma concentrations of nifedipine when nifedipine extended-release tablets is taken after a fatty meal result in slightly lower peaks compared to the same daily dose of the immediate release formulation administered in three divided doses. This may be, in part, because nifedipine extended-release tablets are less bioavailable than the immediate release formulation.
Nifedipine is extensively metabolized to highly water soluble, inactive metabolites accounting for 60% to 80% of the dose excreted in the urine. Only traces (less than 0.1% of the dose) of the unchanged form can be detected in the urine. The remainder is excreted in the feces in metabolized form, most likely as a result of biliary excretion.
No studies have been performed with nifedipine extended release tablets in patients with renal failure; however, significant alterations in the pharmacokinetics of nifedipine immediate release capsules have not been reported in patients undergoing hemodialysis or chronic ambulatory peritoneal dialysis. Since the absorption of nifedipine from nifedipine could be modified by renal disease, caution should be exercised in treating such patients.
Because hepatic biotransformation is the predominant route for the disposition of nifedipine, its pharmacokinetics may be altered in patients with chronic liver disease. Nifedipine extended-release tablets have not been studied in patients with hepatic disease; however, in patients with hepatic impairment (liver cirrhosis) nifedipine has a longer elimination half-life and higher bioavailability than in healthy volunteers.
The degree of protein binding of nifedipine is high (92%- 98%). Protein binding may be greatly reduced in patients with renal or hepatic impairment.
After administration of nifedipine extended-release tablets to healthy elderly men and women (age > 60 years), the mean Cmax is 36% higher and the average plasma concentration is 70% greater than in younger patients.
In healthy subjects, the elimination half-life of a different sustained release nifedipine formulation was longer in elderly subjects (6.7 h) compared to young subjects (3.8 h) following oral administration. A decreased clearance was also observed in the elderly (348 mL/min) compared to young subjects (519 mL/min) following intravenous administration.
Co-administration of nifedipine with grapefruit juice results in up to a 2-fold increase in AUC and Cmax, due to inhibition of CYP3A4 related first-pass metabolism.
## Nonclinical Toxicology
Nifedipine was administered orally to rats for two years and was not shown to be carcinogenic. When given to rats prior to mating, nifedipine caused reduced fertility at a dose approximately 30 times the maximum recommended human dose. There is a literature report of reversible reduction in the ability of human sperm obtained from a limited number of infertile men taking recommended doses of nifedipine to bind to and fertilize an ovum in vitro. In vivo mutagenicity studies were negative.
# Clinical Studies
Nifedipine extended-release tablets produced dose-related decreases in systolic blood pressure and diastolic blood pressure as demonstrated in two double-blind, randomized, placebo-controlled trials in which over 350 patients were treated with nifedipine extended-release tablets 30, 60 or 90 mg once daily for 6 weeks. In the first study, nifedipine extended-release tablets was given as monotherapy and in the second study, nifedipine extended-release tablets was added to a beta-blocker in patients not controlled on a beta-blocker alone. The mean trough (24 hours post-dose) blood pressure results from these studies are shown below:
The trough/peak ratios estimated from 24 hour blood pressure monitoring ranged from 41%-78% for diastolic and 46%-91% for systolic blood pressure.
Like other slow-channel blockers, nifedipine exerts a negative inotropic effect on isolated myocardial tissue. This is rarely, if ever, seen in intact animals or man, probably because of reflex responses to its vasodilating effects. In man, nifedipine decreases peripheral vascular resistance which leads to a fall in systolic and diastolic pressures, usually minimal in normotensive volunteers (less than 5 to 10 mm Hg systolic), but sometimes larger. With nifedipine extended-release tablets, these decreases in blood pressure are not accompanied by any significant change in heart rate. Hemodynamic studies of the immediate release nifedipine formulation in patients with normal ventricular function have generally found a small increase in cardiac index without major effects on ejection fraction, left ventricular end-diastolic pressure (LVEDP) or volume (LVEDV). In patients with impaired ventricular function, most acute studies have shown some increase in ejection fraction and reduction in left ventricular filling pressure.
Although, like other members of its class, nifedipine causes a slight depression of sinoatrial node function and atrioventricular conduction in isolated myocardial preparations, such effects have not been seen in studies in intact animals or in man. In formal electro-physiologic studies, predominantly in patients with normal conduction systems, nifedipine administered as the immediate release capsule has had no tendency to prolong atrioventricular conduction or sinus node recovery time, or to slow sinus rate.
# How Supplied
- Afeditab® CR, 30 mg, is available as round, brownish-red, film-coated, unscored tablets, imprinted with ELN 30, and are supplied in bottles of 100 and 500.
- Afeditab® CR, 60 mg, is available as round, brownish-red, film-coated, unscored tablets, imprinted with ELN 60, and are supplied in bottles of 100 and 500.
## Storage
- The tablets should be protected from light and moisture and stored below 30°C (86°F). Dispense in tight, light resistant containers as defined in USP/NF.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
(Patient Counseling Information)
# Precautions with Alcohol
Alcohol-Nifedipine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Adalat CC
- Procardia
- Procardia XL
- Afeditab CR
- Nifediac CC
- Nifedical XL
# Look-Alike Drug Names
- Nifedipine - Nicardipine
- Nifedipine - Nimodipine
- Procardia XL - Protain XL
# Drug Shortage Status
Drug Shortage
# Price | Nifedipine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alonso Alvarado, M.D. [2]
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# Overview
Nifedipine is a calcium channel blocker, dihydropirydine calcium channel blocker that is FDA approved for the treatment of hypertension, vasospastic angina, stable angina. Common adverse reactions include hypotension, palpitations, peripheral edema, flushing, nausea, dizziness, headache, feeling nervous, cough, dyspnea.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- Dosage should be adjusted according to each patient’s needs. It is recommended that nifedipine extended-release tablets be administered orally once daily on an empty stomach. In general, titration should proceed over a 7 to 14 day period starting with 30 mg once daily. Upward titration should be based on therapeutic efficacy and safety. The usual maintenance dose is 30 mg to 60 mg once daily. Titration to doses above 90 mg daily is not recommended. If discontinuation of nifedipine is necessary, sound clinical practice suggests that the dosage should be decreased gradually with close physician supervision. Co-administration of nifedipine with grapefruit juice is to be avoided. Care should be taken when dispensing nifedipine to assure that the extended-release dosage form has been prescribed.
- Dosing Information
- Nifedipine is indicated for the management of vasospastic angina confirmed by any of the following criteria: 1) classical pattern of angina at rest accompanied by ST segment elevation, 2) angina or coronary artery spasm provoked by ergonovine, or 3) angiographically demonstrated coronary artery spasm. In those patients who have had angiography, the presence of significant fixed obstructive disease is not incompatible with the diagnosis of vasospastic angina, provided that the above criteria are satisfied. Nifedipine may also be used where the clinical presentation suggests a possible vasospastic component but where vasospasm has not been confirmed, e.g., where pain has a variable threshold on exertion or when angina is refractory to nitrates and/or adequate doses of beta-blockers.
- Dosing information
- Nifedipine is indicated for the management of chronic stable angina (effort-associated angina) without evidence of vasospasm in patients who remain symptomatic despite adequate doses of beta-blockers and/or organic nitrates or who cannot tolerate those agents. In chronic stable angina (effort-associated angina) nifedipine has been effective in controlled trials of up to eight weeks duration in reducing angina frequency and increasing exercise tolerance, but confirmation of sustained effectiveness and evaluation of long-term safety in these patients are incomplete. Controlled studies in small numbers of patients suggest concomitant use of nifedipine and beta-blocking agents may be beneficial in patients with chronic stable angina, but available information is not sufficient to predict with confidence the effects of concurrent treatment, especially in patients with compromised left ventricular function or cardiac conduction abnormalities. When introducing such concomitant therapy, care must be taken to monitor blood pressure closely since severe hypotension can occur from the combined effects of the drugs.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- Developed by: American College of Obstetritians and Gynecologists (ACOG)
- Class of Recommendation: Strong recommendation
- Strength of Evidence: Moderate
- Dosing Information/Recommendation
- 10 to 20 mg PO q30m if necessary, continue treatment with 10-20 mg q2-6h.[1]
### Non–Guideline-Supported Use
- Dosing Information
- 10 mg PO/SL.[2]
- Dosing Information
- IV infusion 10 mcg/kg/hour to a total of 24 hours, starting concomitantly with the extracorporeal circulation.[3]
- Dosing Information
- 60-80 mg/day.
- Dosing Information
- 10 to 30 mg PO/SL q8h.[4]
- Dosing Information
- Increased anal sphincter pressure: 20 mg.[5]
- Acute anal fissures: 0.2% gel q12h.[6]
- External thrombosed hemorroids: Nifedipine 0.3% + lidocaine 1.5% q12h.[7]
- Dosing Information
- 10 mg PO q30m to total of 3 doses.[8]
- Dosing Information
- 20 mg at bedtime 2 and 3 days prior to the ascent, followed by 20 mg q8h through the ascent.[9]
- Dosing Information
- Renal transplant: 10-40 mg PO q12h.[10][11]
- Liver transplant: 10 mg/day.[12]
- Bone marrow transplant: 10 mg PO q8h.[13]
- Dosing Information
- 20 mg SL q12h.[14][15][16]
- Dosing Information
- 20 mg SL q12h.[17][18]
- Dosing Information
- 10-20 mg PO q8h.[19]
- Dosing Information
- 10 mg SL (administer immediately), followed by 30-40 mg/day (maintenance therapy).[20]
- Dosing Information
- 20 mg/day.[21]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Nifedipine 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 Nifedipine in pediatric patients.
### Non–Guideline-Supported Use
- Dosing Information
- 10 mg PO q8h 10 to 15 minutes before meals.[22]
- Dosing Information
- 0.24 mg/kg SL.[23]
# Contraindications
- Hypersensitivity to nifedipine
# Warnings
Although, in most patients, the hypotensive effect of nifedipine is modest and well tolerated, occasional patients have had excessive and poorly tolerated hypotension. These responses have usually occurred during initial titration or at the time of subsequent upward dosage adjustment. Although patients have rarely experienced excessive hypotension on nifedipine alone, this may be more common in patients on concomitant beta blocker therapy. Although not approved for this purpose, nifedipine capsules have been used (orally and sublingually) for acute reduction of blood pressure. Several well-documented reports describe cases of profound hypotension, myocardial infarction, and death when immediate-release nifedipine was used in this way. Nifedipine capsules should not be used for the acute reduction of blood pressure.
Severe hypotension and/or increased fluid volume requirements have been reported in patients receiving nifedipine together with a beta-blocking agent who underwent coronary artery bypass surgery using high dose fentanyl anesthesia. The interaction with high dose fentanyl appears to be due to the combination of nifedipine and a beta blocker, but the possibility that it may occur with nifedipine alone, with low doses of fentanyl, in other surgical procedures, or with other narcotic analgesics cannot be ruled out. In nifedipine treated patients where surgery using high dose fentanyl anesthesia is contemplated, the physician should be aware of these potential problems and, if the patient's condition permits, sufficient time (at least 36 hours) should be allowed for nifedipine to be washed out of the body prior to surgery.
Rarely, patients, particularly those who have severe obstructive coronary artery disease, have developed well documented increased frequency, duration, and/or severity of angina or acute myocardial infarction on starting nifedipine or at the time of dosage increase. The mechanism of this effect is not established.
Several well-controlled, randomized trials studied the use of immediate-release nifedipine in patients who had just sustained myocardial infarctions. In none of these trials did immediate-release nifedipine appear to provide any benefit. In some of the trials, patients who received immediate-release nifedipine had significantly worse outcomes than patients who received placebo. Nifedipine capsules should not be administered within the first week or two after myocardial infarction, and they should also be avoided in the setting of acute coronary syndrome (when infarction may be imminent).
Nifedipine and other immediate-release nifedipine capsules have also been used for the long-term control of essential hypertension, although nifedipine capsules have not been approved for this purpose and no properly controlled studies have been conducted to define an appropriate dose or dose interval for such treatment. Nifedipine capsules should not be used for the control of essential hypertension.
Patients recently withdrawn from beta-blockers may develop a withdrawal syndrome with increased angina, probably related to increased sensitivity to catecholamines. Initiation of nifedipine treatment will not prevent this occurrence and might be expected to exacerbate it by provoking reflex catecholamine release. There have been occasional reports of increased angina in a setting of beta blocker withdrawal and nifedipine initiation. It is important to taper beta blockers if possible, rather than stopping them abruptly before beginning nifedipine.
Rarely, patients, usually those receiving a beta blocker, have developed heart failure after beginning nifedipine. Patients with tight aortic stenosis may be at greater risk for such an event, as the unloading effect of nifedipine would be expected to be of less benefit to these patients, owing to their fixed impedance to flow across the aortic valve.
### Precausions
Because nifedipine decreases peripheral vascular resistance, careful monitoring of blood pressure during the initial administration and titration of nifedipine is suggested. Close observation is especially recommended for patients already taking medications that are known to lower blood pressure.
Mild to moderate peripheral edema occurs in a dose dependent manner with an incidence ranging from approximately 10% to about 30% at the highest dose studied (180 mg). It is a localized phenomenon thought to be associated with vasodilation of dependent arterioles and small blood vessels and not due to left ventricular dysfunction or generalized fluid retention. With patients whose angina or hypertension is complicated by congestive heart failure, care should be taken to differentiate this peripheral edema from the effects of increasing left ventricular dysfunction.
As with any other non-deformable material, caution should be used when administering nifedipine extended-release in patients with preexisting severe gastrointestinal narrowing (pathologic or iatrogenic). There have been rare reports of obstructive symptoms in patients with known strictures in association with the ingestion of nifedipine extended-release.
Rare, usually transient, but occasionally significant elevations of enzymes such as alkaline phosphatase, CPK, LDH, SGOT and SGPT have been noted. The relationship to nifedipine therapy is uncertain in most cases, but probable in some. These laboratory abnormalities have rarely been associated with clinical symptoms; however, cholestasis with or without jaundicehas been reported. A small (5.4%) increase in mean alkaline phosphatase was noted in patients treated with nifedipine extended-release. This was an isolated finding not associated with clinical symptoms and it rarely resulted in values which fell outside the normal range. Rare instances of allergic hepatitis have been reported. In controlled studies, nifedipine extended-release did not adversely affect serum uric acid, glucose, or cholesterol. Serum potassium was unchanged in patients receiving nifedipine extended-release in the absence of concomitant diuretic therapy, and slightly decreased in patients receiving concomitant diuretics.
Nifedipine, like other calcium channel blockers, decreases platelet aggregation in vitro. Limited clinical studies have demonstrated a moderate but statistically significant decrease in platelet aggregation and an increase in bleeding time in some nifedipine patients. This is thought to be a function of inhibition of calcium transport across the platelet membrane. No clinical significance for these findings has been demonstrated.
Positive direct Coombs test with/without hemolytic anemia has been reported but a causal relationship between nifedipine administration and positivity of this laboratory test, including hemolysis, could not be determined.
Although nifedipine has been used safely in patients with renal dysfunction and has been reported to exert a beneficial effect, in certain cases, rare, reversible elevations in BUN and serum creatinine have been reported in patients with pre-existing chronic renal insufficiency. The relationship to nifedipine therapy is uncertain in most cases but probable in some.
# Adverse Reactions
## Clinical Trials Experience
Over 1000 patients from both controlled and open trials with nifedipine extended-release tablets in hypertension and angina were included in the evaluation of adverse experiences. All side effects reported during nifedipine extended-release tablet therapy were tabulated independent of their causal relation to medication. The most common side effect reported with nifedipine extended-release was edema which was dose related and ranged in frequency from approximately 10% to about 30% at the highest dose studied (180 mg). Other common adverse experiences reported in placebo-controlled trials include:
Where the frequency of adverse events with nifedipine extended-release tablets and placebo is similar, causal relationship cannot be established.
The following adverse events were reported with an incidence of 3% or less in daily doses up to 90 mg:
- Body as a Whole/Systemic: Chest pain, leg pain.
- Central Nervous System: Paresthesia, vertigo.
- Dermatologic: Rash.
- Gastrointestinal: Constipation.
- Musculoskeletal: Leg cramps.
- Respiratory: Epistaxis, rhinitis.
- Urogenital: Impotence, urinary frequency
Other adverse events reported with an incidence of less than 1.0% were:
- Body as a Whole/Systemic: Allergic reaction, asthenia, cellulitis, substernal chest pain, chills, facial edema, lab test abnormal, malaise, neck pain, pelvic pain, pain, photosensitivity reaction.
- Cardiovascular: Atrial fibrillation, bradycardia, cardiac arrest, extrasystole, hypotension, migraine, palpitations, phlebitis, postural hypotension, tachycardia, cutaneous angiectases
- Central Nervous System: Anxiety, confusion, decreased libido, depression, hypertonia, hypesthesia, insomnia, somnolence.
- Dermatologic: Angioedema, petechial rash, pruritus, sweating.
- Gastrointestinal: Abdominal pain, diarrhea, dry mouth, dysphagia, dyspepsia, eructation, esophagitis, flatulence, gastrointestinal disorder, gastrointestinal hemorrhage, GGT increased, gum disorder, gum hemorrhage, vomiting.
- Hematologic: Eosinophilia, lymphadenopathy.
- Metabolic: Gout, weight loss.
- Musculoskeletal: Arthralgia, arthritis, joint disorder, myalgia, myasthenia.
- Respiratory: Dyspnea, increased cough, rales, pharyngitis, stridor.
- Special Senses: Abnormal vision, amblyopia, conjunctivitis, diplopia, eye disorder, eye hemorrhage, tinnitus.
- Urogenital/Reproductive: Dysuria, kidney calculus, nocturia, breast engorgement, polyuria, urogenital disorder
The following adverse events have been reported rarely in patients given nifedipine in coat core or other formulations: Allergenic hepatitis, alopecia, anaphylactic reaction, anemia, arthritis with ANA (+), depression, erythromelalgia, exfoliative dermatitis, fever, gingival hyperplasia, gynecomastia, hyperglycemia, jaundice, leukopenia, mood changes, muscle cramps, nervousness, paranoid syndrome, purpura, shakiness, sleep disturbances, Stevens-Johnson syndrome, syncope, taste perversion, thrombocytopenia, toxic epidermal necrolysis, transient blindness at the peak of plasma level, tremor and urticaria.
## Postmarketing Experience
There is limited information regarding Nifedipine Postmarketing Experience in the drug label.
# Drug Interactions
Nifedipine is mainly eliminated by metabolism and is a substrate of CYP3A. Inhibitors and inducers of CYP3A4 can impact the exposure to nifedipine and consequently its desirable and undesirable effects. In vitro and in vivo data indicate that nifedipine can inhibit the metabolism of drugs that are substrates of CYP3A, thereby increasing the exposure to other drugs. Nifedipine is a vasodilator, and co-administration of other drugs affecting blood pressure may result in pharmacodynamic interactions.
- Quinidine: Quinidine is a substrate of CYP3A and has been shown to inhibit CYP3A in vitro. Co-administration of multiple doses of quinidine sulfate, 200 mg t.i.d., and nifedipine, 20 mg t.i.d., increased Cmax and AUC of nifedipine in healthy volunteers by factors of 2.30 and 1.37, respectively. The heart rate in the initial interval after drug administration was increased by up to 17.9 beats/minute. The exposure to quinidine was not importantly changed in the presence of nifedipine. Monitoring of heart rate and adjustment of the nifedipine dose, if necessary, are recommended when quinidine is added to a treatment with nifedipine.
- Flecainide: There has been too little experience with the co-administration of flecainide with nifedipine to recommend concomitant use.
- Diltiazem: Pre-treatment of healthy volunteers with 30 mg or 90 mg t.i.d. diltiazem p.o. increased the AUC of nifedipine after a single dose of 20 mg nifedipine by factors of 2.2 and 3.1, respectively. The corresponding Cmax values of nifedipine increased by factors of 2.0 and 1.7, respectively. Caution should be exercised when co-administering diltiazem and nifedipine and a reduction of the dose of nifedipine should be considered.
- Verapamil: Verapamil, a CYP3A inhibitor, can inhibit the metabolism of nifedipine and increase the exposure to nifedipine during concomitant therapy. Blood pressure should be monitored and reduction of the dose of nifedipine considered.
- Benazepril: In healthy volunteers receiving single dose of 20 mg nifedipine ER and benazepril 20 mg, the plasma concentrations of benazeprilat and nifedipine in the presence and absence of each other were not statistically significantly different. A hypotensive effect was only seen after co-administration of the two drugs. The tachycardic effect of nifedipine was attenuated in the presence of benazepril.
- Irbesartan: In vitro studies show significant inhibition of the formation of oxidized irbesartan metabolites by nifedipine. However, in clinical studies, concomitant nifedipine had no effect on irbesartan pharmacokinetics.
- Candesartan: No significant drug interaction has been reported in studies with candesartan cilexitil given together with nifedipine. Because candesartan is not significantly metabolized by the cytochrome P450 system and at therapeutic concentrations has no effect on cytochrome P450 enzymes, interactions with drugs that inhibit or are metabolized by those enzymes would not be expected.
- Nifedipine was well tolerated when administered in combination with beta-blockers in 187 hypertensive patients in a placebo-controlled clinical trial. However, there have been occasional literature reports suggesting that the combination of nifedipine and beta-blocking drugs may increase the likelihood of congestive heart failure, severe hypotension or exacerbation of angina in patients with cardiovascular disease. Clinical monitoring is recommended and a dose adjustment of nifedipine should be considered.
- Timolol: Hypotension is more likely to occur if dihydropryridine calcium channel blockers such as nifedipine are co-administered with timolol.
- Doxazosin: Healthy volunteers participating in a multiple dose doxazosin-nifedipine interaction study received 2 mg doxazosin q.d. alone or combined with 20 mg nifedipine ER b.i.d. Co-administration of nifedipine resulted in a decrease in AUC and Cmax of doxazosin to 83% and 86% of the values in the absence of nifedipine, respectively. In the presence of doxazosin, AUC and Cmax of nifedipine were increased by factors of 1.13 and 1.23, respectively. Compared to nifedipine monotherapy, blood pressure was lower in the presence of doxazosin. Blood pressure should be monitored when doxazosin is co-administered with nifedipine, and dose reduction of nifedipine considered.
- Digoxin: Since there have been isolated reports of patients with elevated digoxin levels, and there is a possible interaction between digoxin and nifedipine, it is recommended that digoxin levels be monitored when initiating, adjusting and discontinuing nifedipine extended-release tablets to avoid possible over- or under-digitalization.
- Coumarins: There have been rare reports of increased prothrombin time in patients taking coumarin anticoagulants to whom nifedipine was administered. However, the relationship to nifedipine therapy is uncertain.
- Clopidogrel: No clinically significant pharmacodynamic interactions were observed when clopidrogrel was co-administered with nifedipine.
- Tirofiban: Co-administration of nifedipine did not alter the exposure to tirofiban importantly.
Ketoconazole, itraconazole and fluconazole are CYP3A inhibitors and can inhibit the metabolism of nifedipine and increase the exposure to nifedipine during concomitant therapy. Blood pressure should be monitored and a dose reduction of nifedipine considered.
- Omeprazole: In healthy volunteers receiving a single dose of 10 mg nifedipine, AUC and Cmax of nifedipine after pretreatment with omeprazole 20 mg q.d. for 8 days were 1.26 and 0.87 times those after pre-treatment with placebo. Pretreatment with or co-administration of omeprazole did not impact the effect of nifedipine on blood pressure or heart rate. The impact of omeprazole on nifedipine is not likely to be of clinical relevance.
- Pantoprazole: In healthy volunteers the exposure to neither drug was changed significantly in the presence of the other drug.
- Ranitidine: Five studies in healthy volunteers investigated the impact of multiple ranitidine doses on the single or multiple dose pharmacokinetics of nifedipine. Two studies investigated the impact of coadministered ranitidine on blood pressure in hypertensive subjects on nifedipine. Co-administration of ranitidine did not have relevant effects on the exposure to nifedipine that affected the blood pressure or heart rate in normotensive or hypertensive subjects.
- Cimetidine: Five studies in healthy volunteers investigated the impact of multiple cimetidine doses on the single or multiple dose pharmacokinetics of nifedipine. Two studies investigated the impact of coadministered cimetidine on blood pressure in hypertensive subjects on nifedipine. In normotensive subjects receiving single doses of 10 mg or multiple doses of up to 20 mg nifedipine t.i.d. alone or together with cimetidine up to 1000 mg/day, the AUC values of nifedipine in the presence of cimetidine were between 1.52 and 2.01 times those in the absence of cimetidine. The Cmax values of nifedipine in the presence of cimetidine were increased by factors ranging between 1.60 and 2.02. The increase in exposure to nifedipine by cimetidine was accompanied by relevant changes in blood pressure or heart rate in normotensive subjects. Hypertensive subjects receiving 10 mg q.d. nifedipine alone or in combination with cimetidine 1000 mg q.d. also experienced relevant changes in blood pressure when cimetidine was added to nifedipine. The interaction between cimetidine and nifedipine is of clinical relevance and blood pressure should be monitored and a reduction of the dose of nifedipine considered.
Quinupristin/Dalfopristin: In vitro drug interaction studies have demonstrated that quinupristin/dalfopristin significantly inhibits the CYP3A metabolism of nifedipine. Concomitant administration of quinupristin/dalfopristin and nifedipine (repeated oral dose) in healthy volunteers increased AUC and Cmax for nifedipine by factors of 1.44 and 1.18, respectively, compared to nifedipine monotherapy. Upon co-administration of quinupristin/dalfopristin with nifedipine, blood pressure should be monitored and a reduction of the dose of nifedipine considered.
Erythromycin: Erythromycin, a CYP3A inhibitor, can inhibit the metabolism of nifedipine and increase the exposure to nifedipine during concomitant therapy. Blood pressure should be monitored and reduction of the dose of nifedipine considered.
- Rifampin: Pretreatment of healthy volunteers with 600 mg/day rifampin p.o. decreased the exposure to oral nifedipine (20 μg/kg) to 13%. The exposure to intravenous nifedipine by the same rifampin treatment was decreased to 70%. Dose adjustment of nifedipine may be necessary if nifedipine is co-administered with rifampin.
- Rifapentine: Rifapentine, as an inducer of CYP3A4, can decrease the exposure to nifedipine. A dose adjustment of nifedipine when co-administered with rifapentine should be considered.
Amprenavir, atanazavir, delavirine, fosamprinavir, indinavir, nelfinavir and ritonavir, as CYP3A inhibitors, can inhibit the metabolism of nifedipine and increase the exposure to nifedipine. Caution is warranted and clinical monitoring of patients recommended.
- Nefazodone, a CYP3A inhibitor, can inhibit the metabolism of nifedipine and increase the exposure to nifedipine during concomitant therapy. Blood pressure should be monitored and a reduction of the dose of nifedipine considered.
- Valproic acid may increase the exposure to nifedipine during concomitant therapy. Blood pressure should be monitored and a dose reduction of nifedipine considered.
- Phenytoin: Nifedipine is metabolized by CYP3A4. Co-administration of nifedipine 10 mg capsule and 60 mg nifedipine coat-core tablet with phenytoin, an inducer of CYP3A4, lowered the AUC and Cmax of nifedipine by approximately 70%. When using nifedipine with phenytoin, the clinical response to nifedipine should be monitored and its dose adjusted if necessary.
- Phenobarbitone and carbamazepine as inducers of CYP3A can decrease the exposure to nifedipine. Dose adjustment of nifedipine may be necessary if phenobarbitone, carbamazepine or phenytoin is coadministered.
- Dolasetron: In patients taking dolasetron by the oral or intravenous route and nifedipine, no effect was shown on the clearance of hydrodolasetron.
- Tacrolimus: Nifedipine has been shown to inhibit the metabolism of tacrolimus in vitro. Transplant patients on tacrolimus and nifedipine required from 26% to 38% smaller doses than patients not receiving nifedipine. Nifedipine can increase the exposure to tacrolimus. When nifedipine is co-administered with tacrolimus the blood concentrations of tacrolimus should be monitored and a reduction of the dose of tacrolimus considered.
- Sirolimus: A single 60 mg dose of nifedipine and a single 10 mg dose of sirolimus oral solution were administered to 24 healthy volunteers. Clinically significant pharmacokinetic drug interactions were not observed.
- Pioglitazone: Co-administration of pioglitazone for 7 days with 30 mg nifedipine ER administered orally q.d. for 4 days to male and female volunteers resulted in least square mean (90% CI) values for unchanged nifedipine of 0.83 (0.73-0.95) for Cmax and 0.88 (0.80-0.96) for AUC relative to nifedipine monotherapy. In view of the high variability of nifedipine pharmacokinetics, the clinical significance of this finding is unknown.
- Rosiglitazone: Co-administration of rosiglitazone (4 mg b.i.d.) was shown to have no clinically relevant effect on the pharmacokinetics of nifedipine.
- Metformin: A single dose metformin-nifedipine interaction study in normal healthy volunteers demonstrated that co-administration of nifedipine increased plasma metformin Cmax and AUC by 20% and 9%, respectively, and increased the amount of metformin excreted in urine. Tmax and half-life were unaffected. Nifedipine appears to enhance the absorption of metformin.
- Miglitol: No effect of miglitol was observed on the pharmacokinetics and pharmacodynamics of nifedipine.
- Repaglinide: Co-administration of 10 mg nifedipine with a single dose of 2 mg repaglinide (after 4 days nifedipine 10 mg t.i.d. and repaglinide 2 mg t.i.d.) resulted in unchanged AUC and Cmax values for both drugs.
- Acarbose: Nifedipine tends to produce hyperglycemia and may lead to loss of glucose control. If nifedipine is co-administered with acarbose, blood glucose levels should be monitored carefully and a dose adjustment of nifedipine considered.
- Orlistat: In 17 normal-weight subjects receiving orlistat 120 mg t.i.d. for 6 days, orlistat did not alter the bioavailability of 60 mg nifedipine (extended-release tablets).
- Grapefruit Juice: In healthy volunteers, a single dose co-administration of 250 mL double strength grapefruit juice with 10 mg nifedipine increased AUC and Cmax by factors of 1.35 and 1.13, respectively. Ingestion of repeated doses of grapefruit juice (5 x 200 mL in 12 hours) after administration of 20 mg nifedipine ER increased AUC and Cmax of nifedipine by a factor of 2.0. Grapefruit juice should be avoided by patients on nifedipine. The intake of grapefruit juice should be stopped at least 3 days prior to initiating patients on nifedipine.
- Herbals
- St. John’s Wort: Is an inducer of CYP3A4 and may decrease the exposure to nifedipine. Dose adjustment of nifedipine may be necessary if St. John’s Wort is co-administered.
CYP2D6 Probe Drug
- Debrisoquine: In healthy volunteers, pretreatment with nifedipine 20 mg t.i.d. for 5 days did not change the metabolic ratio of hydroxydebrisoquine to debrisoquine measured in urine after a single dose of 10 mg debrisoquine. Thus, it is improbable that nifedipine inhibits in vivo the metabolism of other drugs that are substrates of CYP2D6.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
In rodents, rabbits and monkeys, nifedipine has been shown to have a variety of embryotoxic, placentotoxic and fetotoxic effects, including stunted fetuses (rats, mice and rabbits), digital anomalies (rats and rabbits), rib deformities (mice), cleft palate (mice), small placentas and underdeveloped chorionic villi (monkeys), embryonic and fetal deaths (rats, mice and rabbits), prolonged pregnancy (rats; not evaluated in other species), and decreased neonatal survival (rats; not evaluated in other species). On a mg/kg or mg/m2 basis, some of the doses associated with these various effects are higher than the maximum recommended human dose and some are lower, but all are within an order of magnitude of it.
The digital anomalies seen in nifedipine-exposed rabbit pups are strikingly similar to those seen in pups exposed to phenytoin, and these are in turn similar to the phalangeal deformities that are the most common malformation seen in human children with in utero exposure to phenytoin.
There are no adequate and well-controlled studies in pregnant women. Nifedipine should generally be avoided during pregnancy and used only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Nifedipine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Nifedipine during labor and delivery.
### Nursing Mothers
Nifedipine is excreted in human milk. Therefore, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
There is no FDA guidance on the use of Nifedipine in pediatric settings.
### Geriatic Use
Although small pharmacokinetic studies have identified an increased half-life and increased Cmax and AUC, clinical studies of nifedipine 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 Nifedipine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Nifedipine with respect to specific racial populations.
### Renal Impairment
No studies have been performed with nifedipine extended release tablets in patients with renal failure; however, significant alterations in the pharmacokinetics of nifedipine immediate release capsules have not been reported in patients undergoing hemodialysis or chronic ambulatory peritoneal dialysis. Since the absorption of nifedipine could be modified by renal disease, caution should be exercised in treating such patients.
### Hepatic Impairment
Because hepatic biotransformation is the predominant route for the disposition of nifedipine, its pharmacokinetics may be altered in patients with chronic liver disease. Nifedipine extended-release tablets have not been studied in patients with hepatic disease; however, in patients with hepatic impairment (liver cirrhosis) nifedipine has a longer elimination half-life and higher bioavailability than in healthy volunteers.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Nifedipine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Nifedipine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Oral
### Monitoring
Because nifedipine decreases peripheral vascular resistance, careful monitoring of blood pressure during the initial administration and titration of nifedipine is suggested. Close observation is especially recommended for patients already taking medications that are known to lower blood pressure.
# IV Compatibility
There is limited information regarding the compatibility of Nifedipine and IV administrations.
# Overdosage
Experience with nifedipine overdosage is limited. Symptoms associated with severe nifedipine overdosage include:
- Loss of consciousness.
- Drop in blood pressure.
- Heart rhythm disturbances.
- Metabolic acidosis.
- Hypoxia.
- Cardiogenic shock with pulmonary edema.
Generally, overdosage with nifedipine leading to pronounced hypotension calls for active cardiovascular support including monitoring of cardiovascular and respiratory function, elevation of extremities, judicious use of calcium infusion, pressor agents and fluids. Clearance of nifedipine would be expected to be prolonged in patients with impaired liver function. Since nifedipine is highly protein bound, dialysis is not likely to be of any benefit; however, plasmapheresis may be beneficial.
There has been one reported case of massive overdosage with tablets of another extended-release formulation of nifedipine. The main effects of ingestion of approximately 4800 mg of nifedipine in a young man attempting suicide as a result of cocaine-induced depression was initial dizziness, palpitations, flushing, and nervousness. Within several hours of ingestion, nausea, vomiting, and generalized edema developed. No significant hypotension was apparent at presentation, 18 hours post ingestion. Blood chemistry abnormalities consisted of a mild, transient elevation of serum creatinine, and modest elevations of LDH and CPK, but normal SGOT. Vital signs remained stable, no electrocardiographic abnormalities were noted and renal function returned to normal within 24 to 48 hours with routine supportive measures alone. No prolonged sequelae were observed.
The effect of a single 900 mg ingestion of nifedipine capsules in a depressed anginal patient on tricyclic antidepressants was loss of consciousness within 30 minutes of ingestion, and profound hypotension, which responded to calcium infusion, pressor agents, and fluid replacement. A variety of ECG abnormalities were seen in this patient with a history of bundle branch block, including sinus bradycardia and varying degrees of AV block. These dictated the prophylactic placement of a temporary ventricular pacemaker, but otherwise resolved spontaneously. Significant hyperglycemia was seen initially in this patient, but plasma glucose levels rapidly normalized without further treatment.
A young hypertensive patient with advanced renal failure ingested 280 mg of nifedipine capsules at one time, with resulting marked hypotension responding to calcium infusion and fluids. No AV conduction abnormalities, arrhythmias, or pronounced changes in heart rate were noted, nor was there any further deterioration in renal function.
# Pharmacology
## Mechanism of Action
The mechanism by which nifedipine reduces arterial blood pressure involves peripheral arterial vasodilatation and, consequently, a reduction in peripheral vascular resistance. The increased peripheral vascular resistance that is an underlying cause of hypertension results from an increase in active tension in the vascular smooth muscle. Studies have demonstrated that the increase in active tension reflects an increase in cytosolic free calcium.
Nifedipine is a peripheral arterial vasodilator which acts directly on vascular smooth muscle. The binding of nifedipine to voltage-dependent and possibly receptor-operated channels in vascular smooth muscle results in an inhibition of calcium influx through these channels. Stores of intracellular calcium in vascular smooth muscle are limited and thus dependent upon the influx of extracellular calcium for contraction to occur. The reduction in calcium influx by nifedipine causes arterial vasodilation and decreased peripheral vascular resistance which results in reduced arterial blood pressure.
## Structure
Nifedipine is an extended release tablet dosage form of the calcium channel blocker nifedipine. Nifedipine is 3,5-pyridinedicarboxylic acid, 1,4-dihydro-2,6-dimethyl-4-(2- nitrophenyl)-dimethyl ester, C17H18N2O6, and has the structural formula:
Nifedipine is a yellow crystalline substance, practically insoluble in water but soluble in ethanol. It has a molecular weight of 346.3.
Nifedipine tablets contain either 30 mg or 60 mg of nifedipine for once-a-day oral administration.
Each tablet also contains the following inactive ingredients: colloidal silicon dioxide, hypromellose, lactose monohydrate (60 mg), magnesium stearate, and microcrystalline cellulose (30 mg). The inert ingredients in the film coating are: hypromellose, iron oxide, polyethylene glycol, and titanium dioxide. The ingredients of the printing ink are: ammonium hydroxide, iron oxide black, isopropyl alcohol, n-butyl alcohol, propylene glycol and shellac.
## Pharmacodynamics
Nifedipine is a calcium ion influx inhibitor (slow-channel blocker or calcium ion antagonist) which inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. The contractile processes of vascular smooth muscle and cardiac muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. Nifedipine selectively inhibits calcium ion influx across the cell membrane of vascular smooth muscle and cardiac muscle without altering serum calcium concentrations.
## Pharmacokinetics
Nifedipine is completely absorbed after oral administration. The bioavailability of nifedipine as extended release relative to immediate release nifedipine is in the range of 84%-89%. After ingestion of nifedipine tablets under fasting conditions, plasma concentrations peak at about 2.5-5 hours with a second small peak or shoulder evident at approximately 6-12 hours post dose. The elimination half-life of nifedipine administered as nifedipine is approximately 7 hours in contrast to the known 2 hour elimination half-life of nifedipine administered as an immediate release capsule.
When nifedipine is administered as multiples of 30 mg tablets over a dose range of 30 mg to 90 mg, the area under the curve (AUC) is dose proportional: however, the peak plasma concentration for the 90 mg dose given as 3 x 30 mg is 29% greater than predicted from the 30 mg and 60 mg doses.
Two 30 mg nifedipine tablets may be interchanged with a 60 mg nifedipine CR tablet. Three 30 mg nifedipine tablets, however, result in substantially higher Cmax values than those after a single 90 mg nifedipine tablet. Three 30 mg tablets should, therefore, not be considered interchangeable with a 90 mg tablet.
Once daily dosing of nifedipine extended-release tablets under fasting conditions results in decreased fluctuations in the plasma concentration of nifedipine when compared to t.i.d. dosing with immediate-release nifedipine capsules. The mean peak plasma concentration of nifedipine following a 90 mg nifedipine extended-release tablets, administered under fasting conditions, is approximately 115 ng/mL. When nifedipine extended-release tablets is given immediately after a high fat meal in healthy volunteers, there is an average increase of 60% in the peak plasma nifedipine concentration, a prolongation in the time to peak concentration, but no significant change in the AUC. Plasma concentrations of nifedipine when nifedipine extended-release tablets is taken after a fatty meal result in slightly lower peaks compared to the same daily dose of the immediate release formulation administered in three divided doses. This may be, in part, because nifedipine extended-release tablets are less bioavailable than the immediate release formulation.
Nifedipine is extensively metabolized to highly water soluble, inactive metabolites accounting for 60% to 80% of the dose excreted in the urine. Only traces (less than 0.1% of the dose) of the unchanged form can be detected in the urine. The remainder is excreted in the feces in metabolized form, most likely as a result of biliary excretion.
No studies have been performed with nifedipine extended release tablets in patients with renal failure; however, significant alterations in the pharmacokinetics of nifedipine immediate release capsules have not been reported in patients undergoing hemodialysis or chronic ambulatory peritoneal dialysis. Since the absorption of nifedipine from nifedipine could be modified by renal disease, caution should be exercised in treating such patients.
Because hepatic biotransformation is the predominant route for the disposition of nifedipine, its pharmacokinetics may be altered in patients with chronic liver disease. Nifedipine extended-release tablets have not been studied in patients with hepatic disease; however, in patients with hepatic impairment (liver cirrhosis) nifedipine has a longer elimination half-life and higher bioavailability than in healthy volunteers.
The degree of protein binding of nifedipine is high (92%- 98%). Protein binding may be greatly reduced in patients with renal or hepatic impairment.
After administration of nifedipine extended-release tablets to healthy elderly men and women (age > 60 years), the mean Cmax is 36% higher and the average plasma concentration is 70% greater than in younger patients.
In healthy subjects, the elimination half-life of a different sustained release nifedipine formulation was longer in elderly subjects (6.7 h) compared to young subjects (3.8 h) following oral administration. A decreased clearance was also observed in the elderly (348 mL/min) compared to young subjects (519 mL/min) following intravenous administration.
Co-administration of nifedipine with grapefruit juice results in up to a 2-fold increase in AUC and Cmax, due to inhibition of CYP3A4 related first-pass metabolism.
## Nonclinical Toxicology
Nifedipine was administered orally to rats for two years and was not shown to be carcinogenic. When given to rats prior to mating, nifedipine caused reduced fertility at a dose approximately 30 times the maximum recommended human dose. There is a literature report of reversible reduction in the ability of human sperm obtained from a limited number of infertile men taking recommended doses of nifedipine to bind to and fertilize an ovum in vitro. In vivo mutagenicity studies were negative.
# Clinical Studies
Nifedipine extended-release tablets produced dose-related decreases in systolic blood pressure and diastolic blood pressure as demonstrated in two double-blind, randomized, placebo-controlled trials in which over 350 patients were treated with nifedipine extended-release tablets 30, 60 or 90 mg once daily for 6 weeks. In the first study, nifedipine extended-release tablets was given as monotherapy and in the second study, nifedipine extended-release tablets was added to a beta-blocker in patients not controlled on a beta-blocker alone. The mean trough (24 hours post-dose) blood pressure results from these studies are shown below:
The trough/peak ratios estimated from 24 hour blood pressure monitoring ranged from 41%-78% for diastolic and 46%-91% for systolic blood pressure.
Like other slow-channel blockers, nifedipine exerts a negative inotropic effect on isolated myocardial tissue. This is rarely, if ever, seen in intact animals or man, probably because of reflex responses to its vasodilating effects. In man, nifedipine decreases peripheral vascular resistance which leads to a fall in systolic and diastolic pressures, usually minimal in normotensive volunteers (less than 5 to 10 mm Hg systolic), but sometimes larger. With nifedipine extended-release tablets, these decreases in blood pressure are not accompanied by any significant change in heart rate. Hemodynamic studies of the immediate release nifedipine formulation in patients with normal ventricular function have generally found a small increase in cardiac index without major effects on ejection fraction, left ventricular end-diastolic pressure (LVEDP) or volume (LVEDV). In patients with impaired ventricular function, most acute studies have shown some increase in ejection fraction and reduction in left ventricular filling pressure.
Although, like other members of its class, nifedipine causes a slight depression of sinoatrial node function and atrioventricular conduction in isolated myocardial preparations, such effects have not been seen in studies in intact animals or in man. In formal electro-physiologic studies, predominantly in patients with normal conduction systems, nifedipine administered as the immediate release capsule has had no tendency to prolong atrioventricular conduction or sinus node recovery time, or to slow sinus rate.
# How Supplied
- Afeditab® CR, 30 mg, is available as round, brownish-red, film-coated, unscored tablets, imprinted with ELN 30, and are supplied in bottles of 100 and 500.
- Afeditab® CR, 60 mg, is available as round, brownish-red, film-coated, unscored tablets, imprinted with ELN 60, and are supplied in bottles of 100 and 500.
## Storage
- The tablets should be protected from light and moisture and stored below 30°C (86°F). Dispense in tight, light resistant containers as defined in USP/NF.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
(Patient Counseling Information)
# Precautions with Alcohol
Alcohol-Nifedipine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Adalat CC
- Procardia
- Procardia XL
- Afeditab CR
- Nifediac CC
- Nifedical XL
# Look-Alike Drug Names
- Nifedipine - Nicardipine
- Nifedipine - Nimodipine
- Procardia XL - Protain XL
# Drug Shortage Status
Drug Shortage
# Price | https://www.wikidoc.org/index.php/Adalat | |
94f39b6c412d240ef8114447e119c7304f2354dc | wikidoc | Adalimumab | Adalimumab
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# Black Box Warning
# Overview
Adalimumab is a Tumor Necrosis Factor Blocker that is FDA approved for the {{{indicationType}}} of Rheumatoid Arthritis, Juvenile Idiopathic Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis, Crohn’s Disease, Ulcerative Colitis, Plaque Psoriasis. There is a Black Box Warning for this drug as shown here. Common adverse reactions include Injection site pain, Injection site reaction, Rash, Antibody development, to adalimumab ,Antinuclear antibody positive , Headache, Sinusitis, Upper respiratory infection.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Rheumatoid Arthritis, Psoriatic Arthritis, and Ankylosing Spondylitis
- Dosing information
- Recommended dosage: 40 mg administered every other week.
- Methotrexate (MTX), other non-biologic DMARDS, glucocorticoids, nonsteroidal anti-inflammatory drugs (NSAIDs), and/or analgesics may be continued during treatment with adalimumab. In the treatment of RA, some patients not taking concomitant MTX may derive additional benefit from increasing the dosing frequency of adalimumab to 40 mg every week.
### Crohn’s Disease
- Dosing information
- Recommended dosage:
- Day 1: 160 mg (given as four 40 mg injections in one day or as two 40 mg injections per day for two consecutive days),
- Day 15: 80 mg .
- Day 29: 40 mg every other week.
- Aminosalicylates and/or corticosteroids may be continued during treatment with adalimumab. Azathioprine, 6-mercaptopurine (6-MP) or MTX may be continued during treatment with adalimumab if necessary. The use of adalimumab in CD beyond one year has not been evaluated in controlled clinical studies.
### Ulcerative Colitis
- Dosing information
- Recommended dosage:
- Day 1: 160 mg (given as four 40 mg injections in one day or as two 40 mg injections per day for two consecutive days),
- Day 15: 80 mg .
- Day 29: 40 mg every other week.
- Only continue adalimumab in patients who have shown evidence of clinical remission by eight weeks (Day 57) of therapy. Aminosalicylates and/or corticosteroids may be continued during treatment with adalimumab. Azathioprine and 6-mercaptopurine (6-MP) may be continued during treatment with adalimumab if necessary.
### Plaque Psoriasis
- Dosing information
- Recommended dosage: 80 mg, followed by 40 mg given every other week starting one week after the initial dose.
- The use of adalimumab in moderate to severe chronic Ps beyond one year has not been evaluated in controlled clinical studies.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Adalimumab in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Adalimumab in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
### Juvenile Idiopathic Arthritis
- Dosing information
- Recommended dosage: of adalimumab for pediatric patients 4 to 17 years of age with polyarticular juvenile idiopathic arthritis (JIA) is based on weight as shown below. MTX, glucocorticoids, NSAIDs, and/or analgesics may be continued during treatment with adalimumab.
- Limited data are available for adalimumab treatment in pediatric patients with a weight below 15 kg.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Adalimumab in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Adalimumab in pediatric patients.
# Contraindications
None.
# Warnings
## Serious Infections
Patients treated with adalimumab are at increased risk for developing serious infections involving various organ systems and sites that may lead to hospitalization or death . Opportunistic infections due to bacterial, mycobacterial, invasive fungal, viral, parasitic, or other opportunistic pathogens including aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis, legionellosis, listeriosis, pneumocystosis and tuberculosis have been reported with TNF blockers. Patients have frequently presented with disseminated rather than localized disease.
The concomitant use of a TNF blocker and abatacept or anakinra was associated with a higher risk of serious infections in patients with rheumatoid arthritis (RA); therefore, the concomitant use of adalimumab and these biologic products is not recommended in the treatment of patients with RA.
Treatment with adalimumab should not be initiated in patients with an active infection, including localized infections. Patients greater than 65 years of age, patients with co-morbid conditions and/or patients taking concomitant immunosuppressants (such as corticosteroids or methotrexate), may be at greater risk of infection. Consider the risks and benefits of treatment prior to initiating therapy in patients:
- with chronic or recurrent infection;
- who have been exposed to tuberculosis;
- with a history of an opportunistic infection;
- who have resided or traveled in areas of endemic tuberculosis or endemic mycoses, such as histoplasmosis, coccidioidomycosis, or blastomycosis; or
- with underlying conditions that may predispose them to infection.
### tuberculosis
Cases of reactivation of tuberculosis and new onset tuberculosis infections have been reported in patients receiving adalimumab, including patients who have previously received treatment for latent or active tuberculosis. Reports included cases of pulmonary and extrapulmonary (i.e., disseminated) tuberculosis. Evaluate patients for tuberculosis risk factors and test for latent infection prior to initiating adalimumab and periodically during therapy.
Treatment of latent tuberculosis infection prior to therapy with TNF blocking agents has been shown to reduce the risk of tuberculosis reactivation during therapy. Prior to initiating adalimumab, assess if treatment for latent tuberculosis is needed; and consider an induration of ≥ 5 mm a positive tuberculin skin test result, even for patients previously vaccinated with Bacille Calmette-Guerin (BCG).
Consider anti-tuberculosis therapy prior to initiation of adalimumab in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but having risk factors for tuberculosis infection. Despite prophylactic treatment for tuberculosis, cases of reactivated tuberculosis have occurred in patients treated with adalimumab. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision whether initiating anti-tuberculosis therapy is appropriate for an individual patient.
Strongly consider tuberculosis in the differential diagnosis in patients who develop a new infection during adalimumab treatment, especially in patients who have previously or recently traveled to countries with a high prevalence of tuberculosis, or who have had close contact with a person with active tuberculosis.
### Monitoring
Closely monitor patients for the development of signs and symptoms of infection during and after treatment with adalimumab, including the development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy. Tests for latent tuberculosis infection may also be falsely negative while on therapy with adalimumab.
Discontinue adalimumab if a patient develops a serious infection or sepsis. For a patient who develops a new infection during treatment with adalimumab, closely monitor them, perform a prompt and complete diagnostic workup appropriate for an immunocompromised patient, and initiate appropriate antimicrobial therapy.
### Invasive Fungal Infections
If patients develop a serious systemic illness and they reside or travel in regions where mycoses are endemic, consider invasive fungal infection in the differential diagnosis. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. Consider appropriate empiric antifungal therapy, taking into account both the risk for severe fungal infection and the risks of antifungal therapy, while a diagnostic workup is being performed. To aid in the management of such patients, consider consultation with a physician with expertise in the diagnosis and treatment of invasive fungal infections.
## Malignancies
Consider the risks and benefits of TNF-blocker treatment including adalimumab prior to initiating therapy in patients with a known malignancy other than a successfully treated non-melanoma skin cancer (NMSC) or when considering continuing a TNF blocker in patients who develop a malignancy.
### Malignancies in Adults
In the controlled portions of clinical trials of some TNF-blockers, including adalimumab, more cases of malignancies have been observed among TNF-blocker-treated adult patients compared to control-treated adult patients. During the controlled portions of 34 global adalimumab clinical trials in adult patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), Crohn’s disease (CD), ulcerative colitis (UC) and plaque psoriasis (Ps), malignancies, other than non-melanoma (basal cell and squamous cell) skin cancer, were observed at a rate (95% confidence interval) of 0.6 (0.38, 0.91) per 100 patient-years among 7304 adalimumab-treated patients versus a rate of 0.6 (0.30, 1.03) per 100 patient-years among 4232 control-treated patients (median duration of treatment of 4 months for adalimumab-treated patients and 4 months for control-treated patients). In 47 global controlled and uncontrolled clinical trials of adalimumab in adult patients with RA, PsA, AS, CD, UC, and Ps, the most frequently observed malignancies, other than lymphoma and NMSC, were breast, colon, prostate, lung, and melanoma. The malignancies in adalimumab-treated patients in the controlled and uncontrolled portions of the studies were similar in type and number to what would be expected in the general U.S. population according to the SEER database (adjusted for age, gender, and race).1
In controlled trials of other TNF blockers in adult patients at higher risk for malignancies (i.e., patients with COPD with a significant smoking history and cyclophosphamide-treated patients with Wegener’s granulomatosis), a greater portion of malignancies occurred in the TNF blocker group compared to the control group.
### Non-Melanoma Skin Cancer
During the controlled portions of 34 global adalimumab clinical trials in adult patients with RA, PsA, AS, CD, UC, and Ps, the rate (95% confidence interval) of NMSC was 0.7 (0.49, 1.08) per 100 patient-years among adalimumab-treated patients and 0.2 (0.08, 0.59) per 100 patient-years among control-treated patients. Examine all patients, and in particular patients with a medical history of prior prolonged immunosuppressant therapy or psoriasis patients with a history of PUVA treatment for the presence of NMSC prior to and during treatment with adalimumab.
### Lymphoma and Leukemia
In the controlled portions of clinical trials of all the TNF-blockers in adults, more cases of lymphoma have been observed among TNF-blocker-treated patients compared to control-treated patients. In the controlled portions of 34 global adalimumab clinical trials in adult patients with RA, PsA, AS, CD, UC and Ps, 3 lymphomas occurred among 7304 adalimumab-treated patients versus 1 among 4232 control-treated patients. In 47 global controlled and uncontrolled clinical trials of adalimumab in adult patients with RA, PsA, AS, CD, UC and Ps with a median duration of approximately 0.6 years, including 23,036 patients and over 34,000 patient-years of adalimumab, the observed rate of lymphomas was approximately 0.11 per 100 patient-years. This is approximately 3-fold higher than expected in the general U.S. population according to the SEER database (adjusted for age, gender, and race).1 Rates of lymphoma in clinical trials of adalimumab cannot be compared to rates of lymphoma in clinical trials of other TNF blockers and may not predict the rates observed in a broader patient population. Patients with RA and other chronic inflammatory diseases, particularly those with highly active disease and/or chronic exposure to immunosuppressant therapies, may be at a higher risk (up to several fold) than the general population for the development of lymphoma, even in the absence of TNF blockers. Post-marketing cases of acute and chronic leukemia have been reported in association with TNF-blocker use in RA and other indications. Even in the absence of TNF-blocker therapy, patients with RA may be at a higher risk (approximately 2-fold) than the general population for the development of leukemia.
### Malignancies in Pediatric Patients and Young Adults
Malignancies, some fatal, have been reported among children, adolescents, and young adults who received treatment with TNF-blockers (initiation of therapy ≤ 18 years of age), of which adalimumab is a member . Approximately half the cases were lymphomas, including Hodgkin's and non-Hodgkin's lymphoma. The other cases represented a variety of different malignancies and included rare malignancies usually associated with immunosuppression and malignancies that are not usually observed in children and adolescents. The malignancies occurred after a median of 30 months of therapy (range 1 to 84 months). Most of the patients were receiving concomitant immunosuppressants. These cases were reported post-marketing and are derived from a variety of sources including registries and spontaneous postmarketing reports.
Postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers including adalimumab . These cases have had a very aggressive disease course and have been fatal. The majority of reported TNF blocker cases have occurred in patients with Crohn's disease or ulcerative colitis and the majority were in adolescent and young adult males. Almost all of these patients had received treatment with the immunosuppressants azathioprine or 6-mercaptopurine (6–MP) concomitantly with a TNF blocker at or prior to diagnosis. It is uncertain whether the occurrence of HSTCL is related to use of a TNF blocker or a TNF blocker in combination with these other immunosuppressants. The potential risk with the combination of azathioprine or 6-mercaptopurine and adalimumab should be carefully considered.
## Hypersensitivity Reactions
Anaphylaxis and angioneurotic edema have been reported following adalimumab administration. If an anaphylactic or other serious allergic reaction occurs, immediately discontinue administration of adalimumab and institute appropriate therapy. In clinical trials of adalimumab in adults, allergic reactions (e.g., allergic rash, anaphylactoid reaction, fixed drug reaction, non-specified drug reaction, urticaria) have been observed.
## Hepatitis B Virus Reactivation
Use of TNF blockers, including adalimumab, may increase the risk of reactivation of hepatitis B virus (HBV) in patients who are chronic carriers of this virus. In some instances, HBV reactivation occurring in conjunction with TNF blocker therapy has been fatal. The majority of these reports have occurred in patients concomitantly receiving other medications that suppress the immune system, which may also contribute to HBV reactivation. Evaluate patients at risk for HBV infection for prior evidence of HBV infection before initiating TNF blocker therapy. Exercise caution in prescribing TNF blockers for patients identified as carriers of HBV. Adequate data are not available on the safety or efficacy of treating patients who are carriers of HBV with anti-viral therapy in conjunction with TNF blocker therapy to prevent HBV reactivation. For patients who are carriers of HBV and require treatment with TNF blockers, closely monitor such patients for clinical and laboratory signs of active HBV infection throughout therapy and for several months following termination of therapy. In patients who develop HBV reactivation, stop adalimumab and initiate effective anti-viral therapy with appropriate supportive treatment. The safety of resuming TNF blocker therapy after HBV reactivation is controlled is not known. Therefore, exercise caution when considering resumption of adalimumab therapy in this situation and monitor patients closely.
## Neurologic Reactions
Use of TNF blocking agents, including adalimumab, has been associated with rare cases of new onset or exacerbation of clinical symptoms and/or radiographic evidence of central nervous system demyelinating disease, including multiple sclerosis (MS) and optic neuritis, and peripheral demyelinating disease, including Guillain-Barré syndrome. Exercise caution in considering the use of adalimumab in patients with preexisting or recent-onset central or peripheral nervous system demyelinating disorders.
## Hematological Reactions
Rare reports of pancytopenia including aplastic anemia have been reported with TNF blocking agents. Adverse reactions of the hematologic system, including medically significant cytopenia (e.g., thrombocytopenia, leukopenia) have been infrequently reported with adalimumab. The causal relationship of these reports to adalimumab remains unclear. Advise all patients to seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias or infection (e.g., persistent fever, bruising, bleeding, pallor) while on adalimumab. Consider discontinuation of adalimumab therapy in patients with confirmed significant hematologic abnormalities.
## Use with anakinra
Concurrent use of anakinra (an interleukin-1 antagonist) and another TNF-blocker, was associated with a greater proportion of serious infections and neutropenia and no added benefit compared with the TNF-blocker alone in patients with RA. Therefore, the combination of adalimumab and anakinra is not recommended
## Heart Failure
Cases of worsening congestive heart failure (CHF) and new onset CHF have been reported with TNF blockers. Cases of worsening CHF have also been observed with adalimumab. adalimumab has not been formally studied in patients with CHF; however, in clinical trials of another TNF blocker, a higher rate of serious CHF-related adverse reactions was observed. Exercise caution when using adalimumab in patients who have heart failure and monitor them carefully.
## Autoimmunity
Treatment with adalimumab may result in the formation of autoantibodies and, rarely, in the development of a lupus-like syndrome. If a patient develops symptoms suggestive of a lupus-like syndrome following treatment with adalimumab, discontinue treatment
## Immunizations
In a placebo-controlled clinical trial of patients with RA, no difference was detected in anti-pneumococcal antibody response between adalimumab and placebo treatment groups when the pneumococcal polysaccharide vaccine and influenza vaccine were administered concurrently with adalimumab. Similar proportions of patients developed protective levels of anti-influenza antibodies between adalimumab and placebo treatment groups; however, titers in aggregate to influenza antigens were moderately lower in patients receiving adalimumab. The clinical significance of this is unknown. Patients on adalimumab may receive concurrent vaccinations, except for live vaccines. No data are available on the secondary transmission of infection by live vaccines in patients receiving adalimumab.
It is recommended that JIA patients, if possible, be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating adalimumab therapy. Patients on adalimumab may receive concurrent vaccinations, except for live vaccines.
## Use with abatacept
In controlled trials, the concurrent administration of TNF-blockers and abatacept was associated with a greater proportion of serious infections than the use of a TNF-blocker alone; the combination therapy, compared to the use of a TNF-blocker alone, has not demonstrated improved clinical benefit in the treatment of RA. Therefore, the combination of abatacept with TNF-blockers including adalimumab is not recommended
# Adverse Reactions
## Clinical Trials Experience
Because clinical trials are conducted under widely varying and controlled conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not predict the rates observed in a broader patient population in clinical practice.
The most common adverse reaction with adalimumab was injection site reactions. In placebo-controlled trials, 20% of patients treated with adalimumab developed injection site reactions (erythema and/or itching, hemorrhage, pain or swelling), compared to 14% of patients receiving placebo. Most injection site reactions were described as mild and generally did not necessitate drug discontinuation.
The proportion of patients who discontinued treatment due to adverse reactions during the double-blind, placebo-controlled portion of studies in patients with RA (i.e., Studies RA-I, RA-II, RA-III and RA-IV) was 7% for patients taking adalimumab and 4% for placebo-treated patients. The most common adverse reactions leading to discontinuation of adalimumab in these RA studies were clinical flare reaction (0.7%), rash (0.3%) and pneumonia (0.3%).
Infections
In the controlled portions of the 34 global adalimumab clinical trials in adult patients with RA, PsA, AS, CD, UC and Ps, the rate of serious infections was 4.6 per 100 patient-years in 7304 adalimumab-treated patients versus a rate of 3.1 per 100 patient-years in 4232 control-treated patients. Serious infections observed included pneumonia, septic arthritis, prosthetic and post-surgical infections, erysipelas, cellulitis, diverticulitis, and pyelonephritis .
Tuberculosis and Opportunistic Infections
In 47 global controlled and uncontrolled clinical trials in RA, PsA, AS, CD, UC and Ps that included 23,036 adalimumab-treated patients, the rate of reported active tuberculosis was 0.22 per 100 patient-years and the rate of positive PPD conversion was 0.08 per 100 patient-years. In a subgroup of 9396 U.S. and Canadian adalimumab-treated patients, the rate of reported active TB was 0.07 per 100 patient-years and the rate of positive PPD conversion was 0.08 per 100 patient-years. These trials included reports of miliary, lymphatic, peritoneal, and pulmonary TB. Most of the TB cases occurred within the first eight months after initiation of therapy and may reflect recrudescence of latent disease. In these global clinical trials, cases of serious opportunistic infections have been reported at an overall rate of 0.08 per 100 patient-years. Some cases of serious opportunistic infections and TB have been fatal .
Autoantibodies
In the rheumatoid arthritis controlled trials, 12% of patients treated with adalimumab and 7% of placebo-treated patients that had negative baseline ANA titers developed positive titers at week 24. Two patients out of 3046 treated with adalimumab developed clinical signs suggestive of new-onset lupus-like syndrome. The patients improved following discontinuation of therapy. No patients developed lupus nephritis or central nervous system symptoms. The impact of long-term treatment with adalimumab on the development of autoimmune diseases is unknown.
Liver Enzyme Elevations
There have been reports of severe hepatic reactions including acute liver failure in patients receiving TNF-blockers. In controlled Phase 3 trials of adalimumab (40 mg SC every other week) in patients with RA, PsA, and AS with control period duration ranging from 4 to 104 weeks, ALT elevations ≥ 3 x ULN occurred in 3.5% of adalimumab-treated patients and 1.5% of control-treated patients. Since many of these patients in these trials were also taking medications that cause liver enzyme elevations (e.g., NSAIDS, MTX), the relationship between adalimumab and the liver enzyme elevations is not clear. In controlled Phase 3 trials of adalimumab (initial doses of 160 mg and 80 mg, or 80 mg and 40 mg on Days 1 and 15, respectively, followed by 40 mg every other week) in patients with CD with control period duration ranging from 4 to 52 weeks, ALT elevations ≥ 3 x ULN occurred in 0.9% of adalimumab-treated patients and 0.9% of control-treated patients. In controlled Phase 3 trials of adalimumab (initial doses of 160 mg and 80 mg on Days 1 and 15 respectively, followed by 40 mg every other week) in patients with UC with control period duration ranging from 1 to 52 weeks, ALT elevations ≥3 x ULN occurred in 1.5% of adalimumab-treated patients and 1.0% of control-treated patients. In controlled Phase 3 trials of adalimumab (initial dose of 80 mg then 40 mg every other week) in patients with Ps with control period duration ranging from 12 to 24 weeks, ALT elevations ≥ 3 x ULN occurred in 1.8% of adalimumab-treated patients and 1.8% of control-treated patients.
Immunogenicity
Patients in Studies RA-I, RA-II, and RA-III were tested at multiple time points for antibodies to adalimumab during the 6- to 12-month period. Approximately 5% (58 of 1062) of adult RA patients receiving adalimumab developed low-titer antibodies to adalimumab at least once during treatment, which were neutralizing in vitro. Patients treated with concomitant methotrexate (MTX) had a lower rate of antibody development than patients on adalimumab monotherapy (1% versus 12%). No apparent correlation of antibody development to adverse reactions was observed. With monotherapy, patients receiving every other week dosing may develop antibodies more frequently than those receiving weekly dosing. In patients receiving the recommended dosage of 40 mg every other week as monotherapy, the ACR 20 response was lower among antibody-positive patients than among antibody-negative patients. The long-term immunogenicity of adalimumab is unknown.
In patients with JIA, adalimumab antibodies were identified in 16% of adalimumab-treated patients. In patients receiving concomitant MTX, the incidence was 6% compared to 26% with adalimumab monotherapy.
In patients with AS, the rate of development of antibodies to adalimumab in adalimumab-treated patients was comparable to patients with RA.
In patients with PsA, the rate of antibody development in patients receiving adalimumab monotherapy was comparable to patients with RA; however, in patients receiving concomitant MTX the rate was 7% compared to 1% in RA.
In patients with CD, the rate of antibody development was 3%.
In patients with moderately to severely active UC, the rate of antibody development in patients receiving adalimumab was 5%. However, due to the limitation of the assay conditions, antibodies to adalimumab could be detected only when serum adalimumab levels were < 2 ug/ml. Among the patients whose serum adalimumab levels were < 2 ug/ml (approximately 25% of total patients studied), the immunogenicity rate was 20.7%.
In patients with Ps, the rate of antibody development with adalimumab monotherapy was 8%. However, due to the limitation of the assay conditions, antibodies to adalimumab could be detected only when serum adalimumab levels were < 2 ug/ml. Among the patients whose serum adalimumab levels were < 2 ug/ml (approximately 40% of total patients studied), the immunogenicity rate was 20.7%. In Ps patients who were on adalimumab monotherapy and subsequently withdrawn from the treatment, the rate of antibodies to adalimumab after retreatment was similar to the rate observed prior to withdrawal.
The data reflect the percentage of patients whose test results were considered positive for antibodies to adalimumab in an ELISA assay, and are highly dependent on the sensitivity and specificity of the assay. The observed incidence of antibody (including neutralizing antibody) positivity in an assay is highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to adalimumab with the incidence of antibodies to other products may be misleading.
Other Adverse Reactions
Rheumatoid Arthritis Clinical Studies
The data described below reflect exposure to adalimumab in 2468 patients, including 2073 exposed for 6 months, 1497 exposed for greater than one year and 1380 in adequate and well-controlled studies (Studies RA-I, RA-II, RA-III, and RA-IV). adalimumab was studied primarily in placebo-controlled trials and in long-term follow up studies for up to 36 months duration. The population had a mean age of 54 years, 77% were female, 91% were Caucasian and had moderately to severely active rheumatoid arthritis. Most patients received 40 mg adalimumab every other week.
Table 1 summarizes reactions reported at a rate of at least 5% in patients treated with adalimumab 40 mg every other week compared to placebo and with an incidence higher than placebo. In Study RA-III, the types and frequencies of adverse reactions in the second year open-label extension were similar to those observed in the one-year double-blind portion.
Less Common Adverse Reactions in Rheumatoid Arthritis Clinical Studies
Other infrequent serious adverse reactions that do not appear in the Warnings and Precautions or Adverse Reaction sections that occurred at an incidence of less than 5% in adalimumab-treated patients in RA studies were:
Body As A Whole: Pain in extremity, pelvic pain, surgery, thorax pain
Cardiovascular System: Arrhythmia, atrial fibrillation, chest pain, coronary artery disorder, heart arrest, hypertensive encephalopathy, myocardial infarct, palpitation, pericardial effusion, pericarditis, syncope, tachycardia
Digestive System: Cholecystitis, cholelithiasis, esophagitis, gastroenteritis, gastrointestinal hemorrhage, hepatic necrosis, vomiting
Endocrine System: Parathyroid disorder
Hemic And Lymphatic System: Agranulocytosis, polycythemia
Metabolic And Nutritional Disorders: Dehydration, healing abnormal, ketosis, paraproteinemia, peripheral edema
Musculo-Skeletal System: Arthritis, bone disorder, bone fracture (not spontaneous), bone necrosis, joint disorder, muscle cramps, myasthenia, pyogenic arthritis, synovitis, tendon disorder
Neoplasia: Adenoma
Nervous System: Confusion, paresthesia, subdural hematoma, tremor
Respiratory System: Asthma, bronchospasm, dyspnea, lung function decreased, pleural effusion
Special Senses: Cataract
Thrombosis: Thrombosis leg
Urogenital System: Cystitis, kidney calculus, menstrual disorder
Juvenile Idiopathic Arthritis Clinical Studies
In general, the adverse reactions in the adalimumab-treated pediatric patients in the juvenile idiopathic arthritis (JIA) trial were similar in frequency and type to those seen in adult patients . Important findings and differences from adults are discussed in the following paragraphs.
adalimumab was studied in 171 pediatric patients, 4 to 17 years of age, with polyarticular JIA. Severe adverse reactions reported in the study included neutropenia, streptococcal pharyngitis, increased aminotransferases, herpes zoster, myositis, metrorrhagia, appendicitis. Serious infections were observed in 4% of patients within approximately 2 years of initiation of treatment with adalimumab and included cases of herpes simplex, pneumonia, urinary tract infection, pharyngitis, and herpes zoster.
A total of 45% of children experienced an infection while receiving adalimumab with or without concomitant MTX in the first 16 weeks of treatment. The types of infections reported in adalimumab-treated patients were generally similar to those commonly seen in JIA patients who are not treated with TNF blockers. Upon initiation of treatment, the most common adverse reactions occurring in the pediatric population treated with adalimumab were injection site pain and injection site reaction (19% and 16%, respectively). A less commonly reported adverse event in children receiving adalimumab was granuloma annulare which did not lead to discontinuation of adalimumab treatment.
In the first 48 weeks of treatment, non-serious hypersensitivity reactions were seen in approximately 6% of children and included primarily localized allergic hypersensitivity reactions and allergic rash.
Isolated mild to moderate elevations of liver aminotransferases (ALT more common than AST) were observed in children with JIA exposed to adalimumab alone; liver enzyme test elevations were more frequent among those treated with the combination of adalimumab and MTX than those treated with adalimumab alone. In general, these elevations did not lead to discontinuation of adalimumab treatment.
In the JIA trial, 10% of patients treated with adalimumab who had negative baseline anti-dsDNA antibodies developed positive titers after 48 weeks of treatment. No patient developed clinical signs of autoimmunity during the clinical trial.
Approximately 15% of children treated with adalimumab developed mild-to-moderate elevations of creatine phosphokinase (CPK). Elevations exceeding 5 times the upper limit of normal were observed in several patients. CPK levels decreased or returned to normal in all patients. Most patients were able to continue adalimumab without interruption.
Psoriatic Arthritis and Ankylosing Spondylitis Clinical Studies
adalimumab has been studied in 395 patients with psoriatic arthritis (PsA) in two placebo-controlled trials and in an open label study and in 393 patients with ankylosing spondylitis (AS) in two placebo-controlled studies. The safety profile for patients with PsA and AS treated with adalimumab 40 mg every other week was similar to the safety profile seen in patients with RA, adalimumab Studies RA-I through IV.
Crohn’s Disease Clinical Studies
adalimumab has been studied in 1478 patients with Crohn’s disease (CD) in four placebo-controlled and two open-label extension studies. The safety profile for patients with CD treated with adalimumab was similar to the safety profile seen in patients with RA.
Ulcerative Colitis Clinical Studies
adalimumab has been studied in 1010 patients with ulcerative colitis (UC) in two placebo-controlled studies and one open-label extension study. The safety profile for patients with UC treated with adalimumab was similar to the safety profile seen in patients with RA.
Plaque Psoriasis Clinical Studies
adalimumab has been studied in 1696 patients with plaque psoriasis (Ps) in placebo-controlled and open-label extension studies. The safety profile for patients with Ps treated with adalimumab was similar to the safety profile seen in patients with RA with the following exceptions. In the placebo-controlled portions of the clinical trials in Ps patients, adalimumab-treated patients had a higher incidence of arthralgia when compared to controls (3% vs. 1%).
## Postmarketing Experience
The following adverse reactions have been identified during post-approval use of adalimumab. 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 adalimumab exposure.
Gastrointestinal disorders: Diverticulitis, large bowel perforations including perforations associated with diverticulitis and appendiceal perforations associated with appendicitis, pancreatitis
General disorders and administration site conditions: Pyrexia
Hepato-biliary disorders: Liver failure, hepatitis
Immune system disorders: Sarcoidosis
Neoplasms benign, malignant and unspecified (incl cysts and polyps): Merkel Cell Carcinoma (neuroendocrine carcinoma of the skin)
Nervous system disorders: Demyelinating disorders (e.g., optic neuritis, Guillain-Barré syndrome), cerebrovascular accident
Respiratory disorders: Interstitial lung disease, including pulmonary fibrosis, pulmonary embolism
Skin reactions: Stevens Johnson Syndrome, cutaneous vasculitis, erythema multiforme, new or worsening psoriasis (all sub-types including pustular and palmoplantar), alopecia
Vascular disorders: Systemic vasculitis, deep vein thrombosis
# Drug Interactions
## Methotrexate
adalimumab has been studied in rheumatoid arthritis (RA) patients taking concomitant methotrexate (MTX). Although MTX reduced the apparent adalimumab clearance, the data do not suggest the need for dose adjustment of either adalimumab or MTX .
## Biological Products
In clinical studies in patients with RA, an increased risk of serious infections has been seen with the combination of TNF blockers with anakinra or abatacept, with no added benefit; therefore, use of adalimumab with abatacept or anakinra is not recommended in patients with RA . A higher rate of serious infections has also been observed in patients with RA treated with rituximab who received subsequent treatment with a TNF blocker. There is insufficient information regarding the concomitant use of adalimumab and other biologic products for the treatment of RA, PsA, AS, CD, UC, and Ps. Concomitant administration of adalimumab with other biologic DMARDS (e.g., anakinra and abatacept) or other TNF blockers is not recommended based upon the possible increased risk for infections and other potential pharmacological interactions.
## Live Vaccines
Avoid the use of live vaccines with adalimumab .
## Cytochrome P450 Substrates
The formation of CYP450 enzymes may be suppressed by increased levels of cytokines (e.g., TNFα, IL-6) during chronic inflammation. It is possible for a molecule that antagonizes cytokine activity, such as adalimumab, to influence the formation of CYP450 enzymes. Upon initiation or discontinuation of adalimumab in patients being treated with CYP450 substrates with a narrow therapeutic index, monitoring of the effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) is recommended and the individual dose of the drug product may be adjusted as needed.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
### Risk Summary
Adequate and well controlled studies with adalimumab have not been conducted in pregnant women. Adalimumab is an IgG1 monoclonal antibody and IgG1 is actively transferred across the placenta during the third trimester of pregnancy. Adalimumab serum levels were obtained from ten women treated with adalimumab during pregnancy and eight newborn infants suggest active placental transfer of adalimumab. No fetal harm was observed in reproductive studies performed in cynomolgus monkeys. Because animal reproductive studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
### Clinical Considerations
In general, monoclonal antibodies are transported across the placenta in a linear fashion as pregnancy progresses, with the largest amount transferred during the third trimester.
### Human Data
In an independent clinical study conducted in ten pregnant women with inflammatory bowel disease treated with adalimumab, adalimumab concentrations were measured in maternal blood as well as in cord (n=10) and infant blood (n=8) on the day of birth. The last dose of adalimumab was given between 1 and 56 days prior to delivery. Adalimumab concentrations were 0.16-19.7 µg/mL in cord blood, 4.28-17.7 µg/mL in infant blood, and 0-16.1 µg/mL in maternal blood. In all but one case, the cord blood level of adalimumab was higher than the maternal level, suggesting adalimumab actively crosses the placenta. In addition, one infant had levels at each of the following: 6 weeks (1.94 µg/mL), 7 weeks (1.31 µg/mL), 8 weeks (0.93 µg/mL), and 11 weeks (0.53 µg/mL), suggesting adalimumab can be detected in the serum of infants exposed in utero for at least 3 months from birth.
### Animal Data
An embryo-fetal perinatal developmental toxicity study has been performed in cynomolgus monkeys at dosages up to 100 mg/kg (266 times human AUC when given 40 mg subcutaneously with methotrexate every week or 373 times human AUC when given 40 mg subcutaneously without methotrexate) and has revealed no evidence of harm to the fetuses due to adalimumab.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Adalimumab in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Adalimumab during labor and delivery.
### Nursing Mothers
Limited data from published literature indicate that adalimumab is present in low levels in human milk and is not likely to be absorbed by a breastfed infant. However, no data is available on the absorption of adalimumab from breastmilk in newborn or preterm infants. Caution should be exercised when adalimumab is administered to a nursing woman.
### Pediatric Use
Safety and efficacy of adalimumab in pediatric patients for uses other than juvenile idiopathic arthritis (JIA) have not been established. Due to its inhibition of TNFα, adalimumab administered during pregnancy could affect immune response in the in utero-exposed newborn and infant. Data from eight infants exposed to adalimumab in utero, suggest adalimumab crosses the placenta. The clinical significance of elevated adalimumab levels in infants is unknown. The safety of administering live or live-attenuated vaccines in exposed infants is unknown. Risks and benefits should be considered prior to vaccinating (live or live-attenuated) exposed infants.
Post-marketing cases of lymphoma, including hepatosplenic T-cell lymphoma and other malignancies, some fatal, have been reported among children, adolescents, and young adults who received treatment with TNF-blockers including adalimumab
Juvenile Idiopathic Arthritis
In the JIA trial, adalimumab was shown to reduce signs and symptoms of active polyarticular JIA in patients 4 to 17 years of age . adalimumab has not been studied in children less than 4 years of age, and there are limited data on adalimumab treatment in children with weight <15 kg.
The safety of adalimumab in pediatric patients in the JIA trial was generally similar to that observed in adults with certain exceptions
### Geriatic Use
A total of 519 RA patients 65 years of age and older, including 107 patients 75 years of age and older, received adalimumab in clinical studies RA-I through IV. No overall difference in effectiveness was observed between these patients and younger patients. The frequency of serious infection and malignancy among adalimumab treated patients over 65 years of age was higher than for those under 65 years of age. Because there is a higher incidence of infections and malignancies in the elderly population, use caution when treating the elderly.
### Gender
There is no FDA guidance on the use of Adalimumab with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Adalimumab with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Adalimumab in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Adalimumab in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Adalimumab in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Adalimumab in patients who are immunocompromised.
# Administration and Monitoring
### Administration
adalimumab is administered by subcutaneous injection.
adalimumab is intended for use under the guidance and supervision of a physician. A patient may self-inject adalimumab if a physician determines that it is appropriate, and with medical follow-up, as necessary, after proper training in subcutaneous injection technique.
Carefully inspect the solution in the adalimumab Pen or prefilled syringe for particulate matter and discoloration prior to subcutaneous administration. If particulates and discolorations are noted, do not use the product. adalimumab does not contain preservatives; therefore, discard unused portions of drug remaining from the syringe. NOTE: Instruct patients sensitive to latex not to handle the needle cover of the syringe because it contains dry rubber (latex).
Instruct patients using the adalimumab Pen or prefilled syringe to inject the full amount in the syringe (0.8 mL), which provides 40 mg of adalimumab, according to the directions provided in the Instructions for Use .
Instruct patients (15 kg to <30 kg) using the pediatric pre-filled syringe, or their caregivers, to inject the full amount in the syringe (0.4 mL), which provides 20 mg of adalimumab, according to the directions provided in the Instructions for Use.
Rotate injection sites and do not give injections into areas where the skin is tender, bruised, red or hard.
The adalimumab institutional use vial is for use and administration within an institutional setting only, such as a hospital, physician’s office or clinic. Withdraw the dose using a sterile needle and syringe and administer promptly by a healthcare provider within an institutional setting. Only administer one dose per vial. The vial does not contain preservatives; therefore, discard unused portions.
### Monitoring
Prior to initiating adalimumab and periodically during therapy, evaluate patients for active tuberculosis and test for latent infection
# IV Compatibility
There is limited information about the IV Compatibility.
# Overdosage
Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately.
# Pharmacology
## Mechanism of Action
Adalimumab binds specifically to TNF-alpha and blocks its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface TNF expressing cells in vitro in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (TNF-beta). TNF is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. Elevated levels of TNF are found in the synovial fluid of patients with RA, JIA, PsA, and AS and play an important role in both the pathologic inflammation and the joint destruction that are hallmarks of these diseases. Increased levels of TNF are also found in psoriasis plaques. In Ps, treatment with adalimumab may reduce the epidermal thickness and infiltration of inflammatory cells. The relationship between these pharmacodynamic activities and the mechanism(s) by which adalimumab exerts its clinical effects is unknown.
Adalimumab also modulates biological responses that are induced or regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M).
## Structure
adalimumab (adalimumab) is a recombinant human IgG1 monoclonal antibody specific for human tumor necrosis factor (TNF). adalimumab was created using phage display technology resulting in an antibody with human derived heavy and light chain variable regions and human IgG1:k constant regions. Adalimumab is produced by recombinant DNA technology in a mammalian cell expression system and is purified by a process that includes specific viral inactivation and removal steps. It consists of 1330 amino acids and has a molecular weight of approximately 148 kilodaltons.
adalimumab is supplied as a sterile, preservative-free solution of adalimumab for subcutaneous administration. The drug product is supplied as either a single-use, prefilled pen (adalimumab Pen) or as a single-use, 1 mL prefilled glass syringe. Enclosed within the pen is a single-use, 1 mL prefilled glass syringe. The solution of adalimumab is clear and colorless, with a pH of about 5.2.
Each prefilled syringe delivers 0.8 mL (40 mg) of drug product. Each 0.8 mL of adalimumab contains 40 mg adalimumab, 4.93 mg sodium chloride, 0.69 mg monobasic sodium phosphate dihydrate, 1.22 mg dibasic sodium phosphate dihydrate, 0.24 mg sodium citrate, 1.04 mg citric acid monohydrate, 9.6 mg mannitol, 0.8 mg polysorbate 80, and Water for Injection, USP. Sodium hydroxide added as necessary to adjust pH.
Each pediatric prefilled syringe delivers 0.4 mL (20 mg) of drug product. Each 0.4 mL of adalimumab contains 20 mg adalimumab, 2.47 mg sodium chloride, 0.34 mg monobasic sodium phosphate dihydrate, 0.61 mg dibasic sodium phosphate dihydrate, 0.12 mg sodium citrate, 0.52 mg citric acid monohydrate, 4.8 mg mannitol, 0.4 mg polysorbate 80, and Water for Injection, USP. Sodium hydroxide added as necessary to adjust pH.
## Pharmacodynamics
After treatment with adalimumab, a decrease in levels of acute phase reactants of inflammation (C-reactive protein and erythrocyte sedimentation rate ) and serum cytokines (IL-6) was observed compared to baseline in patients with rheumatoid arthritis. A decrease in CRP levels was also observed in patients with Crohn’s disease and ulcerative colitis. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that produce tissue remodeling responsible for cartilage destruction were also decreased after adalimumab administration.
## Pharmacokinetics
The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 µg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three studies following a single 40 mg subcutaneous dose was 64%. The pharmacokinetics of adalimumab were linear over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose.
The single dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The distribution volume (Vss) ranged from 4.7 to 6.0 L. The systemic clearance of adalimumab is approximately 12 mL/hr. The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. Adalimumab concentrations in the synovial fluid from five rheumatoid arthritis patients ranged from 31 to 96% of those in serum.
In RA patients receiving 40 mg adalimumab every other week, adalimumab mean steady-state trough concentrations of approximately 5 µg/mL and 8 to 9 µg/mL, were observed without and with methotrexate (MTX), respectively. MTX reduced adalimumab apparent clearance after single and multiple dosing by 29% and 44% respectively, in patients with RA. Mean serum adalimumab trough levels at steady state increased approximately proportionally with dose following 20, 40, and 80 mg every other week and every week subcutaneous dosing. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time.
Adalimumab mean steady-state trough concentrations were slightly higher in psoriatic arthritis patients treated with 40 mg adalimumab every other week (6 to 10 µg/mL and 8.5 to 12 µg/mL, without and with MTX, respectively) compared to the concentrations in RA patients treated with the same dose.
The pharmacokinetics of adalimumab in patients with AS were similar to those in patients with RA.
In patients with CD, the loading dose of 160 mg adalimumab on Week 0 followed by 80 mg adalimumab on Week 2 achieves mean serum adalimumab trough levels of approximately 12 µg/mL at Week 2 and Week 4. Mean steady-state trough levels of approximately 7 µg/mL were observed at Week 24 and Week 56 in CD patients after receiving a maintenance dose of 40 mg adalimumab every other week.
In patients with UC, the loading dose of 160 mg adalimumab on Week 0 followed by 80 mg adalimumab on Week 2 achieves mean serum adalimumab trough levels of approximately 12 µg/mL at Week 2 and Week 4. Mean steady-state trough level of approximately 8 µg/mL was observed at Week 52 in UC patients after receiving a dose of 40 mg adalimumab every other week, and approximately 15 µg/mL at Week 52 in UC patients who increased to a dose of 40 mg adalimumab every week.
In patients with Ps, the mean steady-state trough concentration was approximately 5 to 6 µg/mL during adalimumab 40 mg every other week monotherapy treatment.
Population pharmacokinetic analyses in patients with RA revealed that there was a trend toward higher apparent clearance of adalimumab in the presence of anti-adalimumab antibodies, and lower clearance with increasing age in patients aged 40 to >75 years.
Minor increases in apparent clearance were also predicted in RA patients receiving doses lower than the recommended dose and in RA patients with high rheumatoid factor or CRP concentrations. These increases are not likely to be clinically important.
No gender-related pharmacokinetic differences were observed after correction for a patient’s body weight. Healthy volunteers and patients with rheumatoid arthritis displayed similar adalimumab pharmacokinetics.
No pharmacokinetic data are available in patients with hepatic or renal impairment.
In subjects with JIA (4 to 17 years of age), the mean steady-state trough serum adalimumab concentrations for subjects weighing <30 kg receiving 20 mg adalimumab subcutaneously every other week as monotherapy or with concomitant methotrexate were 6.8 µg/mL and 10.9 µg/mL, respectively. The mean steady-state trough serum adalimumab concentrations for subjects weighing ≥30 kg receiving 40 mg adalimumab subcutaneously every other week as monotherapy or with concomitant methotrexate were 6.6 µg/mL and 8.1 µg/mL, respectively.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term animal studies of adalimumab have not been conducted to evaluate the carcinogenic potential or its effect on fertility. No clastogenic or mutagenic effects of adalimumab were observed in the in vivo mouse micronucleus test or the Salmonella-Escherichia coli (Ames) assay, respectively.
# Clinical Studies
## Rheumatoid Arthritis
The efficacy and safety of adalimumab were assessed in five randomized, double-blind studies in patients ≥18 years of age with active rheumatoid arthritis (RA) diagnosed according to American College of Rheumatology (ACR) criteria. Patients had at least 6 swollen and 9 tender joints. adalimumab was administered subcutaneously in combination with methotrexate (MTX) (12.5 to 25 mg, Studies RA-I, RA-III and RA-V) or as monotherapy (Studies RA-II and RA-V) or with other disease-modifying anti-rheumatic drugs (DMARDs) (Study RA-IV).
Study RA-I evaluated 271 patients who had failed therapy with at least one but no more than four DMARDs and had inadequate response to MTX. Doses of 20, 40 or 80 mg of adalimumab or placebo were given every other week for 24 weeks.
Study RA-II evaluated 544 patients who had failed therapy with at least one DMARD. Doses of placebo, 20 or 40 mg of adalimumab were given as monotherapy every other week or weekly for 26 weeks.
Study RA-III evaluated 619 patients who had an inadequate response to MTX. Patients received placebo, 40 mg of adalimumab every other week with placebo injections on alternate weeks, or 20 mg of adalimumab weekly for up to 52 weeks. Study RA-III had an additional primary endpoint at 52 weeks of inhibition of disease progression (as detected by X-ray results). Upon completion of the first 52 weeks, 457 patients enrolled in an open-label extension phase in which 40 mg of adalimumab was administered every other week for up to 5 years.
Study RA-IV assessed safety in 636 patients who were either DMARD-naive or were permitted to remain on their pre-existing rheumatologic therapy provided that therapy was stable for a minimum of 28 days. Patients were randomized to 40 mg of adalimumab or placebo every other week for 24 weeks.
Study RA-V evaluated 799 patients with moderately to severely active RA of less than 3 years duration who were ≥18 years old and MTX naïve. Patients were randomized to receive either MTX (optimized to 20 mg/week by week 8), adalimumab 40 mg every other week or adalimumab/MTX combination therapy for 104 weeks. Patients were evaluated for signs and symptoms, and for radiographic progression of joint damage. The median disease duration among patients enrolled in the study was 5 months. The median MTX dose achieved was 20 mg.
Clinical Response
The percent of adalimumab treated patients achieving ACR 20, 50 and 70 responses in Studies RA-II and III are shown in Table 2.
The results of Study RA-I were similar to Study RA-III; patients receiving adalimumab 40 mg every other week in Study RA-I also achieved ACR 20, 50 and 70 response rates of 65%, 52% and 24%, respectively, compared to placebo responses of 13%, 7% and 3% respectively, at 6 months (p<0.01).
The results of the components of the ACR response criteria for Studies RA-II and RA-III are shown in Table 3. ACR response rates and improvement in all components of ACR response were maintained to week 104. Over the 2 years in Study RA-III, 20% of adalimumab patients receiving 40 mg every other week (EOW) achieved a major clinical response, defined as maintenance of an ACR 70 response over a 6-month period. ACR responses were maintained in similar proportions of patients for up to 5 years with continuous adalimumab treatment in the open-label portion of Study RA-III.
The time course of ACR 20 response for Study RA-III is shown in Figure 1.
In Study RA-III, 85% of patients with ACR 20 responses at week 24 maintained the response at 52 weeks. The time course of ACR 20 response for Study RA-I and Study RA-II were similar.
In Study RA-IV, 53% of patients treated with adalimumab 40 mg every other week plus standard of care had an ACR 20 response at week 24 compared to 35% on placebo plus standard of care (p<0.001). No unique adverse reactions related to the combination of adalimumab (adalimumab) and other DMARDs were observed.
In Study RA-V with MTX naïve patients with recent onset RA, the combination treatment with adalimumab plus MTX led to greater percentages of patients achieving ACR responses than either MTX monotherapy or adalimumab monotherapy at Week 52 and responses were sustained at Week 104 (see Table 4).
At Week 52, all individual components of the ACR response criteria for Study RA-V improved in the adalimumab/MTX group and improvements were maintained to Week 104.
Radiographic Response
In Study RA-III, structural joint damage was assessed radiographically and expressed as change in Total Sharp Score (TSS) and its components, the erosion score and Joint Space Narrowing (JSN) score, at month 12 compared to baseline. At baseline, the median TSS was approximately 55 in the placebo and 40 mg every other week groups. The results are shown in Table 5. adalimumab/MTX treated patients demonstrated less radiographic progression than patients receiving MTX alone at 52 weeks.
In the open-label extension of Study RA-III, 77% of the original patients treated with any dose of adalimumab were evaluated radiographically at 2 years. Patients maintained inhibition of structural damage, as measured by the TSS. Fifty-four percent had no progression of structural damage as defined by a change in the TSS of zero or less. Fifty-five percent (55%) of patients originally treated with 40 mg adalimumab every other week have been evaluated radiographically at 5 years. Patients had continued inhibition of structural damage with 50% showing no progression of structural damage defined by a change in the TSS of zero or less.
In Study RA-V, structural joint damage was assessed as in Study RA-III. Greater inhibition of radiographic progression, as assessed by changes in TSS, erosion score and JSN was observed in the adalimumab/MTX combination group as compared to either the MTX or adalimumab monotherapy group at Week 52 as well as at Week 104 (see Table 6).
Physical Function Response
In studies RA-I through IV, adalimumab showed significantly greater improvement than placebo in the disability index of Health Assessment Questionnaire (HAQ-DI) from baseline to the end of study, and significantly greater improvement than placebo in the health-outcomes as assessed by The Short Form Health Survey (SF 36). Improvement was seen in both the Physical Component Summary (PCS) and the Mental Component Summary (MCS).
In Study RA-III, the mean (95% CI) improvement in HAQ-DI from baseline at week 52 was 0.60 (0.55, 0.65) for the adalimumab patients and 0.25 (0.17, 0.33) for placebo/MTX (p<0.001) patients. Sixty-three percent of adalimumab-treated patients achieved a 0.5 or greater improvement in HAQ-DI at week 52 in the double-blind portion of the study. Eighty-two percent of these patients maintained that improvement through week 104 and a similar proportion of patients maintained this response through week 260 (5 years) of open-label treatment. Mean improvement in the SF-36 was maintained through the end of measurement at week 156 (3 years).
In Study RA-V, the HAQ-DI and the physical component of the SF-36 showed greater improvement (p<0.001) for the adalimumab/MTX combination therapy group versus either the MTX monotherapy or the adalimumab monotherapy group at Week 52, which was maintained through Week 104.
## Juvenile Idiopathic Arthritis
The safety and efficacy of adalimumab were assessed in a multicenter, randomized, withdrawal, double-blind, parallel-group study in 171 children (4 to 17 years of age) with polyarticular juvenile idiopathic arthritis (JIA). In the study, the patients were stratified into two groups: MTX-treated or non-MTX-treated. All subjects had to show signs of active moderate or severe disease despite previous treatment with NSAIDs, analgesics, corticosteroids, or DMARDS. Subjects who received prior treatment with any biologic DMARDS were excluded from the study.
The study included four phases: an open-label lead in phase (OL-LI; 16 weeks), a double-blind randomized withdrawal phase (DB; 32 weeks), an open-label extension phase (OLE-BSA; up to 136 weeks), and an open-label fixed dose phase (OLE-FD; 16 weeks). In the first three phases of the study, adalimumab was administered based on body surface area at a dose of 24 mg/m2 up to a maximum total body dose of 40 mg subcutaneously (SC) every other week. In the OLE-FD phase, the patients were treated with 20 mg of adalimumab SC every other week if their weight was less than 30 kg and with 40 mg of adalimumab SC every other week if their weight was 30 kg or greater. Patients remained on stable doses of NSAIDs and or prednisone (≤0.2 mg/kg/day or 10 mg/day maximum).
Patients demonstrating a Pediatric ACR 30 response at the end of OL-LI phase were randomized into the double blind (DB) phase of the study and received either adalimumab or placebo every other week for 32 weeks or until disease flare. Disease flare was defined as a worsening of ≥30% from baseline in ≥3 of 6 Pediatric ACR core criteria, ≥2 active joints, and improvement of >30% in no more than 1 of the 6 criteria. After 32 weeks or at the time of disease flare during the DB phase, patients were treated in the open-label extension phase based on the BSA regimen (OLE-BSA), before converting to a fixed dose regimen based on body weight (OLE-FD phase).
Clinical Response
At the end of the 16-week OL-LI phase, 94% of the patients in the MTX stratum and 74% of the patients in the non-MTX stratum were Pediatric ACR 30 responders. In the DB phase significantly fewer patients who received adalimumab experienced disease flare compared to placebo, both without MTX (43% vs. 71%) and with MTX (37% vs. 65%). More patients treated with adalimumab continued to show pediatric ACR 30/50/70 responses at Week 48 compared to patients treated with placebo. Pediatric ACR responses were maintained for up to two years in the OLE phase in patients who received adalimumab throughout the study.
## Psoriatic Arthritis
The safety and efficacy of adalimumab was assessed in two randomized, double-blind, placebo controlled studies in 413 patients with psoriatic arthritis (PsA). Upon completion of both studies, 383 patients enrolled in an open-label extension study, in which 40 mg adalimumab was administered every other week.
Study PsA-I enrolled 313 adult patients with moderately to severely active PsA (>3 swollen and >3 tender joints) who had an inadequate response to NSAID therapy in one of the following forms: (1) distal interphalangeal (DIP) involvement (N=23); (2) polyarticular arthritis (absence of rheumatoid nodules and presence of plaque psoriasis) (N=210); (3) arthritis mutilans (N=1); (4) asymmetric PsA (N=77); or (5) AS-like (N=2). Patients on MTX therapy (158 of 313 patients) at enrollment (stable dose of ≤30 mg/week for >1 month) could continue MTX at the same dose. Doses of adalimumab 40 mg or placebo every other week were administered during the 24-week double-blind period of the study.
Compared to placebo, treatment with adalimumab resulted in improvements in the measures of disease activity (see Tables 7 and 8). Among patients with PsA who received adalimumab, the clinical responses were apparent in some patients at the time of the first visit (two weeks) and were maintained up to 88 weeks in the ongoing open-label study. Similar responses were seen in patients with each of the subtypes of psoriatic arthritis, although few patients were enrolled with the arthritis mutilans and ankylosing spondylitis-like subtypes. Responses were similar in patients who were or were not receiving concomitant MTX therapy at baseline.
Patients with psoriatic involvement of at least three percent body surface area (BSA) were evaluated for Psoriatic Area and Severity Index (PASI) responses. At 24 weeks, the proportions of patients achieving a 75% or 90% improvement in the PASI were 59% and 42% respectively, in the adalimumab group (N=69), compared to 1% and 0% respectively, in the placebo group (N=69) (p<0.001). PASI responses were apparent in some patients at the time of the first visit (two weeks). Responses were similar in patients who were or were not receiving concomitant MTX therapy at baseline.
Similar results were seen in an additional, 12-week study in 100 patients with moderate to severe psoriatic arthritis who had suboptimal response to DMARD therapy as manifested by ≥3 tender joints and ≥3 swollen joints at enrollment.
Radiographic Response
Radiographic changes were assessed in the PsA studies. Radiographs of hands, wrists, and feet were obtained at baseline and Week 24 during the double-blind period when patients were on adalimumab or placebo and at Week 48 when all patients were on open-label adalimumab. A modified Total Sharp Score (mTSS), which included distal interphalangeal joints (i.e., not identical to the TSS used for rheumatoid arthritis), was used by readers blinded to treatment group to assess the radiographs.
adalimumab-treated patients demonstrated greater inhibition of radiographic progression compared to placebo-treated patients and this effect was maintained at 48 weeks (see Table 9).
Physical Function Response
In Study PsA-I, physical function and disability were assessed using the HAQ Disability Index (HAQ-DI) and the SF-36 Health Survey. Patients treated with 40 mg of adalimumab every other week showed greater improvement from baseline in the HAQ-DI score (mean decreases of 47% and 49% at Weeks 12 and 24 respectively) in comparison to placebo (mean decreases of 1% and 3% at Weeks 12 and 24 respectively). At Weeks 12 and 24, patients treated with adalimumab showed greater improvement from baseline in the SF-36 Physical Component Summary score compared to patients treated with placebo, and no worsening in the SF-36 Mental Component Summary score. Improvement in physical function based on the HAQ-DI was maintained for up to 84 weeks through the open-label portion of the study.
## Ankylosing Spondylitis
The safety and efficacy of adalimumab 40 mg every other week was assessed in 315 adult patients in a randomized, 24 week double-blind, placebo-controlled study in patients with active ankylosing spondylitis (AS) who had an inadequate response to glucocorticoids, NSAIDs, analgesics, methotrexate or sulfasalazine. Active AS was defined as patients who fulfilled at least two of the following three criteria: (1) a Bath AS disease activity index (BASDAI) score ≥4 cm, (2) a visual analog score (VAS) for total back pain ≥ 40 mm, and (3) morning stiffness ≥ 1 hour. The blinded period was followed by an open-label period during which patients received adalimumab 40 mg every other week subcutaneously for up to an additional 28 weeks.
Improvement in measures of disease activity was first observed at Week 2 and maintained through 24 weeks as shown in Figure 2 and Table 10.
Responses of patients with total spinal ankylosis (n=11) were similar to those without total ankylosis.
Physical Function Response
In Study PsA-I, physical function and disability were assessed using the HAQ Disability Index (HAQ-DI) and the SF-36 Health Survey. Patients treated with 40 mg of adalimumab every other week showed greater improvement from baseline in the HAQ-DI score (mean decreases of 47% and 49% at Weeks 12 and 24 respectively) in comparison to placebo (mean decreases of 1% and 3% at Weeks 12 and 24 respectively). At Weeks 12 and 24, patients treated with adalimumab showed greater improvement from baseline in the SF-36 Physical Component Summary score compared to patients treated with placebo, and no worsening in the SF-36 Mental Component Summary score. Improvement in physical function based on the HAQ-DI was maintained for up to 84 weeks through the open-label portion of the study.
## Ankylosing Spondylitis
The safety and efficacy of adalimumab 40 mg every other week was assessed in 315 adult patients in a randomized, 24 week double-blind, placebo-controlled study in patients with active ankylosing spondylitis (AS) who had an inadequate response to glucocorticoids, NSAIDs, analgesics, methotrexate or sulfasalazine. Active AS was defined as patients who fulfilled at least two of the following three criteria: (1) a Bath AS disease activity index (BASDAI) score ≥4 cm, (2) a visual analog score (VAS) for total back pain ≥ 40 mm, and (3) morning stiffness ≥ 1 hour. The blinded period was followed by an open-label period during which patients received adalimumab 40 mg every other week subcutaneously for up to an additional 28 weeks.
Improvement in measures of disease activity was first observed at Week 2 and maintained through 24 weeks as shown in Figure 2 and Table 10.
Responses of patients with total spinal ankylosis (n=11) were similar to those without total ankylosis.
At 12 weeks, the ASAS 20/50/70 responses were achieved by 58%, 38%, and 23%, respectively, of patients receiving adalimumab, compared to 21%, 10%, and 5% respectively, of patients receiving placebo (p <0.001). Similar responses were seen at Week 24 and were sustained in patients receiving open-label adalimumab for up to 52 weeks.
A greater proportion of patients treated with adalimumab (22%) achieved a low level of disease activity at 24 weeks (defined as a value <20 in each of the four ASAS response parameters) compared to patients treated with placebo (6%).
A second randomized, multicenter, double-blind, placebo-controlled study of 82 patients with ankylosing spondylitis showed similar results.
Patients treated with adalimumab achieved improvement from baseline in the Ankylosing Spondylitis Quality of Life Questionnaire (ASQoL) score (-3.6 vs. -1.1) and in the Short Form Health Survey (SF-36) Physical Component Summary (PCS) score (7.4 vs. 1.9) compared to placebo-treated patients at Week 24.
## Crohn’s Disease
The safety and efficacy of multiple doses of adalimumab were assessed in adult patients with moderately to severely active Crohn’s disease, CD, (Crohn’s Disease Activity Index (CDAI) ≥ 220 and ≤ 450) in randomized, double-blind, placebo-controlled studies. Concomitant stable doses of aminosalicylates, corticosteroids, and/or immunomodulatory agents were permitted, and 79% of patients continued to receive at least one of these medications.
Induction of clinical remission (defined as CDAI < 150) was evaluated in two studies. In Study CD-I, 299 TNF-blocker naïve patients were randomized to one of four treatment groups: the placebo group received placebo at Weeks 0 and 2, the 160/80 group received 160 mg adalimumab at Week 0 and 80 mg at Week 2, the 80/40 group received 80 mg at Week 0 and 40 mg at Week 2, and the 40/20 group received 40 mg at Week 0 and 20 mg at Week 2. Clinical results were assessed at Week 4.
In the second induction study, Study CD-II, 325 patients who had lost response to, or were intolerant to, previous infliximab therapy were randomized to receive either 160 mg adalimumab at Week 0 and 80 mg at Week 2, or placebo at Weeks 0 and 2. Clinical results were assessed at Week 4.
Maintenance of clinical remission was evaluated in Study CD-III. In this study, 854 patients with active disease received open-label adalimumab, 80 mg at week 0 and 40 mg at Week 2. Patients were then randomized at Week 4 to 40 mg adalimumab every other week, 40 mg adalimumab every week, or placebo. The total study duration was 56 weeks. Patients in clinical response (decrease in CDAI ≥70) at Week 4 were stratified and analyzed separately from those not in clinical response at Week 4.
Induction of Clinical Remission
A greater percentage of the patients treated with 160/80 mg adalimumab achieved induction of clinical remission versus placebo at Week 4 regardless of whether the patients were TNF blocker naïve (CD-I), or had lost response to or were intolerant to infliximab (CD-II) (see Table 11).
Maintenance of Clinical Remission
In Study CD-III at Week 4, 58% (499/854) of patients were in clinical response and were assessed in the primary analysis. At Weeks 26 and 56, greater proportions of patients who were in clinical response at Week 4 achieved clinical remission in the adalimumab 40 mg every other week maintenance group compared to patients in the placebo maintenance group (see Table 12). The group that received adalimumab therapy every week did not demonstrate significantly higher remission rates compared to the group that received adalimumab every other week.
Of those in response at Week 4 who attained remission during the study, patients in the adalimumab every other week group maintained remission for a longer time than patients in the placebo maintenance group. Among patients who were not in response by Week 12, therapy continued beyond 12 weeks did not result in significantly more responses.
## Ulcerative Colitis
The safety and efficacy of adalimumab were assessed in adult patients with moderately to severely active ulcerative colitis (Mayo score 6 to 12 on a 12 point scale, with an endoscopy subscore of 2 to 3 on a scale of 0 to 3) despite concurrent or prior treatment with immunosuppressants such as corticosteroids, azathioprine, or 6-MP in two randomized, double-blind, placebo-controlled clinical studies (Studies UC-I and UC-II). Both studies enrolled TNF-blocker naïve patients, but Study UC-II also allowed entry of patients who lost response to or were intolerant to TNF-blockers. Forty percent (40%) of patients enrolled in Study UC-II had previously used another TNF-blocker.
Concomitant stable doses of aminosalicylates and immunosuppressants were permitted. In Studies UC-I and II, patients were receiving aminosalicylates (69%), corticosteroids (59%) and/or azathioprine or 6-MP (37%) at baseline. In both studies, 92% of patients received at least one of these medications.
Induction of clinical remission (defined as Mayo score ≤ 2 with no individual subscores > 1) at Week 8 was evaluated in both studies. Clinical remission at Week 52 and sustained clinical remission (defined as clinical remission at both Weeks 8 and 52) were evaluated in Study UC-II.
In Study UC-I, 390 TNF-blocker naïve patients were randomized to one of three treatment groups for the primary efficacy analysis. The placebo group received placebo at Weeks 0, 2, 4 and 6. The 160/80 group received 160 mg adalimumab at Week 0 and 80 mg at Week 2, and the 80/40 group received 80 mg adalimumab at Week 0 and 40 mg at Week 2. After Week 2, patients in both adalimumab treatment groups received 40 mg every other week (eow).
In Study UC-II, 518 patients were randomized to receive either adalimumab 160 mg at Week 0, 80 mg at Week 2, and 40 mg eow starting at Week 4 through Week 50, or placebo starting at Week 0 and eow through Week 50. Corticosteroid taper was permitted starting at Week 8.
In both Studies UC-I and UC-II, a greater percentage of the patients treated with 160/80 mg of adalimumab compared to patients treated with placebo achieved induction of clinical remission. In Study UC-II, a greater percentage of the patients treated with 160/80 mg of adalimumab compared to patients treated with placebo achieved sustained clinical remission (clinical remission at both Weeks 8 and 52) (Table 13).
In Study UC-I, there was no statistically significant difference in clinical remission observed between the adalimumab 80/40 mg group and the placebo group at Week 8.
In Study UC-II, 17.3% (43/248) in the adalimumab group were in clinical remission at Week 52 compared to 8.5% (21/246) in the placebo group (treatment difference: 8.8%; 95% confidence interval (CI): ; p<0.05).
In the subgroup of patients in Study UC-II with prior TNF-blocker use, the treatment difference for induction of clinical remission appeared to be lower than that seen in the whole study population, and the treatment differences for sustained clinical remission and clinical remission at Week 52 appeared to be similar to those seen in the whole study population. The subgroup of patients with prior TNF-blocker use achieved induction of clinical remission at 9% (9/98) in the adalimumab group versus 7% (7/101) in the placebo group, and sustained clinical remission at 5% (5/98) in the adalimumab group versus 1% (1/101) in the placebo group. In the subgroup of patients with prior TNF-blocker use, 10% (10/98) were in clinical remission at Week 52 in the adalimumab group versus 3% (3/101) in the placebo group.
## Plaque Psoriasis
The safety and efficacy of adalimumab were assessed in randomized, double-blind, placebo-controlled studies in 1696 adult patients with moderate to severe chronic plaque psoriasis (Ps) who were candidates for systemic therapy or phototherapy.
Study Ps-I evaluated 1212 patients with chronic Ps with ≥10% body surface area (BSA) involvement, Physician’s Global Assessment (PGA) of at least moderate disease severity, and Psoriasis Area and Severity Index (PASI) ≥12 within three treatment periods. In period A, patients received placebo or adalimumab at an initial dose of 80 mg at Week 0 followed by a dose of 40 mg every other week starting at Week 1. After 16 weeks of therapy, patients who achieved at least a PASI 75 response at Week 16, defined as a PASI score improvement of at least 75% relative to baseline, entered period B and received open-label 40 mg adalimumab every other week. After 17 weeks of open label therapy, patients who maintained at least a PASI 75 response at Week 33 and were originally randomized to active therapy in period A were re-randomized in period C to receive 40 mg adalimumab every other week or placebo for an additional 19 weeks. Across all treatment groups the mean baseline PASI score was 19 and the baseline Physician’s Global Assessment score ranged from “moderate” (53%) to “severe” (41%) to “very severe” (6%).
Study Ps-II evaluated 99 patients randomized to adalimumab and 48 patients randomized to placebo with chronic plaque psoriasis with ≥10% BSA involvement and PASI ≥12. Patients received placebo, or an initial dose of 80 mg adalimumab at Week 0 followed by 40 mg every other week starting at Week 1 for 16 weeks. Across all treatment groups the mean baseline PASI score was 21 and the baseline PGA score ranged from “moderate” (41%) to “severe” (51%) to “very severe” (8%).
Studies Ps-I and II evaluated the proportion of patients who achieved “clear” or “minimal” disease on the 6-point PGA scale and the proportion of patients who achieved a reduction in PASI score of at least 75% (PASI 75) from baseline at Week 16 (see Table 14 and 15).
Additionally, Study Ps-I evaluated the proportion of subjects who maintained a PGA of “clear” or “minimal” disease or a PASI 75 response after Week 33 and on or before Week 52.
Additionally, in Study Ps-I, subjects on adalimumab who maintained a PASI 75 were re-randomized to adalimumab (N = 250) or placebo (N = 240) at Week 33. After 52 weeks of treatment with adalimumab, more patients on adalimumab maintained efficacy when compared to subjects who were re-randomized to placebo based on maintenance of PGA of “clear” or “minimal” disease (68% vs. 28%) or a PASI 75 (79% vs. 43%).
A total of 347 stable responders participated in a withdrawal and retreatment evaluation in an open-label extension study. Median time to relapse (decline to PGA “moderate” or worse) was approximately 5 months. During the withdrawal period, no subject experienced transformation to either pustular or erythrodermic psoriasis. A total of 178 subjects who relapsed re-initiated treatment with 80 mg of adalimumab, then 40 mg eow beginning at week 1. At week 16, 69% (123/178) of subjects had a response of PGA “clear” or “minimal”.
# How Supplied
adalimumab® (adalimumab) is supplied as a preservative-free, sterile solution for subcutaneous administration. The following packaging configurations are available.
- adalimumab Pen Carton
adalimumab is dispensed in a carton containing two alcohol preps and two dose trays. Each dose tray consists of a single-use pen, containing a 1 mL prefilled glass syringe with a fixed 27 gauge ½ inch needle, providing 40 mg (0.8 mL) of adalimumab. The NDC number is 0074-4339-02.
- adalimumab Pen – Crohn's Disease/Ulcerative Colitis Starter Package
adalimumab is dispensed in a carton containing 6 alcohol preps and 6 dose trays (Crohn’s Disease/Ulcerative Colitis Starter Package). Each dose tray consists of a single-use pen, containing a 1 mL prefilled glass syringe with a fixed 27 gauge ½ inch needle, providing 40 mg (0.8 mL) of adalimumab. The NDC number is 0074-4339-06.
- adalimumab Pen – Psoriasis Starter Package
adalimumab is dispensed in a carton containing 4 alcohol preps and 4 dose trays (Psoriasis Starter Package). Each dose tray consists of a single-use pen, containing a 1 mL prefilled glass syringe with a fixed 27 gauge ½ inch needle, providing 40 mg (0.8 mL) of adalimumab. The NDC number is 0074-4339-07.
- Prefilled Syringe Carton – 40 mg
adalimumab is dispensed in a carton containing two alcohol preps and two dose trays. Each dose tray consists of a single-use, 1 mL prefilled glass syringe with a fixed 27 gauge ½ inch needle, providing 40 mg (0.8 mL) of adalimumab. The NDC number is 0074-3799-02.
- Pediatric Prefilled Syringe Carton – 20 mg
adalimumab is supplied for pediatric use only in a carton containing two alcohol preps and two dose trays. Each dose tray consists of a single-use, 1 mL pre-filled glass syringe with a fixed 27 gauge ½ inch needle, providing 20 mg (0.4 mL) of adalimumab. The NDC number is 0074-9374-02.
- Institutional Use Vial Carton – 40 mg
adalimumab is supplied for institutional use only in a carton containing a single-use, glass vial, providing 40 mg (0.8 mL) of adalimumab. The NDC number is 0074-3797-01.
## Storage
Do not use beyond the expiration date on the container. adalimumab must be refrigerated at 36°F to 46°F (2°C to 8°C). DO NOT FREEZE. Do not use if frozen even if it has been thawed. When traveling, store adalimumab in a cool carrier with an ice pack. Protect the prefilled syringe from exposure to light. Store in original carton until time of administration.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
## Patient Counseling
Provide the adalimumab “Medication Guide” to patients or their caregivers, and provide them an opportunity to read it and ask questions prior to initiation of therapy and prior to each time the prescription is renewed. If patients develop signs and symptoms of infection, instruct them to seek medical evaluation immediately.
Advise patients of the potential benefits and risks of adalimumab.
- Infections
Inform patients that adalimumab may lower the ability of their immune system to fight infections. Instruct patients of the importance of contacting their doctor if they develop any symptoms of infection, including tuberculosis, invasive fungal infections, and reactivation of hepatitis B virus infections.
- Malignancies
Counsel patients about the risk of malignancies while receiving adalimumab.
- Allergic Reactions
Advise patients to seek immediate medical attention if they experience any symptoms of severe allergic reactions. Advise latex-sensitive patients that the needle cap of the prefilled syringe contains latex.
- Other Medical Conditions
Advise patients to report any signs of new or worsening medical conditions such as congestive heart failure, neurological disease, autoimmune disorders, or cytopenias. Advise patients to report any symptoms suggestive of a cytopenia such as bruising, bleeding, or persistent fever.
## Instruction on Injection Technique
Inform patients that the first injection is to be performed under the supervision of a qualified health care professional. If a patient or caregiver is to administer adalimumab, instruct them in injection techniques and assess their ability to inject subcutaneously to ensure the proper administration of adalimumab .
For patients who will use the adalimumab Pen, tell them that they:
- Will hear a loud ‘click’ when the plum-colored activator button is pressed. The loud click means the start of the injection.
- Must keep holding the adalimumab Pen against their squeezed, raised skin until all of the medicine is injected. This can take up to 10 seconds.
- Will know that the injection has finished when the yellow marker fully appears in the window view and stops moving.
Instruct patients to dispose of their used needles and syringes or used Pen in a FDA-cleared sharps disposal container immediately after use. Instruct patients not to dispose of loose needles and syringes or Pen in their household trash. Instruct patients that if they do not have a FDA-cleared sharps disposal container, they may use a household container that is made of a heavy-duty plastic, can be closed with a tight-fitting and puncture-resistant lid without sharps being able to come out, upright and stable during use, leak-resistant, and properly labeled to warn of hazardous waste inside the container.
Instruct patients that when their sharps disposal container is almost full, they will need to follow their community guidelines for the correct way to dispose of their sharps disposal container. Instruct patients that there may be state or local laws regarding disposal of used needles and syringes. Refer patients to the FDA’s website at for more information about safe sharps disposal, and for specific information about sharps disposal in the state that they live in.
Instruct patients not to dispose of their used sharps disposal container in their household trash unless their community guidelines permit this. Instruct patients not to recycle their used sharps disposal container.
# Precautions with Alcohol
Alcohol-Adalimumab interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
HUMIRA
# Look-Alike Drug Names
There is limited information about the look-alike drugs.
# Drug Shortage Status
# Price | Adalimumab
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2]
# Disclaimer
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# Black Box Warning
# Overview
Adalimumab is a Tumor Necrosis Factor Blocker that is FDA approved for the {{{indicationType}}} of Rheumatoid Arthritis, Juvenile Idiopathic Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis, Crohn’s Disease, Ulcerative Colitis, Plaque Psoriasis. There is a Black Box Warning for this drug as shown here. Common adverse reactions include Injection site pain, Injection site reaction, Rash, Antibody development, to adalimumab ,Antinuclear antibody positive , Headache, Sinusitis, Upper respiratory infection.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Rheumatoid Arthritis, Psoriatic Arthritis, and Ankylosing Spondylitis
- Dosing information
- Recommended dosage: 40 mg administered every other week.
- Methotrexate (MTX), other non-biologic DMARDS, glucocorticoids, nonsteroidal anti-inflammatory drugs (NSAIDs), and/or analgesics may be continued during treatment with adalimumab. In the treatment of RA, some patients not taking concomitant MTX may derive additional benefit from increasing the dosing frequency of adalimumab to 40 mg every week.
### Crohn’s Disease
- Dosing information
- Recommended dosage:
- Day 1: 160 mg (given as four 40 mg injections in one day or as two 40 mg injections per day for two consecutive days),
- Day 15: 80 mg .
- Day 29: 40 mg every other week.
- Aminosalicylates and/or corticosteroids may be continued during treatment with adalimumab. Azathioprine, 6-mercaptopurine (6-MP) or MTX may be continued during treatment with adalimumab if necessary. The use of adalimumab in CD beyond one year has not been evaluated in controlled clinical studies.
### Ulcerative Colitis
- Dosing information
- Recommended dosage:
- Day 1: 160 mg (given as four 40 mg injections in one day or as two 40 mg injections per day for two consecutive days),
- Day 15: 80 mg .
- Day 29: 40 mg every other week.
- Only continue adalimumab in patients who have shown evidence of clinical remission by eight weeks (Day 57) of therapy. Aminosalicylates and/or corticosteroids may be continued during treatment with adalimumab. Azathioprine and 6-mercaptopurine (6-MP) [see Warnings and Precautions (5.2)] may be continued during treatment with adalimumab if necessary.
### Plaque Psoriasis
- Dosing information
- Recommended dosage: 80 mg, followed by 40 mg given every other week starting one week after the initial dose.
- The use of adalimumab in moderate to severe chronic Ps beyond one year has not been evaluated in controlled clinical studies.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Adalimumab in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Adalimumab in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
### Juvenile Idiopathic Arthritis
- Dosing information
- Recommended dosage: of adalimumab for pediatric patients 4 to 17 years of age with polyarticular juvenile idiopathic arthritis (JIA) is based on weight as shown below. MTX, glucocorticoids, NSAIDs, and/or analgesics may be continued during treatment with adalimumab.
- Limited data are available for adalimumab treatment in pediatric patients with a weight below 15 kg.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Adalimumab in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Adalimumab in pediatric patients.
# Contraindications
None.
# Warnings
## Serious Infections
Patients treated with adalimumab are at increased risk for developing serious infections involving various organ systems and sites that may lead to hospitalization or death [see Boxed Warning]. Opportunistic infections due to bacterial, mycobacterial, invasive fungal, viral, parasitic, or other opportunistic pathogens including aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis, legionellosis, listeriosis, pneumocystosis and tuberculosis have been reported with TNF blockers. Patients have frequently presented with disseminated rather than localized disease.
The concomitant use of a TNF blocker and abatacept or anakinra was associated with a higher risk of serious infections in patients with rheumatoid arthritis (RA); therefore, the concomitant use of adalimumab and these biologic products is not recommended in the treatment of patients with RA.
Treatment with adalimumab should not be initiated in patients with an active infection, including localized infections. Patients greater than 65 years of age, patients with co-morbid conditions and/or patients taking concomitant immunosuppressants (such as corticosteroids or methotrexate), may be at greater risk of infection. Consider the risks and benefits of treatment prior to initiating therapy in patients:
- with chronic or recurrent infection;
- who have been exposed to tuberculosis;
- with a history of an opportunistic infection;
- who have resided or traveled in areas of endemic tuberculosis or endemic mycoses, such as histoplasmosis, coccidioidomycosis, or blastomycosis; or
- with underlying conditions that may predispose them to infection.
### tuberculosis
Cases of reactivation of tuberculosis and new onset tuberculosis infections have been reported in patients receiving adalimumab, including patients who have previously received treatment for latent or active tuberculosis. Reports included cases of pulmonary and extrapulmonary (i.e., disseminated) tuberculosis. Evaluate patients for tuberculosis risk factors and test for latent infection prior to initiating adalimumab and periodically during therapy.
Treatment of latent tuberculosis infection prior to therapy with TNF blocking agents has been shown to reduce the risk of tuberculosis reactivation during therapy. Prior to initiating adalimumab, assess if treatment for latent tuberculosis is needed; and consider an induration of ≥ 5 mm a positive tuberculin skin test result, even for patients previously vaccinated with Bacille Calmette-Guerin (BCG).
Consider anti-tuberculosis therapy prior to initiation of adalimumab in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but having risk factors for tuberculosis infection. Despite prophylactic treatment for tuberculosis, cases of reactivated tuberculosis have occurred in patients treated with adalimumab. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision whether initiating anti-tuberculosis therapy is appropriate for an individual patient.
Strongly consider tuberculosis in the differential diagnosis in patients who develop a new infection during adalimumab treatment, especially in patients who have previously or recently traveled to countries with a high prevalence of tuberculosis, or who have had close contact with a person with active tuberculosis.
### Monitoring
Closely monitor patients for the development of signs and symptoms of infection during and after treatment with adalimumab, including the development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy. Tests for latent tuberculosis infection may also be falsely negative while on therapy with adalimumab.
Discontinue adalimumab if a patient develops a serious infection or sepsis. For a patient who develops a new infection during treatment with adalimumab, closely monitor them, perform a prompt and complete diagnostic workup appropriate for an immunocompromised patient, and initiate appropriate antimicrobial therapy.
### Invasive Fungal Infections
If patients develop a serious systemic illness and they reside or travel in regions where mycoses are endemic, consider invasive fungal infection in the differential diagnosis. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. Consider appropriate empiric antifungal therapy, taking into account both the risk for severe fungal infection and the risks of antifungal therapy, while a diagnostic workup is being performed. To aid in the management of such patients, consider consultation with a physician with expertise in the diagnosis and treatment of invasive fungal infections.
## Malignancies
Consider the risks and benefits of TNF-blocker treatment including adalimumab prior to initiating therapy in patients with a known malignancy other than a successfully treated non-melanoma skin cancer (NMSC) or when considering continuing a TNF blocker in patients who develop a malignancy.
### Malignancies in Adults
In the controlled portions of clinical trials of some TNF-blockers, including adalimumab, more cases of malignancies have been observed among TNF-blocker-treated adult patients compared to control-treated adult patients. During the controlled portions of 34 global adalimumab clinical trials in adult patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), Crohn’s disease (CD), ulcerative colitis (UC) and plaque psoriasis (Ps), malignancies, other than non-melanoma (basal cell and squamous cell) skin cancer, were observed at a rate (95% confidence interval) of 0.6 (0.38, 0.91) per 100 patient-years among 7304 adalimumab-treated patients versus a rate of 0.6 (0.30, 1.03) per 100 patient-years among 4232 control-treated patients (median duration of treatment of 4 months for adalimumab-treated patients and 4 months for control-treated patients). In 47 global controlled and uncontrolled clinical trials of adalimumab in adult patients with RA, PsA, AS, CD, UC, and Ps, the most frequently observed malignancies, other than lymphoma and NMSC, were breast, colon, prostate, lung, and melanoma. The malignancies in adalimumab-treated patients in the controlled and uncontrolled portions of the studies were similar in type and number to what would be expected in the general U.S. population according to the SEER database (adjusted for age, gender, and race).1
In controlled trials of other TNF blockers in adult patients at higher risk for malignancies (i.e., patients with COPD with a significant smoking history and cyclophosphamide-treated patients with Wegener’s granulomatosis), a greater portion of malignancies occurred in the TNF blocker group compared to the control group.
### Non-Melanoma Skin Cancer
During the controlled portions of 34 global adalimumab clinical trials in adult patients with RA, PsA, AS, CD, UC, and Ps, the rate (95% confidence interval) of NMSC was 0.7 (0.49, 1.08) per 100 patient-years among adalimumab-treated patients and 0.2 (0.08, 0.59) per 100 patient-years among control-treated patients. Examine all patients, and in particular patients with a medical history of prior prolonged immunosuppressant therapy or psoriasis patients with a history of PUVA treatment for the presence of NMSC prior to and during treatment with adalimumab.
### Lymphoma and Leukemia
In the controlled portions of clinical trials of all the TNF-blockers in adults, more cases of lymphoma have been observed among TNF-blocker-treated patients compared to control-treated patients. In the controlled portions of 34 global adalimumab clinical trials in adult patients with RA, PsA, AS, CD, UC and Ps, 3 lymphomas occurred among 7304 adalimumab-treated patients versus 1 among 4232 control-treated patients. In 47 global controlled and uncontrolled clinical trials of adalimumab in adult patients with RA, PsA, AS, CD, UC and Ps with a median duration of approximately 0.6 years, including 23,036 patients and over 34,000 patient-years of adalimumab, the observed rate of lymphomas was approximately 0.11 per 100 patient-years. This is approximately 3-fold higher than expected in the general U.S. population according to the SEER database (adjusted for age, gender, and race).1 Rates of lymphoma in clinical trials of adalimumab cannot be compared to rates of lymphoma in clinical trials of other TNF blockers and may not predict the rates observed in a broader patient population. Patients with RA and other chronic inflammatory diseases, particularly those with highly active disease and/or chronic exposure to immunosuppressant therapies, may be at a higher risk (up to several fold) than the general population for the development of lymphoma, even in the absence of TNF blockers. Post-marketing cases of acute and chronic leukemia have been reported in association with TNF-blocker use in RA and other indications. Even in the absence of TNF-blocker therapy, patients with RA may be at a higher risk (approximately 2-fold) than the general population for the development of leukemia.
### Malignancies in Pediatric Patients and Young Adults
Malignancies, some fatal, have been reported among children, adolescents, and young adults who received treatment with TNF-blockers (initiation of therapy ≤ 18 years of age), of which adalimumab is a member [see Boxed Warning]. Approximately half the cases were lymphomas, including Hodgkin's and non-Hodgkin's lymphoma. The other cases represented a variety of different malignancies and included rare malignancies usually associated with immunosuppression and malignancies that are not usually observed in children and adolescents. The malignancies occurred after a median of 30 months of therapy (range 1 to 84 months). Most of the patients were receiving concomitant immunosuppressants. These cases were reported post-marketing and are derived from a variety of sources including registries and spontaneous postmarketing reports.
Postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers including adalimumab [see Boxed Warning]. These cases have had a very aggressive disease course and have been fatal. The majority of reported TNF blocker cases have occurred in patients with Crohn's disease or ulcerative colitis and the majority were in adolescent and young adult males. Almost all of these patients had received treatment with the immunosuppressants azathioprine or 6-mercaptopurine (6–MP) concomitantly with a TNF blocker at or prior to diagnosis. It is uncertain whether the occurrence of HSTCL is related to use of a TNF blocker or a TNF blocker in combination with these other immunosuppressants. The potential risk with the combination of azathioprine or 6-mercaptopurine and adalimumab should be carefully considered.
## Hypersensitivity Reactions
Anaphylaxis and angioneurotic edema have been reported following adalimumab administration. If an anaphylactic or other serious allergic reaction occurs, immediately discontinue administration of adalimumab and institute appropriate therapy. In clinical trials of adalimumab in adults, allergic reactions (e.g., allergic rash, anaphylactoid reaction, fixed drug reaction, non-specified drug reaction, urticaria) have been observed.
## Hepatitis B Virus Reactivation
Use of TNF blockers, including adalimumab, may increase the risk of reactivation of hepatitis B virus (HBV) in patients who are chronic carriers of this virus. In some instances, HBV reactivation occurring in conjunction with TNF blocker therapy has been fatal. The majority of these reports have occurred in patients concomitantly receiving other medications that suppress the immune system, which may also contribute to HBV reactivation. Evaluate patients at risk for HBV infection for prior evidence of HBV infection before initiating TNF blocker therapy. Exercise caution in prescribing TNF blockers for patients identified as carriers of HBV. Adequate data are not available on the safety or efficacy of treating patients who are carriers of HBV with anti-viral therapy in conjunction with TNF blocker therapy to prevent HBV reactivation. For patients who are carriers of HBV and require treatment with TNF blockers, closely monitor such patients for clinical and laboratory signs of active HBV infection throughout therapy and for several months following termination of therapy. In patients who develop HBV reactivation, stop adalimumab and initiate effective anti-viral therapy with appropriate supportive treatment. The safety of resuming TNF blocker therapy after HBV reactivation is controlled is not known. Therefore, exercise caution when considering resumption of adalimumab therapy in this situation and monitor patients closely.
## Neurologic Reactions
Use of TNF blocking agents, including adalimumab, has been associated with rare cases of new onset or exacerbation of clinical symptoms and/or radiographic evidence of central nervous system demyelinating disease, including multiple sclerosis (MS) and optic neuritis, and peripheral demyelinating disease, including Guillain-Barré syndrome. Exercise caution in considering the use of adalimumab in patients with preexisting or recent-onset central or peripheral nervous system demyelinating disorders.
## Hematological Reactions
Rare reports of pancytopenia including aplastic anemia have been reported with TNF blocking agents. Adverse reactions of the hematologic system, including medically significant cytopenia (e.g., thrombocytopenia, leukopenia) have been infrequently reported with adalimumab. The causal relationship of these reports to adalimumab remains unclear. Advise all patients to seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias or infection (e.g., persistent fever, bruising, bleeding, pallor) while on adalimumab. Consider discontinuation of adalimumab therapy in patients with confirmed significant hematologic abnormalities.
## Use with anakinra
Concurrent use of anakinra (an interleukin-1 antagonist) and another TNF-blocker, was associated with a greater proportion of serious infections and neutropenia and no added benefit compared with the TNF-blocker alone in patients with RA. Therefore, the combination of adalimumab and anakinra is not recommended
## Heart Failure
Cases of worsening congestive heart failure (CHF) and new onset CHF have been reported with TNF blockers. Cases of worsening CHF have also been observed with adalimumab. adalimumab has not been formally studied in patients with CHF; however, in clinical trials of another TNF blocker, a higher rate of serious CHF-related adverse reactions was observed. Exercise caution when using adalimumab in patients who have heart failure and monitor them carefully.
## Autoimmunity
Treatment with adalimumab may result in the formation of autoantibodies and, rarely, in the development of a lupus-like syndrome. If a patient develops symptoms suggestive of a lupus-like syndrome following treatment with adalimumab, discontinue treatment
## Immunizations
In a placebo-controlled clinical trial of patients with RA, no difference was detected in anti-pneumococcal antibody response between adalimumab and placebo treatment groups when the pneumococcal polysaccharide vaccine and influenza vaccine were administered concurrently with adalimumab. Similar proportions of patients developed protective levels of anti-influenza antibodies between adalimumab and placebo treatment groups; however, titers in aggregate to influenza antigens were moderately lower in patients receiving adalimumab. The clinical significance of this is unknown. Patients on adalimumab may receive concurrent vaccinations, except for live vaccines. No data are available on the secondary transmission of infection by live vaccines in patients receiving adalimumab.
It is recommended that JIA patients, if possible, be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating adalimumab therapy. Patients on adalimumab may receive concurrent vaccinations, except for live vaccines.
## Use with abatacept
In controlled trials, the concurrent administration of TNF-blockers and abatacept was associated with a greater proportion of serious infections than the use of a TNF-blocker alone; the combination therapy, compared to the use of a TNF-blocker alone, has not demonstrated improved clinical benefit in the treatment of RA. Therefore, the combination of abatacept with TNF-blockers including adalimumab is not recommended
# Adverse Reactions
## Clinical Trials Experience
Because clinical trials are conducted under widely varying and controlled conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not predict the rates observed in a broader patient population in clinical practice.
The most common adverse reaction with adalimumab was injection site reactions. In placebo-controlled trials, 20% of patients treated with adalimumab developed injection site reactions (erythema and/or itching, hemorrhage, pain or swelling), compared to 14% of patients receiving placebo. Most injection site reactions were described as mild and generally did not necessitate drug discontinuation.
The proportion of patients who discontinued treatment due to adverse reactions during the double-blind, placebo-controlled portion of studies in patients with RA (i.e., Studies RA-I, RA-II, RA-III and RA-IV) was 7% for patients taking adalimumab and 4% for placebo-treated patients. The most common adverse reactions leading to discontinuation of adalimumab in these RA studies were clinical flare reaction (0.7%), rash (0.3%) and pneumonia (0.3%).
Infections
In the controlled portions of the 34 global adalimumab clinical trials in adult patients with RA, PsA, AS, CD, UC and Ps, the rate of serious infections was 4.6 per 100 patient-years in 7304 adalimumab-treated patients versus a rate of 3.1 per 100 patient-years in 4232 control-treated patients. Serious infections observed included pneumonia, septic arthritis, prosthetic and post-surgical infections, erysipelas, cellulitis, diverticulitis, and pyelonephritis [see Warnings and Precautions (5.1)].
Tuberculosis and Opportunistic Infections
In 47 global controlled and uncontrolled clinical trials in RA, PsA, AS, CD, UC and Ps that included 23,036 adalimumab-treated patients, the rate of reported active tuberculosis was 0.22 per 100 patient-years and the rate of positive PPD conversion was 0.08 per 100 patient-years. In a subgroup of 9396 U.S. and Canadian adalimumab-treated patients, the rate of reported active TB was 0.07 per 100 patient-years and the rate of positive PPD conversion was 0.08 per 100 patient-years. These trials included reports of miliary, lymphatic, peritoneal, and pulmonary TB. Most of the TB cases occurred within the first eight months after initiation of therapy and may reflect recrudescence of latent disease. In these global clinical trials, cases of serious opportunistic infections have been reported at an overall rate of 0.08 per 100 patient-years. Some cases of serious opportunistic infections and TB have been fatal [see Warnings and Precautions (5.1)].
Autoantibodies
In the rheumatoid arthritis controlled trials, 12% of patients treated with adalimumab and 7% of placebo-treated patients that had negative baseline ANA titers developed positive titers at week 24. Two patients out of 3046 treated with adalimumab developed clinical signs suggestive of new-onset lupus-like syndrome. The patients improved following discontinuation of therapy. No patients developed lupus nephritis or central nervous system symptoms. The impact of long-term treatment with adalimumab on the development of autoimmune diseases is unknown.
Liver Enzyme Elevations
There have been reports of severe hepatic reactions including acute liver failure in patients receiving TNF-blockers. In controlled Phase 3 trials of adalimumab (40 mg SC every other week) in patients with RA, PsA, and AS with control period duration ranging from 4 to 104 weeks, ALT elevations ≥ 3 x ULN occurred in 3.5% of adalimumab-treated patients and 1.5% of control-treated patients. Since many of these patients in these trials were also taking medications that cause liver enzyme elevations (e.g., NSAIDS, MTX), the relationship between adalimumab and the liver enzyme elevations is not clear. In controlled Phase 3 trials of adalimumab (initial doses of 160 mg and 80 mg, or 80 mg and 40 mg on Days 1 and 15, respectively, followed by 40 mg every other week) in patients with CD with control period duration ranging from 4 to 52 weeks, ALT elevations ≥ 3 x ULN occurred in 0.9% of adalimumab-treated patients and 0.9% of control-treated patients. In controlled Phase 3 trials of adalimumab (initial doses of 160 mg and 80 mg on Days 1 and 15 respectively, followed by 40 mg every other week) in patients with UC with control period duration ranging from 1 to 52 weeks, ALT elevations ≥3 x ULN occurred in 1.5% of adalimumab-treated patients and 1.0% of control-treated patients. In controlled Phase 3 trials of adalimumab (initial dose of 80 mg then 40 mg every other week) in patients with Ps with control period duration ranging from 12 to 24 weeks, ALT elevations ≥ 3 x ULN occurred in 1.8% of adalimumab-treated patients and 1.8% of control-treated patients.
Immunogenicity
Patients in Studies RA-I, RA-II, and RA-III were tested at multiple time points for antibodies to adalimumab during the 6- to 12-month period. Approximately 5% (58 of 1062) of adult RA patients receiving adalimumab developed low-titer antibodies to adalimumab at least once during treatment, which were neutralizing in vitro. Patients treated with concomitant methotrexate (MTX) had a lower rate of antibody development than patients on adalimumab monotherapy (1% versus 12%). No apparent correlation of antibody development to adverse reactions was observed. With monotherapy, patients receiving every other week dosing may develop antibodies more frequently than those receiving weekly dosing. In patients receiving the recommended dosage of 40 mg every other week as monotherapy, the ACR 20 response was lower among antibody-positive patients than among antibody-negative patients. The long-term immunogenicity of adalimumab is unknown.
In patients with JIA, adalimumab antibodies were identified in 16% of adalimumab-treated patients. In patients receiving concomitant MTX, the incidence was 6% compared to 26% with adalimumab monotherapy.
In patients with AS, the rate of development of antibodies to adalimumab in adalimumab-treated patients was comparable to patients with RA.
In patients with PsA, the rate of antibody development in patients receiving adalimumab monotherapy was comparable to patients with RA; however, in patients receiving concomitant MTX the rate was 7% compared to 1% in RA.
In patients with CD, the rate of antibody development was 3%.
In patients with moderately to severely active UC, the rate of antibody development in patients receiving adalimumab was 5%. However, due to the limitation of the assay conditions, antibodies to adalimumab could be detected only when serum adalimumab levels were < 2 ug/ml. Among the patients whose serum adalimumab levels were < 2 ug/ml (approximately 25% of total patients studied), the immunogenicity rate was 20.7%.
In patients with Ps, the rate of antibody development with adalimumab monotherapy was 8%. However, due to the limitation of the assay conditions, antibodies to adalimumab could be detected only when serum adalimumab levels were < 2 ug/ml. Among the patients whose serum adalimumab levels were < 2 ug/ml (approximately 40% of total patients studied), the immunogenicity rate was 20.7%. In Ps patients who were on adalimumab monotherapy and subsequently withdrawn from the treatment, the rate of antibodies to adalimumab after retreatment was similar to the rate observed prior to withdrawal.
The data reflect the percentage of patients whose test results were considered positive for antibodies to adalimumab in an ELISA assay, and are highly dependent on the sensitivity and specificity of the assay. The observed incidence of antibody (including neutralizing antibody) positivity in an assay is highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to adalimumab with the incidence of antibodies to other products may be misleading.
Other Adverse Reactions
Rheumatoid Arthritis Clinical Studies
The data described below reflect exposure to adalimumab in 2468 patients, including 2073 exposed for 6 months, 1497 exposed for greater than one year and 1380 in adequate and well-controlled studies (Studies RA-I, RA-II, RA-III, and RA-IV). adalimumab was studied primarily in placebo-controlled trials and in long-term follow up studies for up to 36 months duration. The population had a mean age of 54 years, 77% were female, 91% were Caucasian and had moderately to severely active rheumatoid arthritis. Most patients received 40 mg adalimumab every other week.
Table 1 summarizes reactions reported at a rate of at least 5% in patients treated with adalimumab 40 mg every other week compared to placebo and with an incidence higher than placebo. In Study RA-III, the types and frequencies of adverse reactions in the second year open-label extension were similar to those observed in the one-year double-blind portion.
Less Common Adverse Reactions in Rheumatoid Arthritis Clinical Studies
Other infrequent serious adverse reactions that do not appear in the Warnings and Precautions or Adverse Reaction sections that occurred at an incidence of less than 5% in adalimumab-treated patients in RA studies were:
Body As A Whole: Pain in extremity, pelvic pain, surgery, thorax pain
Cardiovascular System: Arrhythmia, atrial fibrillation, chest pain, coronary artery disorder, heart arrest, hypertensive encephalopathy, myocardial infarct, palpitation, pericardial effusion, pericarditis, syncope, tachycardia
Digestive System: Cholecystitis, cholelithiasis, esophagitis, gastroenteritis, gastrointestinal hemorrhage, hepatic necrosis, vomiting
Endocrine System: Parathyroid disorder
Hemic And Lymphatic System: Agranulocytosis, polycythemia
Metabolic And Nutritional Disorders: Dehydration, healing abnormal, ketosis, paraproteinemia, peripheral edema
Musculo-Skeletal System: Arthritis, bone disorder, bone fracture (not spontaneous), bone necrosis, joint disorder, muscle cramps, myasthenia, pyogenic arthritis, synovitis, tendon disorder
Neoplasia: Adenoma
Nervous System: Confusion, paresthesia, subdural hematoma, tremor
Respiratory System: Asthma, bronchospasm, dyspnea, lung function decreased, pleural effusion
Special Senses: Cataract
Thrombosis: Thrombosis leg
Urogenital System: Cystitis, kidney calculus, menstrual disorder
Juvenile Idiopathic Arthritis Clinical Studies
In general, the adverse reactions in the adalimumab-treated pediatric patients in the juvenile idiopathic arthritis (JIA) trial were similar in frequency and type to those seen in adult patients [see Warnings and Precautions (5), Adverse Reactions (6)]. Important findings and differences from adults are discussed in the following paragraphs.
adalimumab was studied in 171 pediatric patients, 4 to 17 years of age, with polyarticular JIA. Severe adverse reactions reported in the study included neutropenia, streptococcal pharyngitis, increased aminotransferases, herpes zoster, myositis, metrorrhagia, appendicitis. Serious infections were observed in 4% of patients within approximately 2 years of initiation of treatment with adalimumab and included cases of herpes simplex, pneumonia, urinary tract infection, pharyngitis, and herpes zoster.
A total of 45% of children experienced an infection while receiving adalimumab with or without concomitant MTX in the first 16 weeks of treatment. The types of infections reported in adalimumab-treated patients were generally similar to those commonly seen in JIA patients who are not treated with TNF blockers. Upon initiation of treatment, the most common adverse reactions occurring in the pediatric population treated with adalimumab were injection site pain and injection site reaction (19% and 16%, respectively). A less commonly reported adverse event in children receiving adalimumab was granuloma annulare which did not lead to discontinuation of adalimumab treatment.
In the first 48 weeks of treatment, non-serious hypersensitivity reactions were seen in approximately 6% of children and included primarily localized allergic hypersensitivity reactions and allergic rash.
Isolated mild to moderate elevations of liver aminotransferases (ALT more common than AST) were observed in children with JIA exposed to adalimumab alone; liver enzyme test elevations were more frequent among those treated with the combination of adalimumab and MTX than those treated with adalimumab alone. In general, these elevations did not lead to discontinuation of adalimumab treatment.
In the JIA trial, 10% of patients treated with adalimumab who had negative baseline anti-dsDNA antibodies developed positive titers after 48 weeks of treatment. No patient developed clinical signs of autoimmunity during the clinical trial.
Approximately 15% of children treated with adalimumab developed mild-to-moderate elevations of creatine phosphokinase (CPK). Elevations exceeding 5 times the upper limit of normal were observed in several patients. CPK levels decreased or returned to normal in all patients. Most patients were able to continue adalimumab without interruption.
Psoriatic Arthritis and Ankylosing Spondylitis Clinical Studies
adalimumab has been studied in 395 patients with psoriatic arthritis (PsA) in two placebo-controlled trials and in an open label study and in 393 patients with ankylosing spondylitis (AS) in two placebo-controlled studies. The safety profile for patients with PsA and AS treated with adalimumab 40 mg every other week was similar to the safety profile seen in patients with RA, adalimumab Studies RA-I through IV.
Crohn’s Disease Clinical Studies
adalimumab has been studied in 1478 patients with Crohn’s disease (CD) in four placebo-controlled and two open-label extension studies. The safety profile for patients with CD treated with adalimumab was similar to the safety profile seen in patients with RA.
Ulcerative Colitis Clinical Studies
adalimumab has been studied in 1010 patients with ulcerative colitis (UC) in two placebo-controlled studies and one open-label extension study. The safety profile for patients with UC treated with adalimumab was similar to the safety profile seen in patients with RA.
Plaque Psoriasis Clinical Studies
adalimumab has been studied in 1696 patients with plaque psoriasis (Ps) in placebo-controlled and open-label extension studies. The safety profile for patients with Ps treated with adalimumab was similar to the safety profile seen in patients with RA with the following exceptions. In the placebo-controlled portions of the clinical trials in Ps patients, adalimumab-treated patients had a higher incidence of arthralgia when compared to controls (3% vs. 1%).
## Postmarketing Experience
The following adverse reactions have been identified during post-approval use of adalimumab. 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 adalimumab exposure.
Gastrointestinal disorders: Diverticulitis, large bowel perforations including perforations associated with diverticulitis and appendiceal perforations associated with appendicitis, pancreatitis
General disorders and administration site conditions: Pyrexia
Hepato-biliary disorders: Liver failure, hepatitis
Immune system disorders: Sarcoidosis
Neoplasms benign, malignant and unspecified (incl cysts and polyps): Merkel Cell Carcinoma (neuroendocrine carcinoma of the skin)
Nervous system disorders: Demyelinating disorders (e.g., optic neuritis, Guillain-Barré syndrome), cerebrovascular accident
Respiratory disorders: Interstitial lung disease, including pulmonary fibrosis, pulmonary embolism
Skin reactions: Stevens Johnson Syndrome, cutaneous vasculitis, erythema multiforme, new or worsening psoriasis (all sub-types including pustular and palmoplantar), alopecia
Vascular disorders: Systemic vasculitis, deep vein thrombosis
# Drug Interactions
## Methotrexate
adalimumab has been studied in rheumatoid arthritis (RA) patients taking concomitant methotrexate (MTX). Although MTX reduced the apparent adalimumab clearance, the data do not suggest the need for dose adjustment of either adalimumab or MTX [see Clinical Pharmacology (12.3)].
## Biological Products
In clinical studies in patients with RA, an increased risk of serious infections has been seen with the combination of TNF blockers with anakinra or abatacept, with no added benefit; therefore, use of adalimumab with abatacept or anakinra is not recommended in patients with RA [see Warnings and Precautions (5.7 and 5.11)]. A higher rate of serious infections has also been observed in patients with RA treated with rituximab who received subsequent treatment with a TNF blocker. There is insufficient information regarding the concomitant use of adalimumab and other biologic products for the treatment of RA, PsA, AS, CD, UC, and Ps. Concomitant administration of adalimumab with other biologic DMARDS (e.g., anakinra and abatacept) or other TNF blockers is not recommended based upon the possible increased risk for infections and other potential pharmacological interactions.
## Live Vaccines
Avoid the use of live vaccines with adalimumab [see Warnings and Precautions (5.10)].
## Cytochrome P450 Substrates
The formation of CYP450 enzymes may be suppressed by increased levels of cytokines (e.g., TNFα, IL-6) during chronic inflammation. It is possible for a molecule that antagonizes cytokine activity, such as adalimumab, to influence the formation of CYP450 enzymes. Upon initiation or discontinuation of adalimumab in patients being treated with CYP450 substrates with a narrow therapeutic index, monitoring of the effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) is recommended and the individual dose of the drug product may be adjusted as needed.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
### Risk Summary
Adequate and well controlled studies with adalimumab have not been conducted in pregnant women. Adalimumab is an IgG1 monoclonal antibody and IgG1 is actively transferred across the placenta during the third trimester of pregnancy. Adalimumab serum levels were obtained from ten women treated with adalimumab during pregnancy and eight newborn infants suggest active placental transfer of adalimumab. No fetal harm was observed in reproductive studies performed in cynomolgus monkeys. Because animal reproductive studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
### Clinical Considerations
In general, monoclonal antibodies are transported across the placenta in a linear fashion as pregnancy progresses, with the largest amount transferred during the third trimester.
### Human Data
In an independent clinical study conducted in ten pregnant women with inflammatory bowel disease treated with adalimumab, adalimumab concentrations were measured in maternal blood as well as in cord (n=10) and infant blood (n=8) on the day of birth. The last dose of adalimumab was given between 1 and 56 days prior to delivery. Adalimumab concentrations were 0.16-19.7 µg/mL in cord blood, 4.28-17.7 µg/mL in infant blood, and 0-16.1 µg/mL in maternal blood. In all but one case, the cord blood level of adalimumab was higher than the maternal level, suggesting adalimumab actively crosses the placenta. In addition, one infant had levels at each of the following: 6 weeks (1.94 µg/mL), 7 weeks (1.31 µg/mL), 8 weeks (0.93 µg/mL), and 11 weeks (0.53 µg/mL), suggesting adalimumab can be detected in the serum of infants exposed in utero for at least 3 months from birth.
### Animal Data
An embryo-fetal perinatal developmental toxicity study has been performed in cynomolgus monkeys at dosages up to 100 mg/kg (266 times human AUC when given 40 mg subcutaneously with methotrexate every week or 373 times human AUC when given 40 mg subcutaneously without methotrexate) and has revealed no evidence of harm to the fetuses due to adalimumab.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Adalimumab in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Adalimumab during labor and delivery.
### Nursing Mothers
Limited data from published literature indicate that adalimumab is present in low levels in human milk and is not likely to be absorbed by a breastfed infant. However, no data is available on the absorption of adalimumab from breastmilk in newborn or preterm infants. Caution should be exercised when adalimumab is administered to a nursing woman.
### Pediatric Use
Safety and efficacy of adalimumab in pediatric patients for uses other than juvenile idiopathic arthritis (JIA) have not been established. Due to its inhibition of TNFα, adalimumab administered during pregnancy could affect immune response in the in utero-exposed newborn and infant. Data from eight infants exposed to adalimumab in utero, suggest adalimumab crosses the placenta. The clinical significance of elevated adalimumab levels in infants is unknown. The safety of administering live or live-attenuated vaccines in exposed infants is unknown. Risks and benefits should be considered prior to vaccinating (live or live-attenuated) exposed infants.
Post-marketing cases of lymphoma, including hepatosplenic T-cell lymphoma and other malignancies, some fatal, have been reported among children, adolescents, and young adults who received treatment with TNF-blockers including adalimumab
Juvenile Idiopathic Arthritis
In the JIA trial, adalimumab was shown to reduce signs and symptoms of active polyarticular JIA in patients 4 to 17 years of age . adalimumab has not been studied in children less than 4 years of age, and there are limited data on adalimumab treatment in children with weight <15 kg.
The safety of adalimumab in pediatric patients in the JIA trial was generally similar to that observed in adults with certain exceptions
### Geriatic Use
A total of 519 RA patients 65 years of age and older, including 107 patients 75 years of age and older, received adalimumab in clinical studies RA-I through IV. No overall difference in effectiveness was observed between these patients and younger patients. The frequency of serious infection and malignancy among adalimumab treated patients over 65 years of age was higher than for those under 65 years of age. Because there is a higher incidence of infections and malignancies in the elderly population, use caution when treating the elderly.
### Gender
There is no FDA guidance on the use of Adalimumab with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Adalimumab with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Adalimumab in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Adalimumab in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Adalimumab in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Adalimumab in patients who are immunocompromised.
# Administration and Monitoring
### Administration
adalimumab is administered by subcutaneous injection.
adalimumab is intended for use under the guidance and supervision of a physician. A patient may self-inject adalimumab if a physician determines that it is appropriate, and with medical follow-up, as necessary, after proper training in subcutaneous injection technique.
Carefully inspect the solution in the adalimumab Pen or prefilled syringe for particulate matter and discoloration prior to subcutaneous administration. If particulates and discolorations are noted, do not use the product. adalimumab does not contain preservatives; therefore, discard unused portions of drug remaining from the syringe. NOTE: Instruct patients sensitive to latex not to handle the needle cover of the syringe because it contains dry rubber (latex).
Instruct patients using the adalimumab Pen or prefilled syringe to inject the full amount in the syringe (0.8 mL), which provides 40 mg of adalimumab, according to the directions provided in the Instructions for Use [see Instructions for Use].
Instruct patients (15 kg to <30 kg) using the pediatric pre-filled syringe, or their caregivers, to inject the full amount in the syringe (0.4 mL), which provides 20 mg of adalimumab, according to the directions provided in the Instructions for Use.
Rotate injection sites and do not give injections into areas where the skin is tender, bruised, red or hard.
The adalimumab institutional use vial is for use and administration within an institutional setting only, such as a hospital, physician’s office or clinic. Withdraw the dose using a sterile needle and syringe and administer promptly by a healthcare provider within an institutional setting. Only administer one dose per vial. The vial does not contain preservatives; therefore, discard unused portions.
### Monitoring
Prior to initiating adalimumab and periodically during therapy, evaluate patients for active tuberculosis and test for latent infection
# IV Compatibility
There is limited information about the IV Compatibility.
# Overdosage
Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately.
# Pharmacology
## Mechanism of Action
Adalimumab binds specifically to TNF-alpha and blocks its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface TNF expressing cells in vitro in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (TNF-beta). TNF is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. Elevated levels of TNF are found in the synovial fluid of patients with RA, JIA, PsA, and AS and play an important role in both the pathologic inflammation and the joint destruction that are hallmarks of these diseases. Increased levels of TNF are also found in psoriasis plaques. In Ps, treatment with adalimumab may reduce the epidermal thickness and infiltration of inflammatory cells. The relationship between these pharmacodynamic activities and the mechanism(s) by which adalimumab exerts its clinical effects is unknown.
Adalimumab also modulates biological responses that are induced or regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M).
## Structure
adalimumab (adalimumab) is a recombinant human IgG1 monoclonal antibody specific for human tumor necrosis factor (TNF). adalimumab was created using phage display technology resulting in an antibody with human derived heavy and light chain variable regions and human IgG1:k constant regions. Adalimumab is produced by recombinant DNA technology in a mammalian cell expression system and is purified by a process that includes specific viral inactivation and removal steps. It consists of 1330 amino acids and has a molecular weight of approximately 148 kilodaltons.
adalimumab is supplied as a sterile, preservative-free solution of adalimumab for subcutaneous administration. The drug product is supplied as either a single-use, prefilled pen (adalimumab Pen) or as a single-use, 1 mL prefilled glass syringe. Enclosed within the pen is a single-use, 1 mL prefilled glass syringe. The solution of adalimumab is clear and colorless, with a pH of about 5.2.
Each prefilled syringe delivers 0.8 mL (40 mg) of drug product. Each 0.8 mL of adalimumab contains 40 mg adalimumab, 4.93 mg sodium chloride, 0.69 mg monobasic sodium phosphate dihydrate, 1.22 mg dibasic sodium phosphate dihydrate, 0.24 mg sodium citrate, 1.04 mg citric acid monohydrate, 9.6 mg mannitol, 0.8 mg polysorbate 80, and Water for Injection, USP. Sodium hydroxide added as necessary to adjust pH.
Each pediatric prefilled syringe delivers 0.4 mL (20 mg) of drug product. Each 0.4 mL of adalimumab contains 20 mg adalimumab, 2.47 mg sodium chloride, 0.34 mg monobasic sodium phosphate dihydrate, 0.61 mg dibasic sodium phosphate dihydrate, 0.12 mg sodium citrate, 0.52 mg citric acid monohydrate, 4.8 mg mannitol, 0.4 mg polysorbate 80, and Water for Injection, USP. Sodium hydroxide added as necessary to adjust pH.
## Pharmacodynamics
After treatment with adalimumab, a decrease in levels of acute phase reactants of inflammation (C-reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was observed compared to baseline in patients with rheumatoid arthritis. A decrease in CRP levels was also observed in patients with Crohn’s disease and ulcerative colitis. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that produce tissue remodeling responsible for cartilage destruction were also decreased after adalimumab administration.
## Pharmacokinetics
The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 µg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three studies following a single 40 mg subcutaneous dose was 64%. The pharmacokinetics of adalimumab were linear over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose.
The single dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The distribution volume (Vss) ranged from 4.7 to 6.0 L. The systemic clearance of adalimumab is approximately 12 mL/hr. The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. Adalimumab concentrations in the synovial fluid from five rheumatoid arthritis patients ranged from 31 to 96% of those in serum.
In RA patients receiving 40 mg adalimumab every other week, adalimumab mean steady-state trough concentrations of approximately 5 µg/mL and 8 to 9 µg/mL, were observed without and with methotrexate (MTX), respectively. MTX reduced adalimumab apparent clearance after single and multiple dosing by 29% and 44% respectively, in patients with RA. Mean serum adalimumab trough levels at steady state increased approximately proportionally with dose following 20, 40, and 80 mg every other week and every week subcutaneous dosing. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time.
Adalimumab mean steady-state trough concentrations were slightly higher in psoriatic arthritis patients treated with 40 mg adalimumab every other week (6 to 10 µg/mL and 8.5 to 12 µg/mL, without and with MTX, respectively) compared to the concentrations in RA patients treated with the same dose.
The pharmacokinetics of adalimumab in patients with AS were similar to those in patients with RA.
In patients with CD, the loading dose of 160 mg adalimumab on Week 0 followed by 80 mg adalimumab on Week 2 achieves mean serum adalimumab trough levels of approximately 12 µg/mL at Week 2 and Week 4. Mean steady-state trough levels of approximately 7 µg/mL were observed at Week 24 and Week 56 in CD patients after receiving a maintenance dose of 40 mg adalimumab every other week.
In patients with UC, the loading dose of 160 mg adalimumab on Week 0 followed by 80 mg adalimumab on Week 2 achieves mean serum adalimumab trough levels of approximately 12 µg/mL at Week 2 and Week 4. Mean steady-state trough level of approximately 8 µg/mL was observed at Week 52 in UC patients after receiving a dose of 40 mg adalimumab every other week, and approximately 15 µg/mL at Week 52 in UC patients who increased to a dose of 40 mg adalimumab every week.
In patients with Ps, the mean steady-state trough concentration was approximately 5 to 6 µg/mL during adalimumab 40 mg every other week monotherapy treatment.
Population pharmacokinetic analyses in patients with RA revealed that there was a trend toward higher apparent clearance of adalimumab in the presence of anti-adalimumab antibodies, and lower clearance with increasing age in patients aged 40 to >75 years.
Minor increases in apparent clearance were also predicted in RA patients receiving doses lower than the recommended dose and in RA patients with high rheumatoid factor or CRP concentrations. These increases are not likely to be clinically important.
No gender-related pharmacokinetic differences were observed after correction for a patient’s body weight. Healthy volunteers and patients with rheumatoid arthritis displayed similar adalimumab pharmacokinetics.
No pharmacokinetic data are available in patients with hepatic or renal impairment.
In subjects with JIA (4 to 17 years of age), the mean steady-state trough serum adalimumab concentrations for subjects weighing <30 kg receiving 20 mg adalimumab subcutaneously every other week as monotherapy or with concomitant methotrexate were 6.8 µg/mL and 10.9 µg/mL, respectively. The mean steady-state trough serum adalimumab concentrations for subjects weighing ≥30 kg receiving 40 mg adalimumab subcutaneously every other week as monotherapy or with concomitant methotrexate were 6.6 µg/mL and 8.1 µg/mL, respectively.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term animal studies of adalimumab have not been conducted to evaluate the carcinogenic potential or its effect on fertility. No clastogenic or mutagenic effects of adalimumab were observed in the in vivo mouse micronucleus test or the Salmonella-Escherichia coli (Ames) assay, respectively.
# Clinical Studies
## Rheumatoid Arthritis
The efficacy and safety of adalimumab were assessed in five randomized, double-blind studies in patients ≥18 years of age with active rheumatoid arthritis (RA) diagnosed according to American College of Rheumatology (ACR) criteria. Patients had at least 6 swollen and 9 tender joints. adalimumab was administered subcutaneously in combination with methotrexate (MTX) (12.5 to 25 mg, Studies RA-I, RA-III and RA-V) or as monotherapy (Studies RA-II and RA-V) or with other disease-modifying anti-rheumatic drugs (DMARDs) (Study RA-IV).
Study RA-I evaluated 271 patients who had failed therapy with at least one but no more than four DMARDs and had inadequate response to MTX. Doses of 20, 40 or 80 mg of adalimumab or placebo were given every other week for 24 weeks.
Study RA-II evaluated 544 patients who had failed therapy with at least one DMARD. Doses of placebo, 20 or 40 mg of adalimumab were given as monotherapy every other week or weekly for 26 weeks.
Study RA-III evaluated 619 patients who had an inadequate response to MTX. Patients received placebo, 40 mg of adalimumab every other week with placebo injections on alternate weeks, or 20 mg of adalimumab weekly for up to 52 weeks. Study RA-III had an additional primary endpoint at 52 weeks of inhibition of disease progression (as detected by X-ray results). Upon completion of the first 52 weeks, 457 patients enrolled in an open-label extension phase in which 40 mg of adalimumab was administered every other week for up to 5 years.
Study RA-IV assessed safety in 636 patients who were either DMARD-naive or were permitted to remain on their pre-existing rheumatologic therapy provided that therapy was stable for a minimum of 28 days. Patients were randomized to 40 mg of adalimumab or placebo every other week for 24 weeks.
Study RA-V evaluated 799 patients with moderately to severely active RA of less than 3 years duration who were ≥18 years old and MTX naïve. Patients were randomized to receive either MTX (optimized to 20 mg/week by week 8), adalimumab 40 mg every other week or adalimumab/MTX combination therapy for 104 weeks. Patients were evaluated for signs and symptoms, and for radiographic progression of joint damage. The median disease duration among patients enrolled in the study was 5 months. The median MTX dose achieved was 20 mg.
Clinical Response
The percent of adalimumab treated patients achieving ACR 20, 50 and 70 responses in Studies RA-II and III are shown in Table 2.
The results of Study RA-I were similar to Study RA-III; patients receiving adalimumab 40 mg every other week in Study RA-I also achieved ACR 20, 50 and 70 response rates of 65%, 52% and 24%, respectively, compared to placebo responses of 13%, 7% and 3% respectively, at 6 months (p<0.01).
The results of the components of the ACR response criteria for Studies RA-II and RA-III are shown in Table 3. ACR response rates and improvement in all components of ACR response were maintained to week 104. Over the 2 years in Study RA-III, 20% of adalimumab patients receiving 40 mg every other week (EOW) achieved a major clinical response, defined as maintenance of an ACR 70 response over a 6-month period. ACR responses were maintained in similar proportions of patients for up to 5 years with continuous adalimumab treatment in the open-label portion of Study RA-III.
The time course of ACR 20 response for Study RA-III is shown in Figure 1.
In Study RA-III, 85% of patients with ACR 20 responses at week 24 maintained the response at 52 weeks. The time course of ACR 20 response for Study RA-I and Study RA-II were similar.
In Study RA-IV, 53% of patients treated with adalimumab 40 mg every other week plus standard of care had an ACR 20 response at week 24 compared to 35% on placebo plus standard of care (p<0.001). No unique adverse reactions related to the combination of adalimumab (adalimumab) and other DMARDs were observed.
In Study RA-V with MTX naïve patients with recent onset RA, the combination treatment with adalimumab plus MTX led to greater percentages of patients achieving ACR responses than either MTX monotherapy or adalimumab monotherapy at Week 52 and responses were sustained at Week 104 (see Table 4).
At Week 52, all individual components of the ACR response criteria for Study RA-V improved in the adalimumab/MTX group and improvements were maintained to Week 104.
Radiographic Response
In Study RA-III, structural joint damage was assessed radiographically and expressed as change in Total Sharp Score (TSS) and its components, the erosion score and Joint Space Narrowing (JSN) score, at month 12 compared to baseline. At baseline, the median TSS was approximately 55 in the placebo and 40 mg every other week groups. The results are shown in Table 5. adalimumab/MTX treated patients demonstrated less radiographic progression than patients receiving MTX alone at 52 weeks.
In the open-label extension of Study RA-III, 77% of the original patients treated with any dose of adalimumab were evaluated radiographically at 2 years. Patients maintained inhibition of structural damage, as measured by the TSS. Fifty-four percent had no progression of structural damage as defined by a change in the TSS of zero or less. Fifty-five percent (55%) of patients originally treated with 40 mg adalimumab every other week have been evaluated radiographically at 5 years. Patients had continued inhibition of structural damage with 50% showing no progression of structural damage defined by a change in the TSS of zero or less.
In Study RA-V, structural joint damage was assessed as in Study RA-III. Greater inhibition of radiographic progression, as assessed by changes in TSS, erosion score and JSN was observed in the adalimumab/MTX combination group as compared to either the MTX or adalimumab monotherapy group at Week 52 as well as at Week 104 (see Table 6).
Physical Function Response
In studies RA-I through IV, adalimumab showed significantly greater improvement than placebo in the disability index of Health Assessment Questionnaire (HAQ-DI) from baseline to the end of study, and significantly greater improvement than placebo in the health-outcomes as assessed by The Short Form Health Survey (SF 36). Improvement was seen in both the Physical Component Summary (PCS) and the Mental Component Summary (MCS).
In Study RA-III, the mean (95% CI) improvement in HAQ-DI from baseline at week 52 was 0.60 (0.55, 0.65) for the adalimumab patients and 0.25 (0.17, 0.33) for placebo/MTX (p<0.001) patients. Sixty-three percent of adalimumab-treated patients achieved a 0.5 or greater improvement in HAQ-DI at week 52 in the double-blind portion of the study. Eighty-two percent of these patients maintained that improvement through week 104 and a similar proportion of patients maintained this response through week 260 (5 years) of open-label treatment. Mean improvement in the SF-36 was maintained through the end of measurement at week 156 (3 years).
In Study RA-V, the HAQ-DI and the physical component of the SF-36 showed greater improvement (p<0.001) for the adalimumab/MTX combination therapy group versus either the MTX monotherapy or the adalimumab monotherapy group at Week 52, which was maintained through Week 104.
## Juvenile Idiopathic Arthritis
The safety and efficacy of adalimumab were assessed in a multicenter, randomized, withdrawal, double-blind, parallel-group study in 171 children (4 to 17 years of age) with polyarticular juvenile idiopathic arthritis (JIA). In the study, the patients were stratified into two groups: MTX-treated or non-MTX-treated. All subjects had to show signs of active moderate or severe disease despite previous treatment with NSAIDs, analgesics, corticosteroids, or DMARDS. Subjects who received prior treatment with any biologic DMARDS were excluded from the study.
The study included four phases: an open-label lead in phase (OL-LI; 16 weeks), a double-blind randomized withdrawal phase (DB; 32 weeks), an open-label extension phase (OLE-BSA; up to 136 weeks), and an open-label fixed dose phase (OLE-FD; 16 weeks). In the first three phases of the study, adalimumab was administered based on body surface area at a dose of 24 mg/m2 up to a maximum total body dose of 40 mg subcutaneously (SC) every other week. In the OLE-FD phase, the patients were treated with 20 mg of adalimumab SC every other week if their weight was less than 30 kg and with 40 mg of adalimumab SC every other week if their weight was 30 kg or greater. Patients remained on stable doses of NSAIDs and or prednisone (≤0.2 mg/kg/day or 10 mg/day maximum).
Patients demonstrating a Pediatric ACR 30 response at the end of OL-LI phase were randomized into the double blind (DB) phase of the study and received either adalimumab or placebo every other week for 32 weeks or until disease flare. Disease flare was defined as a worsening of ≥30% from baseline in ≥3 of 6 Pediatric ACR core criteria, ≥2 active joints, and improvement of >30% in no more than 1 of the 6 criteria. After 32 weeks or at the time of disease flare during the DB phase, patients were treated in the open-label extension phase based on the BSA regimen (OLE-BSA), before converting to a fixed dose regimen based on body weight (OLE-FD phase).
Clinical Response
At the end of the 16-week OL-LI phase, 94% of the patients in the MTX stratum and 74% of the patients in the non-MTX stratum were Pediatric ACR 30 responders. In the DB phase significantly fewer patients who received adalimumab experienced disease flare compared to placebo, both without MTX (43% vs. 71%) and with MTX (37% vs. 65%). More patients treated with adalimumab continued to show pediatric ACR 30/50/70 responses at Week 48 compared to patients treated with placebo. Pediatric ACR responses were maintained for up to two years in the OLE phase in patients who received adalimumab throughout the study.
## Psoriatic Arthritis
The safety and efficacy of adalimumab was assessed in two randomized, double-blind, placebo controlled studies in 413 patients with psoriatic arthritis (PsA). Upon completion of both studies, 383 patients enrolled in an open-label extension study, in which 40 mg adalimumab was administered every other week.
Study PsA-I enrolled 313 adult patients with moderately to severely active PsA (>3 swollen and >3 tender joints) who had an inadequate response to NSAID therapy in one of the following forms: (1) distal interphalangeal (DIP) involvement (N=23); (2) polyarticular arthritis (absence of rheumatoid nodules and presence of plaque psoriasis) (N=210); (3) arthritis mutilans (N=1); (4) asymmetric PsA (N=77); or (5) AS-like (N=2). Patients on MTX therapy (158 of 313 patients) at enrollment (stable dose of ≤30 mg/week for >1 month) could continue MTX at the same dose. Doses of adalimumab 40 mg or placebo every other week were administered during the 24-week double-blind period of the study.
Compared to placebo, treatment with adalimumab resulted in improvements in the measures of disease activity (see Tables 7 and 8). Among patients with PsA who received adalimumab, the clinical responses were apparent in some patients at the time of the first visit (two weeks) and were maintained up to 88 weeks in the ongoing open-label study. Similar responses were seen in patients with each of the subtypes of psoriatic arthritis, although few patients were enrolled with the arthritis mutilans and ankylosing spondylitis-like subtypes. Responses were similar in patients who were or were not receiving concomitant MTX therapy at baseline.
Patients with psoriatic involvement of at least three percent body surface area (BSA) were evaluated for Psoriatic Area and Severity Index (PASI) responses. At 24 weeks, the proportions of patients achieving a 75% or 90% improvement in the PASI were 59% and 42% respectively, in the adalimumab group (N=69), compared to 1% and 0% respectively, in the placebo group (N=69) (p<0.001). PASI responses were apparent in some patients at the time of the first visit (two weeks). Responses were similar in patients who were or were not receiving concomitant MTX therapy at baseline.
Similar results were seen in an additional, 12-week study in 100 patients with moderate to severe psoriatic arthritis who had suboptimal response to DMARD therapy as manifested by ≥3 tender joints and ≥3 swollen joints at enrollment.
Radiographic Response
Radiographic changes were assessed in the PsA studies. Radiographs of hands, wrists, and feet were obtained at baseline and Week 24 during the double-blind period when patients were on adalimumab or placebo and at Week 48 when all patients were on open-label adalimumab. A modified Total Sharp Score (mTSS), which included distal interphalangeal joints (i.e., not identical to the TSS used for rheumatoid arthritis), was used by readers blinded to treatment group to assess the radiographs.
adalimumab-treated patients demonstrated greater inhibition of radiographic progression compared to placebo-treated patients and this effect was maintained at 48 weeks (see Table 9).
Physical Function Response
In Study PsA-I, physical function and disability were assessed using the HAQ Disability Index (HAQ-DI) and the SF-36 Health Survey. Patients treated with 40 mg of adalimumab every other week showed greater improvement from baseline in the HAQ-DI score (mean decreases of 47% and 49% at Weeks 12 and 24 respectively) in comparison to placebo (mean decreases of 1% and 3% at Weeks 12 and 24 respectively). At Weeks 12 and 24, patients treated with adalimumab showed greater improvement from baseline in the SF-36 Physical Component Summary score compared to patients treated with placebo, and no worsening in the SF-36 Mental Component Summary score. Improvement in physical function based on the HAQ-DI was maintained for up to 84 weeks through the open-label portion of the study.
## Ankylosing Spondylitis
The safety and efficacy of adalimumab 40 mg every other week was assessed in 315 adult patients in a randomized, 24 week double-blind, placebo-controlled study in patients with active ankylosing spondylitis (AS) who had an inadequate response to glucocorticoids, NSAIDs, analgesics, methotrexate or sulfasalazine. Active AS was defined as patients who fulfilled at least two of the following three criteria: (1) a Bath AS disease activity index (BASDAI) score ≥4 cm, (2) a visual analog score (VAS) for total back pain ≥ 40 mm, and (3) morning stiffness ≥ 1 hour. The blinded period was followed by an open-label period during which patients received adalimumab 40 mg every other week subcutaneously for up to an additional 28 weeks.
Improvement in measures of disease activity was first observed at Week 2 and maintained through 24 weeks as shown in Figure 2 and Table 10.
Responses of patients with total spinal ankylosis (n=11) were similar to those without total ankylosis.
Physical Function Response
In Study PsA-I, physical function and disability were assessed using the HAQ Disability Index (HAQ-DI) and the SF-36 Health Survey. Patients treated with 40 mg of adalimumab every other week showed greater improvement from baseline in the HAQ-DI score (mean decreases of 47% and 49% at Weeks 12 and 24 respectively) in comparison to placebo (mean decreases of 1% and 3% at Weeks 12 and 24 respectively). At Weeks 12 and 24, patients treated with adalimumab showed greater improvement from baseline in the SF-36 Physical Component Summary score compared to patients treated with placebo, and no worsening in the SF-36 Mental Component Summary score. Improvement in physical function based on the HAQ-DI was maintained for up to 84 weeks through the open-label portion of the study.
## Ankylosing Spondylitis
The safety and efficacy of adalimumab 40 mg every other week was assessed in 315 adult patients in a randomized, 24 week double-blind, placebo-controlled study in patients with active ankylosing spondylitis (AS) who had an inadequate response to glucocorticoids, NSAIDs, analgesics, methotrexate or sulfasalazine. Active AS was defined as patients who fulfilled at least two of the following three criteria: (1) a Bath AS disease activity index (BASDAI) score ≥4 cm, (2) a visual analog score (VAS) for total back pain ≥ 40 mm, and (3) morning stiffness ≥ 1 hour. The blinded period was followed by an open-label period during which patients received adalimumab 40 mg every other week subcutaneously for up to an additional 28 weeks.
Improvement in measures of disease activity was first observed at Week 2 and maintained through 24 weeks as shown in Figure 2 and Table 10.
Responses of patients with total spinal ankylosis (n=11) were similar to those without total ankylosis.
At 12 weeks, the ASAS 20/50/70 responses were achieved by 58%, 38%, and 23%, respectively, of patients receiving adalimumab, compared to 21%, 10%, and 5% respectively, of patients receiving placebo (p <0.001). Similar responses were seen at Week 24 and were sustained in patients receiving open-label adalimumab for up to 52 weeks.
A greater proportion of patients treated with adalimumab (22%) achieved a low level of disease activity at 24 weeks (defined as a value <20 [on a scale of 0 to 100 mm] in each of the four ASAS response parameters) compared to patients treated with placebo (6%).
A second randomized, multicenter, double-blind, placebo-controlled study of 82 patients with ankylosing spondylitis showed similar results.
Patients treated with adalimumab achieved improvement from baseline in the Ankylosing Spondylitis Quality of Life Questionnaire (ASQoL) score (-3.6 vs. -1.1) and in the Short Form Health Survey (SF-36) Physical Component Summary (PCS) score (7.4 vs. 1.9) compared to placebo-treated patients at Week 24.
## Crohn’s Disease
The safety and efficacy of multiple doses of adalimumab were assessed in adult patients with moderately to severely active Crohn’s disease, CD, (Crohn’s Disease Activity Index (CDAI) ≥ 220 and ≤ 450) in randomized, double-blind, placebo-controlled studies. Concomitant stable doses of aminosalicylates, corticosteroids, and/or immunomodulatory agents were permitted, and 79% of patients continued to receive at least one of these medications.
Induction of clinical remission (defined as CDAI < 150) was evaluated in two studies. In Study CD-I, 299 TNF-blocker naïve patients were randomized to one of four treatment groups: the placebo group received placebo at Weeks 0 and 2, the 160/80 group received 160 mg adalimumab at Week 0 and 80 mg at Week 2, the 80/40 group received 80 mg at Week 0 and 40 mg at Week 2, and the 40/20 group received 40 mg at Week 0 and 20 mg at Week 2. Clinical results were assessed at Week 4.
In the second induction study, Study CD-II, 325 patients who had lost response to, or were intolerant to, previous infliximab therapy were randomized to receive either 160 mg adalimumab at Week 0 and 80 mg at Week 2, or placebo at Weeks 0 and 2. Clinical results were assessed at Week 4.
Maintenance of clinical remission was evaluated in Study CD-III. In this study, 854 patients with active disease received open-label adalimumab, 80 mg at week 0 and 40 mg at Week 2. Patients were then randomized at Week 4 to 40 mg adalimumab every other week, 40 mg adalimumab every week, or placebo. The total study duration was 56 weeks. Patients in clinical response (decrease in CDAI ≥70) at Week 4 were stratified and analyzed separately from those not in clinical response at Week 4.
Induction of Clinical Remission
A greater percentage of the patients treated with 160/80 mg adalimumab achieved induction of clinical remission versus placebo at Week 4 regardless of whether the patients were TNF blocker naïve (CD-I), or had lost response to or were intolerant to infliximab (CD-II) (see Table 11).
Maintenance of Clinical Remission
In Study CD-III at Week 4, 58% (499/854) of patients were in clinical response and were assessed in the primary analysis. At Weeks 26 and 56, greater proportions of patients who were in clinical response at Week 4 achieved clinical remission in the adalimumab 40 mg every other week maintenance group compared to patients in the placebo maintenance group (see Table 12). The group that received adalimumab therapy every week did not demonstrate significantly higher remission rates compared to the group that received adalimumab every other week.
Of those in response at Week 4 who attained remission during the study, patients in the adalimumab every other week group maintained remission for a longer time than patients in the placebo maintenance group. Among patients who were not in response by Week 12, therapy continued beyond 12 weeks did not result in significantly more responses.
## Ulcerative Colitis
The safety and efficacy of adalimumab were assessed in adult patients with moderately to severely active ulcerative colitis (Mayo score 6 to 12 on a 12 point scale, with an endoscopy subscore of 2 to 3 on a scale of 0 to 3) despite concurrent or prior treatment with immunosuppressants such as corticosteroids, azathioprine, or 6-MP in two randomized, double-blind, placebo-controlled clinical studies (Studies UC-I and UC-II). Both studies enrolled TNF-blocker naïve patients, but Study UC-II also allowed entry of patients who lost response to or were intolerant to TNF-blockers. Forty percent (40%) of patients enrolled in Study UC-II had previously used another TNF-blocker.
Concomitant stable doses of aminosalicylates and immunosuppressants were permitted. In Studies UC-I and II, patients were receiving aminosalicylates (69%), corticosteroids (59%) and/or azathioprine or 6-MP (37%) at baseline. In both studies, 92% of patients received at least one of these medications.
Induction of clinical remission (defined as Mayo score ≤ 2 with no individual subscores > 1) at Week 8 was evaluated in both studies. Clinical remission at Week 52 and sustained clinical remission (defined as clinical remission at both Weeks 8 and 52) were evaluated in Study UC-II.
In Study UC-I, 390 TNF-blocker naïve patients were randomized to one of three treatment groups for the primary efficacy analysis. The placebo group received placebo at Weeks 0, 2, 4 and 6. The 160/80 group received 160 mg adalimumab at Week 0 and 80 mg at Week 2, and the 80/40 group received 80 mg adalimumab at Week 0 and 40 mg at Week 2. After Week 2, patients in both adalimumab treatment groups received 40 mg every other week (eow).
In Study UC-II, 518 patients were randomized to receive either adalimumab 160 mg at Week 0, 80 mg at Week 2, and 40 mg eow starting at Week 4 through Week 50, or placebo starting at Week 0 and eow through Week 50. Corticosteroid taper was permitted starting at Week 8.
In both Studies UC-I and UC-II, a greater percentage of the patients treated with 160/80 mg of adalimumab compared to patients treated with placebo achieved induction of clinical remission. In Study UC-II, a greater percentage of the patients treated with 160/80 mg of adalimumab compared to patients treated with placebo achieved sustained clinical remission (clinical remission at both Weeks 8 and 52) (Table 13).
In Study UC-I, there was no statistically significant difference in clinical remission observed between the adalimumab 80/40 mg group and the placebo group at Week 8.
In Study UC-II, 17.3% (43/248) in the adalimumab group were in clinical remission at Week 52 compared to 8.5% (21/246) in the placebo group (treatment difference: 8.8%; 95% confidence interval (CI): [2.8%, 14.5%]; p<0.05).
In the subgroup of patients in Study UC-II with prior TNF-blocker use, the treatment difference for induction of clinical remission appeared to be lower than that seen in the whole study population, and the treatment differences for sustained clinical remission and clinical remission at Week 52 appeared to be similar to those seen in the whole study population. The subgroup of patients with prior TNF-blocker use achieved induction of clinical remission at 9% (9/98) in the adalimumab group versus 7% (7/101) in the placebo group, and sustained clinical remission at 5% (5/98) in the adalimumab group versus 1% (1/101) in the placebo group. In the subgroup of patients with prior TNF-blocker use, 10% (10/98) were in clinical remission at Week 52 in the adalimumab group versus 3% (3/101) in the placebo group.
## Plaque Psoriasis
The safety and efficacy of adalimumab were assessed in randomized, double-blind, placebo-controlled studies in 1696 adult patients with moderate to severe chronic plaque psoriasis (Ps) who were candidates for systemic therapy or phototherapy.
Study Ps-I evaluated 1212 patients with chronic Ps with ≥10% body surface area (BSA) involvement, Physician’s Global Assessment (PGA) of at least moderate disease severity, and Psoriasis Area and Severity Index (PASI) ≥12 within three treatment periods. In period A, patients received placebo or adalimumab at an initial dose of 80 mg at Week 0 followed by a dose of 40 mg every other week starting at Week 1. After 16 weeks of therapy, patients who achieved at least a PASI 75 response at Week 16, defined as a PASI score improvement of at least 75% relative to baseline, entered period B and received open-label 40 mg adalimumab every other week. After 17 weeks of open label therapy, patients who maintained at least a PASI 75 response at Week 33 and were originally randomized to active therapy in period A were re-randomized in period C to receive 40 mg adalimumab every other week or placebo for an additional 19 weeks. Across all treatment groups the mean baseline PASI score was 19 and the baseline Physician’s Global Assessment score ranged from “moderate” (53%) to “severe” (41%) to “very severe” (6%).
Study Ps-II evaluated 99 patients randomized to adalimumab and 48 patients randomized to placebo with chronic plaque psoriasis with ≥10% BSA involvement and PASI ≥12. Patients received placebo, or an initial dose of 80 mg adalimumab at Week 0 followed by 40 mg every other week starting at Week 1 for 16 weeks. Across all treatment groups the mean baseline PASI score was 21 and the baseline PGA score ranged from “moderate” (41%) to “severe” (51%) to “very severe” (8%).
Studies Ps-I and II evaluated the proportion of patients who achieved “clear” or “minimal” disease on the 6-point PGA scale and the proportion of patients who achieved a reduction in PASI score of at least 75% (PASI 75) from baseline at Week 16 (see Table 14 and 15).
Additionally, Study Ps-I evaluated the proportion of subjects who maintained a PGA of “clear” or “minimal” disease or a PASI 75 response after Week 33 and on or before Week 52.
Additionally, in Study Ps-I, subjects on adalimumab who maintained a PASI 75 were re-randomized to adalimumab (N = 250) or placebo (N = 240) at Week 33. After 52 weeks of treatment with adalimumab, more patients on adalimumab maintained efficacy when compared to subjects who were re-randomized to placebo based on maintenance of PGA of “clear” or “minimal” disease (68% vs. 28%) or a PASI 75 (79% vs. 43%).
A total of 347 stable responders participated in a withdrawal and retreatment evaluation in an open-label extension study. Median time to relapse (decline to PGA “moderate” or worse) was approximately 5 months. During the withdrawal period, no subject experienced transformation to either pustular or erythrodermic psoriasis. A total of 178 subjects who relapsed re-initiated treatment with 80 mg of adalimumab, then 40 mg eow beginning at week 1. At week 16, 69% (123/178) of subjects had a response of PGA “clear” or “minimal”.
# How Supplied
adalimumab® (adalimumab) is supplied as a preservative-free, sterile solution for subcutaneous administration. The following packaging configurations are available.
- adalimumab Pen Carton
adalimumab is dispensed in a carton containing two alcohol preps and two dose trays. Each dose tray consists of a single-use pen, containing a 1 mL prefilled glass syringe with a fixed 27 gauge ½ inch needle, providing 40 mg (0.8 mL) of adalimumab. The NDC number is 0074-4339-02.
- adalimumab Pen – Crohn's Disease/Ulcerative Colitis Starter Package
adalimumab is dispensed in a carton containing 6 alcohol preps and 6 dose trays (Crohn’s Disease/Ulcerative Colitis Starter Package). Each dose tray consists of a single-use pen, containing a 1 mL prefilled glass syringe with a fixed 27 gauge ½ inch needle, providing 40 mg (0.8 mL) of adalimumab. The NDC number is 0074-4339-06.
- adalimumab Pen – Psoriasis Starter Package
adalimumab is dispensed in a carton containing 4 alcohol preps and 4 dose trays (Psoriasis Starter Package). Each dose tray consists of a single-use pen, containing a 1 mL prefilled glass syringe with a fixed 27 gauge ½ inch needle, providing 40 mg (0.8 mL) of adalimumab. The NDC number is 0074-4339-07.
- Prefilled Syringe Carton – 40 mg
adalimumab is dispensed in a carton containing two alcohol preps and two dose trays. Each dose tray consists of a single-use, 1 mL prefilled glass syringe with a fixed 27 gauge ½ inch needle, providing 40 mg (0.8 mL) of adalimumab. The NDC number is 0074-3799-02.
- Pediatric Prefilled Syringe Carton – 20 mg
adalimumab is supplied for pediatric use only in a carton containing two alcohol preps and two dose trays. Each dose tray consists of a single-use, 1 mL pre-filled glass syringe with a fixed 27 gauge ½ inch needle, providing 20 mg (0.4 mL) of adalimumab. The NDC number is 0074-9374-02.
- Institutional Use Vial Carton – 40 mg
adalimumab is supplied for institutional use only in a carton containing a single-use, glass vial, providing 40 mg (0.8 mL) of adalimumab. The NDC number is 0074-3797-01.
## Storage
Do not use beyond the expiration date on the container. adalimumab must be refrigerated at 36°F to 46°F (2°C to 8°C). DO NOT FREEZE. Do not use if frozen even if it has been thawed. When traveling, store adalimumab in a cool carrier with an ice pack. Protect the prefilled syringe from exposure to light. Store in original carton until time of administration.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
## Patient Counseling
Provide the adalimumab “Medication Guide” to patients or their caregivers, and provide them an opportunity to read it and ask questions prior to initiation of therapy and prior to each time the prescription is renewed. If patients develop signs and symptoms of infection, instruct them to seek medical evaluation immediately.
Advise patients of the potential benefits and risks of adalimumab.
- Infections
Inform patients that adalimumab may lower the ability of their immune system to fight infections. Instruct patients of the importance of contacting their doctor if they develop any symptoms of infection, including tuberculosis, invasive fungal infections, and reactivation of hepatitis B virus infections.
- Malignancies
Counsel patients about the risk of malignancies while receiving adalimumab.
- Allergic Reactions
Advise patients to seek immediate medical attention if they experience any symptoms of severe allergic reactions. Advise latex-sensitive patients that the needle cap of the prefilled syringe contains latex.
- Other Medical Conditions
Advise patients to report any signs of new or worsening medical conditions such as congestive heart failure, neurological disease, autoimmune disorders, or cytopenias. Advise patients to report any symptoms suggestive of a cytopenia such as bruising, bleeding, or persistent fever.
## Instruction on Injection Technique
Inform patients that the first injection is to be performed under the supervision of a qualified health care professional. If a patient or caregiver is to administer adalimumab, instruct them in injection techniques and assess their ability to inject subcutaneously to ensure the proper administration of adalimumab [see Instructions for Use].
For patients who will use the adalimumab Pen, tell them that they:
- Will hear a loud ‘click’ when the plum-colored activator button is pressed. The loud click means the start of the injection.
- Must keep holding the adalimumab Pen against their squeezed, raised skin until all of the medicine is injected. This can take up to 10 seconds.
- Will know that the injection has finished when the yellow marker fully appears in the window view and stops moving.
Instruct patients to dispose of their used needles and syringes or used Pen in a FDA-cleared sharps disposal container immediately after use. Instruct patients not to dispose of loose needles and syringes or Pen in their household trash. Instruct patients that if they do not have a FDA-cleared sharps disposal container, they may use a household container that is made of a heavy-duty plastic, can be closed with a tight-fitting and puncture-resistant lid without sharps being able to come out, upright and stable during use, leak-resistant, and properly labeled to warn of hazardous waste inside the container.
Instruct patients that when their sharps disposal container is almost full, they will need to follow their community guidelines for the correct way to dispose of their sharps disposal container. Instruct patients that there may be state or local laws regarding disposal of used needles and syringes. Refer patients to the FDA’s website at http://www.fda.gov/safesharpsdisposal for more information about safe sharps disposal, and for specific information about sharps disposal in the state that they live in.
Instruct patients not to dispose of their used sharps disposal container in their household trash unless their community guidelines permit this. Instruct patients not to recycle their used sharps disposal container.
# Precautions with Alcohol
Alcohol-Adalimumab interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
HUMIRA
# Look-Alike Drug Names
There is limited information about the look-alike drugs.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Adalimumab | |
d3c9d5910500281e41d6bbe1491355e0550c4ea6 | wikidoc | Adamantane | Adamantane
# Overview
Adamantane (tricyclodecane) is a colourless, crystalline compound with a camphor-like odour. With a formula C10H16, it is a cycloalkane and also the simplest diamondoid. Adamantane was discovered in petroleum in 1933. Its name derived from the Greek adamantinos (relating to steel or diamond), due to its diamond-like structure. Adamantane is the most stable isomer of C10H16.
# Synthesis
Adamantane was first synthesised by Prelog in 1941. A more convenient method was found by Schleyer in 1957, from dicyclopentadiene by hydrogenation followed by acid-catalysed skeletal rearrangement.
# Uses
Adamantane itself enjoys few applications since it is merely an unfunctionalised hydrocarbon. It is used in some dry etching masks. It is also used in some polymer formulations.
In solid-state NMR spectroscopy, adamantane is a common standard for chemical shift referencing.
In dye lasers, adamantane may be used to extend the life of the gain medium; it cannot be photoionised under atmosphere because its absorption bands lie in the vacuum-ultraviolet region of the spectrum. Photoionization energies have been determined recently for adamantane as well as for several bigger diamondoids.
# Adamantane derivatives
Adamantane derivatives are useful in medicine, e.g. amantadine, memantine and rimantadine. Condensed adamantanes or diamondoids have been isolated from petroleum fractions, where they occur in small amounts. These species are of interest as molecular approximations of the cubic diamond framework, terminated with C-H bonds. 1,3-Dehydroadamantane is a member of the propellane family.
Due to its stability, specific steric properties and conformational rigidity, the 1-adamantyl group is a (bulky) substituent in organic and organometallic chemistry. Some of the first persistent carbenes featured adamantyl substituents.
# Adamantane analogues
Many molecules adopt cage structures with adamantanoid structures. Particularly useful compounds with this motif include P4O6, As4O6, P4O10 (= (PO)4O6), P4S10 (= (PS)4S6), and N4(CH2)6. | Adamantane
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Adamantane (tricyclo[3.3.1.13,7]decane) is a colourless, crystalline compound with a camphor-like odour.[1][2] With a formula C10H16, it is a cycloalkane and also the simplest diamondoid. Adamantane was discovered in petroleum in 1933.[3] Its name derived from the Greek adamantinos (relating to steel or diamond), due to its diamond-like structure.[4] Adamantane is the most stable isomer of C10H16.
# Synthesis
Adamantane was first synthesised by Prelog in 1941.[5] A more convenient method was found by Schleyer in 1957, from dicyclopentadiene by hydrogenation followed by acid-catalysed skeletal rearrangement.[6][7]
# Uses
Adamantane itself enjoys few applications since it is merely an unfunctionalised hydrocarbon. It is used in some dry etching masks.[8] It is also used in some polymer formulations.
In solid-state NMR spectroscopy, adamantane is a common standard for chemical shift referencing.[9]
In dye lasers, adamantane may be used to extend the life of the gain medium; it cannot be photoionised under atmosphere because its absorption bands lie in the vacuum-ultraviolet region of the spectrum. Photoionization energies have been determined recently for adamantane as well as for several bigger diamondoids.[10]
# Adamantane derivatives
Adamantane derivatives are useful in medicine, e.g. amantadine, memantine and rimantadine. Condensed adamantanes or diamondoids have been isolated from petroleum fractions, where they occur in small amounts. These species are of interest as molecular approximations of the cubic diamond framework, terminated with C-H bonds. 1,3-Dehydroadamantane is a member of the propellane family.
Due to its stability, specific steric properties and conformational rigidity, the 1-adamantyl group is a (bulky) substituent in organic and organometallic chemistry. Some of the first persistent carbenes featured adamantyl substituents.
# Adamantane analogues
Many molecules adopt cage structures with adamantanoid structures. Particularly useful compounds with this motif include P4O6, As4O6, P4O10 (= (PO)4O6), P4S10 (= (PS)4S6), and N4(CH2)6.[11] | https://www.wikidoc.org/index.php/Adamantane | |
08681501920bd20b14cd94426b98d778efca371d | wikidoc | Ameloblast | Ameloblast
# Overview
Ameloblasts are cells that deposit enamel, the hard outer most layer that forms the chewing surface.
Ameloblasts are cells which secrete the enamel proteins enamelin and amelogen which will later mineralise to form enamel on teeth, the strongest substance in the human body. Each Ameloblast is approximately 4 micrometers in diameter, 40 micrometers in length and has a hexagonal cross section. The secretory end of the ameloblast ends in a six sided pyramid like projection known as the Tomes' process. The angulation of the Tomes' process is significant in the orientation of enamel rods.
Ameloblasts are derived from oral epithelium tissue of ectodermal origin. Their differentiation is a result of signalling from the ectomesenchymal cells of the dental papilla. The ameloblasts will only become fully functional after the first layer of dentine has been formed, as such dentine is a precursor to enamel.
Ameloblasts control ionic and organic compositions of enamel. They adjust their secretory and re absorptive activities to maintain favorable conditions for biomineralization. | Ameloblast
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Ameloblasts are cells that deposit enamel, the hard outer most layer that forms the chewing surface.
Ameloblasts are cells which secrete the enamel proteins enamelin and amelogen which will later mineralise to form enamel on teeth, the strongest substance in the human body. Each Ameloblast is approximately 4 micrometers in diameter, 40 micrometers in length and has a hexagonal cross section. The secretory end of the ameloblast ends in a six sided pyramid like projection known as the Tomes' process. The angulation of the Tomes' process is significant in the orientation of enamel rods.
Ameloblasts are derived from oral epithelium tissue of ectodermal origin. Their differentiation is a result of signalling from the ectomesenchymal cells of the dental papilla. The ameloblasts will only become fully functional after the first layer of dentine has been formed, as such dentine is a precursor to enamel.
Ameloblasts control ionic and organic compositions of enamel. They adjust their secretory and re absorptive activities to maintain favorable conditions for biomineralization. | https://www.wikidoc.org/index.php/Adamantoblasts | |
81461161d1f3f33ea509fdbf66c63b89d86a1e2b | wikidoc | Adaptation | Adaptation
An adaptation is a positive characteristic of an organism that has been favored by natural selection. The concept is central to biology, particularly in evolutionary biology. The term adaptation is also sometimes used as a synonym for natural selection, but most biologists discourage this usage.
Adaptation is the change in organisms that allow them to live successfully in an environment. Adaptations enable living organisms to cope with environmental stresses and pressures. Adaptation can be structural or behavioral. Structural adaptations are special body parts of an organism that help it to survive in its natural habitat (e.g., skin colour, shape, body covering). Behavioural adaptations are special ways a particular organism behaves to survive in its natural habitat. Physiological adaptations are systems present in an organism that allow it to perform certain biochemical reactions (e.g., making venom, secreting slime, being able to keep a constant body temperature).
Adaptations are traits that have been selected for by natural selection. The underlying genetic basis for the adaptive trait did not arise as a consequence of the environment; the genetic variant pre-existed and was subsequently selected because it provided the bearer of that variant some advantage. The first experimental evidence of the pre-existing nature of genetic variants was provided by Joshua Lederberg and colleagues who developed fluctuation analysis, a method to show the random fluctuation of pre-exisitng genetic changes that conferred resistance to antibiotics by the bacterium Escherichia coli
While many traits have obvious adaptive purposes, it is worthwhile to point out that many traits are not adaptive, that is, there is no obvious reason scientists can divine for the presence of a certain trait. This situation is common and there are many causes: the utility of a trait is lost and hence does not now appear adaptive, the utility of a trait is unknown, the trait is a consequence of another trait that is adaptive (the Spandrel idea). This observation underscores two other important points: genetic variants arise randomly and hence traits can appear randomly and that because the environment for all living things is constantly in flux, the utility of adaptations will naturally ebb and flow.
Organisms that are not suitably adapted to their environment will either have to move out of the habitat or die out. The term die out in the context of adaptation simply means that the death rate over the entire species (population, gene pool ...) exceeds the birth rate for a long enough period for the species to disappear; due to individual phenotypic plasticity, individuals will be more or less successful. The opposite is selection which in this context means that the birth rate of those carrying the adaptive trait and the hence the underlying genetic variant exceeds over time the birth rate of those that do not carry the adaptive traitTemplate:Unicode.
# Adaptation vs. adaptiveness
A trait being adaptive, i.e. increasing the organism's fitness, is neither a necessary nor sufficient condition for it to be an adaptation. Of course, an adaptation must have been adaptive at some point in an organism's evolutionary history, but such an organism's environment and ecological niche can change over time, leading to adaptations becoming redundant or even a hindrance (maladaptations). Such adaptations are termed vestigial.
# Adaptation vs. acclimation
There is a great difference between adaptation and acclimation. Adaptation occurs over many generations; it is a gradual process caused by natural selection. Acclimatization generally occurs within a single lifetime and copes with issues that are less threatening. For example, if a human was to move to a higher altitude, respiration and physical exertion would become a problem, but after spending time in high altitude conditions one may acclimate to the pressure and function and no longer notice the change. This ability to acclimate is an adaptation, but not the acclimation itself.
A counter-adaptation is an adaptation that has evolved due to the selective pressure of another adaptation. This occurs in an evolutionary arms race, where a new adaptation giving one species an advantage is countered by the appearance and spread of a new feature that reduces the effectiveness of the first adaptation.
# Theories
The theory of adaptation was first put forth by Jean-Baptiste Lamarck. His theories are also referred to as the inheritance of acquired traits.
Lamarck's theory was for a time held as an alternative scientific explanation for evolutionary change observed by Darwin in the The Origin of Species. The classic giraffe analogy offers the best delineation between the two.
- According to Darwin, more long-necked giraffes reproduce than short-necked giraffes and as such giraffes today have long necks.
- According to Lamarck, it was giraffes stretching their necks in response to higher leaves that resulted in giraffes having long necks. (This trait being passed on to the next generation)
Although neither theory in its conception could provide a complete description of the mechanism of transmission of trait variation (i.e., particulate inheritance), many recognized Darwin's theory immediately upon publication as a more complete and empirically supported theory. Modern genetics have since established the fundamental implausibility of Lamarckian inheritance, due to the one-way nature of transcription. However, see epigenetics and Baldwinian evolution for analogous processes in modern evolutionary theory. | Adaptation
Template:Evolution3
An adaptation is a positive characteristic of an organism that has been favored by natural selection.[1] The concept is central to biology, particularly in evolutionary biology. The term adaptation is also sometimes used as a synonym for natural selection,[citation needed] but most biologists discourage this usage.
Adaptation is the change in organisms that allow them to live successfully in an environment. Adaptations enable living organisms to cope with environmental stresses and pressures. Adaptation can be structural or behavioral. Structural adaptations are special body parts of an organism that help it to survive in its natural habitat (e.g., skin colour, shape, body covering). Behavioural adaptations are special ways a particular organism behaves to survive in its natural habitat. Physiological adaptations are systems present in an organism that allow it to perform certain biochemical reactions (e.g., making venom, secreting slime, being able to keep a constant body temperature).
Adaptations are traits that have been selected for by natural selection. The underlying genetic basis for the adaptive trait did not arise as a consequence of the environment; the genetic variant pre-existed and was subsequently selected because it provided the bearer of that variant some advantage. The first experimental evidence of the pre-existing nature of genetic variants was provided by Joshua Lederberg and colleagues who developed fluctuation analysis, a method to show the random fluctuation of pre-exisitng genetic changes that conferred resistance to antibiotics by the bacterium Escherichia coli
While many traits have obvious adaptive purposes, it is worthwhile to point out that many traits are not adaptive, that is, there is no obvious reason scientists can divine for the presence of a certain trait. This situation is common and there are many causes: the utility of a trait is lost and hence does not now appear adaptive, the utility of a trait is unknown, the trait is a consequence of another trait that is adaptive (the Spandrel idea). This observation underscores two other important points: genetic variants arise randomly and hence traits can appear randomly and that because the environment for all living things is constantly in flux, the utility of adaptations will naturally ebb and flow.
Organisms that are not suitably adapted to their environment will either have to move out of the habitat or die out. The term die out in the context of adaptation simply means that the death rate over the entire species (population, gene pool ...) exceeds the birth rate for a long enough period for the species to disappear; due to individual phenotypic plasticity, individuals will be more or less successful. The opposite is selection which in this context means that the birth rate of those carrying the adaptive trait and the hence the underlying genetic variant exceeds over time the birth rate of those that do not carry the adaptive traitTemplate:Unicode.
# Adaptation vs. adaptiveness
A trait being adaptive, i.e. increasing the organism's fitness, is neither a necessary nor sufficient condition for it to be an adaptation.[2] Of course, an adaptation must have been adaptive at some point in an organism's evolutionary history, but such an organism's environment and ecological niche can change over time, leading to adaptations becoming redundant or even a hindrance (maladaptations). Such adaptations are termed vestigial.
# Adaptation vs. acclimation
There is a great difference between adaptation and acclimation. Adaptation occurs over many generations; it is a gradual process caused by natural selection. Acclimatization generally occurs within a single lifetime and copes with issues that are less threatening. For example, if a human was to move to a higher altitude, respiration and physical exertion would become a problem, but after spending time in high altitude conditions one may acclimate to the pressure and function and no longer notice the change. This ability to acclimate is an adaptation, but not the acclimation itself.
A counter-adaptation is an adaptation that has evolved due to the selective pressure of another adaptation. This occurs in an evolutionary arms race, where a new adaptation giving one species an advantage is countered by the appearance and spread of a new feature that reduces the effectiveness of the first adaptation.
# Theories
The theory of adaptation was first put forth by Jean-Baptiste Lamarck. His theories are also referred to as the inheritance of acquired traits.
Lamarck's theory was for a time held as an alternative scientific explanation for evolutionary change observed by Darwin in the The Origin of Species. The classic giraffe analogy offers the best delineation between the two.
- According to Darwin, more long-necked giraffes reproduce than short-necked giraffes and as such giraffes today have long necks.
- According to Lamarck, it was giraffes stretching their necks in response to higher leaves that resulted in giraffes having long necks. (This trait being passed on to the next generation)
Although neither theory in its conception could provide a complete description of the mechanism of transmission of trait variation (i.e., particulate inheritance), many recognized Darwin's theory immediately upon publication as a more complete and empirically supported theory. Modern genetics have since established the fundamental implausibility of Lamarckian inheritance, due to the one-way nature of transcription. However, see epigenetics and Baldwinian evolution for analogous processes in modern evolutionary theory. | https://www.wikidoc.org/index.php/Adaptation | |
13fd59cd3c20bc331a2110dd647e5694aa254f5c | wikidoc | Prednisone | Prednisone
# 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
Prednisone is a synthetic corticosteroid that is FDA approved for the treatment of thyroiditis, SLE, psoriasis, contact dermatitis, atopic dermatitis, optic neuritis, ulcerative colitis, symptomatic sarcoidosis, multiple sclerosis. Common adverse reactions include osteoporosis, fluid retention,hypokalemia, muscle weakness, hypertension, vertigo, headache, glaucoma, urticaria.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
# Indications
Prednisone tablets, USP are indicated in the following conditions:
## Endocrine Disorders
- Primary or secondary adrenocortical insufficiency (hydrocortisone or cortisone is the first choice; synthetic analogs may be used in conjunction with mineralocorticoids where applicable; in infancy mineralocorticoid supplementation is of particular importance)
- Congenital adrenal hyperplasia
- Non suppurative thyroiditis
## Rheumatic Disorders
As adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in:
- Psoriatic arthritis
- Rheumatoid arthritis, including juvenile rheumatoid arthritis (selected cases may require low-dose maintenance therapy)
- Ankylosing spondylitis
- Acute and subacute bursitis
- Acute non specific tenosynovitis
- Acute gouty arthritis
- Post-traumatic osteoarthritis
- Synovitis of osteoarthritis
- Epicondylitis.
## Collagen Diseases
During an exacerbation or as maintenance therapy in selected cases of:
- Systemic lupus erythematosus
- Systemic dermatomyositis (polymyositis)
- Acute rheumatic carditis
## Dermatologic Diseases
- Pemphigus
- Bullous dermatitis herpetiformis
- Severe erythema multiforme (Stevens-Johnson syndrome)
- Exfoliative dermatitis
- Mycosis fungoides
- Severe psoriasis
- Severe seborrheic dermatitis
## Allergic States
Control of severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment:
- Seasonal or perennial allergic rhinitis
- Bronchial asthma
- Contact dermatitis
- Atopic dermatitis
- Serum sickness
- Drug hypersensitivity reactions
## Ophthalmic Diseases
Severe acute and chronic allergic and inflammatory processes involving the eye and its adnexa such as:
- Allergic corneal marginal ulcers
- Herpes zoster ophthalmicus
- Anterior segment inflammation
- Diffuse posterior uveitis and choroiditis
- Sympathetic ophthalmia
- Allergic conjunctivitis
- Keratitis
- Chorioretinitis
- Optic neuritis
- Iritis and iridocyclitis
## Respiratory Diseases
- Symptomatic sarcoidosis
- Loeffler’s syndrome not manageable by other means
- Berylliosis
- Fulminating or disseminated pulmonary tuberculosis when used concurrently with appropriate antituberculous chemotherapy.
- Aspiration pneumonitis
## Hematologic Disorders
- Idiopathic thrombocytopenic purpura in adults
- Secondary thrombocytopenia in adults
- Acquired (autoimmune)hemolytic anemia
- Erythroblastopenia (RBC anemia)
- Congenital (erythroid) hypoplastic anemia
## Neoplastic Diseases
For palliative management of:
- Leukemias and lymphomas in adults
- Acute leukemia of childhood
## Edematous States
- To induce a diuresis or remission of proteinuria in the nephrotic syndrome, without uremia, of the idiopathic type or that due to lupus erythematosus
## Gastrointestinal Diseases
To tide the patient over a critical period of the disease in:
- Ulcerative colitis
- Regional enteritis
## Nervous System
- Acute exacerbations of multiple sclerosis
## Miscellaneous
- Tuberculous meningitis with subarachnoid block or, impending block when used concurrently with appropriate antituberculous chemotherapy
- Trichinosis with neurologic or myocardial involvement
# Dosage
- The initial dosage of prednisone tablets, USP may vary from 5 mg to 60 mg prednisone per day depending on the specific disease entity being treated. In situations of less severity lower doses will generally suffice while in selected patients higher initial doses may be required. The initial dosage should be maintained or adjusted until a satisfactory response is noted. If after a reasonable period of time there is a lack of satisfactory clinical response, Prednisone should be discontinued and the patient transferred to other appropriate therapy.IT SHOULD BE EMPHASIZED THAT DOSAGE REQUIREMENTS ARE VARIABLE AND MUST BE INDIVIDUALIZED ON THE BASIS OF THE DISEASE UNDER TREATMENT AND THE RESPONSE OF THE PATIENT.
- After a favorable response is noted, the proper maintenance dosage should be determined by decreasing the initial drug dosage in small decrements at appropriate time intervals until the lowest dosage which will maintain an adequate clinical response is reached. It should be kept in mind that constant monitoring is needed in regard to drug dosage. Included in the situations which may make dosage adjustments necessary are changes in clinical status secondary to remissions or exacerbations in the disease process, the patient’s individual drug responsiveness, and the effect of patient exposure to stressful situations not directly related to the disease entity under treatment; in this latter situation it may be necessary to increase the dosage of Prednisone for a period of time consistent with the patient’s condition. If after long-term therapy the drug is to be stopped, it is recommended that it be withdrawn gradually rather than abruptly.
## Multiple Sclerosis
- In the treatment of acute exacerbations of multiple sclerosis daily doses of 200 mg of prednisolone for a week followed by 80 mg every other day for 1 month have been shown to be effective. (Dosage range is the same for prednisone and prednisolone.)
## ADT ® (Alternate Day Therapy)
- ADT is a corticosteroid dosing regimen in which twice the usual daily dose of corticoid is administered every other morning. The purpose of this mode of therapy is to provide the patient requiring long-term pharmacologic dose treatment with the beneficial effects of corticoids while minimizing certain undesirable effects, including pituitary-adrenal suppression, the Cushingoid state, corticoid withdrawal symptoms, and growth suppression in children. The rationale for this treatment schedule is based on two major premises: (a) the anti-inflammatory or therapeutic effect of corticoids persists longer than their physical presence and metabolic effects and (b) administration of the corticosteroid every other morning allows for re-establishment of more nearly normal hypothalamic-pituitary-adrenal (HPA) activity on the off-steroid day.
- A brief review of the HPA physiology may be helpful in understanding this rationale. Acting primarily through the hypothalamus a fall in free cortisol stimulates the pituitary gland to produce increasing amounts of corticotropin (ACTH) while a rise in free cortisol inhibits ACTH secretion. Normally the HPA system is characterized by diurnal (circadian) rhythm. Serum levels of ACTH rise from a low point about 10 pm to a peak level about 6 am. Increasing levels of ACTH stimulate adrenocortical activity resulting in a rise in plasma cortisol with maximal levels occurring between 2 am and 8 am. This rise in cortisol dampens ACTH production and in turn adrenocortical activity. There is a gradual fall in plasma corticoids during the day with lowest levels occurring about midnight.
- The diurnal rhythm of the HPA axis is lost in Cushing’s disease a syndrome of adrenocortical hyperfunction characterized by obesity with centripetal fat distribution, thinning of the skin with easy bruisability, muscle wasting with weakness, hypertension , latent diabetes, osteoporosis, electrolyte imbalance, etc. The same clinical findings of hyperadrenocorticism may be noted during long-term pharmacologic dose corticoid therapy administered in conventional daily divided doses. It would appear, then, that a disturbance in the diurnal cycle with maintenance of elevated corticoid values during the night may play a significant role in the development of undesirable corticoid effects. Escape from these constantly elevated plasma levels for even short periods of time may be instrumental in protecting against undesirable pharmacologic effects.
- During conventional pharmacologic dose corticosteroid therapy, ACTH production is inhibited with subsequent suppression of cortisol production by the adrenal cortex. Recovery time for normal HPA activity is variable depending upon the dose and duration of treatment. During this time the patient is vulnerable to any stressful situation. Although it has been shown that there is considerably less adrenal suppression following a single morning dose of prednisolone (10 mg) as opposed to a quarter of that dose administered every 6 hours, there is evidence that some suppressive effect on adrenal activity may be carried over into the following day when pharmacologic doses are used. Further, it has been shown that a single dose of certain corticosteroids will produce adrenocortical suppression for two or more days. Other corticoids, including methylprednisolone, hydrocortisone, prednisone, and prednisolone, are considered to be short acting (producing adrenocortical suppression for 1 ¼ to 1 ½ days following a single dose) and thus are recommended for alternate day therapy.
The following should be kept in mind when considering alternate day therapy:
- Basic principles and indications for corticosteroid therapy should apply. The benefits of ADT should not encourage the indiscriminate use of steroids.
- ADT is a therapeutic technique primarily designed for patients in whom long-term pharmacologic corticoid therapy is anticipated.
- In less severe disease processes in which corticoid therapy is indicated, it may be possible to initiate treatment with ADT. More severe disease states usually will require daily divided high dose therapy for initial control of the disease process. The initial suppressive dose level should be continued until satisfactory clinical response is obtained, usually four to ten days in the case of many allergic and collagen diseases. It is important to keep the period of initial suppressive dose as brief as possible particularly when subsequent use of alternate day therapy is intended.
- Once control has been established, two courses are available: (a) change to ADT and then gradually reduce the amount of corticoid given every other day or (b) following control of the disease process reduce the daily dose of corticoid to the lowest effective level as rapidly as possible and then change over to an alternate day schedule. Theoretically, course (a) may be preferable.
- Because of the advantages of ADT, it may be desirable to try patients on this form of therapy who have been on daily corticoids for long periods of time (eg, patients with rheumatoid arthritis). Since these patients may already have a suppressed HPA axis, establishing them on ADT may be difficult and not always successful. However, it is recommended that regular attempts be made to change them over. It may be helpful to triple or even quadruple the daily maintenance dose and administer this every other day rather than just doubling the daily dose if difficulty is encountered. Once the patient is again controlled, an attempt should be made to reduce this dose to a minimum.
- As indicated above, certain corticosteroids, because of their prolonged suppressive effect on adrenal activity, are not recommended for alternate day therapy (eg; dexamethasone and betamethasone).
- The maximal activity of the adrenal cortex is between 2 am and 8 am, and it is minimal between 4 pm and midnight. Exogenous corticosteroids suppress adrenocortical activity the least, when given at the time of maximal activity (am).
- In using ADT it is important, as in all therapeutic situations to individualize and tailor the therapy to each patient. Complete control of symptoms will not be possible in all patients. An explanation of the benefits of ADT will help the patient to understand and tolerate the possible flare-up in symptoms which may occur in the latter part of the off-steroid day. Other symptomatic therapy may be added or increased at this time if needed.
- In the event of an acute flare-up of the disease process, it may be necessary to return to a full suppressive daily divided corticoid dose for control. Once control is again established alternate day therapy may be re-instituted.
- Although many of the undesirable features of corticosteroid therapy can be minimized by ADT, as in any therapeutic situation, the physician must carefully weigh the benefit-risk ratio for each patient in whom corticoid therapy is being considered.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Prednisone in adult patients.
### Non–Guideline-Supported Use
# Indications
- Bell's palsy
- Myasthenia gravis
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Prednisone 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 Prednisone in pediatric patients.
### Non–Guideline-Supported Use
# Indications
- Henoch-Schönlein nephritis
# Contraindications
- Systemic fungal infections and known hypersensitivity to components.
# Warnings
- In patients on corticosteroid therapy subjected to unusual stress, increased dosage of rapidly acting corticosteroids before, during, and after the stressful situation is indicated.
- Corticosteroids may mask some signs of infection, and new infections may appear during their use. There may be decreased resistance and inability to localize infection when corticosteroids are used.
- Prolonged use of corticosteroids may produce posterior subcapsular cataracts, glaucoma with possible damage to the optic nerves, and may enhance the establishment of secondary ocular infections due to fungi or viruses.
- Usage in pregnancy: Since adequate human reproduction studies have not been done with corticosteroids, the use of these drugs in pregnancy, nursing mothers or women of childbearing potential requires that the possible benefits of the drug be weighed against the potential hazards to the mother and embryo or fetus. Infants born of mothers who have received substantial doses of corticosteroids during pregnancy, should be carefully observed for signs of hypoadrenalism.
- Average and large doses of hydrocortisone or cortisone can cause elevation of blood pressure, salt and water retention, and increased excretion of potassium. These effects are less likely to occur with the synthetic derivatives except when used in large doses. Dietary salt restriction and potassium supplementation may be necessary. All corticosteroids increase calcium excretion.
While on corticosteroid therapy patients should not be vaccinated against smallpox. Other immunization procedures should not be undertaken in patients who are on corticosteroids, especially on high dose, because of possible hazards of neurological complications and a lack of antibody response.
- The use of Prednisone Tablets, USP in active tuberculosis should be restricted to those cases of fulminating or disseminated tuberculosis in which the corticosteroid is used for the management of the disease in conjunction with an appropriate anti-tuberculous regimen.
- If corticosteroids are indicated in patients with latent tuberculosis or tuberculin reactivity, close observation is necessary as reactivation of the disease may occur. During prolonged corticosteroid therapy, these patients should receive chemoprophylaxis.
- Persons who are on drugs which suppress the immune system are more susceptible to infections than healthy individuals. Chickenpox and measles, for example, can have a more serious or even fatal course in non-immune children or adults on corticosteroids. In such children or adults who have not had these diseases, particular care should be taken to avoid exposure. How the dose, route and duration of corticosteroid administration affects the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If exposed to chickenpox, prophylaxis with varicella-zoster immune globulin (VZIG) may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information.) If chickenpox develops, treatment with antiviral agents may be considered.
# Adverse Reactions
## Clinical Trials Experience
## Fluid and Electrolyte Disturbances
- Sodium retention
- Fluid retention
- Congestive heart failure in susceptible patients
- Potassium loss
- Hypokalemic alkalosis
- Hypertension
## Musculoskeletal
- Muscle weakness
- Steroid myopathy
- Loss of muscle mass
- Osteoporosis
- Vertebral compression fractures
- Aseptic necrosis of femoral and humeral heads
- Pathologic fracture of long bones
## Gastrointestinal
- Peptic ulcer with possible perforation and hemorrhage
- Pancreatitis
- Abdominal distention
- Ulcerative esophagitis
## Dermatologic
- Impaired wound healing
- Thin fragile skin
- Petechiae and ecchymoses
- Facial erythema
- Increased sweating
- May suppress reactions to skin tests
## Metabolic
- Negative nitrogen balance due to protein catabolism
## Neurological
- Increased intracranial pressure with papilledema (pseudo-tumor cerebri) usually after treatment
- Convulsions
- Vertigo
- Headache
## Endocrine
- Menstrual irregularities
- Development of Cushingoid state
- Secondary adrenocortical and pituitary unresponsiveness, particularly in times of stress, as in trauma, surgery or illness
- Suppression of growth in children
- Decreased carbohydrate tolerance
- Manifestations of latent diabetes melliltus
- Increased requirements for insulin or oral hypoglycemic agents in diabetics
## Ophthalmic
- Posterior subcapsular cataracts
- Increased intraocular pressure
- Glaucoma
- Exophthalmos
## Additional Reactions
Urticaria and other allergic, anaphylactic or hypersensitivity reactions
## Postmarketing Experience
There is limited information regarding Prednisone Postmarketing Experience in the drug label.
# Drug Interactions
There is limited information regarding Prednisone Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
There is no FDA guidance on usage of Prednisone in women who are pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Prednisone in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Prednisone during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Prednisone in women who are nursing.
### Pediatric Use
There is no FDA guidance on the use of Prednisone in pediatric settings.
### Geriatic Use
There is no FDA guidance on the use of Prednisone in geriatric settings.
### Gender
There is no FDA guidance on the use of Prednisone with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Prednisone with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Prednisone in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Prednisone in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Prednisone in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Prednisone in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Oral
### Monitoring
There is limited information regarding Prednisone Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Prednisone and IV administrations.
# Overdosage
There is limited information regarding Prednisone overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
- Naturally occurring glucocorticoids (hydrocortisone and cortisone), which also have salt-retaining properties, are used as replacement therapy in adrenocortical deficiency states. Their synthetic analogs are primarily used for their potent anti-inflammatory effects in disorders of many organ systems.
- Glucocorticoids cause profound and varied metabolic effects. In addition, they modify the body's immune responses to diverse stimuli.
## Structure
Prednisone is a glucocorticoid. Glucocorticoids are adrenocortical steroids, both naturally occurring and synthetic, which are readily absorbed from the gastrointestinal tract. Prednisone is a white to practically white, odorless, crystalline powder. It is very slightly soluble in water; slightly soluble in alcohol, in chloroform, in dioxane, and in methanol. The chemical name for prednisone is pregna-1, 4-diene-3, 11, 20-trione, 17, 21-dihydroxy-
Prednisone tablets, USP are available in three strengths: 5 mg, 10 mg, and 20 mg. In addition, each tablet contains the following Inactive Ingredients: Lactose Monohydrate, Magnesium Stearate, Pregelatinized Starch, Sodium Lauryl Sulfate and Sodium Starch Glycolate. Also Prednisone Tablets USP, 20 mg contains FD & C yellow #6 aluminum lake HT 15-18%.
## Pharmacodynamics
There is limited information regarding Prednisone Pharmacodynamics in the drug label.
## Pharmacokinetics
There is limited information regarding Prednisone Pharmacokinetics in the drug label.
## Nonclinical Toxicology
There is limited information regarding Prednisone Nonclinical Toxicology in the drug label.
# Clinical Studies
There is limited information regarding Prednisone Clinical Studies in the drug label.
# How Supplied
Prednisone Tablets, USP are available in the following strengths and package sizes:
- 5 mg (white, round, scored, imprinted with TL172)
- Bottles of 100 NDC 59746-172-06
- Bottles of 1000 NDC 59746-172-10
- 10 mg (white, round, scored, imprinted with TL173)
- Bottles of 100 NDC 59746-173-06
- Bottles of 500 NDC 59746-173-09
- Bottles of 1000 NDC 59746-173-10
- 20mg (peach, round, scored, imprinted with TL175)
- Bottles of 100 NDC 59746-175-06
- Bottles of 500 NDC 59746-175-09
- Bottles of 1000 NDC 59746-175-10
## Storage
Store at 20° to 25° C (68° to 77° F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Prednisone in the drug label.
# Precautions with Alcohol
- Alcohol-Prednisone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- PREDNISONE ®
# Look-Alike Drug Names
- A® — B®
# Drug Shortage Status
# Price | Prednisone
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Prednisone is a synthetic corticosteroid that is FDA approved for the treatment of thyroiditis, SLE, psoriasis, contact dermatitis, atopic dermatitis, optic neuritis, ulcerative colitis, symptomatic sarcoidosis, multiple sclerosis. Common adverse reactions include osteoporosis, fluid retention,hypokalemia, muscle weakness, hypertension, vertigo, headache, glaucoma, urticaria.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
# Indications
Prednisone tablets, USP are indicated in the following conditions:
## Endocrine Disorders
- Primary or secondary adrenocortical insufficiency (hydrocortisone or cortisone is the first choice; synthetic analogs may be used in conjunction with mineralocorticoids where applicable; in infancy mineralocorticoid supplementation is of particular importance)
- Congenital adrenal hyperplasia
- Non suppurative thyroiditis
## Rheumatic Disorders
As adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in:
- Psoriatic arthritis
- Rheumatoid arthritis, including juvenile rheumatoid arthritis (selected cases may require low-dose maintenance therapy)
- Ankylosing spondylitis
- Acute and subacute bursitis
- Acute non specific tenosynovitis
- Acute gouty arthritis
- Post-traumatic osteoarthritis
- Synovitis of osteoarthritis
- Epicondylitis.
## Collagen Diseases
During an exacerbation or as maintenance therapy in selected cases of:
- Systemic lupus erythematosus
- Systemic dermatomyositis (polymyositis)
- Acute rheumatic carditis
## Dermatologic Diseases
- Pemphigus
- Bullous dermatitis herpetiformis
- Severe erythema multiforme (Stevens-Johnson syndrome)
- Exfoliative dermatitis
- Mycosis fungoides
- Severe psoriasis
- Severe seborrheic dermatitis
## Allergic States
Control of severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment:
- Seasonal or perennial allergic rhinitis
- Bronchial asthma
- Contact dermatitis
- Atopic dermatitis
- Serum sickness
- Drug hypersensitivity reactions
## Ophthalmic Diseases
Severe acute and chronic allergic and inflammatory processes involving the eye and its adnexa such as:
- Allergic corneal marginal ulcers
- Herpes zoster ophthalmicus
- Anterior segment inflammation
- Diffuse posterior uveitis and choroiditis
- Sympathetic ophthalmia
- Allergic conjunctivitis
- Keratitis
- Chorioretinitis
- Optic neuritis
- Iritis and iridocyclitis
## Respiratory Diseases
- Symptomatic sarcoidosis
- Loeffler’s syndrome not manageable by other means
- Berylliosis
- Fulminating or disseminated pulmonary tuberculosis when used concurrently with appropriate antituberculous chemotherapy.
- Aspiration pneumonitis
## Hematologic Disorders
- Idiopathic thrombocytopenic purpura in adults
- Secondary thrombocytopenia in adults
- Acquired (autoimmune)hemolytic anemia
- Erythroblastopenia (RBC anemia)
- Congenital (erythroid) hypoplastic anemia
## Neoplastic Diseases
For palliative management of:
- Leukemias and lymphomas in adults
- Acute leukemia of childhood
## Edematous States
- To induce a diuresis or remission of proteinuria in the nephrotic syndrome, without uremia, of the idiopathic type or that due to lupus erythematosus
## Gastrointestinal Diseases
To tide the patient over a critical period of the disease in:
- Ulcerative colitis
- Regional enteritis
## Nervous System
- Acute exacerbations of multiple sclerosis
## Miscellaneous
- Tuberculous meningitis with subarachnoid block or, impending block when used concurrently with appropriate antituberculous chemotherapy
- Trichinosis with neurologic or myocardial involvement
# Dosage
- The initial dosage of prednisone tablets, USP may vary from 5 mg to 60 mg prednisone per day depending on the specific disease entity being treated. In situations of less severity lower doses will generally suffice while in selected patients higher initial doses may be required. The initial dosage should be maintained or adjusted until a satisfactory response is noted. If after a reasonable period of time there is a lack of satisfactory clinical response, Prednisone should be discontinued and the patient transferred to other appropriate therapy.IT SHOULD BE EMPHASIZED THAT DOSAGE REQUIREMENTS ARE VARIABLE AND MUST BE INDIVIDUALIZED ON THE BASIS OF THE DISEASE UNDER TREATMENT AND THE RESPONSE OF THE PATIENT.
- After a favorable response is noted, the proper maintenance dosage should be determined by decreasing the initial drug dosage in small decrements at appropriate time intervals until the lowest dosage which will maintain an adequate clinical response is reached. It should be kept in mind that constant monitoring is needed in regard to drug dosage. Included in the situations which may make dosage adjustments necessary are changes in clinical status secondary to remissions or exacerbations in the disease process, the patient’s individual drug responsiveness, and the effect of patient exposure to stressful situations not directly related to the disease entity under treatment; in this latter situation it may be necessary to increase the dosage of Prednisone for a period of time consistent with the patient’s condition. If after long-term therapy the drug is to be stopped, it is recommended that it be withdrawn gradually rather than abruptly.
## Multiple Sclerosis
- In the treatment of acute exacerbations of multiple sclerosis daily doses of 200 mg of prednisolone for a week followed by 80 mg every other day for 1 month have been shown to be effective. (Dosage range is the same for prednisone and prednisolone.)
## ADT ® (Alternate Day Therapy)
- ADT is a corticosteroid dosing regimen in which twice the usual daily dose of corticoid is administered every other morning. The purpose of this mode of therapy is to provide the patient requiring long-term pharmacologic dose treatment with the beneficial effects of corticoids while minimizing certain undesirable effects, including pituitary-adrenal suppression, the Cushingoid state, corticoid withdrawal symptoms, and growth suppression in children. The rationale for this treatment schedule is based on two major premises: (a) the anti-inflammatory or therapeutic effect of corticoids persists longer than their physical presence and metabolic effects and (b) administration of the corticosteroid every other morning allows for re-establishment of more nearly normal hypothalamic-pituitary-adrenal (HPA) activity on the off-steroid day.
- A brief review of the HPA physiology may be helpful in understanding this rationale. Acting primarily through the hypothalamus a fall in free cortisol stimulates the pituitary gland to produce increasing amounts of corticotropin (ACTH) while a rise in free cortisol inhibits ACTH secretion. Normally the HPA system is characterized by diurnal (circadian) rhythm. Serum levels of ACTH rise from a low point about 10 pm to a peak level about 6 am. Increasing levels of ACTH stimulate adrenocortical activity resulting in a rise in plasma cortisol with maximal levels occurring between 2 am and 8 am. This rise in cortisol dampens ACTH production and in turn adrenocortical activity. There is a gradual fall in plasma corticoids during the day with lowest levels occurring about midnight.
- The diurnal rhythm of the HPA axis is lost in Cushing’s disease a syndrome of adrenocortical hyperfunction characterized by obesity with centripetal fat distribution, thinning of the skin with easy bruisability, muscle wasting with weakness, hypertension , latent diabetes, osteoporosis, electrolyte imbalance, etc. The same clinical findings of hyperadrenocorticism may be noted during long-term pharmacologic dose corticoid therapy administered in conventional daily divided doses. It would appear, then, that a disturbance in the diurnal cycle with maintenance of elevated corticoid values during the night may play a significant role in the development of undesirable corticoid effects. Escape from these constantly elevated plasma levels for even short periods of time may be instrumental in protecting against undesirable pharmacologic effects.
- During conventional pharmacologic dose corticosteroid therapy, ACTH production is inhibited with subsequent suppression of cortisol production by the adrenal cortex. Recovery time for normal HPA activity is variable depending upon the dose and duration of treatment. During this time the patient is vulnerable to any stressful situation. Although it has been shown that there is considerably less adrenal suppression following a single morning dose of prednisolone (10 mg) as opposed to a quarter of that dose administered every 6 hours, there is evidence that some suppressive effect on adrenal activity may be carried over into the following day when pharmacologic doses are used. Further, it has been shown that a single dose of certain corticosteroids will produce adrenocortical suppression for two or more days. Other corticoids, including methylprednisolone, hydrocortisone, prednisone, and prednisolone, are considered to be short acting (producing adrenocortical suppression for 1 ¼ to 1 ½ days following a single dose) and thus are recommended for alternate day therapy.
The following should be kept in mind when considering alternate day therapy:
- Basic principles and indications for corticosteroid therapy should apply. The benefits of ADT should not encourage the indiscriminate use of steroids.
- ADT is a therapeutic technique primarily designed for patients in whom long-term pharmacologic corticoid therapy is anticipated.
- In less severe disease processes in which corticoid therapy is indicated, it may be possible to initiate treatment with ADT. More severe disease states usually will require daily divided high dose therapy for initial control of the disease process. The initial suppressive dose level should be continued until satisfactory clinical response is obtained, usually four to ten days in the case of many allergic and collagen diseases. It is important to keep the period of initial suppressive dose as brief as possible particularly when subsequent use of alternate day therapy is intended.
- Once control has been established, two courses are available: (a) change to ADT and then gradually reduce the amount of corticoid given every other day or (b) following control of the disease process reduce the daily dose of corticoid to the lowest effective level as rapidly as possible and then change over to an alternate day schedule. Theoretically, course (a) may be preferable.
- Because of the advantages of ADT, it may be desirable to try patients on this form of therapy who have been on daily corticoids for long periods of time (eg, patients with rheumatoid arthritis). Since these patients may already have a suppressed HPA axis, establishing them on ADT may be difficult and not always successful. However, it is recommended that regular attempts be made to change them over. It may be helpful to triple or even quadruple the daily maintenance dose and administer this every other day rather than just doubling the daily dose if difficulty is encountered. Once the patient is again controlled, an attempt should be made to reduce this dose to a minimum.
- As indicated above, certain corticosteroids, because of their prolonged suppressive effect on adrenal activity, are not recommended for alternate day therapy (eg; dexamethasone and betamethasone).
- The maximal activity of the adrenal cortex is between 2 am and 8 am, and it is minimal between 4 pm and midnight. Exogenous corticosteroids suppress adrenocortical activity the least, when given at the time of maximal activity (am).
- In using ADT it is important, as in all therapeutic situations to individualize and tailor the therapy to each patient. Complete control of symptoms will not be possible in all patients. An explanation of the benefits of ADT will help the patient to understand and tolerate the possible flare-up in symptoms which may occur in the latter part of the off-steroid day. Other symptomatic therapy may be added or increased at this time if needed.
- In the event of an acute flare-up of the disease process, it may be necessary to return to a full suppressive daily divided corticoid dose for control. Once control is again established alternate day therapy may be re-instituted.
- Although many of the undesirable features of corticosteroid therapy can be minimized by ADT, as in any therapeutic situation, the physician must carefully weigh the benefit-risk ratio for each patient in whom corticoid therapy is being considered.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Prednisone in adult patients.
### Non–Guideline-Supported Use
# Indications
- Bell's palsy
- Myasthenia gravis
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Prednisone 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 Prednisone in pediatric patients.
### Non–Guideline-Supported Use
# Indications
- Henoch-Schönlein nephritis
# Contraindications
- Systemic fungal infections and known hypersensitivity to components.
# Warnings
- In patients on corticosteroid therapy subjected to unusual stress, increased dosage of rapidly acting corticosteroids before, during, and after the stressful situation is indicated.
- Corticosteroids may mask some signs of infection, and new infections may appear during their use. There may be decreased resistance and inability to localize infection when corticosteroids are used.
- Prolonged use of corticosteroids may produce posterior subcapsular cataracts, glaucoma with possible damage to the optic nerves, and may enhance the establishment of secondary ocular infections due to fungi or viruses.
- Usage in pregnancy: Since adequate human reproduction studies have not been done with corticosteroids, the use of these drugs in pregnancy, nursing mothers or women of childbearing potential requires that the possible benefits of the drug be weighed against the potential hazards to the mother and embryo or fetus. Infants born of mothers who have received substantial doses of corticosteroids during pregnancy, should be carefully observed for signs of hypoadrenalism.
- Average and large doses of hydrocortisone or cortisone can cause elevation of blood pressure, salt and water retention, and increased excretion of potassium. These effects are less likely to occur with the synthetic derivatives except when used in large doses. Dietary salt restriction and potassium supplementation may be necessary. All corticosteroids increase calcium excretion.
While on corticosteroid therapy patients should not be vaccinated against smallpox. Other immunization procedures should not be undertaken in patients who are on corticosteroids, especially on high dose, because of possible hazards of neurological complications and a lack of antibody response.
- The use of Prednisone Tablets, USP in active tuberculosis should be restricted to those cases of fulminating or disseminated tuberculosis in which the corticosteroid is used for the management of the disease in conjunction with an appropriate anti-tuberculous regimen.
- If corticosteroids are indicated in patients with latent tuberculosis or tuberculin reactivity, close observation is necessary as reactivation of the disease may occur. During prolonged corticosteroid therapy, these patients should receive chemoprophylaxis.
- Persons who are on drugs which suppress the immune system are more susceptible to infections than healthy individuals. Chickenpox and measles, for example, can have a more serious or even fatal course in non-immune children or adults on corticosteroids. In such children or adults who have not had these diseases, particular care should be taken to avoid exposure. How the dose, route and duration of corticosteroid administration affects the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If exposed to chickenpox, prophylaxis with varicella-zoster immune globulin (VZIG) may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information.) If chickenpox develops, treatment with antiviral agents may be considered.
# Adverse Reactions
## Clinical Trials Experience
## Fluid and Electrolyte Disturbances
- Sodium retention
- Fluid retention
- Congestive heart failure in susceptible patients
- Potassium loss
- Hypokalemic alkalosis
- Hypertension
## Musculoskeletal
- Muscle weakness
- Steroid myopathy
- Loss of muscle mass
- Osteoporosis
- Vertebral compression fractures
- Aseptic necrosis of femoral and humeral heads
- Pathologic fracture of long bones
## Gastrointestinal
- Peptic ulcer with possible perforation and hemorrhage
- Pancreatitis
- Abdominal distention
- Ulcerative esophagitis
## Dermatologic
- Impaired wound healing
- Thin fragile skin
- Petechiae and ecchymoses
- Facial erythema
- Increased sweating
- May suppress reactions to skin tests
## Metabolic
- Negative nitrogen balance due to protein catabolism
## Neurological
- Increased intracranial pressure with papilledema (pseudo-tumor cerebri) usually after treatment
- Convulsions
- Vertigo
- Headache
## Endocrine
- Menstrual irregularities
- Development of Cushingoid state
- Secondary adrenocortical and pituitary unresponsiveness, particularly in times of stress, as in trauma, surgery or illness
- Suppression of growth in children
- Decreased carbohydrate tolerance
- Manifestations of latent diabetes melliltus
- Increased requirements for insulin or oral hypoglycemic agents in diabetics
## Ophthalmic
- Posterior subcapsular cataracts
- Increased intraocular pressure
- Glaucoma
- Exophthalmos
## Additional Reactions
Urticaria and other allergic, anaphylactic or hypersensitivity reactions
## Postmarketing Experience
There is limited information regarding Prednisone Postmarketing Experience in the drug label.
# Drug Interactions
There is limited information regarding Prednisone Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
There is no FDA guidance on usage of Prednisone in women who are pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Prednisone in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Prednisone during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Prednisone in women who are nursing.
### Pediatric Use
There is no FDA guidance on the use of Prednisone in pediatric settings.
### Geriatic Use
There is no FDA guidance on the use of Prednisone in geriatric settings.
### Gender
There is no FDA guidance on the use of Prednisone with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Prednisone with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Prednisone in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Prednisone in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Prednisone in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Prednisone in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Oral
### Monitoring
There is limited information regarding Prednisone Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Prednisone and IV administrations.
# Overdosage
There is limited information regarding Prednisone overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
- Naturally occurring glucocorticoids (hydrocortisone and cortisone), which also have salt-retaining properties, are used as replacement therapy in adrenocortical deficiency states. Their synthetic analogs are primarily used for their potent anti-inflammatory effects in disorders of many organ systems.
- Glucocorticoids cause profound and varied metabolic effects. In addition, they modify the body's immune responses to diverse stimuli.
## Structure
Prednisone is a glucocorticoid. Glucocorticoids are adrenocortical steroids, both naturally occurring and synthetic, which are readily absorbed from the gastrointestinal tract. Prednisone is a white to practically white, odorless, crystalline powder. It is very slightly soluble in water; slightly soluble in alcohol, in chloroform, in dioxane, and in methanol. The chemical name for prednisone is pregna-1, 4-diene-3, 11, 20-trione, 17, 21-dihydroxy-
Prednisone tablets, USP are available in three strengths: 5 mg, 10 mg, and 20 mg. In addition, each tablet contains the following Inactive Ingredients: Lactose Monohydrate, Magnesium Stearate, Pregelatinized Starch, Sodium Lauryl Sulfate and Sodium Starch Glycolate. Also Prednisone Tablets USP, 20 mg contains FD & C yellow #6 aluminum lake HT 15-18%.
## Pharmacodynamics
There is limited information regarding Prednisone Pharmacodynamics in the drug label.
## Pharmacokinetics
There is limited information regarding Prednisone Pharmacokinetics in the drug label.
## Nonclinical Toxicology
There is limited information regarding Prednisone Nonclinical Toxicology in the drug label.
# Clinical Studies
There is limited information regarding Prednisone Clinical Studies in the drug label.
# How Supplied
Prednisone Tablets, USP are available in the following strengths and package sizes:
- 5 mg (white, round, scored, imprinted with TL172)
- Bottles of 100 NDC 59746-172-06
- Bottles of 1000 NDC 59746-172-10
- 10 mg (white, round, scored, imprinted with TL173)
- Bottles of 100 NDC 59746-173-06
- Bottles of 500 NDC 59746-173-09
- Bottles of 1000 NDC 59746-173-10
- 20mg (peach, round, scored, imprinted with TL175)
- Bottles of 100 NDC 59746-175-06
- Bottles of 500 NDC 59746-175-09
- Bottles of 1000 NDC 59746-175-10
## Storage
Store at 20° to 25° C (68° to 77° F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Prednisone in the drug label.
# Precautions with Alcohol
- Alcohol-Prednisone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- PREDNISONE ®[1]
# Look-Alike Drug Names
- A® — B®[2]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Adasone | |
1712fa3bfe01d387a6ac5a598a40106dafb79fe2 | wikidoc | References | References
# Overview
WikiDoc has a reference manager that allows users to insert references based upon their PubMed ID number. If you move the text, the reference moves with it! All the references are automatically inserted at the bottom. You click on the reference and you go to the article. It is simple!
# Where do I type in the references?
Usually you would type a number in the text like this (1) or this 1 which refers to a reference you would like to cite. You would then type in the reference at the end of the article. This is not the preferred method in WikiDoc.
WikiDoc features an automated reference manager. The advantages of this reference manager are that:
- The references are numbered automatically!
- When you move the text, the reference moves with it!
- You can click on the reference and go directly to the article!
Unlike the usual format where you type in the references at the end of the article, when you use the WikiDoc reference manager, you insert code for the reference right after the material you want to add a reference to. You use a software program to add in the references. The next section describes how to use the software program.
# Using the WikiDoc reference manager
One goal of WikiDoc is to create reference lists that allow you to click on the PubMed ID number at the end of the reference and go to the primary article itself. This greatly facilitates locating references. Therefore, the preferred method of citing references includes the use of a reference manager that uses the PubMed ID number to create the reference. The reference manager uses not only PubMed IDs but also DrugBank ID, HGNC ID, ISBN, PubMed ID, PubMed Central ID, PubChem ID, or URLs.
The preferred method for inserting a reference is as follows:
Step 1: Use PubMed to locate the article you are interested in by clicking here
Step 2: Copy the PubMed ID number from the article. The word PubMed ID is often abbreviated PMID and this number is located at the bottom of the abstract. You can use the search function on Firefox or Internet explorer to locate the word PMID and the number will follow this abbreviation. It will look something like this:
PMID: 19032997
Step 3: Paste the PubMed ID number (PMID) into a software program that creates the Wiki language code for the reference you are going to paste into the text of your article. You can access software for converting a pubmed ID number from one of the following:
- SUMSearch Biomedical Citation Maker (converts PMID into wiki reference markups with embedded sumsearch link)
- DOI Wikipedia reference generator (converts DOI into wiki reference markups)
- DTU Informatics PMID to Cite journal (converts PMID into wiki reference markups)
- OttoBib (converts ISBN into wiki reference markups)
- Dave's Template Filler (converts DrugBank ID, HGNC ID, ISBN, PubMed ID, PubMed Central ID, PubChem ID, or URL into wiki reference markups)
Step 4: When using the reference manager, make sure the button that says add ref tag is checked
Step 5: Press submit to generate the Wiki language that can be inserted in your article.
Step 6: Copy the Wiki language from the software program. For example, the output for the PMID above (19032997) is as follows:
{{cite journal |author=Gibson CM, Pride YB, Frederick PD, ''et al.'' |title=Trends in reperfusion strategies, door-to-needle and door-to-balloon times, and in-hospital mortality among patients with ST-segment elevation myocardial infarction enrolled in the National Registry of Myocardial Infarction from 1990 to 2006 |journal=Am. Heart J. |volume=156 |issue=6 |pages=1035–44 |year=2008 |month=December |pmid=19032997 |doi=10.1016/j.ahj.2008.07.029 |url=}}
Step 7: Paste this output from the reference manager software right where you want the superscript number to appear in the text.
For example, using the above reference, you might type something like this:
Gibson et al recently summarized the improvements made in clincial outcomes as a result of 15 years of quality improvement efforts in the NRMI registry {{cite journal |author=Gibson CM, Pride YB, Frederick PD, ''et al.'' |title=Trends in reperfusion strategies, door-to-needle and door-to-balloon times, and in-hospital mortality among patients with ST-segment elevation myocardial infarction enrolled in the National Registry of Myocardial Infarction from 1990 to 2006 |journal=Am. Heart J. |volume=156 |issue=6 |pages=1035–44 |year=2008 |month=December |pmid=19032997 |doi=10.1016/j.ahj.2008.07.029 |url=}}
This would generate text that looks like this:
Gibson et al recently summarized the improvements made in clincial outcomes as a result of 15 years of quality improvement efforts in the NRMI registry
- ↑ Gibson CM, Pride YB, Frederick PD; et al. (2008). "Trends in reperfusion strategies, door-to-needle and door-to-balloon times, and in-hospital mortality among patients with ST-segment elevation myocardial infarction enrolled in the National Registry of Myocardial Infarction from 1990 to 2006". Am. Heart J. 156 (6): 1035–44. doi:10.1016/j.ahj.2008.07.029. PMID 19032997. Unknown parameter |month= ignored (help)CS1 maint: Explicit use of et al. (link) 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}
# What if I don't want to use the reference manager? What if I just want to type the references in myself?
You are not required to use the reference manager. You can do the following:
Step 1: Place a ... immediately after the sentence where you want a footnote number to appear.
Step 2: Type the text of the note between the ref tags. For example if I typed this
It would appear as this
Note: If you intend on using the same manual reference more than once, you will need to assign a name to the reference. You can do this by writing ... . Your name can be anything you want. Without a name, every manual reference will be viewed as a unique reference. This means that a reference used multiple times will show up as multiple references instead of just the one.
# How do I make the references appear at the bottom of the article?
## The preferred method
Put the following code in:
This will generate your references in small font, in two columns, with links to the original article and abstract. It will return text that looks like this:
- ↑ J Fam Pract. 2000 Oct;49(10):921-3. | References
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
WikiDoc has a reference manager that allows users to insert references based upon their PubMed ID number. If you move the text, the reference moves with it! All the references are automatically inserted at the bottom. You click on the reference and you go to the article. It is simple!
# Where do I type in the references?
Usually you would type a number in the text like this (1) or this 1 which refers to a reference you would like to cite. You would then type in the reference at the end of the article. This is not the preferred method in WikiDoc.
WikiDoc features an automated reference manager. The advantages of this reference manager are that:
- The references are numbered automatically!
- When you move the text, the reference moves with it!
- You can click on the reference and go directly to the article!
Unlike the usual format where you type in the references at the end of the article, when you use the WikiDoc reference manager, you insert code for the reference right after the material you want to add a reference to. You use a software program to add in the references. The next section describes how to use the software program.
# Using the WikiDoc reference manager
One goal of WikiDoc is to create reference lists that allow you to click on the PubMed ID number at the end of the reference and go to the primary article itself. This greatly facilitates locating references. Therefore, the preferred method of citing references includes the use of a reference manager that uses the PubMed ID number to create the reference. The reference manager uses not only PubMed IDs but also DrugBank ID, HGNC ID, ISBN, PubMed ID, PubMed Central ID, PubChem ID, or URLs.
The preferred method for inserting a reference is as follows:
Step 1: Use PubMed to locate the article you are interested in by clicking here
Step 2: Copy the PubMed ID number from the article. The word PubMed ID is often abbreviated PMID and this number is located at the bottom of the abstract. You can use the search function on Firefox or Internet explorer to locate the word PMID and the number will follow this abbreviation. It will look something like this:
PMID: 19032997
Step 3: Paste the PubMed ID number (PMID) into a software program that creates the Wiki language code for the reference you are going to paste into the text of your article. You can access software for converting a pubmed ID number from one of the following:
- SUMSearch Biomedical Citation Maker (converts PMID into wiki reference markups with embedded sumsearch link)
- DOI Wikipedia reference generator (converts DOI into wiki reference markups)
- DTU Informatics PMID to Cite journal (converts PMID into wiki reference markups)
- OttoBib (converts ISBN into wiki reference markups)
- Dave's Template Filler (converts DrugBank ID, HGNC ID, ISBN, PubMed ID, PubMed Central ID, PubChem ID, or URL into wiki reference markups)
Step 4: When using the reference manager, make sure the button that says add ref tag is checked
Step 5: Press submit to generate the Wiki language that can be inserted in your article.
Step 6: Copy the Wiki language from the software program. For example, the output for the PMID above (19032997) is as follows:
<ref name="pmid19032997">{{cite journal |author=Gibson CM, Pride YB, Frederick PD, ''et al.'' |title=Trends in reperfusion strategies, door-to-needle and door-to-balloon times, and in-hospital mortality among patients with ST-segment elevation myocardial infarction enrolled in the National Registry of Myocardial Infarction from 1990 to 2006 |journal=Am. Heart J. |volume=156 |issue=6 |pages=1035–44 |year=2008 |month=December |pmid=19032997 |doi=10.1016/j.ahj.2008.07.029 |url=}}</ref>
Step 7: Paste this output from the reference manager software right where you want the superscript number to appear in the text.
For example, using the above reference, you might type something like this:
Gibson et al recently summarized the improvements made in clincial outcomes as a result of 15 years of quality improvement efforts in the NRMI registry <ref name="pmid19032997">{{cite journal |author=Gibson CM, Pride YB, Frederick PD, ''et al.'' |title=Trends in reperfusion strategies, door-to-needle and door-to-balloon times, and in-hospital mortality among patients with ST-segment elevation myocardial infarction enrolled in the National Registry of Myocardial Infarction from 1990 to 2006 |journal=Am. Heart J. |volume=156 |issue=6 |pages=1035–44 |year=2008 |month=December |pmid=19032997 |doi=10.1016/j.ahj.2008.07.029 |url=}}</ref>
This would generate text that looks like this:
Gibson et al recently summarized the improvements made in clincial outcomes as a result of 15 years of quality improvement efforts in the NRMI registry[1]
- ↑ Gibson CM, Pride YB, Frederick PD; et al. (2008). "Trends in reperfusion strategies, door-to-needle and door-to-balloon times, and in-hospital mortality among patients with ST-segment elevation myocardial infarction enrolled in the National Registry of Myocardial Infarction from 1990 to 2006". Am. Heart J. 156 (6): 1035–44. doi:10.1016/j.ahj.2008.07.029. PMID 19032997. Unknown parameter |month= ignored (help)CS1 maint: Explicit use of et al. (link) 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}
# What if I don't want to use the reference manager? What if I just want to type the references in myself?
You are not required to use the reference manager. You can do the following:
Step 1: Place a <ref> ... </ref> immediately after the sentence where you want a footnote number to appear.
Step 2: Type the text of the note between the ref tags. For example if I typed this
It would appear as this
Note: If you intend on using the same manual reference more than once, you will need to assign a name to the reference. You can do this by writing <ref name="anythingyouwanthere"> ... </ref>. Your name can be anything you want. Without a name, every manual reference will be viewed as a unique reference. This means that a reference used multiple times will show up as multiple references instead of just the one.
# How do I make the references appear at the bottom of the article?
## The preferred method
Put the following code in:
This will generate your references in small font, in two columns, with links to the original article and abstract. It will return text that looks like this:
- ↑ J Fam Pract. 2000 Oct;49(10):921-3.
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Adding_References_to_Articles | |
bd5222423eafb7b9c6f750a58ba4dc89b0e22885 | wikidoc | Adenomyoma | Adenomyoma
# Overview
Adenomyoma is a form of adenomyosis that forms a mass or growth around the tissue of the inner uterus.
Usually occurs in women over 30 who have carried a pregnancy to term.
Conversely, it rarely occurs in women who have not carried to term.
Most cases of adenomyosis are non-symptomatic. | Adenomyoma
For patient information, click here
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Adenomyoma is a form of adenomyosis that forms a mass or growth around the tissue of the inner uterus.
Usually occurs in women over 30 who have carried a pregnancy to term.
Conversely, it rarely occurs in women who have not carried to term.
Most cases of adenomyosis are non-symptomatic.
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Adenomyoma | |
11b4a13743cf3dbe4310e161add6ccc871ec27a7 | wikidoc | Adinazolam | Adinazolam
# Overview
Adinazolam (marketed under the brand name Deracyn) is a benzodiazepine derivative, and more specifically, a triazolobenzodiazepine (TBZD). It possesses anxiolytic, anticonvulsant, sedative, and antidepressant properties. Adinazolam was developed by Dr. Jackson B. Hester, who was seeking to enhance the antidepressant properties of alprazolam, which he also developed. Adinazolam was never FDA approved and never made available to the public market.
# Indications
Adinazolam is indicated as a treatment for depression and anxiety.
# Pharmacodynamics and pharmacokinetics
Adinazolam binds to peripheral-type benzodiazepine receptors that interact allosterically with GABA receptors as an agonist to produce inhibitory effects.
# Metabolism
Adinazolam was reported to have active metabolites in the August 1984 issue of The Journal of Pharmacy and Pharmacology. The main metabolite is N-desmethyladinazolam. NDMAD has an approximately 25-fold high affinity for benzodiazepine receptors as compared to its precursor, accounting for the benzodiazepine-like effects after oral administration. (REF1) Multiple N-dealkylations lead to the removal dimethyl-aminoethyl side chain, leading to the difference in its potency. (REF5) The other two metabolites are alpha-hydroxyalprazolam and estazolam. In the August 1986 issue of that same journal, Sethy, Francis and Day reported that proadifen inhibited the formation of N-desmethyladinazolam. | Adinazolam
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Adinazolam[1] (marketed under the brand name Deracyn) is a benzodiazepine derivative, and more specifically, a triazolobenzodiazepine (TBZD). It possesses anxiolytic, anticonvulsant, sedative, and antidepressant[2] properties. Adinazolam was developed by Dr. Jackson B. Hester, who was seeking to enhance the antidepressant properties of alprazolam, which he also developed.[3] Adinazolam was never FDA approved and never made available to the public market.
# Indications
Adinazolam is indicated as a treatment for depression and anxiety.
# Pharmacodynamics and pharmacokinetics
Adinazolam binds to peripheral-type benzodiazepine receptors that interact allosterically with GABA receptors as an agonist to produce inhibitory effects.
# Metabolism
Adinazolam was reported to have active metabolites in the August 1984 issue of The Journal of Pharmacy and Pharmacology.[4] The main metabolite is N-desmethyladinazolam.[5] NDMAD has an approximately 25-fold high affinity for benzodiazepine receptors as compared to its precursor, accounting for the benzodiazepine-like effects after oral administration. (REF1) Multiple N-dealkylations lead to the removal dimethyl-aminoethyl side chain, leading to the difference in its potency. (REF5) The other two metabolites are alpha-hydroxyalprazolam and estazolam.[6] In the August 1986 issue of that same journal, Sethy, Francis and Day reported that proadifen inhibited the formation of N-desmethyladinazolam.[7] | https://www.wikidoc.org/index.php/Adinazolam | |
5459226c6508ce13657007ffec44bb3ad0354385 | wikidoc | Adrenalone | Adrenalone
# Overview
Adrenalone is an adrenergic agonist used as a topical vasoconstrictor and hemostatic. Formerly, it was also used to prolong the action of local anesthetics. It is the ketone form of epinephrine (adrenaline). Contrary to epinephrine, adrenalone mainly acts on alpha-1 adrenergic receptors, but has little affinity for beta receptors. The drug is largely obsolete, being superseded by other hemostatics such as thrombin, fibrinogen, and vasopressin analogues.
# Contraindications and interactions
Adrenalone does not stop bleeding from large blood vessels. It is not approved for systemic use. Combination with antithrombotics is not useful because they contravene the action of adrenalone.
# Side effects
Vasoconstriction by adrenalone may lead to local necrosis.
# Pregnancy and lactation
Adrenalone passes into breast milk, but adverse effects are unlikely because of its very low systemic resorption.
# Chemical properties
Adrenalone is a derivative of epinephrine, having the alcohol function replaced with a ketone. As a consequence, it is not optically active any more.
Solubility in water, ethanol and diethyl ether is low. The substance is typically used in form of the hydrochloride, a white crystalline powder which tastes bitter and slightly acidic, and is soluble in water (1:8) and 94% ethanol (1:45). The melting point of the hydrochloride is 243 °C (469.4 °F).
# Pharmacology
After local application, only traces of adrenalone are found in the blood, which is partly a consequence of the vasoconstriction caused by the drug via alpha-1 adrenergic receptors. In an (unspecified) pharmacological model, hypertensive (blood pressure increasing) action has been found to be about 0.5% that of epinephrine at equivalent plasma concentrations. Therefore, systemic effects are unlikely.
Like epinephrine, adrenalone is metabolised by catechol-O-methyl transferase (COMT), yielding 3O-methyladrenalone, which in turn is N-demethylized by monoamine oxidase (MAO). Alternatively, it can first undergo metabolization by MAO and then by COMT; in both cases, the resulting 3O-methyl-N-demethyladrenalone is conjugated to sulfate or glucuronide and excreted by the kidney. No reduction to epinephrine has been observed in vivo. | Adrenalone
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Adrenalone is an adrenergic agonist used as a topical vasoconstrictor and hemostatic. Formerly, it was also used to prolong the action of local anesthetics. It is the ketone form of epinephrine (adrenaline). Contrary to epinephrine, adrenalone mainly acts on alpha-1 adrenergic receptors, but has little affinity for beta receptors. The drug is largely obsolete, being superseded by other hemostatics such as thrombin, fibrinogen, and vasopressin analogues.[1]
# Contraindications and interactions
Adrenalone does not stop bleeding from large blood vessels. It is not approved for systemic use. Combination with antithrombotics is not useful because they contravene the action of adrenalone.[1]
# Side effects
Vasoconstriction by adrenalone may lead to local necrosis.[1]
# Pregnancy and lactation
Adrenalone passes into breast milk, but adverse effects are unlikely because of its very low systemic resorption.[1]
# Chemical properties
Adrenalone is a derivative of epinephrine, having the alcohol function replaced with a ketone. As a consequence, it is not optically active any more.
Solubility in water, ethanol and diethyl ether is low. The substance is typically used in form of the hydrochloride, a white crystalline powder which tastes bitter and slightly acidic, and is soluble in water (1:8) and 94% ethanol (1:45). The melting point of the hydrochloride is 243 °C (469.4 °F).[1]
# Pharmacology
After local application, only traces of adrenalone are found in the blood, which is partly a consequence of the vasoconstriction caused by the drug via alpha-1 adrenergic receptors. In an (unspecified) pharmacological model, hypertensive (blood pressure increasing) action has been found to be about 0.5% that of epinephrine at equivalent plasma concentrations. Therefore, systemic effects are unlikely.
Like epinephrine, adrenalone is metabolised by catechol-O-methyl transferase (COMT), yielding 3O-methyladrenalone, which in turn is N-demethylized by monoamine oxidase (MAO). Alternatively, it can first undergo metabolization by MAO and then by COMT; in both cases, the resulting 3O-methyl-N-demethyladrenalone is conjugated to sulfate or glucuronide and excreted by the kidney. No reduction to epinephrine has been observed in vivo.[1] | https://www.wikidoc.org/index.php/Adrenalone | |
502502d7c1b72de99e677918a45dbefb445da70f | wikidoc | Adrenarche | Adrenarche
Adrenarche refers to a stage of maturation of the cortex of the human adrenal glands. It typically occurs between ages 6 and 10 years and involves both structural and functional changes. Adrenarche is a process related to puberty but distinct from hypothalamic-pituitary-gonadal maturation and function.
# Structural and functional changes of adrenarche
Structural changes of adrenarche include increased size and mass of the adrenal cortex, and completion of differentiation into the three zones: zona glomerulosa, zona fasciculata, and zona reticularis.
One of the primary functional changes is further differentiation of sex steroid synthesis among the three zones, so that as in adults, the zona glomerlulosa primarily produces mineralocorticoids such as aldosterone, the zona fasciculata primarily produces glucocorticoids such as cortisol, and the zona reticularis primarily produces androgens such as dehydroepiandrosterone, dehydroepiandrosterone sulfate, and androstenedione.
The second important functional change is a steady increase over several years in the daily production of adrenal androgens. A characteristic aspect of early adrenarche is a diminished activity of 3β-hydroxysteroid dehydrogenase, the enzyme which mediates the hydroxylation of 17-hydroxypregnenolone to 17-hydroxyprogesterone, and DHEA to androstenedione. Blood levels of DHEA, androstenedione, and especially DHEAS are useful measures of adrenal maturation.
# Role of adrenarche as part of puberty
An initiator of adrenarche has not yet been identified. Researchers have unsuccessfully tried to identify a new pituitary peptide, to be called "adrenal androgen stimulating hormone". Others have proposed that adrenarchal maturation is a gradual process intrinsic to the adrenal glands that has no distinct trigger. A third avenue of research is pursuing a possible relationship with either fetal or childhood body mass and related signals such as insulin and leptin. Many children born small for gestational age (SGA) because of intrauterine growth retardation (IUGR) have an earlier onset of adrenarche, which raises the possibility that timing of adrenarche may be affected by physiological programming in infancy. Adrenarche also occurs prematurely in many children who are overweight, suggesting a possible relationship with body mass or adiposity signals.
The principal physical consequences of adrenarche are androgen effects, especially pubic hair and the change of sweat composition that produces adult body odor. Increased oiliness of the skin and hair and mild acne may occur. In most boys, these changes are indistinguishable from early testicular testosterone effects occurring at the beginning of gonadal puberty. In girls, the adrenal androgens of adrenarche produce most of the early androgenic changes of puberty: pubic hair, body odor, skin oiliness, and acne. In most girls the early androgen effects coincide with, or are a few months behind, the earliest estrogenic effects of gonadal puberty (breast development and growth acceleration). As female puberty progresses, the ovaries and peripheral tissues become more important sources of androgens.
Parents and many physicians often infer (incorrectly) the onset of puberty from the first appearance of pubic hair (termed pubarche). However, the independence of adrenarche and gonadal puberty is apparent in children with atypical or abnormal development, when one process may occur without the other. For instance, adrenarche does not occur in many girls with Addison's disease, who will continue to have minimal pubic hair as puberty progresses. Conversely, girls with Turner syndrome will have normal adrenarche and normal pubic hair development, but true gonadal puberty never occurs because their ovaries are defective.
# Premature adrenarche
Premature adrenarche is the most common cause of the early appearance of pubic hair ("premature pubarche") in childhood. In a large proportion of children it seems to be a variation of normal development requiring no treatment. However, there are three clinical issues related to premature adrenarche.
First, when pubic hair appears at an unusually early age in a child, premature adrenarche should be distinguished from true central precocious puberty, from congenital adrenal hyperplasia, and from androgen-producing tumors of the adrenals or gonads. Pediatric endocrinologists do this by demonstrating advanced levels of DHEAS and other adrenal androgens, with prepubertal levels of gonadotropins and gonadal sex steroids.
Second, there is some evidence that premature adrenarche may indicate that there was an abnormality of intrauterine energy environment and growth. As mentioned above, premature adrenarche occurs more often in children with intrauterine growth retardation and in overweight children. Some of these same studes have demonstrated that some girls who display premature adrenarche may continue to have excessive androgen levels in adolescence. This can result in hirsutism or menstrual irregularities due to anovulation referred to as polycystic ovary syndrome.
Third, at least one report found an increased incidence of behavior and school problems in a group of children with premature adrenarche compared with an otherwise similar control group. To date such a relationship has neither been confirmed nor explained and there are no obvious management implications. | Adrenarche
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Phone:617-632-7753
Adrenarche refers to a stage of maturation of the cortex of the human adrenal glands. It typically occurs between ages 6 and 10 years and involves both structural and functional changes. Adrenarche is a process related to puberty but distinct from hypothalamic-pituitary-gonadal maturation and function.
# Structural and functional changes of adrenarche
Structural changes of adrenarche include increased size and mass of the adrenal cortex, and completion of differentiation into the three zones: zona glomerulosa, zona fasciculata, and zona reticularis.
One of the primary functional changes is further differentiation of sex steroid synthesis among the three zones, so that as in adults, the zona glomerlulosa primarily produces mineralocorticoids such as aldosterone, the zona fasciculata primarily produces glucocorticoids such as cortisol, and the zona reticularis primarily produces androgens such as dehydroepiandrosterone, dehydroepiandrosterone sulfate, and androstenedione.
The second important functional change is a steady increase over several years in the daily production of adrenal androgens. A characteristic aspect of early adrenarche is a diminished activity of 3β-hydroxysteroid dehydrogenase, the enzyme which mediates the hydroxylation of 17-hydroxypregnenolone to 17-hydroxyprogesterone, and DHEA to androstenedione. Blood levels of DHEA, androstenedione, and especially DHEAS are useful measures of adrenal maturation.
# Role of adrenarche as part of puberty
An initiator of adrenarche has not yet been identified. Researchers have unsuccessfully tried to identify a new pituitary peptide, to be called "adrenal androgen stimulating hormone". Others have proposed that adrenarchal maturation is a gradual process intrinsic to the adrenal glands that has no distinct trigger. A third avenue of research is pursuing a possible relationship with either fetal or childhood body mass and related signals such as insulin and leptin. Many children born small for gestational age (SGA) because of intrauterine growth retardation (IUGR) have an earlier onset of adrenarche, which raises the possibility that timing of adrenarche may be affected by physiological programming in infancy. Adrenarche also occurs prematurely in many children who are overweight, suggesting a possible relationship with body mass or adiposity signals.
The principal physical consequences of adrenarche are androgen effects, especially pubic hair and the change of sweat composition that produces adult body odor. Increased oiliness of the skin and hair and mild acne may occur. In most boys, these changes are indistinguishable from early testicular testosterone effects occurring at the beginning of gonadal puberty. In girls, the adrenal androgens of adrenarche produce most of the early androgenic changes of puberty: pubic hair, body odor, skin oiliness, and acne. In most girls the early androgen effects coincide with, or are a few months behind, the earliest estrogenic effects of gonadal puberty (breast development and growth acceleration). As female puberty progresses, the ovaries and peripheral tissues become more important sources of androgens.
Parents and many physicians often infer (incorrectly) the onset of puberty from the first appearance of pubic hair (termed pubarche). However, the independence of adrenarche and gonadal puberty is apparent in children with atypical or abnormal development, when one process may occur without the other. For instance, adrenarche does not occur in many girls with Addison's disease, who will continue to have minimal pubic hair as puberty progresses. Conversely, girls with Turner syndrome will have normal adrenarche and normal pubic hair development, but true gonadal puberty never occurs because their ovaries are defective.
# Premature adrenarche
Premature adrenarche is the most common cause of the early appearance of pubic hair ("premature pubarche") in childhood. In a large proportion of children it seems to be a variation of normal development requiring no treatment. However, there are three clinical issues related to premature adrenarche.
First, when pubic hair appears at an unusually early age in a child, premature adrenarche should be distinguished from true central precocious puberty, from congenital adrenal hyperplasia, and from androgen-producing tumors of the adrenals or gonads. Pediatric endocrinologists do this by demonstrating advanced levels of DHEAS and other adrenal androgens, with prepubertal levels of gonadotropins and gonadal sex steroids.
Second, there is some evidence that premature adrenarche may indicate that there was an abnormality of intrauterine energy environment and growth. As mentioned above, premature adrenarche occurs more often in children with intrauterine growth retardation and in overweight children. Some of these same studes have demonstrated that some girls who display premature adrenarche may continue to have excessive androgen levels in adolescence. This can result in hirsutism or menstrual irregularities due to anovulation referred to as polycystic ovary syndrome.
Third, at least one report found an increased incidence of behavior and school problems in a group of children with premature adrenarche compared with an otherwise similar control group. To date such a relationship has neither been confirmed nor explained and there are no obvious management implications. | https://www.wikidoc.org/index.php/Adrenarche | |
bed9bd1343806bb36b484ac69d11ba43b520e1f6 | wikidoc | Ferredoxin | Ferredoxin
Ferredoxins (from Latin ferrum: iron + redox, often abbreviated "fd") are iron–sulfur proteins that mediate electron transfer in a range of metabolic reactions. The term "ferredoxin" was coined by D.C. Wharton of the DuPont Co. and applied to the "iron protein" first purified in 1962 by Mortenson, Valentine, and Carnahan from the anaerobic bacterium Clostridium pasteurianum.
Another redox protein, isolated from spinach chloroplasts, was termed "chloroplast ferredoxin". The chloroplast ferredoxin is involved in both cyclic and non-cyclic photophosphorylation reactions of photosynthesis. In non-cyclic photophosphorylation, ferredoxin is the last electron acceptor thus reducing the enzyme NADP+ reductase. It accepts electrons produced from sunlight-excited chlorophyll and transfers them to the enzyme ferredoxin: NADP+ oxidoreductase EC 1.18.1.2.
Ferredoxins are small proteins containing iron and sulfur atoms organized as iron–sulfur clusters. These biological "capacitors" can accept or discharge electrons, with the effect of a change in the oxidation state of the iron atoms between +2 and +3. In this way, ferredoxin acts as an electron transfer agent in biological redox reactions.
Other bioinorganic electron transport systems include rubredoxins, cytochromes, blue copper proteins, and the structurally related Rieske proteins.
Ferredoxins can be classified according to the nature of their iron–sulfur clusters and by sequence similarity.
# Fe2S2 ferredoxins
Members of the 2Fe-2S ferredoxin family have a general core structure consisting of beta(2)-alpha-beta(2), which includes putidaredoxin, terpredoxin, and adrenodoxin. They are proteins of around one hundred amino acids with four conserved cysteine residues to which the 2Fe-2S cluster is ligated. This conserved region is also found as a domain in various metabolic enzymes and in multidomain proteins, such as aldehyde oxidoreductase (N-terminal), xanthine oxidase (N-terminal), phthalate dioxygenase reductase (C-terminal), succinate dehydrogenase iron–sulphur protein (N-terminal), and methane monooxygenase reductase (N-terminal).
## Plant-type ferredoxins
One group of ferredoxins, originally found in chloroplast membranes, has been termed "chloroplast-type" or "plant-type". Its active center is a cluster, where the iron atoms are tetrahedrally coordinated both by inorganic sulfur atoms and by sulfurs of four conserved cysteine (Cys) residues.
In chloroplasts, Fe2S2 ferredoxins function as electron carriers in the photosynthetic electron transport chain and as electron donors to various cellular proteins, such as glutamate synthase, nitrite reductase and sulfite reductase. In hydroxylating bacterial dioxygenase systems, they serve as intermediate electron-transfer carriers between reductase flavoproteins and oxygenase.
## Thioredoxin-like ferredoxins
The Fe2S2 ferredoxin from Clostridium pasteurianum (Cp2FeFd) has been recognized as distinct protein family on the basis of its amino acid sequence, spectroscopic properties of its iron-sulfur cluster and the unique ligand swapping ability of two cysteine ligands to the cluster. Although the physiological role of this ferredoxin remains unclear, a strong and specific interaction of Cp2FeFd with the molybdenum-iron protein of nitrogenase has been revealed. Homologous ferredoxins from Azotobacter vinelandii (Av2FeFdI) and Aquifex aeolicus (AaFd) have been characterized. The crystal structure of AaFd has been solved. AaFd exists as a dimer. The structure of AaFd monomer is different from other Fe2S2 ferredoxins. The fold belongs to the α+β class, with first four β-strands and two α-helices adopting a variant of the thioredoxin fold.
## Adrenodoxin-type ferredoxins
Adrenodoxin (adrenal ferredoxin) is expressed in mammals including humans. The human variant of adrenodoxin is referred to as ferredoxin 1. Adrenodoxin, putidaredoxin, and terpredoxin are soluble Fe2S2 proteins that act as single electron carriers. In mitochondrial monooxygenase systems, adrenodoxin transfers an electron from NADPH:adrenodoxin reductase to membrane-bound cytochrome P450. In bacteria, putidaredoxin and terpredoxin serve as electron carriers between corresponding NADH-dependent ferredoxin reductases and soluble P450s. The exact functions of other members of this family are not known, although Escherichia coli Fdx is shown to be involved in biogenesis of Fe-S clusters. Despite low sequence similarity between adrenodoxin-type and plant-type ferredoxins, the two classes have a similar folding topology.
Ferredoxin-1 in humans participates in the synthesis of thyroid hormones. It also transfers electrons from adrenodoxin reductase to the cholesterol side chain cleavage cytochrome P450. FDX-1 has the capability to bind to metals and proteins. It can be found within the cellular mitochondrial matrix.
# Fe4S4 and Fe3S4 ferredoxins
The ferredoxins may be further subdivided into low-potential (bacterial-type) and high-potential (HiPIP) ferredoxins.
Low- and high-potential ferredoxins are related by the following redox scheme:
The formal oxidation numbers of the iron ions can be or in low-potential ferredoxins. The oxidation numbers of the iron ions in high-potential ferredoxins can be or .
## Bacterial-type ferredoxins
A group of Fe4S4 ferredoxins, originally found in bacteria, has been termed "bacterial-type". Bacterial-type ferredoxins may in turn be subdivided into further groups, based on their sequence properties. Most contain at least one conserved domain, including four cysteine residues that bind to a cluster. In Pyrococcus furiosus Fe4S4 ferredoxin, one of the conserved Cys residues is substituted with aspartic acid.
During the evolution of bacterial-type ferredoxins, intrasequence gene duplication, transposition and fusion events occurred, resulting in the appearance of proteins with multiple iron-sulfur centers. In some bacterial ferredoxins, one of the duplicated domains has lost one or more of the four conserved Cys residues. These domains have either lost their iron-sulfur binding property or bind to a cluster instead of a cluster and dicluster-type.
3-D structures are known for a number of monocluster and dicluster bacterial-type ferredoxins. The fold belongs to the α+β class, with 2-7 α-helices and four β-strands forming a barrel-like structure, and an extruded loop containing three "proximal" Cys ligands of the iron-sulfur cluster.
## High-potential iron-sulfur proteins
High-potential iron-sulfur proteins (HiPIPs) form a unique family of Fe4S4 ferredoxins that function in anaerobic electron transport chains. Some HiPIPs have a redox potential higher than any other known iron-sulfur protein (e.g., HiPIP from Rhodopila globiformis has a redox potential of ca. 450 mV). Several HiPIPs have so far been characterized structurally, their folds belonging to the α+β class. As in other bacterial ferredoxins, the unit forms a cubane-type cluster and is ligated to the protein via four Cys residues.
# Human proteins from ferredoxin family
- 2Fe-2S: AOX1; FDX1; FDX1L; NDUFS1; SDHB; XDH;
- 4Fe-4S: ABCE1; DPYD; NDUFS8; | Ferredoxin
Ferredoxins (from Latin ferrum: iron + redox, often abbreviated "fd") are iron–sulfur proteins that mediate electron transfer in a range of metabolic reactions. The term "ferredoxin" was coined by D.C. Wharton of the DuPont Co. and applied to the "iron protein" first purified in 1962 by Mortenson, Valentine, and Carnahan from the anaerobic bacterium Clostridium pasteurianum.[1][2]
Another redox protein, isolated from spinach chloroplasts, was termed "chloroplast ferredoxin".[3] The chloroplast ferredoxin is involved in both cyclic and non-cyclic photophosphorylation reactions of photosynthesis. In non-cyclic photophosphorylation, ferredoxin is the last electron acceptor thus reducing the enzyme NADP+ reductase. It accepts electrons produced from sunlight-excited chlorophyll and transfers them to the enzyme ferredoxin: NADP+ oxidoreductase EC 1.18.1.2.
Ferredoxins are small proteins containing iron and sulfur atoms organized as iron–sulfur clusters. These biological "capacitors" can accept or discharge electrons, with the effect of a change in the oxidation state of the iron atoms between +2 and +3. In this way, ferredoxin acts as an electron transfer agent in biological redox reactions.
Other bioinorganic electron transport systems include rubredoxins, cytochromes, blue copper proteins, and the structurally related Rieske proteins.
Ferredoxins can be classified according to the nature of their iron–sulfur clusters and by sequence similarity.
# Fe2S2 ferredoxins
Members of the 2Fe-2S ferredoxin family have a general core structure consisting of beta(2)-alpha-beta(2), which includes putidaredoxin, terpredoxin, and adrenodoxin.[4][5][6][7] They are proteins of around one hundred amino acids with four conserved cysteine residues to which the 2Fe-2S cluster is ligated. This conserved region is also found as a domain in various metabolic enzymes and in multidomain proteins, such as aldehyde oxidoreductase (N-terminal), xanthine oxidase (N-terminal), phthalate dioxygenase reductase (C-terminal), succinate dehydrogenase iron–sulphur protein (N-terminal), and methane monooxygenase reductase (N-terminal).
## Plant-type ferredoxins
One group of ferredoxins, originally found in chloroplast membranes, has been termed "chloroplast-type" or "plant-type". Its active center is a [Fe2S2] cluster, where the iron atoms are tetrahedrally coordinated both by inorganic sulfur atoms and by sulfurs of four conserved cysteine (Cys) residues.
In chloroplasts, Fe2S2 ferredoxins function as electron carriers in the photosynthetic electron transport chain and as electron donors to various cellular proteins, such as glutamate synthase, nitrite reductase and sulfite reductase. In hydroxylating bacterial dioxygenase systems, they serve as intermediate electron-transfer carriers between reductase flavoproteins and oxygenase.
## Thioredoxin-like ferredoxins
The Fe2S2 ferredoxin from Clostridium pasteurianum (Cp2FeFd) has been recognized as distinct protein family on the basis of its amino acid sequence, spectroscopic properties of its iron-sulfur cluster and the unique ligand swapping ability of two cysteine ligands to the [Fe2S2] cluster. Although the physiological role of this ferredoxin remains unclear, a strong and specific interaction of Cp2FeFd with the molybdenum-iron protein of nitrogenase has been revealed. Homologous ferredoxins from Azotobacter vinelandii (Av2FeFdI) and Aquifex aeolicus (AaFd) have been characterized. The crystal structure of AaFd has been solved. AaFd exists as a dimer. The structure of AaFd monomer is different from other Fe2S2 ferredoxins. The fold belongs to the α+β class, with first four β-strands and two α-helices adopting a variant of the thioredoxin fold.
## Adrenodoxin-type ferredoxins
Adrenodoxin (adrenal ferredoxin) is expressed in mammals including humans. The human variant of adrenodoxin is referred to as ferredoxin 1. Adrenodoxin, putidaredoxin, and terpredoxin are soluble Fe2S2 proteins that act as single electron carriers. In mitochondrial monooxygenase systems, adrenodoxin transfers an electron from NADPH:adrenodoxin reductase to membrane-bound cytochrome P450. In bacteria, putidaredoxin and terpredoxin serve as electron carriers between corresponding NADH-dependent ferredoxin reductases and soluble P450s. The exact functions of other members of this family are not known, although Escherichia coli Fdx is shown to be involved in biogenesis of Fe-S clusters. Despite low sequence similarity between adrenodoxin-type and plant-type ferredoxins, the two classes have a similar folding topology.
Ferredoxin-1 in humans participates in the synthesis of thyroid hormones. It also transfers electrons from adrenodoxin reductase to the cholesterol side chain cleavage cytochrome P450. FDX-1 has the capability to bind to metals and proteins. It can be found within the cellular mitochondrial matrix.
# Fe4S4 and Fe3S4 ferredoxins
The [Fe4S4] ferredoxins may be further subdivided into low-potential (bacterial-type) and high-potential (HiPIP) ferredoxins.
Low- and high-potential ferredoxins are related by the following redox scheme:
The formal oxidation numbers of the iron ions can be [2Fe3+, 2Fe2+] or [1Fe3+, 3Fe2+] in low-potential ferredoxins. The oxidation numbers of the iron ions in high-potential ferredoxins can be [3Fe3+, 1Fe2+] or [2Fe3+, 2Fe2+].
## Bacterial-type ferredoxins
A group of Fe4S4 ferredoxins, originally found in bacteria, has been termed "bacterial-type". Bacterial-type ferredoxins may in turn be subdivided into further groups, based on their sequence properties. Most contain at least one conserved domain, including four cysteine residues that bind to a [Fe4S4] cluster. In Pyrococcus furiosus Fe4S4 ferredoxin, one of the conserved Cys residues is substituted with aspartic acid.
During the evolution of bacterial-type ferredoxins, intrasequence gene duplication, transposition and fusion events occurred, resulting in the appearance of proteins with multiple iron-sulfur centers. In some bacterial ferredoxins, one of the duplicated domains has lost one or more of the four conserved Cys residues. These domains have either lost their iron-sulfur binding property or bind to a [Fe3S4] cluster instead of a [Fe4S4] cluster[9] and dicluster-type.[10]
3-D structures are known for a number of monocluster and dicluster bacterial-type ferredoxins. The fold belongs to the α+β class, with 2-7 α-helices and four β-strands forming a barrel-like structure, and an extruded loop containing three "proximal" Cys ligands of the iron-sulfur cluster.
## High-potential iron-sulfur proteins
High-potential iron-sulfur proteins (HiPIPs) form a unique family of Fe4S4 ferredoxins that function in anaerobic electron transport chains. Some HiPIPs have a redox potential higher than any other known iron-sulfur protein (e.g., HiPIP from Rhodopila globiformis has a redox potential of ca. 450 mV). Several HiPIPs have so far been characterized structurally, their folds belonging to the α+β class. As in other bacterial ferredoxins, the [Fe4S4] unit forms a cubane-type cluster and is ligated to the protein via four Cys residues.
# Human proteins from ferredoxin family
- 2Fe-2S: AOX1; FDX1; FDX1L; NDUFS1; SDHB; XDH;
- 4Fe-4S: ABCE1; DPYD; NDUFS8; | https://www.wikidoc.org/index.php/Adrenodoxin | |
e88fe2b4cf42f2b3ac55a207b674ea690ee1b314 | wikidoc | Adsorption | Adsorption
# Overview
Adsorption is a process that occurs when a gas or liquid solute accumulates on the surface of a solid or a liquid (adsorbent), forming a film of molecules or atoms (the adsorbate). It is different from absorption, in which a substance diffuses into a liquid or solid to form a solution. The term sorption encompasses both processes, while desorption is the reverse process.
Adsorption is present in many natural physical, biological, and chemical systems, and is widely used in industrial applications such as activated charcoal, synthetic resins, and water purification. Adsorption, ion exchange, and chromatography are sorption processes in which certain adsorbates are selectively transferred from the fluid phase to the surface of insoluble, rigid particles suspended in a vessel or packed in a column.
Similar to surface tension, adsorption is a consequence of surface energy. In a bulk material, all the bonding requirements (be they ionic, covalent, or metallic) of the constituent atoms of the material are filled by other atoms in the material. However, atoms on the surface of the adsorbent are not wholly surrounded by other adsorbent atoms and therefore can attract adsorbates. The exact nature of the bonding depends on the details of the species involved, but the adsorption process is generally classified as physisorption (characteristic of weak van der Waals forces) or chemisorption (characteristic of covalent bonding).
# Isotherms
Adsorption is usually described through isotherms, that is, the amount of adsorbate on the adsorbent as a function of its pressure (if gas) or concentration (if liquid) at constant temperature. The quantity adsorbed is nearly always normalized by the mass of the adsorbent to allow comparison of different materials.
The first mathematical fit to an isotherm was published by Freundlich and Küster (1894) and is a purely empirical formula for gaseous adsorbates,
where x is the quantity adsorbed, m is the mass of the adsorbent, P is the pressure of adsorbate and k and n are empirical constants for each adsorbent-adsorbate pair at a given temperature. The function has an asymptotic maximum as pressure increases without bound. As the temperature increases, the constants k and n change to reflect the empirical observation that the quantity adsorbed rises more slowly and higher pressures are required to saturate the surface.
## Langmuir
In 1916, Irving Langmuir published a new model isotherm for gases adsorbed on solids, which retained his name. It is a semi-empirical isotherm derived from a proposed kinetic mechanism. It is based on four assumptions:
- The surface of the adsorbent is uniform, that is, all the adsorption sites are equivalent.
- Adsorbed molecules do not interact.
- All adsorption occurs through the same mechanism.
- At the maximum adsorption, only a monolayer is formed: molecules of adsorbate do not deposit on other, already adsorbed, molecules of adsorbate, only on the free surface of the adsorbent.
These four assumptions are seldom all true: there are always imperfections on the surface, adsorbed molecules are not necessarily inert, and the mechanism is clearly not the same for the very first molecules to adsorb as for the last. The fourth condition is the most troublesome, as frequently more molecules will adsorb on the monolayer; this problem is addressed by the BET isotherm for relatively flat (non-microporous) surfaces. The Langmuir isotherm is nonetheless the first choice for most models of adsorption, and has many applications in surface kinetics (usually called Langmuir-Hinshelwood kinetics) and thermodynamics.
Langmuir suggested that adsorption takes place through this mechanism:
A(g) + S Template:Unicode AS, where A is a gas molecule and S is an adsorption site.
The direct and inverse rate constants are k and k-1. If we define surface coverage, \theta, as the fraction of the adsorption sites occupied, in the equilibrium we have
Where P is the partial pressure (gas) or the molar concentration of the solution (liquid)
For very low pressures \theta\approx KP and for high pressures \theta\approx1
\theta is difficult to measure experimentally; usually, the adsorbate is a gas and the quantity adsorbed is given in moles, grams, or gas volumes at standard temperature and pressure (STP) per gram of adsorbent. If we call vmon the STP volume of adsorbate required to form a monolayer on the adsorbent (per gram of adsorbent), \theta = \frac{v}{v_\mathrm{mon}} and we obtain an expression for a straight line:
Through its slope and y-intercept we can obtain vmon and K, which are constants for each adsorbent/adsorbate pair at a given temperature. vmon is related to the number of adsorption sites through the ideal gas law. If we assume that the number of sites is just the whole area of the solid divided into the cross section of the adsorbate molecules, we can easily calculate the surface area of the adsorbent.
The surface area of an adsorbent depends on its structure; the more pores it has, the greater the area, which has a big influence on reactions on surfaces.
If more than one gas adsorbs on the surface, we define \theta_E as the fraction of empty sites and we have
and
where i is each one of the gases that adsorb.
## BET
Often molecules do form multilayers, that is, some are adsorbed on already adsorbed molecules and the Langmuir isotherm is not valid. In 1938 Stephan Brunauer, Paul Emmett, and Edward Teller developed a model isotherm that takes that possibility into account. Their theory is called BET Theory, after the initials in their last names. They modified Langmuir's mechanism as follows:
The derivation of the formula is more complicated than Langmuir's (see links for complete derivation). We obtain:
x is the pressure divided by the vapor pressure for the adsorbate at that temperature (usually denoted P/P^0), v is the STP volume of adsorbed adsorbate, vmon is the STP volume of the amount of adsorbate required to form a monolayer and c is the equilibrium constant K we used in Langmuir isotherm multiplied by the vapor pressure of the adsorbate. The key assumption used in deriving the BET equation that the successive heats of adsorption for all layers except the first are equal to the heat of condensation of the adsorbate.
The Langmuir isotherm is usually better for chemisorption and the BET isotherm works better for physisorption for non-microporous surfaces.
## Adsorption enthalpy
Adsorption constants are equilibrium constants, therefore they obey van 't Hoff's equation:
As can be seen in the formula, the variation of K must be isosteric, that is, at constant coverage.
If we start from the BET isotherm and assume that the entropy change is the same for liquefaction and adsorption we obtain
\Delta H_\mathrm{ads}=\Delta H_\mathrm{liq}-RT\ln c, that is to say, adsorption is more exothermic than liquefaction.
# Adsorbents
## Characteristics and general requirements
Adsorbents are used usually in the form of spherical pellets, rods, moldings, or monoliths with hydrodynamic diameters between 0.5 and 10 mm.
They must have high abrasion resistance, high thermal stability and small pore diameters, which results in higher exposed surface area and hence high surface capacity for adsorption.
The adsorbents must also have a distinct pore structure which enables fast transport of the gaseous vapors.
Most industrial adsorbents fall into one of three classes:
- Oxygen-containing compounds – Are typically hydrophilic and polar, including materials such as silica gel and zeolites.
- Carbon-based compounds – Are typically hydrophobic and non-polar, including materials such as activated carbon and graphite.
- Polymer-based compounds - Are polar or non-polar functional groups in a porous polymer matrix.
## Silica gel
Silica gel is a chemically inert, nontoxic, polar and dimensionally stable (< 400 °C) amorphous form of SiO2. It is prepared by the reaction between sodium silicate and sulfuric acid, which is followed by a series of after-treatment processes such as aging, pickling, etc. These after treatment methods results in various pore size distributions.
Silica is used for drying of process air (e.g. oxygen, natural gas) and adsorption of heavy (polar) hydrocarbons from natural gas.
## Zeolites
Zeolites are natural or synthetic crystalline aluminosilicates which have a repeating pore network and release water at high temperature. Zeolites are polar in nature.
They are manufactured by hydrothermal synthesis of sodium aluminosilicate or another silica source in an autoclave followed by ion exchange with certain cations (Na+, Li+, Ca2+, K+, NH4+). The channel diameter of zeolite cages usually ranges from 2 to 9 Å (200 to 900 pm). The ion exchange process is followed by drying of the crystals, which can be pelletized with a binder to form macroporous pellets.
Zeolites are applied in drying of process air, CO2 removal from natural gas, CO removal from reforming gas, air separation, catalytic cracking, and catalytic synthesis and reforming.
Non-polar (siliceous) zeolites are synthesized from aluminum-free silica sources or by dealumination of aluminum-containing zeolites. The dealumination process is done by treating the zeolite with steam at elevated temperatures, typically greater than 500 °C (1000 °F). This high temperature heat treatment breaks the aluminum-oxygen bonds and the aluminum atom is expelled from the zeolite framework.
## Activated carbon
Activated carbon is a highly porous, amorphous solid consisting of microcrystallites with a graphite lattice, usually prepared in small pellets or a powder. It is non-polar and cheap. One of its main drawbacks is that it is combustible.
Activated carbon can be manufactured from carbonaceous material, including coal (bituminous, subbituminous, and lignite), peat, wood, or nutshells (i.e., coconut). The manufacturing process consists of two phases, carbonization and activation. The carbonization process includes drying and then heating to separate by-products, including tars and other hydrocarbons, from the raw material, as well as to drive off any gases generated. The carbonization process is completed by heating the material at 400–600 °C in an oxygen-deficient atmosphere that cannot support combustion.
The carbonized particles are “activated” by exposing them to an oxidizing agent, usually steam or carbon dioxide at high temperature. This agent burns off the pore blocking structures created during the carbonization phase and so, they develop a porous, three-dimensional graphite lattice structure. The size of the pores developed during activation is a function of the time that they treated in this stage. Longer exposure times result in larger pore sizes. The most popular aqueous phase carbons are bituminous based because of their hardness, abrasion resistance, pore size distribution, and low cost, but their effectiveness needs to be tested in each application to determine the optimal product.
Activated carbon is used for adsorption of organic substances and non-polar adsorbates and it is also usually used for waste gas (and waste water) treatment. It is the most widely used adsorbent. Its usefulness derives mainly from its large micropore and mesopore volumes and the resulting high surface area.
# Portal site mediated adsorption
Portal site mediated adsorption is a model for site-selective activated gas adsorption in metallic catalytic systems which contain a variety of different adsorption sites. In such systems, low-coordination "edge and corner" defect-like sites can exhibit significantly lower adsorption enthalpies than high-coordination (basal plane) sites. As a result, these sites can serve as "portals" for very rapid adsorption to the rest of the surface. The phenomena relies on the common "spillover" effect, where certain adsorbed species exhibit high mobility on some surfaces. The model explains seemingly inconsistent observations of gas adsorption thermodynamics and kinetics in catalytic systems where surfaces can exist in a range of coordination structures, and it has been successfully applied to bimetallic catalytic systems where synergistic activity is observed.
The original model was developed by King and co-workers (Narayan et al. 1998 and VanderWiel et al. 1999) to describe hydrogen adsorption on silica-supported silver-ruthenium and copper-ruthenium bimetallic catalysts. The same group applied the model to CO hydrogenation (Fischer-Tropsch synthesis). Zupanc et al. (2002) subsequently confirmed the same model on magnesia-supported cesium-ruthenium bimetallic catalysts.
# Adsorption in viruses
Adsorption is the first step in the viral infection cycle. The next steps are penetration, uncoating, synthesis (transcription if needed, and translation), and release. The virus replication cycle is similar, if not the same, for all types of viruses. Factors such as transcription may or may not be needed if the virus is able to integrate its genomic information in the cell's nucleus, or if the virus can replicate itself directly within the cell's cytoplasm. | Adsorption
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Adsorption is a process that occurs when a gas or liquid solute accumulates on the surface of a solid or a liquid (adsorbent), forming a film of molecules or atoms (the adsorbate). It is different from absorption, in which a substance diffuses into a liquid or solid to form a solution. The term sorption encompasses both processes, while desorption is the reverse process.
Adsorption is present in many natural physical, biological, and chemical systems, and is widely used in industrial applications such as activated charcoal, synthetic resins, and water purification. Adsorption, ion exchange, and chromatography are sorption processes in which certain adsorbates are selectively transferred from the fluid phase to the surface of insoluble, rigid particles suspended in a vessel or packed in a column.
Similar to surface tension, adsorption is a consequence of surface energy. In a bulk material, all the bonding requirements (be they ionic, covalent, or metallic) of the constituent atoms of the material are filled by other atoms in the material. However, atoms on the surface of the adsorbent are not wholly surrounded by other adsorbent atoms and therefore can attract adsorbates. The exact nature of the bonding depends on the details of the species involved, but the adsorption process is generally classified as physisorption (characteristic of weak van der Waals forces) or chemisorption (characteristic of covalent bonding).
# Isotherms
Adsorption is usually described through isotherms, that is, the amount of adsorbate on the adsorbent as a function of its pressure (if gas) or concentration (if liquid) at constant temperature. The quantity adsorbed is nearly always normalized by the mass of the adsorbent to allow comparison of different materials.
The first mathematical fit to an isotherm was published by Freundlich and Küster (1894) and is a purely empirical formula for gaseous adsorbates,
where <math>x</math> is the quantity adsorbed, <math>m</math> is the mass of the adsorbent, <math>P</math> is the pressure of adsorbate and <math>k</math> and <math>n</math> are empirical constants for each adsorbent-adsorbate pair at a given temperature. The function has an asymptotic maximum as pressure increases without bound. As the temperature increases, the constants <math>k</math> and <math>n</math> change to reflect the empirical observation that the quantity adsorbed rises more slowly and higher pressures are required to saturate the surface.
## Langmuir
In 1916, Irving Langmuir published a new model isotherm for gases adsorbed on solids, which retained his name. It is a semi-empirical isotherm derived from a proposed kinetic mechanism. It is based on four assumptions:
- The surface of the adsorbent is uniform, that is, all the adsorption sites are equivalent.
- Adsorbed molecules do not interact.
- All adsorption occurs through the same mechanism.
- At the maximum adsorption, only a monolayer is formed: molecules of adsorbate do not deposit on other, already adsorbed, molecules of adsorbate, only on the free surface of the adsorbent.
These four assumptions are seldom all true: there are always imperfections on the surface, adsorbed molecules are not necessarily inert, and the mechanism is clearly not the same for the very first molecules to adsorb as for the last. The fourth condition is the most troublesome, as frequently more molecules will adsorb on the monolayer; this problem is addressed by the BET isotherm for relatively flat (non-microporous) surfaces. The Langmuir isotherm is nonetheless the first choice for most models of adsorption, and has many applications in surface kinetics (usually called Langmuir-Hinshelwood kinetics) and thermodynamics.
Langmuir suggested that adsorption takes place through this mechanism:
A(g) + S Template:Unicode AS, where A is a gas molecule and S is an adsorption site.
The direct and inverse rate constants are k and k-1. If we define surface coverage, <math>\theta</math>, as the fraction of the adsorption sites occupied, in the equilibrium we have
Where <math>P</math> is the partial pressure (gas) or the molar concentration of the solution (liquid)
For very low pressures <math>\theta\approx KP</math> and for high pressures <math>\theta\approx1</math>
<math>\theta</math> is difficult to measure experimentally; usually, the adsorbate is a gas and the quantity adsorbed is given in moles, grams, or gas volumes at standard temperature and pressure (STP) per gram of adsorbent. If we call vmon the STP volume of adsorbate required to form a monolayer on the adsorbent (per gram of adsorbent), <math>\theta = \frac{v}{v_\mathrm{mon}}</math> and we obtain an expression for a straight line:
Through its slope and y-intercept we can obtain vmon and K, which are constants for each adsorbent/adsorbate pair at a given temperature. vmon is related to the number of adsorption sites through the ideal gas law. If we assume that the number of sites is just the whole area of the solid divided into the cross section of the adsorbate molecules, we can easily calculate the surface area of the adsorbent.
The surface area of an adsorbent depends on its structure; the more pores it has, the greater the area, which has a big influence on reactions on surfaces.
If more than one gas adsorbs on the surface, we define <math>\theta_E</math> as the fraction of empty sites and we have
and
where i is each one of the gases that adsorb.
## BET
Often molecules do form multilayers, that is, some are adsorbed on already adsorbed molecules and the Langmuir isotherm is not valid. In 1938 Stephan Brunauer, Paul Emmett, and Edward Teller developed a model isotherm that takes that possibility into account. Their theory is called BET Theory, after the initials in their last names. They modified Langmuir's mechanism as follows:
The derivation of the formula is more complicated than Langmuir's (see links for complete derivation). We obtain:
x is the pressure divided by the vapor pressure for the adsorbate at that temperature (usually denoted <math>P/P^0</math>), v is the STP volume of adsorbed adsorbate, vmon is the STP volume of the amount of adsorbate required to form a monolayer and c is the equilibrium constant K we used in Langmuir isotherm multiplied by the vapor pressure of the adsorbate. The key assumption used in deriving the BET equation that the successive heats of adsorption for all layers except the first are equal to the heat of condensation of the adsorbate.
The Langmuir isotherm is usually better for chemisorption and the BET isotherm works better for physisorption for non-microporous surfaces.
## Adsorption enthalpy
Adsorption constants are equilibrium constants, therefore they obey van 't Hoff's equation:
As can be seen in the formula, the variation of K must be isosteric, that is, at constant coverage.
If we start from the BET isotherm and assume that the entropy change is the same for liquefaction and adsorption we obtain
<math>\Delta H_\mathrm{ads}=\Delta H_\mathrm{liq}-RT\ln c</math>, that is to say, adsorption is more exothermic than liquefaction.
# Adsorbents
## Characteristics and general requirements
Adsorbents are used usually in the form of spherical pellets, rods, moldings, or monoliths with hydrodynamic diameters between 0.5 and 10 mm.
They must have high abrasion resistance, high thermal stability and small pore diameters, which results in higher exposed surface area and hence high surface capacity for adsorption.
The adsorbents must also have a distinct pore structure which enables fast transport of the gaseous vapors.
Most industrial adsorbents fall into one of three classes:
- Oxygen-containing compounds – Are typically hydrophilic and polar, including materials such as silica gel and zeolites.
- Carbon-based compounds – Are typically hydrophobic and non-polar, including materials such as activated carbon and graphite.
- Polymer-based compounds - Are polar or non-polar functional groups in a porous polymer matrix.
## Silica gel
Silica gel is a chemically inert, nontoxic, polar and dimensionally stable (< 400 °C) amorphous form of SiO2. It is prepared by the reaction between sodium silicate and sulfuric acid, which is followed by a series of after-treatment processes such as aging, pickling, etc. These after treatment methods results in various pore size distributions.
Silica is used for drying of process air (e.g. oxygen, natural gas) and adsorption of heavy (polar) hydrocarbons from natural gas.
## Zeolites
Zeolites are natural or synthetic crystalline aluminosilicates which have a repeating pore network and release water at high temperature. Zeolites are polar in nature.
They are manufactured by hydrothermal synthesis of sodium aluminosilicate or another silica source in an autoclave followed by ion exchange with certain cations (Na+, Li+, Ca2+, K+, NH4+). The channel diameter of zeolite cages usually ranges from 2 to 9 Å (200 to 900 pm). The ion exchange process is followed by drying of the crystals, which can be pelletized with a binder to form macroporous pellets.
Zeolites are applied in drying of process air, CO2 removal from natural gas, CO removal from reforming gas, air separation, catalytic cracking, and catalytic synthesis and reforming.
Non-polar (siliceous) zeolites are synthesized from aluminum-free silica sources or by dealumination of aluminum-containing zeolites. The dealumination process is done by treating the zeolite with steam at elevated temperatures, typically greater than 500 °C (1000 °F). This high temperature heat treatment breaks the aluminum-oxygen bonds and the aluminum atom is expelled from the zeolite framework.
## Activated carbon
Activated carbon is a highly porous, amorphous solid consisting of microcrystallites with a graphite lattice, usually prepared in small pellets or a powder. It is non-polar and cheap. One of its main drawbacks is that it is combustible.
Activated carbon can be manufactured from carbonaceous material, including coal (bituminous, subbituminous, and lignite), peat, wood, or nutshells (i.e., coconut). The manufacturing process consists of two phases, carbonization and activation. The carbonization process includes drying and then heating to separate by-products, including tars and other hydrocarbons, from the raw material, as well as to drive off any gases generated. The carbonization process is completed by heating the material at 400–600 °C in an oxygen-deficient atmosphere that cannot support combustion.
The carbonized particles are “activated” by exposing them to an oxidizing agent, usually steam or carbon dioxide at high temperature. This agent burns off the pore blocking structures created during the carbonization phase and so, they develop a porous, three-dimensional graphite lattice structure. The size of the pores developed during activation is a function of the time that they treated in this stage. Longer exposure times result in larger pore sizes. The most popular aqueous phase carbons are bituminous based because of their hardness, abrasion resistance, pore size distribution, and low cost, but their effectiveness needs to be tested in each application to determine the optimal product.
Activated carbon is used for adsorption of organic substances and non-polar adsorbates and it is also usually used for waste gas (and waste water) treatment. It is the most widely used adsorbent. Its usefulness derives mainly from its large micropore and mesopore volumes and the resulting high surface area.
# Portal site mediated adsorption
Portal site mediated adsorption is a model for site-selective activated gas adsorption in metallic catalytic systems which contain a variety of different adsorption sites. In such systems, low-coordination "edge and corner" defect-like sites can exhibit significantly lower adsorption enthalpies than high-coordination (basal plane) sites. As a result, these sites can serve as "portals" for very rapid adsorption to the rest of the surface. The phenomena relies on the common "spillover" effect, where certain adsorbed species exhibit high mobility on some surfaces. The model explains seemingly inconsistent observations of gas adsorption thermodynamics and kinetics in catalytic systems where surfaces can exist in a range of coordination structures, and it has been successfully applied to bimetallic catalytic systems where synergistic activity is observed.
The original model was developed by King and co-workers (Narayan et al. 1998 and VanderWiel et al. 1999) to describe hydrogen adsorption on silica-supported silver-ruthenium and copper-ruthenium bimetallic catalysts. The same group applied the model to CO hydrogenation (Fischer-Tropsch synthesis). Zupanc et al. (2002) subsequently confirmed the same model on magnesia-supported cesium-ruthenium bimetallic catalysts.
# Adsorption in viruses
Adsorption is the first step in the viral infection cycle. The next steps are penetration, uncoating, synthesis (transcription if needed, and translation), and release. The virus replication cycle is similar, if not the same, for all types of viruses. Factors such as transcription may or may not be needed if the virus is able to integrate its genomic information in the cell's nucleus, or if the virus can replicate itself directly within the cell's cytoplasm. | https://www.wikidoc.org/index.php/Adsorb | |
c383203d69fec97ec2d33a402c153d8cb8931314 | wikidoc | Hemoglobin | Hemoglobin
# Overview
Hemoglobin, also spelled haemoglobin and abbreviated Hb, is the iron-containing oxygen-transport metalloprotein in the red blood cells of the blood in vertebrates and other animals. In mammals the protein makes up about 97% of the red cell’s dry content, and around 35% of the total content (including water). Hemoglobin transports oxygen from the lungs or gills to the rest of the body, such as to the muscles, where it releases its load of oxygen. Hemoglobin also has a variety of other gas-transport and effect-modulation duties, which vary from species to species, and may be quite diverse in invertebrates.
The name hemoglobin is the concatenation of heme and globin, reflecting the fact that each subunit of hemoglobin is a globular protein with an embedded heme (or haem) group; each heme group contains an iron atom, and this is responsible for the binding of oxygen through ion-induced dipole forces. The most common type of hemoglobin in mammals contains four such subunits, each with one heme group. In humans, each heme group is able to bind one oxygen molecule, and thus, one hemoglobin molecule can bind four oxygen molecules.
Mutations in the genes for the hemoglobin protein in humans result in a group of hereditary diseases termed the hemoglobinopathies, the best known of which is sickle-cell disease. Historically in human medicine, sickle-cell disease was the first disease to be understood in its mechanism of dysfunction, completely down to the molecular level. However, not all such globin-gene mutations result in illness. These mutations are formally recognized as hemoglobin variants rather than diseases. A (mostly) separate set of diseases involves underproduction of normal and sometimes abnormal hemoglobins, through problems and mutations in globin gene regulation. These diseases, which also often produce anemia, are called thalassemias.
Hemoglobin (Hb) is synthesized in a complex series of steps. The heme portion is synthesized in a series of steps which occur in the mitochondria and the cytosol of the immature red blood cell, while the globin protein portions of the molecule are synthesized by ribosomes in the cytosol. Production of Hb continues in the cell throughout its early development from the proerythroblast to the reticulocyte in the bone marrow. At this point, the nucleus is lost in mammalian red blood cells, but not in birds and many other species. Even after the loss of the nucleus in mammals, residual ribosomal RNA allows further synthesis of Hb until the reticulocyte loses its RNA soon after entering the vasculature (this hemoglobin-synthetic RNA in fact gives the reticulocyte its reticulated appearance and name).
The chemical empirical formula of the most common human hemoglobin is C738H1166N812O203S2Fe, but as noted above, hemoglobins vary widely across species, and even (through common mutations) slightly among subgroups of humans.
# Structure
In most humans, the hemoglobin molecule is an assembly of four globular protein subunits. Each subunit is composed of a protein chain tightly associated with a non-protein heme group. Each protein chain arranges into a set of alpha-helix structural segments connected together in a globin fold arrangement, so called because this arrangement is the same folding motif used in other heme/globin proteins such as myoglobin. This folding pattern contains a pocket which strongly binds the heme group.
A heme group consists of an iron (Fe) ion (charged atom) held in a heterocyclic ring, known as a porphyrin. The iron ion, which is the site of oxygen binding, bonds with the four nitrogens in the center of the ring, which all lie in one plane. The iron is also bound strongly to the globular protein via the imidazole ring of the F8 histidine residue below the porphyrin ring. A sixth position can reversibly bind oxygen, completing the octahedral group of six ligands. Oxygen binds in an "end-on bent" geometry where one oxygen atom binds Fe and the other protrudes at an angle. When oxygen is not bound, a very weakly bonded water molecule fills the site, forming a distorted octahedron.
The iron ion may either be in the Fe2+ or Fe3+ state, but ferrihemoglobin (methemoglobin) (Fe3+) cannot bind oxygen. In binding, oxygen temporarily oxidizes Fe to (Fe3+), so iron must exist in the +2 oxidation state in order to bind oxygen. The enzyme methemoglobin reductase reactivates hemoglobin found in the inactive (Fe3+) state by reducing the iron center.
In adult humans, the most common hemoglobin type is a tetramer (which contains 4 subunit proteins) called hemoglobin A, consisting of two α and two β subunits non-covalently bound, each made of 141 and 146 amino acid residues, respectively. This is denoted as α2β2. The subunits are structurally similar and about the same size. Each subunit has a molecular weight of about 17,000 daltons, for a total molecular weight of the tetramer of about 68,000 daltons. Hemoglobin A is the most intensively studied of the hemoglobin molecules.
The four polypeptide chains are bound to each other by salt bridges, hydrogen bonds, and hydrophobic interactions. There are two kinds of contacts between the α and β chains: α1β1 and α1β2.
Oxyhemoglobin is formed during respiration when oxygen binds to the heme component of the protein hemoglobin in red blood cells. This process occurs in the pulmonary capillaries adjacent to the alveoli of the lungs. The oxygen then travels through the blood stream to be dropped off at cells where it is utilized in aerobic glycolysis and in the production of ATP by the process of oxidative phosphorylation. It does not, however, help to counteract a decrease in blood pH. Ventilation, or breathing, may reverse this condition by removal of carbon dioxide, thus causing a shift up in pH.
Deoxyhemoglobin is the form of hemoglobin without the bound oxygen. The absorption spectra of oxyhemoglobin and deoxyhemoglobin differ. The oxyhemoglobin has significantly lower absorption of the 660 nm wavelength than deoxyhemoglobin, while at 940 nm its absorption is slightly higher. This difference is used for measurement of the amount of oxygen in patient's blood by an instrument called pulse oximeter.
# Iron's oxidation state in oxyhemoglobin
Assigning oxygenated hemoglobin's oxidation state is difficult because oxyhemoglobin is diamagnetic (no net unpaired electrons), but the low-energy electron configurations in both oxygen and iron are paramagnetic. Triplet oxygen, the lowest energy oxygen species, has two unpaired electrons in antibonding π- molecular orbitals. Iron(II) tends to be in a high-spin configuration where unpaired electrons exist in Eg antibonding orbitals. Iron(III) has an odd number of electrons and thus has unpaired electrons. All of these molecules are paramagnetic (have unpaired electrons), not diamagnetic, so an unintuitive distribution of electrons must exist to induce diamagnetism.
The three logical possibilities are:
- Low-spin Fe2+ binds to high-energy singlet oxygen. Both low-spin iron and singlet oxygen are diamagnetic.
- Low-spin Fe3+ binds to .O2- (the superoxide ion) and the two unpaired electrons couple antiferromagnetically, giving diamagnetic properties.
- Low-spin Fe4+ binds to O22-. Both are diamagnetic.
X-ray photoelectron spectroscopy suggests iron has an oxidation state of approximately 3.2 and infrared stretching frequencies of the O-O bond suggests a bond length fitting with superoxide. The correct oxidation state of iron is thus the +3 state with oxygen in the -1 state. The diamagnetism in this configuration arises from the unpaired electron on superoxide aligning antiferromagnetically in the opposite direction from the unpaired electron on iron. The second choice being correct is not surprising because singlet oxygen and large separations of charge are both unfavorably high-energy states. Iron's shift to a higher oxidation state decreases the atom's size and allows it into the plane of the porphyrin ring, pulling on the coordinated histidine residue and initiating the allosteric changes seen in the globulins. The assignment of oxidation state, however, is only a formalism so all three models may contribute to some small degree.
Early postulates by bioinorganic chemists claimed that possibility (1) (above) was correct and that iron should exist in oxidation state II (indeed iron oxidation state III as methemoglobin, when not accompanied by superoxide .O2- to "hold" the oxidation electron, is incapable of binding O2). The iron chemistry in this model was elegant, but the presence of singlet oxygen was never explained. It was argued that the binding of an oxygen molecule placed high-spin iron(II) in an octahedral field of strong-field ligands; this change in field would increase the crystal field splitting energy, causing iron's electrons to pair into the diamagnetic low-spin configuration.
# Binding of ligands
As illustrated above, when oxygen binds to the iron center, it causes contraction of the iron atom, and causes it to move back into the center of the porphyrin ring plane (see moving diagram). At the same time, the porphyrin ring plane itself is pushed away from the oxygen and toward the imidizole side chain of the histidine residue interacting at the other pole of the iron. The interaction here forces the ring plane sideways toward the outside of the tetramer, and also induces a strain on the protein helix containing the histidine as it moves nearer to the iron. This causes a tug on the peptide strand which tends to open up heme units in the remainder of the molecule, so that there is more room for oxygen molecules to bind at their heme sites.
In the tetrameric form of normal adult hemoglobin, the binding of oxygen is thus a cooperative process. The binding affinity of hemoglobin for oxygen is increased by the oxygen saturation of the molecule, with the first oxygens bound influencing the shape of the binding sites for the next oxygens, in a way favorable for binding. This positive cooperative binding is achieved through steric conformational changes of the hemoglobin protein complex as discussed above, i.e. when one subunit protein in hemoglobin becomes oxygenated, this induces a conformational or structural change in the whole complex, causing the other subunits to gain an increased affinity for oxygen. As a consequence, the oxygen binding curve of hemoglobin is sigmoidal, or S-shaped, as opposed to the normal hyperbolic curve associated with noncooperative binding.
Hemoglobin's oxygen-binding capacity is decreased in the presence of carbon monoxide because both gases compete for the same binding sites on hemoglobin, carbon monoxide binding preferentially in place of oxygen. Carbon dioxide occupies a different binding site on the hemoglobin. Carbon dioxide is more readily dissolved in deoxygenated blood, facilitating its removal from the body after the oxygen has been released to tissues undergoing metabolism. This increased affinity for carbon dioxide by the venous blood is known as the Haldane effect. Through the enzyme carbonic anhydrase, carbon dioxide reacts with water to give carbonic acid, which decomposes into bicarbonate and protons:
Hence blood with high carbon dioxide levels is also lower in pH (more acidic). Hemoglobin can bind protons and carbon dioxide which causes a conformational change in the protein and facilitates the release of oxygen. Protons bind at various places along the protein, and carbon dioxide binds at the alpha-amino group forming carbamate. Conversely, when the carbon dioxide levels in the blood decrease (i.e., in the lung capillaries), carbon dioxide and protons are released from hemoglobin, increasing the oxygen affinity of the protein. This control of hemoglobin's affinity for oxygen by the binding and release of carbon dioxide and acid, is known as the Bohr effect.
The binding of oxygen is affected by molecules such as carbon monoxide (CO) (for example from tobacco smoking, cars and furnaces). CO competes with oxygen at the heme binding site. Hemoglobin binding affinity for CO is 200 times greater than its affinity for oxygen, meaning that small amounts of CO dramatically reduce hemoglobin's ability to transport oxygen. When hemoglobin combines with CO, it forms a very bright red compound called carboxyhemoglobin. When inspired air contains CO levels as low as 0.02%, headache and nausea occur; if the CO concentration is increased to 0.1%, unconsciousness will follow. In heavy smokers, up to 20% of the oxygen-active sites can be blocked by CO.
In similar fashion, hemoglobin also has competitive binding affinity for cyanide (CN-), sulfur monoxide (SO), nitrogen dioxide (NO2), and sulfide (S2-), including hydrogen sulfide (H2S). All of these bind to iron in heme without changing its oxidation state, but they nevertheless inhibit oxygen-binding, causing grave toxicity.
The iron atom in the heme group must be in the ferrous (Fe2+) oxidation state to support oxygen and other gases' binding and transport. Oxidation to the ferric (Fe3+) state converts hemoglobin into hemiglobin or methaemoglobin (pronounced "MET-hemoglobin"), which cannot bind oxygen. Hemoglobin in normal red blood cells is protected by a reduction system to keep this from happening. Nitrogen dioxide and nitrous oxide are capable of converting a small fraction of hemoglobin to methemoglobin, however this is not usually of medical importance (nitrogen dioxide is poisonous by other mechanisms, and nitrous oxide is routinely used in surgical anesthesia in most people without undue methemoglobin buildup).
In people acclimated to high altitudes, the concentration of 2,3-Bisphosphoglycerate (2,3-BPG) in the blood is increased, which allows these individuals to deliver a larger amount of oxygen to tissues under conditions of lower oxygen tension. This phenomenon, where molecule Y affects the binding of molecule X to a transport molecule Z, is called a heterotropic allosteric effect.
A variant hemoglobin, called fetal hemoglobin (HbF, α2γ2), is found in the developing fetus, and binds oxygen with greater affinity than adult hemoglobin. This means that the oxygen binding curve for fetal hemoglobin is left-shifted (i.e., a higher percentage of hemoglobin has oxygen bound to it at lower oxygen tension), in comparison to that of adult hemoglobin. As a result, fetal blood in the placenta is able to take oxygen from maternal blood.
Hemoglobin also carries nitric oxide in the globin part of the molecule. This improves oxygen delivery in the periphery and contributes to the control of respiration. NO binds reversibly to a specific cysteine residue in globin; the binding depends on the state (R or T) of the hemoglobin. The resulting S-nitrosylated hemoglobin influences various NO-related activities such as the control of vascular resistance, blood pressure and respiration. NO is released not in the cytoplasm of erythrocytes but is transported by an anion exchanger called AE1 out of them.
# Types of hemoglobins in humans
Hemoglobin variants are a part of the normal embryonic and fetal development, but may also be pathologic mutant forms of hemoglobin in a population (usually of humans), caused by variations in genetics. Some well-known hemoglobin such variants such as sickle-cell anemia are responsible for diseases, and are considered hemoglobinopathies. Other variants cause no detectable pathology, and are thus considered non-pathological variants.
In the embryo:
- Gower 1 (ζ2ε2)
- Gower 2 (α2ε2) (PDB: 1A9W)
- Hemoglobin Portland (ζ2γ2)
In the foetus:
- Hemoglobin F (α2γ2) (PDB: 1FDH)
In adults:
- Hemoglobin A (α2β2) (PDB: 1BZ0) - The most common with a normal amount over 95%
- Hemoglobin A2 (α2δ2) - δ chain synthesis begins late in the third trimester and in adults, it has a normal range of 1.5-3.5%
- Hemoglobin F (α2γ2) - In adults Hemoglobin F is restricted to a limited population of red cells called F-cells. However, the level of Hb F can be elevated in persons with sickle-cell disease.
Variant forms which cause disease:
- Hemoglobin S (α2βS2) - A variant form of hemoglobin found in people with sickle cell disease. There is a variation in the β-chain gene, causing a change in the properties of hemoblobin which results in sickling of red blood cells.
- Hemoglobin C (α2βC2) - Another variant due to a variation in the β-chain gene. This variant causes a mild chronic hemolytic anemia.
# Degradation of hemoglobin in vertebrate animals
When red cells reach the end of their life due to aging or defects, they are broken down, the hemoglobin molecule is broken up and the iron gets recycled. When the porphyrin ring
is broken up, the fragments are normally secreted in the bile by the liver. This process also produces one molecule of carbon monoxide for every molecule of heme degraded ; this is one of the few natural sources of carbon monoxide production in the human body, and is responsible for the normal blood levels of carbon monoxide even in people breathing pure air. The other major final product of heme degradation is bilirubin. Increased levels of this chemical are detected in the blood if red cells are being destroyed more rapidly than usual. Improperly degraded hemoglobin protein or hemoglobin that has been released from the blood cells too rapidly can clog small blood vessels, especially the delicate blood filtering vessels of the kidneys, causing kidney damage.
# Role in disease
Decrease of hemoglobin, with or without an absolute decrease of red blood cells, leads to symptoms of anemia. Anemia has many different causes, although iron deficiency and its resultant iron deficiency anemia are the most common causes in the Western world. As absence of iron decreases heme synthesis, red blood cells in iron deficiency anemia are hypochromic (lacking the red hemoglobin pigment) and microcytic (smaller than normal). Other anemias are rarer. In hemolysis (accelerated breakdown of red blood cells), associated jaundice is caused by the hemoglobin metabolite bilirubin, and the circulating hemoglobin can cause renal failure.
Some mutations in the globin chain are associated with the hemoglobinopathies, such as sickle-cell disease and thalassemia. Other mutations, as discussed at the beginning of the article, are benign and are referred to merely as hemoglobin variants.
There is a group of genetic disorders, known as the porphyrias that are characterized by errors in metabolic pathways of heme synthesis. King George III of the United Kingdom was probably the most famous porphyria sufferer.
To a small extent, hemoglobin A slowly combines with glucose at the terminal valine (an alpha aminoacid) of each β chain. The resulting molecule is often referred to as Hb A1c. As the concentration of glucose in the blood increases, the percentage of Hb A that turns into Hb A1c increases. In diabetics whose glucose usually runs high, the percent Hb A1c also runs high. Because of the slow rate of Hb A combination with glucose, the Hb A1c percentage is representative of glucose level in the blood averaged over a longer time (the half-life of red blood cells, which is typically 50-55 days).
# Diagnostic use
Hemoglobin levels are amongst the most commonly performed blood tests, usually as part of a full blood count or complete blood count. Results are reported in g/L, g/dL or mol/L. For conversion, 1 g/dL is 0.621 mmol/L. If the total hemoglobin concentration in the blood falls below a set point, this is called anemia.
Normal values for hemoglobin levels are:
- Women: 12.1 to 15.1 g/dl
- Men: 13.8 to 17.2 g/dl
- Children: 11 to 16 g/dl
- Pregnant women: 11 to 12 g/dl
Anemias are further subclassified by the size of the red blood cells, which are the cells which contain hemoglobin in vertebrates. They can be classified as microcytic (small sized red blood cells), normocytic (normal sized red blood cells), or macrocytic (large sized red blood cells). The hemoglobin is the typical test used for blood donation. A comparison with the hematocrit can be made by multiplying the hemoglobin by three. For example, if the hemoglobin is measured at 17, that compares with a hematocrit of .51.
Blood glucose levels can vary widely throughout a day, so one or only a few samples from a patient analyzed for glucose may not be representative of long-term control of glucose levels. For this reason a blood sample may be analyzed for Hb A1c level, which is more representative of glucose control averaged over a longer time period (determined by the half-life of the individual's red blood cells, which is typically 50-55 days). People whose Hb A1c runs 6.0% or less show good longer-term glucose control. Hb A1c values which are more than 7.0% are elevated. This test is especially useful for diabetics.
## In radiologic imaging: fMRI and its uses with hemoglobin
The FMRI machine may use the signal from oxyhemoglobin as it partially aligns these molecules with the magnetic field. The machine will then send a series of magnetic pulses at the participant's head or other body structure, slowly knocking the molecules out of alignment, and a radio wave is emitted when they come back into alignment. The fMRI machine can then pick up these signals and use them to make scans, which are cross-sectional maps showing blood flow.
# Hemoglobin in the biological range of life
Hemoglobin is by no means unique to vertebrates; there are a variety of oxygen transport and binding proteins throughout the animal (and plant) kingdom. Other organisms including bacteria, protozoans and fungi all have hemoglobin-like proteins whose known and predicted roles include the reversible binding of gaseous ligands. Since many of these proteins contain globins, and also the heme moiety (iron in a flat porphyrin support), these substances are often simply referred to as hemoglobins, even if their overall tertiary structure is very different from that of vertebrate hemoglobin. In particular, the distinction of “myoglobin” and hemoglobin in lower animals is often impossible, because some of these organisms do not contain muscles. Or they may have a recognizable separate circulatory system, but not one which deals with oxygen transport (for example, many insects and other arthropods). In all these groups, heme/globin containing molecules (even monomeric globin ones) which deal with gas-binding are referred to as hemoglobins. In addition to dealing with transport and sensing of oxygen, these molecules may also deal with NO, CO2, sulfide compounds, and even O2 scavenging in environments which must be anaerobic. They may even deal with detoxification of chlorinated materials in a manner analogous to heme-containing P450 enzymes and peroxidases.
The structure of hemoglobins varies across species. Hemoglobin occurs in all kingdoms of organisms, but not in all organisms. Single-globin hemoglobins tend to be found in primitive species such as bacteria, protozoa, algae, and plants. Nematode worms, molluscs and crustaceans, however, many contain very large multisubunit molecules much larger than those in vertebrates. Particularly worth noting are chimeric hemoglobins found in fungi and giant annelids, which may contain both globin and other types of proteins. One of the most striking occurrences and uses of hemoglobin in organisms occurs in the (up to) 2.4 meter giant tube worm (Riftia pachyptila, also called Vestimentifera) which populates ocean volcanic vents at the sea floor. These worms have no digestive tract, but instead contain a population of bacteria constituting half the organism’s weight, which react H2S from the vent and O2 from the water to produce energy to make food from H2O and CO2. These organisms end with a deep red fan-like structure ("plume") which extends into the water and which absorbs H2S and O2 for the bacteria, and also absorbs CO2 for use as synthetic raw material (after the manner of photosynthetic plants). The bright red color of the structures results from several extraordinarily complex hemoglobins found in them which contain up to 144 globin chains (presumably each including associated heme structures). These tube worm hemoglobins are remarkable for being able to carry oxygen in the presence of sulfide, and indeed to also carry sulfide, without being completely "poisoned" or inhibited by this molecule, as hemoglobins in most other species are.
# Other oxygen-binding proteins
Myoglobin: Found in the muscle tissue of many vertebrates, including humans, it gives muscle tissue a distinct red or dark gray color. It is very similar to hemoglobin in structure and sequence, but is not a tetramer; instead, it is a monomer that lacks cooperative binding. It is used to store oxygen rather than transport it.
Hemocyanin: The second most common oxygen transporting protein found in nature, it is found in the blood of many arthropods and molluscs. Uses copper prosthetic groups instead of iron heme groups and is blue in color when oxygenated.
Hemerythrin: Some marine invertebrates and a few species of annelid use this iron containing non-heme protein to carry oxygen in their blood. Appears pink/violet when oxygenated, clear when not.
Chlorocruorin: Found in many annelids, it is very similar to erythrocruorin, but the heme group is significantly different in structure. Appears green when deoxygenated and red when oxygenated.
Vanabins: Also known as vanadium chromagens, they are found in the blood of sea squirts and are hypothesised to use the rare metal vanadium as its oxygen binding prosthetic group.
Erythrocruorin: Found in many annelids, including earthworms, it is a giant free-floating blood protein containing many dozens—possibly hundreds—of iron- and heme-bearing protein subunits bound together into a single protein complex with a molecular mass greater than 3.5 million daltons.
Pinnaglobin: Only seen in the mollusc Pinna squamosa. Brown manganese-based porphyrin protein.
Leghemoglobin: In leguminous plants, such as alfalfa or soybeans, the nitrogen fixing bacteria in the roots are protected from oxygen by this iron heme containing, oxygen binding protein.
# Hemoglobin in history and art
Historically, an association between the color of blood and rust occurs in the association of the planet Mars, with the Roman god of war, since the planet is an orange-red which reminded the ancients of blood. Although the color of the planet is due to iron compounds in combination with oxygen in the Martian soil, it is a common misconception that the iron in hemoglobin and its oxides gives blood its red color. The color is actually due to the porphyrin moiety of hemoglobin to which the iron is bound, not the iron itself, although the ligation and redox state of the iron can influence the pi to pi- electronic transitions of the porphyrin and hence its optical characteristics.
Artist Julian Voss-Andreae created a sculpture called "Heart of Steel (Hemoglobin)" in 2005 based on the protein's backbone. The sculpture was made from glass and weathering steel. The intentional rusting of the initially shiny work of art mirrors hemoglobin's fundamental chemical reaction of iron binding to oxygen. | Hemoglobin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [4]
# Overview
Hemoglobin, also spelled haemoglobin and abbreviated Hb, is the iron-containing oxygen-transport metalloprotein in the red blood cells of the blood in vertebrates and other animals. In mammals the protein makes up about 97% of the red cell’s dry content, and around 35% of the total content (including water). Hemoglobin transports oxygen from the lungs or gills to the rest of the body, such as to the muscles, where it releases its load of oxygen. Hemoglobin also has a variety of other gas-transport and effect-modulation duties, which vary from species to species, and may be quite diverse in invertebrates.
The name hemoglobin is the concatenation of heme and globin, reflecting the fact that each subunit of hemoglobin is a globular protein with an embedded heme (or haem) group; each heme group contains an iron atom, and this is responsible for the binding of oxygen through ion-induced dipole forces. The most common type of hemoglobin in mammals contains four such subunits, each with one heme group. In humans, each heme group is able to bind one oxygen molecule, and thus, one hemoglobin molecule can bind four oxygen molecules.
Mutations in the genes for the hemoglobin protein in humans result in a group of hereditary diseases termed the hemoglobinopathies, the best known of which is sickle-cell disease. Historically in human medicine, sickle-cell disease was the first disease to be understood in its mechanism of dysfunction, completely down to the molecular level. However, not all such globin-gene mutations result in illness. These mutations are formally recognized as hemoglobin variants rather than diseases.[1][2] A (mostly) separate set of diseases involves underproduction of normal and sometimes abnormal hemoglobins, through problems and mutations in globin gene regulation. These diseases, which also often produce anemia, are called thalassemias.[3]
Hemoglobin (Hb) is synthesized in a complex series of steps. The heme portion is synthesized in a series of steps which occur in the mitochondria and the cytosol of the immature red blood cell, while the globin protein portions of the molecule are synthesized by ribosomes in the cytosol.[4] Production of Hb continues in the cell throughout its early development from the proerythroblast to the reticulocyte in the bone marrow. At this point, the nucleus is lost in mammalian red blood cells, but not in birds and many other species. Even after the loss of the nucleus in mammals, residual ribosomal RNA allows further synthesis of Hb until the reticulocyte loses its RNA soon after entering the vasculature (this hemoglobin-synthetic RNA in fact gives the reticulocyte its reticulated appearance and name).
The chemical empirical formula of the most common human hemoglobin is C738H1166N812O203S2Fe, but as noted above, hemoglobins vary widely across species, and even (through common mutations) slightly among subgroups of humans.
# Structure
In most humans, the hemoglobin molecule is an assembly of four globular protein subunits. Each subunit is composed of a protein chain tightly associated with a non-protein heme group. Each protein chain arranges into a set of alpha-helix structural segments connected together in a globin fold arrangement, so called because this arrangement is the same folding motif used in other heme/globin proteins such as myoglobin.[5][6] This folding pattern contains a pocket which strongly binds the heme group.
A heme group consists of an iron (Fe) ion (charged atom) held in a heterocyclic ring, known as a porphyrin. The iron ion, which is the site of oxygen binding, bonds with the four nitrogens in the center of the ring, which all lie in one plane. The iron is also bound strongly to the globular protein via the imidazole ring of the F8 histidine residue below the porphyrin ring. A sixth position can reversibly bind oxygen, completing the octahedral group of six ligands. Oxygen binds in an "end-on bent" geometry where one oxygen atom binds Fe and the other protrudes at an angle. When oxygen is not bound, a very weakly bonded water molecule fills the site, forming a distorted octahedron.
The iron ion may either be in the Fe2+ or Fe3+ state, but ferrihemoglobin (methemoglobin) (Fe3+) cannot bind oxygen.[7] In binding, oxygen temporarily oxidizes Fe to (Fe3+), so iron must exist in the +2 oxidation state in order to bind oxygen. The enzyme methemoglobin reductase reactivates hemoglobin found in the inactive (Fe3+) state by reducing the iron center.
In adult humans, the most common hemoglobin type is a tetramer (which contains 4 subunit proteins) called hemoglobin A, consisting of two α and two β subunits non-covalently bound, each made of 141 and 146 amino acid residues, respectively. This is denoted as α2β2. The subunits are structurally similar and about the same size. Each subunit has a molecular weight of about 17,000 daltons, for a total molecular weight of the tetramer of about 68,000 daltons. Hemoglobin A is the most intensively studied of the hemoglobin molecules.
The four polypeptide chains are bound to each other by salt bridges, hydrogen bonds, and hydrophobic interactions. There are two kinds of contacts between the α and β chains: α1β1 and α1β2.
Oxyhemoglobin is formed during respiration when oxygen binds to the heme component of the protein hemoglobin in red blood cells. This process occurs in the pulmonary capillaries adjacent to the alveoli of the lungs. The oxygen then travels through the blood stream to be dropped off at cells where it is utilized in aerobic glycolysis and in the production of ATP by the process of oxidative phosphorylation. It does not, however, help to counteract a decrease in blood pH. Ventilation, or breathing, may reverse this condition by removal of carbon dioxide, thus causing a shift up in pH.[8]
Deoxyhemoglobin is the form of hemoglobin without the bound oxygen. The absorption spectra of oxyhemoglobin and deoxyhemoglobin differ. The oxyhemoglobin has significantly lower absorption of the 660 nm wavelength than deoxyhemoglobin, while at 940 nm its absorption is slightly higher. This difference is used for measurement of the amount of oxygen in patient's blood by an instrument called pulse oximeter.
# Iron's oxidation state in oxyhemoglobin
Assigning oxygenated hemoglobin's oxidation state is difficult because oxyhemoglobin is diamagnetic (no net unpaired electrons), but the low-energy electron configurations in both oxygen and iron are paramagnetic. Triplet oxygen, the lowest energy oxygen species, has two unpaired electrons in antibonding π* molecular orbitals. Iron(II) tends to be in a high-spin configuration where unpaired electrons exist in Eg antibonding orbitals. Iron(III) has an odd number of electrons and thus has unpaired electrons. All of these molecules are paramagnetic (have unpaired electrons), not diamagnetic, so an unintuitive distribution of electrons must exist to induce diamagnetism.
The three logical possibilities are:
- Low-spin Fe2+ binds to high-energy singlet oxygen. Both low-spin iron and singlet oxygen are diamagnetic.
- Low-spin Fe3+ binds to .O2- (the superoxide ion) and the two unpaired electrons couple antiferromagnetically, giving diamagnetic properties.
- Low-spin Fe4+ binds to O22-. Both are diamagnetic.
X-ray photoelectron spectroscopy suggests iron has an oxidation state of approximately 3.2 and infrared stretching frequencies of the O-O bond suggests a bond length fitting with superoxide. The correct oxidation state of iron is thus the +3 state with oxygen in the -1 state. The diamagnetism in this configuration arises from the unpaired electron on superoxide aligning antiferromagnetically in the opposite direction from the unpaired electron on iron. The second choice being correct is not surprising because singlet oxygen and large separations of charge are both unfavorably high-energy states. Iron's shift to a higher oxidation state decreases the atom's size and allows it into the plane of the porphyrin ring, pulling on the coordinated histidine residue and initiating the allosteric changes seen in the globulins. The assignment of oxidation state, however, is only a formalism so all three models may contribute to some small degree.
Early postulates by bioinorganic chemists claimed that possibility (1) (above) was correct and that iron should exist in oxidation state II (indeed iron oxidation state III as methemoglobin, when not accompanied by superoxide .O2- to "hold" the oxidation electron, is incapable of binding O2). The iron chemistry in this model was elegant, but the presence of singlet oxygen was never explained. It was argued that the binding of an oxygen molecule placed high-spin iron(II) in an octahedral field of strong-field ligands; this change in field would increase the crystal field splitting energy, causing iron's electrons to pair into the diamagnetic low-spin configuration.
# Binding of ligands
As illustrated above, when oxygen binds to the iron center, it causes contraction of the iron atom, and causes it to move back into the center of the porphyrin ring plane (see moving diagram). At the same time, the porphyrin ring plane itself is pushed away from the oxygen and toward the imidizole side chain of the histidine residue interacting at the other pole of the iron. The interaction here forces the ring plane sideways toward the outside of the tetramer, and also induces a strain on the protein helix containing the histidine as it moves nearer to the iron. This causes a tug on the peptide strand which tends to open up heme units in the remainder of the molecule, so that there is more room for oxygen molecules to bind at their heme sites.
In the tetrameric form of normal adult hemoglobin, the binding of oxygen is thus a cooperative process. The binding affinity of hemoglobin for oxygen is increased by the oxygen saturation of the molecule, with the first oxygens bound influencing the shape of the binding sites for the next oxygens, in a way favorable for binding. This positive cooperative binding is achieved through steric conformational changes of the hemoglobin protein complex as discussed above, i.e. when one subunit protein in hemoglobin becomes oxygenated, this induces a conformational or structural change in the whole complex, causing the other subunits to gain an increased affinity for oxygen. As a consequence, the oxygen binding curve of hemoglobin is sigmoidal, or S-shaped, as opposed to the normal hyperbolic curve associated with noncooperative binding.
Hemoglobin's oxygen-binding capacity is decreased in the presence of carbon monoxide because both gases compete for the same binding sites on hemoglobin, carbon monoxide binding preferentially in place of oxygen. Carbon dioxide occupies a different binding site on the hemoglobin. Carbon dioxide is more readily dissolved in deoxygenated blood, facilitating its removal from the body after the oxygen has been released to tissues undergoing metabolism. This increased affinity for carbon dioxide by the venous blood is known as the Haldane effect. Through the enzyme carbonic anhydrase, carbon dioxide reacts with water to give carbonic acid, which decomposes into bicarbonate and protons:
Hence blood with high carbon dioxide levels is also lower in pH (more acidic). Hemoglobin can bind protons and carbon dioxide which causes a conformational change in the protein and facilitates the release of oxygen. Protons bind at various places along the protein, and carbon dioxide binds at the alpha-amino group forming carbamate. Conversely, when the carbon dioxide levels in the blood decrease (i.e., in the lung capillaries), carbon dioxide and protons are released from hemoglobin, increasing the oxygen affinity of the protein. This control of hemoglobin's affinity for oxygen by the binding and release of carbon dioxide and acid, is known as the Bohr effect.
The binding of oxygen is affected by molecules such as carbon monoxide (CO) (for example from tobacco smoking, cars and furnaces). CO competes with oxygen at the heme binding site. Hemoglobin binding affinity for CO is 200 times greater than its affinity for oxygen, meaning that small amounts of CO dramatically reduce hemoglobin's ability to transport oxygen. When hemoglobin combines with CO, it forms a very bright red compound called carboxyhemoglobin. When inspired air contains CO levels as low as 0.02%, headache and nausea occur; if the CO concentration is increased to 0.1%, unconsciousness will follow. In heavy smokers, up to 20% of the oxygen-active sites can be blocked by CO.
In similar fashion, hemoglobin also has competitive binding affinity for cyanide (CN-), sulfur monoxide (SO), nitrogen dioxide (NO2), and sulfide (S2-), including hydrogen sulfide (H2S). All of these bind to iron in heme without changing its oxidation state, but they nevertheless inhibit oxygen-binding, causing grave toxicity.
The iron atom in the heme group must be in the ferrous (Fe2+) oxidation state to support oxygen and other gases' binding and transport. Oxidation to the ferric (Fe3+) state converts hemoglobin into hemiglobin or methaemoglobin (pronounced "MET-hemoglobin"), which cannot bind oxygen. Hemoglobin in normal red blood cells is protected by a reduction system to keep this from happening. Nitrogen dioxide and nitrous oxide are capable of converting a small fraction of hemoglobin to methemoglobin, however this is not usually of medical importance (nitrogen dioxide is poisonous by other mechanisms, and nitrous oxide is routinely used in surgical anesthesia in most people without undue methemoglobin buildup).
In people acclimated to high altitudes, the concentration of 2,3-Bisphosphoglycerate (2,3-BPG) in the blood is increased, which allows these individuals to deliver a larger amount of oxygen to tissues under conditions of lower oxygen tension. This phenomenon, where molecule Y affects the binding of molecule X to a transport molecule Z, is called a heterotropic allosteric effect.
A variant hemoglobin, called fetal hemoglobin (HbF, α2γ2), is found in the developing fetus, and binds oxygen with greater affinity than adult hemoglobin. This means that the oxygen binding curve for fetal hemoglobin is left-shifted (i.e., a higher percentage of hemoglobin has oxygen bound to it at lower oxygen tension), in comparison to that of adult hemoglobin. As a result, fetal blood in the placenta is able to take oxygen from maternal blood.
Hemoglobin also carries nitric oxide in the globin part of the molecule. This improves oxygen delivery in the periphery and contributes to the control of respiration. NO binds reversibly to a specific cysteine residue in globin; the binding depends on the state (R or T) of the hemoglobin. The resulting S-nitrosylated hemoglobin influences various NO-related activities such as the control of vascular resistance, blood pressure and respiration. NO is released not in the cytoplasm of erythrocytes but is transported by an anion exchanger called AE1 out of them.[9]
# Types of hemoglobins in humans
Hemoglobin variants are a part of the normal embryonic and fetal development, but may also be pathologic mutant forms of hemoglobin in a population (usually of humans), caused by variations in genetics. Some well-known hemoglobin such variants such as sickle-cell anemia are responsible for diseases, and are considered hemoglobinopathies. Other variants cause no detectable pathology, and are thus considered non-pathological variants.[10][11]
In the embryo:
- Gower 1 (ζ2ε2)
- Gower 2 (α2ε2) (PDB: 1A9W)
- Hemoglobin Portland (ζ2γ2)
In the foetus:
- Hemoglobin F (α2γ2) (PDB: 1FDH)
In adults:
- Hemoglobin A (α2β2) (PDB: 1BZ0) - The most common with a normal amount over 95%
- Hemoglobin A2 (α2δ2) - δ chain synthesis begins late in the third trimester and in adults, it has a normal range of 1.5-3.5%
- Hemoglobin F (α2γ2) - In adults Hemoglobin F is restricted to a limited population of red cells called F-cells. However, the level of Hb F can be elevated in persons with sickle-cell disease.
Variant forms which cause disease:
- Hemoglobin S (α2βS2) - A variant form of hemoglobin found in people with sickle cell disease. There is a variation in the β-chain gene, causing a change in the properties of hemoblobin which results in sickling of red blood cells.
- Hemoglobin C (α2βC2) - Another variant due to a variation in the β-chain gene. This variant causes a mild chronic hemolytic anemia.
# Degradation of hemoglobin in vertebrate animals
When red cells reach the end of their life due to aging or defects, they are broken down, the hemoglobin molecule is broken up and the iron gets recycled. When the porphyrin ring
is broken up, the fragments are normally secreted in the bile by the liver. This process also produces one molecule of carbon monoxide for every molecule of heme degraded [5]; this is one of the few natural sources of carbon monoxide production in the human body, and is responsible for the normal blood levels of carbon monoxide even in people breathing pure air. The other major final product of heme degradation is bilirubin. Increased levels of this chemical are detected in the blood if red cells are being destroyed more rapidly than usual. Improperly degraded hemoglobin protein or hemoglobin that has been released from the blood cells too rapidly can clog small blood vessels, especially the delicate blood filtering vessels of the kidneys, causing kidney damage.
# Role in disease
Decrease of hemoglobin, with or without an absolute decrease of red blood cells, leads to symptoms of anemia. Anemia has many different causes, although iron deficiency and its resultant iron deficiency anemia are the most common causes in the Western world. As absence of iron decreases heme synthesis, red blood cells in iron deficiency anemia are hypochromic (lacking the red hemoglobin pigment) and microcytic (smaller than normal). Other anemias are rarer. In hemolysis (accelerated breakdown of red blood cells), associated jaundice is caused by the hemoglobin metabolite bilirubin, and the circulating hemoglobin can cause renal failure.
Some mutations in the globin chain are associated with the hemoglobinopathies, such as sickle-cell disease and thalassemia. Other mutations, as discussed at the beginning of the article, are benign and are referred to merely as hemoglobin variants.
There is a group of genetic disorders, known as the porphyrias that are characterized by errors in metabolic pathways of heme synthesis. King George III of the United Kingdom was probably the most famous porphyria sufferer.
To a small extent, hemoglobin A slowly combines with glucose at the terminal valine (an alpha aminoacid) of each β chain. The resulting molecule is often referred to as Hb A1c. As the concentration of glucose in the blood increases, the percentage of Hb A that turns into Hb A1c increases. In diabetics whose glucose usually runs high, the percent Hb A1c also runs high. Because of the slow rate of Hb A combination with glucose, the Hb A1c percentage is representative of glucose level in the blood averaged over a longer time (the half-life of red blood cells, which is typically 50-55 days).
# Diagnostic use
Hemoglobin levels are amongst the most commonly performed blood tests, usually as part of a full blood count or complete blood count. Results are reported in g/L, g/dL or mol/L. For conversion, 1 g/dL is 0.621 mmol/L. If the total hemoglobin concentration in the blood falls below a set point, this is called anemia.
Normal values for hemoglobin levels are:
- Women: 12.1 to 15.1 g/dl
- Men: 13.8 to 17.2 g/dl
- Children: 11 to 16 g/dl
- Pregnant women: 11 to 12 g/dl [12]
Anemias are further subclassified by the size of the red blood cells, which are the cells which contain hemoglobin in vertebrates. They can be classified as microcytic (small sized red blood cells), normocytic (normal sized red blood cells), or macrocytic (large sized red blood cells). The hemoglobin is the typical test used for blood donation. A comparison with the hematocrit can be made by multiplying the hemoglobin by three. For example, if the hemoglobin is measured at 17, that compares with a hematocrit of .51.[13]
Blood glucose levels can vary widely throughout a day, so one or only a few samples from a patient analyzed for glucose may not be representative of long-term control of glucose levels. For this reason a blood sample may be analyzed for Hb A1c level, which is more representative of glucose control averaged over a longer time period (determined by the half-life of the individual's red blood cells, which is typically 50-55 days). People whose Hb A1c runs 6.0% or less show good longer-term glucose control. Hb A1c values which are more than 7.0% are elevated. This test is especially useful for diabetics.[14]
## In radiologic imaging: fMRI and its uses with hemoglobin
The FMRI machine may use the signal from oxyhemoglobin as it partially aligns these molecules with the magnetic field. The machine will then send a series of magnetic pulses at the participant's head or other body structure, slowly knocking the molecules out of alignment, and a radio wave is emitted when they come back into alignment. The fMRI machine can then pick up these signals and use them to make scans, which are cross-sectional maps showing blood flow.
# Hemoglobin in the biological range of life
Hemoglobin is by no means unique to vertebrates; there are a variety of oxygen transport and binding proteins throughout the animal (and plant) kingdom. Other organisms including bacteria, protozoans and fungi all have hemoglobin-like proteins whose known and predicted roles include the reversible binding of gaseous ligands. Since many of these proteins contain globins, and also the heme moiety (iron in a flat porphyrin support), these substances are often simply referred to as hemoglobins, even if their overall tertiary structure is very different from that of vertebrate hemoglobin. In particular, the distinction of “myoglobin” and hemoglobin in lower animals is often impossible, because some of these organisms do not contain muscles. Or they may have a recognizable separate circulatory system, but not one which deals with oxygen transport (for example, many insects and other arthropods). In all these groups, heme/globin containing molecules (even monomeric globin ones) which deal with gas-binding are referred to as hemoglobins. In addition to dealing with transport and sensing of oxygen, these molecules may also deal with NO, CO2, sulfide compounds, and even O2 scavenging in environments which must be anaerobic. They may even deal with detoxification of chlorinated materials in a manner analogous to heme-containing P450 enzymes and peroxidases.
The structure of hemoglobins varies across species. Hemoglobin occurs in all kingdoms of organisms, but not in all organisms. Single-globin hemoglobins tend to be found in primitive species such as bacteria, protozoa, algae, and plants. Nematode worms, molluscs and crustaceans, however, many contain very large multisubunit molecules much larger than those in vertebrates. Particularly worth noting are chimeric hemoglobins found in fungi and giant annelids, which may contain both globin and other types of proteins.[15] One of the most striking occurrences and uses of hemoglobin in organisms occurs in the (up to) 2.4 meter giant tube worm (Riftia pachyptila, also called Vestimentifera) which populates ocean volcanic vents at the sea floor. These worms have no digestive tract, but instead contain a population of bacteria constituting half the organism’s weight, which react H2S from the vent and O2 from the water to produce energy to make food from H2O and CO2. These organisms end with a deep red fan-like structure ("plume") which extends into the water and which absorbs H2S and O2 for the bacteria, and also absorbs CO2 for use as synthetic raw material (after the manner of photosynthetic plants). The bright red color of the structures results from several extraordinarily complex hemoglobins found in them which contain up to 144 globin chains (presumably each including associated heme structures). These tube worm hemoglobins are remarkable for being able to carry oxygen in the presence of sulfide, and indeed to also carry sulfide, without being completely "poisoned" or inhibited by this molecule, as hemoglobins in most other species are.[16][17]
# Other oxygen-binding proteins
Myoglobin: Found in the muscle tissue of many vertebrates, including humans, it gives muscle tissue a distinct red or dark gray color. It is very similar to hemoglobin in structure and sequence, but is not a tetramer; instead, it is a monomer that lacks cooperative binding. It is used to store oxygen rather than transport it.
Hemocyanin: The second most common oxygen transporting protein found in nature, it is found in the blood of many arthropods and molluscs. Uses copper prosthetic groups instead of iron heme groups and is blue in color when oxygenated.
Hemerythrin: Some marine invertebrates and a few species of annelid use this iron containing non-heme protein to carry oxygen in their blood. Appears pink/violet when oxygenated, clear when not.
Chlorocruorin: Found in many annelids, it is very similar to erythrocruorin, but the heme group is significantly different in structure. Appears green when deoxygenated and red when oxygenated.
Vanabins: Also known as vanadium chromagens, they are found in the blood of sea squirts and are hypothesised to use the rare metal vanadium as its oxygen binding prosthetic group.
Erythrocruorin: Found in many annelids, including earthworms, it is a giant free-floating blood protein containing many dozens—possibly hundreds—of iron- and heme-bearing protein subunits bound together into a single protein complex with a molecular mass greater than 3.5 million daltons.
Pinnaglobin: Only seen in the mollusc Pinna squamosa. Brown manganese-based porphyrin protein.
Leghemoglobin: In leguminous plants, such as alfalfa or soybeans, the nitrogen fixing bacteria in the roots are protected from oxygen by this iron heme containing, oxygen binding protein.
# Hemoglobin in history and art
Historically, an association between the color of blood and rust occurs in the association of the planet Mars, with the Roman god of war, since the planet is an orange-red which reminded the ancients of blood. Although the color of the planet is due to iron compounds in combination with oxygen in the Martian soil, it is a common misconception that the iron in hemoglobin and its oxides gives blood its red color. The color is actually due to the porphyrin moiety of hemoglobin to which the iron is bound, not the iron itself,[18] although the ligation and redox state of the iron can influence the pi to pi* electronic transitions of the porphyrin and hence its optical characteristics.
Artist Julian Voss-Andreae created a sculpture called "Heart of Steel (Hemoglobin)" in 2005 based on the protein's backbone. The sculpture was made from glass and weathering steel. The intentional rusting of the initially shiny work of art mirrors hemoglobin's fundamental chemical reaction of iron binding to oxygen.[19] | https://www.wikidoc.org/index.php/Adult_hemoglobin | |
8c05037e977f7446defe41428ee021dec1d82406 | wikidoc | Adulterant | Adulterant
Adulterants are chemical substances which should not be contained within other substances (eg. food, beverages, fuels or pesticides) for legal or other reasons. Adulterants may be intentionally added to substances to reduce manufacturing costs, or for some deceptive or malicious purpose. Adulterants may also be accidentally or unknowingly introduced into substances. The addition of adulterants is called adulteration.
# In food and beverages
Examples of adulteration include:
- Mogdad coffee, whose seeds have been used as an adulterant for coffee
- Roasted chicory roots were used for the same purpose, starting during the Napoleonic era in France (and still is a moderately popular additive there for cheaper coffee)
- Roasted ground peas, beans, or wheat used to adulterate roasted chicory
- Diethylene glycol, used by some winemakers to fake sweet wines
- Oleomargarine or lard, added to butter
- Rapeseed oil, commonly added to sunflower oil and soybean oil, brassicasterol being a marker of its presence
- Rye flour, corn meal or potato starch used to dilute more expensive flours; alum is also added to disguise usage of lower-quality flour
- Apple jellies were substituted for more expensive fruit jellies, with added colorant and sometimes even little pieces of wood that simulated strawberry seeds
- Artificial colorants, often toxic - eg. copper, zinc, or indigo-based green dyes added to absinthe
- Sudan I yellow color, added to chili powder
- Water, for diluting milk and beer and hard drinks
- Lower-quality black tea disguised as higher class
- Starch, added to sausages
- Cutting agents are often used to adulterate (or "cut") illicit drugs, for example shoe polish in solid cannabis
- Urea and other non-protein nitrogen sources added to protein products in order to inflate crude protein content measurements
- Powdered beechnut husk aromatized with cinnamic aldehyde may be marketed as powdered cinnamon.
- High fructose corn syrup can be used to adulterate honey.
# History
Historically, usage of adulterants has been common in free market societies with few legal controls on food quality and/or poor or nonexistent monitoring by authorities; sometimes this usage has even extended to exceedingly dangerous chemicals and poisons. In the United Kingdom during the Victorian era, adulterants were quite common; for example, cheeses were sometimes colored with lead. Similar adulteration issues were seen in industry in the United States until the passage of the Pure Food and Drug Act in 1906. More recently, adulterant use in the People's Republic of China has inspired much public attention. (See: Food safety in the People's Republic of China).
Adulterant usage was first investigated in 1820 by the German chemist Frederick Accum, who identified many toxic metal colourings in food and drink. His work antagonised food suppliers and he was discredited by a scandal over his alleged mutilation of Royal Institution library books. The physician Arthur Hill Hassall later conducted extensive studies in the early 1850s, which were published in The Lancet and led to the 1860 Food Adulteration Act and subsequent further legislation.
At the turn of the twentieth century, industrialization saw an uprise in adulteration and this inspired some protest. Accounts of adulteration led the New York Evening Post to parody:
Mary had a little lamb,
And when she saw it sicken,
She shipped it off to Packingtown,
And now its labeled chicken.
# In drug tests
Adulterants can be also added to urine, in order to interfere with the accuracy of drug tests. They are often oxidative in nature - hydrogen peroxide, and bleach have been used, sometimes with pH-adjusting substances like vinegar or sodium bicarbonate. These can be detected by drug testing labs, but some of the less expensive tests do not look for them.
# Notable incidents of adulteration
- In 1987, Beech-Nut paid $2.2 million in fines for violating the Federal Food, Drug, and Cosmetic Act by selling artificially flavored sugar water as apple juice.
- In 1997, ConAgra Foods pled guilty to federal criminal charges that one of its units illegally sprayed water on stored grain to increase its weight and value.
- In 2007, samples of wheat gluten mixed with melamine, presumably to produce artificially inflated results from common tests for protein content, were discovered in many U.S. pet food brands, as well as in the human food supply. This adulterated gluten was found to have come from China, and U.S. authorities concluded that its origin was the Xuzhou Anying Biologic Technology Development Company, a Xuzhou, China-based company. (See: Chinese protein export contamination.) | Adulterant
Adulterants are chemical substances which should not be contained within other substances (eg. food, beverages, fuels or pesticides) for legal or other reasons. Adulterants may be intentionally added to substances to reduce manufacturing costs, or for some deceptive or malicious purpose. Adulterants may also be accidentally or unknowingly introduced into substances. The addition of adulterants is called adulteration.
# In food and beverages
Examples of adulteration include:
- Mogdad coffee, whose seeds have been used as an adulterant for coffee
- Roasted chicory roots were used for the same purpose, starting during the Napoleonic era in France (and still is a moderately popular additive there for cheaper coffee)
- Roasted ground peas, beans, or wheat used to adulterate roasted chicory
- Diethylene glycol, used by some winemakers to fake sweet wines
- Oleomargarine or lard, added to butter
- Rapeseed oil, commonly added to sunflower oil and soybean oil, brassicasterol being a marker of its presence
- Rye flour, corn meal or potato starch used to dilute more expensive flours; alum is also added to disguise usage of lower-quality flour
- Apple jellies were substituted for more expensive fruit jellies, with added colorant and sometimes even little pieces of wood that simulated strawberry seeds
- Artificial colorants, often toxic - eg. copper, zinc, or indigo-based green dyes added to absinthe
- Sudan I yellow color, added to chili powder
- Water, for diluting milk and beer and hard drinks
- Lower-quality black tea disguised as higher class
- Starch, added to sausages
- Cutting agents are often used to adulterate (or "cut") illicit drugs, for example shoe polish in solid cannabis
- Urea and other non-protein nitrogen sources added to protein products in order to inflate crude protein content measurements[1]
- Powdered beechnut husk aromatized with cinnamic aldehyde may be marketed as powdered cinnamon.
- High fructose corn syrup can be used to adulterate honey.
# History
Historically, usage of adulterants has been common in free market societies with few legal controls on food quality and/or poor or nonexistent monitoring by authorities; sometimes this usage has even extended to exceedingly dangerous chemicals and poisons. In the United Kingdom during the Victorian era, adulterants were quite common; for example, cheeses were sometimes colored with lead. Similar adulteration issues were seen in industry in the United States until the passage of the Pure Food and Drug Act in 1906. More recently, adulterant use in the People's Republic of China has inspired much public attention. (See: Food safety in the People's Republic of China).
Adulterant usage was first investigated in 1820 by the German chemist Frederick Accum, who identified many toxic metal colourings in food and drink. His work antagonised food suppliers and he was discredited by a scandal over his alleged mutilation of Royal Institution library books. The physician Arthur Hill Hassall later conducted extensive studies in the early 1850s, which were published in The Lancet and led to the 1860 Food Adulteration Act and subsequent further legislation.[2]
At the turn of the twentieth century, industrialization saw an uprise in adulteration and this inspired some protest. Accounts of adulteration led the New York Evening Post to parody:
Mary had a little lamb,
And when she saw it sicken,
She shipped it off to Packingtown,
And now its labeled chicken.
[3]
# In drug tests
Adulterants can be also added to urine, in order to interfere with the accuracy of drug tests. They are often oxidative in nature - hydrogen peroxide, and bleach have been used, sometimes with pH-adjusting substances like vinegar or sodium bicarbonate. These can be detected by drug testing labs, but some of the less expensive tests do not look for them.
# Notable incidents of adulteration
- In 1987, Beech-Nut paid $2.2 million in fines for violating the Federal Food, Drug, and Cosmetic Act by selling artificially flavored sugar water as apple juice. [4]
- In 1997, ConAgra Foods pled guilty to federal criminal charges that one of its units illegally sprayed water on stored grain to increase its weight and value. [5]
- In 2007, samples of wheat gluten mixed with melamine, presumably to produce artificially inflated results from common tests for protein content, were discovered in many U.S. pet food brands, as well as in the human food supply. This adulterated gluten was found to have come from China, and U.S. authorities concluded that its origin was the Xuzhou Anying Biologic Technology Development Company, a Xuzhou, China-based company. (See: Chinese protein export contamination.) | https://www.wikidoc.org/index.php/Adulterant | |
29b257c73f564c72559711d9f5d3f3c468a5c9d5 | wikidoc | Adventitia | Adventitia
# Overview
Adventitia is the outermost connective tissue covering of any organ, vessel, or other structure.
For example, the connective tissue that surrounds an artery is called the tunica adventitia because it is considered extraneous to the artery.
To some degree, its role is complimentary to that of the serosa, which also provides a layer of tissue surrounding an organ. In the abdomen, whether an organ is covered in adventitia or serosa depends upon whether it is peritoneal or retroperitoneal:
- peritoneal organs are covered in serosa (a layer of mesothelium, the visceral peritoneum)
- retroperitoneal organs are covered in adventitia (loose connective tissue)
In the gastrointestinal tract, the muscularis externa is bounded in most cases by serosa. However, at (the thoracic esophagus, ascending colon, descending colon and the rectum), the muscularis externa is instead bounded by adventitia. (The muscularis externa of the duodenum is bounded by both tissue types.)
The connective tissue of the gallbladder is covered by adventitia where the gallbladder bounds the liver, but by serosa for the rest of its surface. | Adventitia
Template:Infobox Anatomy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Adventitia is the outermost connective tissue covering of any organ, vessel, or other structure.
For example, the connective tissue that surrounds an artery is called the tunica adventitia because it is considered extraneous to the artery.
To some degree, its role is complimentary to that of the serosa, which also provides a layer of tissue surrounding an organ. In the abdomen, whether an organ is covered in adventitia or serosa depends upon whether it is peritoneal or retroperitoneal:
- peritoneal organs are covered in serosa (a layer of mesothelium, the visceral peritoneum)
- retroperitoneal organs are covered in adventitia (loose connective tissue)
In the gastrointestinal tract, the muscularis externa is bounded in most cases by serosa. However, at (the thoracic esophagus, ascending colon, descending colon and the rectum), the muscularis externa is instead bounded by adventitia. (The muscularis externa of the duodenum is bounded by both tissue types.)
The connective tissue of the gallbladder is covered by adventitia where the gallbladder bounds the liver, but by serosa for the rest of its surface. | https://www.wikidoc.org/index.php/Adventitia | |
02dab7dd506172489d8f2405da6677e7fed83762 | wikidoc | Lovastatin | Lovastatin
# 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
Lovastatin is a HMG-CoA Reductase Inhibitor that is FDA approved for the {{{indicationType}}} of prevention of coronary heart disease, hyperlipidemia, limitations of use. Common adverse reactions include abdominal pain, constipation, arthralgia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- 20-60 mg/day, in single doses taken in the evening at bedtime.
### Prevention of Coronary Heart Disease
- Dosing Information
- 20 to 60 mg rally once daily at bedtime; adjust dose at intervals of 4 weeks or more
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information about Off-Label Guideline-Supported Use of Lovastatin in adult patients.
### Non–Guideline-Supported Use
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Lovastatin FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information about Off-Label Guideline-Supported Use of Lovastatin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information about Off-Label Non–Guideline-Supported Use of Lovastatin in pediatric patients.
# Contraindications
- Concomitant administration of strong CYP3A inhibitors
- Concomitant administration of erythromycin.
- Hypersensitivity to any component of this product.
- Women who are pregnant or may become pregnant.
- Because HMG-CoA reductase inhibitors decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol. Additionally, there is no apparent benefit to therapy during pregnancy, and safety in pregnant women has not been established. If the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus and the lack of known clinical benefit with continued use during pregnancy.
- Nursing mothers.
- Because another drug in this class passes into breast milk, and because HMG-CoA reductase inhibitors have the potential to cause serious adverse reactions in nursing infants.
# Warnings
Cases of myopathy and rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with HMG-CoA reductase inhibitors, including lovastatin. These risks can occur at any dose level, but increase in a dose-dependent manner. Predisposing factors for myopathy include advanced age (≥65 years), female gender, renal impairment, and inadequately treated hypothyroidism. In a clinical study (EXCEL) in which patients were carefully monitored and some interacting drugs were excluded, there was one case of myopathy among 4933 patients randomized to lovastatin 20-40 mg daily for 48 weeks, and 4 among 1649 patients randomized to 80 mg daily.
There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation; improvement with immunosuppressive agents.
All patients starting therapy with lovastatin, or whose dose of lovastatin is being increased, should be advised of the risk of myopathy, including rhabdomyolysis, and told to report promptly any unexplained muscle pain, tenderness or weakness particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing lovastatin. Lovastatin therapy should be discontinued immediately if myopathy is diagnosed or suspected.
Lovastatin therapy should be discontinued if markedly elevated creatine kinase (CK) levels occur or myopathy is diagnosed or suspected. Lovastatin therapy should also be temporarily withheld in any patient experiencing an acute or serious condition predisposing to the development of renal failure secondary to rhabdomyolysis, e.g., sepsis; hypotension; dehydration; major surgery; trauma; severe metabolic, endocrine, and electrolyte disorders; or uncontrolled epilepsy.
Drug Interactions that can cause skeletal muscle effects
- Strong CYP3A Inhibitors
- The risk of myopathy and rhabdomyolysis is increased by high levels of statin activity in plasma. Lovastatin is metabolized by the cytochrome P450 isoform 3A4. Certain drugs which inhibit this metabolic pathway can raise the plasma levels of lovastatin and may increase the risk of myopathy. Co-administration of these drugs with lovastatin is contraindicated. If treatment with strong CYP3A inhibitors is unavoidable, therapy with lovastatin should be suspended during the course of treatment.
- Erythromycin
- Co-administration of erythromycin with lovastatin is contraindicated. If treatment with erythromycin is unavoidable, therapy with lovastatin should be suspended during the course of treatment.
- Gemfibrozil
- Avoid the combined use of lovastatin with gemfibrozil.
- Other lipid-lowering drugs (other fibrates, or lipid-lowering doses (≥ 1 g/day) of niacin
- Use caution when prescribing other fibrates or lipid-lowering doses (≥ 1 g/day) of niacin with lovastatin, as these agents can cause myopathy when given alone and the risk is increased when they are coadministered with lovastatin. Carefully weigh the expected benefit of further alterations in lipid levels by the combined use of lovastatin with other fibrates or niacin against the potential risks of these combinations.
- Cyclosporine
- Avoid the combined use of lovastatin with cyclosporine.
- Danazol, diltiazem, dronedarone or verapamil with higher doses of lovastatin
- Do not exceed 20 mg of lovastatin daily in patients receiving concomitant therapy with danazol, diltiazem, dronedarone or verapamil. Weigh carefully the benefits of the use of lovastatin in patients receiving danazol, diltiazem, dronedarone or verapamil against the risks of these combinations.
- Amiodarone
- Do not exceed 40 mg of lovastatin daily in patients receiving concomitant therapy with amiodarone. Avoid the combined use of lovastatin at doses exceeding 40 mg daily with amiodarone unless the clinical benefit is likely to outweigh the increased risk of myopathy. The concomitant use of higher doses of a closely related member of the HMG-CoA reductase inhibitor class with amiodarone increased the risk of myopathy/rhabdomyolysis.
- Colchicine
- There have been cases of myopathy, including rhabdomyolysis, reported in patients receiving lovastatin coadministered with colchicine. Use caution when prescribing lovastatin with colchicine.
- Ranolazine
- Concomitant use of ranolazine and lovastatin may increase the risk of myopathy, including rhabdomyolysis. Consider dose adjustment of lovastatin if coadministering with ranolazine.
Prescribing recommendations for interacting agents are summarized in the table below.
### Liver Enzyme Abnormalities
Increases in serum transaminases (aspartate aminotransferase or alanine aminotransferase ) have been reported with HMG-CoA reductase inhibitors, including lovastatin.
Persistent increases (to more than 3 times the upper limit of normal) in serum transaminases occurred in 1.9% of adult patients who received lovastatin for at least one year in early clinical trials. When the drug was interrupted or discontinued in these patients, the transaminase levels usually fell slowly to pretreatment levels.
It is recommended that liver enzyme tests be obtained prior to initiating therapy with lovastatin and repeated as clinically indicated. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including lovastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with lovastatin, promptly interrupt therapy. If an alternate etiology is not found, do not restart lovastatin.
The drug should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of chronic liver disease. Active liver disease or unexplained transaminase elevations are contraindications to the use of lovastatin.
In controlled clinical trials (467 patients treated with lovastatin and 329 patients treated with lovastatin immediate-release) no meaningful differences in transaminase elevations between the two treatments were observed.
Lovastatin
In the EXCEL study , the incidence of persistent increases in serum transaminases over 48 weeks was 0.1% for placebo, 0.1% at 20 mg/day, 0.9% at 40 mg/day, and 1.5% at 80 mg/day in patients on lovastatin. However, in post-marketing experience with lovastatin immediate-release, symptomatic liver disease has been reported rarely at all dosages.
In AFCAPS/TexCAPS, the number of participants with consecutive elevations of either alanine aminotransferase (ALT) or aspartate aminotransferase (AST) (>3 times the upper limit of normal), over a median of 5.1 years of follow-up, was not significantly different between the lovastatin immediate-release and placebo groups . Elevated transaminases resulted in discontinuation of 6 (0.2%) participants from therapy in the lovastatin immediate-release group (n=3,304) and 4 (0.1%) in the placebo group (n=3,301).
### Endocrine Effects
Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including lovastatin.
HMG-CoA reductase inhibitors interfere with cholesterol synthesis and as such might theoretically blunt adrenal and/or gonadal steroid production. Results of clinical trials with drugs in this class have been inconsistent with regard to drug effects on basal and reserve steroid levels. However, clinical studies have shown that lovastatin does not reduce basal plasma cortisol concentration or impair adrenal reserve, and does not reduce basal plasma testosterone concentration. Another HMG-CoA reductase inhibitor has been shown to reduce the plasma testosterone response to HCG. The effects of HMG-CoA reductase inhibitors on male fertility have not been studied in adequate numbers of male patients. The effects, if any, on the pituitary-gonadal axis in premenopausal women are unknown. Patients treated with lovastatin who develop clinical evidence of endocrine dysfunction should be evaluated appropriately. Caution should also be exercised if an HMG-CoA reductase inhibitor or other agent used to lower cholesterol levels is administered to patients also receiving other drugs (e.g., spironolactone, cimetidine) that may decrease the levels or activity of endogenous steroid hormones.
# Adverse Reactions
## Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
In controlled clinical trials with lovastatin, (467 patients with mean exposure to study drug of approximately 11.6 weeks), 3.2% of patients were discontinued due to adverse reactions. This was similar to the discontinuation rate in the placebo (2/34, 5.9%) and lovastatin immediate-release (3.3%) treatment groups.
Pooled results from clinical trials with v show that the most frequently reported adverse reactions in the lovastatin group were infection, headache and accidental injury. Similar incidences of these adverse reactions were seen in the lovastatin and placebo groups. In controlled clinical trials, clinical adverse reactions reported in >5% of patients in any treatment group are shown in the table below.
In AFCAPS/TexCAPS
involving 6,605 participants treated with 20-40 mg/day of lovastatin immediate-release (n=3,304) or placebo (n=3,301), the safety and tolerability profile of the group treated with lovastatin immediate-release was comparable to that of the group treated with placebo during a median of 5.1 years of follow-up.
AFCAPS/TexCAPS
The number of participants with consecutive elevations of either alanine aminotransferase (ALT) or aspartate aminotransferase (AST) (>3 times the upper limit of normal), over a median of 5.1 years of follow-up, was not significantly different between the lovastatin immediate-release and placebo groups . The starting dose of lovastatin immediate-release was 20 mg/day; 50% of the lovastatin immediate-release treated participants were titrated to 40 mg/day at Week 18. Of the 18 participants on lovastatin immediate-release with consecutive elevations of either ALT or AST, 11 (0.7%) elevations occurred in participants taking 20 mg/day, while 7 (0.4%) elevations occurred in participants titrated to 40 mg/day. Elevated transaminases resulted in discontinuation of 6 (0.2%) participants from therapy in the lovastatin immediate-release group (n=3,304) and 4 (0.1%) in the placebo group (n=3,301).
## Postmarketing Experience
The following adverse reactions have been identified during post-approval use of lovastatin and/or are class effects of HMG CoA reductase inhibitors (statins). 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.
- Skeletal: muscle cramps, myalgia, myopathy, rhabdomyolysis, arthralgias.
- There have been rare reports of immune-mediated necrotizing myopathy associated with statin use.
- Neurological: dysfunction of certain cranial nerves (including alteration of taste, impairment of extra-ocular movement, facial paresis), tremor, dizziness, vertigo, paresthesia, peripheral neuropathy, peripheral nerve palsy, psychic disturbances, anxiety, insomnia, depression.
- There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been reported for all statins. The reports are generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).
- Hypersensitivity Reactions: An apparent hypersensitivity syndrome has been reported rarely which has included one or more of the following features: anaphylaxis, angioedema, lupus erythematous-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, purpura, thrombocytopenia, leukopenia, hemolytic anemia, positive ANA, ESR increase, eosinophilia, arthritis, arthralgia, urticaria, asthenia, photosensitivity, fever, chills, flushing, malaise, dyspnea, toxic epidermal necrolysis, erythema multiforme, including Stevens-Johnson syndrome.
- Gastrointestinal: pancreatitis, hepatitis, including chronic active hepatitis, cholestatic jaundice, fatty change in liver; and rarely, cirrhosis, fulminant hepatic necrosis, and hepatoma; anorexia, vomiting, fatal and non-fatal hepatic failure.
- Skin: alopecia, pruritus. A variety of skin changes (e.g., nodules, discoloration, dryness of skin/mucous membranes, changes to hair/nails) have been reported.
- Reproductive: gynecomastia, loss of libido, erectile dysfunction.
- Eye: progression of cataracts (lens opacities), ophthalmoplegia.
- Laboratory Abnormalities: elevated transaminases, alkaline phosphatase, gamma-glutamyl transpeptidase, and bilirubin; thyroid function abnormalities.
# Drug Interactions
Drug interaction studies have not been performed with lovastatin. The types, frequencies and magnitude of drug interactions that may be encountered whenlovastatin is administered with other drugs may differ from the drug interactions encountered with the lovastatin immediate-release formulation. In addition, as the drug exposure with lovastatin 60 mg is greater than that with lovastatin immediate-release 80 mg (maximum recommended dose), the severity and magnitude of drug interactions that may be encountered with lovastatin 60 mg are not known. It is therefore recommended that the following precautions and recommendations for the concomitant administration of lovastatin immediate-release with other drugs be interpreted with caution, and that the monitoring of the pharmacologic effects of lovastatin and/or other concomitantly administered drugs be undertaken where appropriate.
- Strong CYP3A Inhibitors
- Lovastatin is metabolized by CYP3A4 but has no CYP3A inhibitory activity; therefore it is not expected to affect the plasma concentrations of other drugs metabolized by CYP3A. Strong inhibitors of CYP3A (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, and nefazodone), increase the risk of myopathy by reducing the elimination of lovastatin. The use of lovastatin with strong CYP3A inhibitors is contraindicated.
- Erythromycin
- Do not use lovastatin concomitantly with erythromycin.
- Interactions with lipid-lowering drugs that can cause myopathy when given alone
- The risk of myopathy is also increased by the following lipid-lowering drugs that are not strong CYP3A inhibitors, but which can cause myopathy when given alone.
- Gemfibrozil – Avoid the concomitant use of lovastatin with gemfibrozil.
- Other fibrates - Use caution when prescribing lovastatin with other fibrates.
- Niacin (nicotinic acid) (≥1 g/day)
- Use caution when prescribing lovastatin with lipid-modifying (≥1 g/day) doses of niacin.
- Cyclosporine
- Avoid the concomitant use of lovastatin with cyclosporine.
- Danazol, diltiazem, dronedarone or verapamil
- Do not exceed 20 mg of lovastatin daily in patients receiving concomitant therapy with danazol, diltiazem, dronedarone or verapamil.
- Amiodarone
- Do not exceed 40 mg of lovastatin daily in patients receiving concomitant therapy with amiodarone.
- Coumarin Anticoagulants
- In a small clinical trial in which lovastatin was administered to warfarin treated patients, no effect on prothrombin time was detected. However, another HMG-CoA reductase inhibitor has been found to produce a less than two second increase in prothrombin time in healthy volunteers receiving low doses of warfarin. Also, bleeding and/or increased prothrombin time has been reported in a few patients taking coumarin anticoagulants concomitantly with lovastatin. In patients taking anticoagulants, prothrombin time should be determined before starting lovastatin and frequently enough during early therapy to ensure that no significant alteration of prothrombin time occurs. Once a stable prothrombin time has been documented, prothrombin times can be monitored at the intervals usually recommended for patients on coumarin anticoagulants. If the dose of lovastatin is changed, the same procedure should be repeated. Lovastatin therapy has not been associated with bleeding or with changes in prothrombin time in patients not taking anticoagulants.
- Colchicine
- Cases of myopathy, including rhabdomyolysis have been reported with lovastatin coadministered with colchicine. Exercise caution when prescribing lovastatin with colchicine.
- Ranolazine
- The risk of myopathy, including rhabdomyolysis, may be increased by concomitant administration of ranolazine. Exercise caution when prescribing lovastatin with ranolazine. Dose adjustment of lovastatin may be necessary during coadministration with ranolazine.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): X
Safety in pregnant women has not been established. Lovastatin immediate-release has been shown to produce skeletal malformations at plasma levels 40 times the human exposure (for mouse fetus) and 80 times the human exposure (for rat fetus) based on mg/m2 surface area (doses were 800 mg/kg/day). No drug-induced changes were seen in either species at multiples of 8 times (rat) or 4 times (mouse) based on surface area. No evidence of malformations was noted in rabbits at exposures up to 3 times the human exposure (dose of 15 mg/kg/day, highest tolerated dose of lovastatin immediate-release).
Rare reports of congenital anomalies have been received following intrauterine exposure to HMG-CoA reductase inhibitors. In a review2 of approximately 100 prospectively followed pregnancies in women exposed to lovastatin immediate-release or another structurally related HMG-CoA reductase inhibitor, the incidences of congenital anomalies, spontaneous abortions and fetal deaths/stillbirths did not exceed what would be expected in the general population. The number of cases is adequate only to exclude a 3 to 4-fold increase in congenital anomalies over the background incidence. In 89% of the prospectively followed pregnancies, drug treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified. As safety in pregnant women has not been established and there is no apparent benefit to therapy with lovastatin during pregnancy, treatment should be immediately discontinued as soon as pregnancy is recognized. Lovastatin should be administered to women of child-bearing potential only when such patients are highly unlikely to conceive and have been informed of the potential hazard.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Lovastatin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Lovastatin during labor and delivery.
### Nursing Mothers
It is not known whether lovastatin is excreted in human milk. Because a small amount of another drug in this class is excreted in human breast milk and because of the potential for serious adverse reactions in nursing infants, women taking lovastatin should not nurse their infants.
### Pediatric Use
Safety and effectiveness in pediatric patients have not been established. Because pediatric patients are not likely to benefit from cholesterol lowering for at least a decade and because experience with this drug is limited (no studies in subjects below the age of 20 years), treatment of pediatric patients with lovastatin is not recommended at this time.
### Geriatic Use
Of the 467 patients who received lovastatin in controlled clinical studies, 18% were 65 years and older. Of the 297 patients who received lovastatin in uncontrolled clinical studies, 22% were 65 years and older. No overall differences in effectiveness or safety were observed between these patients and other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Thus, lower starting doses of lovastatin are recommended for elderly patients.
In pharmacokinetic studies with lovastatin immediate-release, the mean plasma level of HMG-CoA reductase inhibitory activity was shown to be approximately 45% higher in elderly patients between 70-78 years of age compared with patients between 18-30 years of age; however, clinical study experience in the elderly indicates that dosage adjustment based on this age-related pharmacokinetic difference is not needed. In the two large clinical studies conducted with lovastatin immediate-release (EXCEL and AFCAPS/TexCAPS), 21% (3094/14850) of patients were ≥65 years of age. Lipid-lowering efficacy with lovastatin was at least as great in elderly patients compared with younger patients, and there were no overall differences in safety over the 20 to 80 mg dosage range.
### Gender
There is no FDA guidance on the use of Lovastatin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Lovastatin with respect to specific racial populations.
### Renal Impairment
In a study of patients with severe renal impairment (creatinine clearance 10–30 mL/min), the plasma concentrations of total inhibitors after a single dose of lovastatin were approximately two-fold higher than those in healthy volunteers.
### Hepatic Impairment
There is no FDA guidance on the use of Lovastatin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Lovastatin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Lovastatin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Oral
### Monitoring
There is limited information regarding Lovastatin Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Lovastatin and IV administrations.
# Overdosage
- After oral administration of lovastatin immediate-release to mice the median lethal dose observed was >15 g/m2.
- Five healthy human volunteers have received up to 200 mg of lovastatin as a single dose without clinically significant adverse experiences. A few cases of accidental overdosage with lovastatin immediate-release have been reported; no patients had any specific symptoms, and all patients recovered without sequelae. The maximum dose taken was 5 g to 6 g.
- Until further experience is obtained, no specific treatment of overdosage with lovastatin can be recommended.
- The dialyzability of lovastatin and its metabolites in man is not known at present.
# Pharmacology
## Mechanism of Action
Lovastatin is a lactone that is readily hydrolyzed in vivo to the corresponding β-hydroxyacid, a strong inhibitor of HMG-CoA reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonate. The conversion of HMG-CoA to mevalonate is an early step in the biosynthetic pathway for cholesterol.
## Structure
Lovastatin tablets contain a cholesterol-lowering agent isolated from a strain of Aspergillus terreus. After oral ingestion, lovastatin, which is an inactive lactone, is hydrolyzed to the corresponding β-hydroxyacid form. This is a principal metabolite and inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, which is an early and rate limiting step in the biosynthesis of cholesterol.
Lovastatin is ]-1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8--1-naphthalenyl 2-methylbutanoate. The empirical formula of lovastatin is C24H36O5 and its molecular weight is 404.55. Its structural formula is:
Lovastatin is a white, nonhygroscopic crystalline powder that is insoluble in water and sparingly soluble in ethanol, methanol, and acetonitrile.
Tablets are designed for once-a-day oral administration and deliver 20 mg, 40 mg, or 60 mg of lovastatin. In addition to the active ingredient lovastatin, each tablet contains the following inactive ingredients: acetyltributyl citrate; butylated hydroxy anisole; candellila wax; cellulose acetate; confectioner’s sugar (contains corn starch); F D & C yellow # 6; glyceryl monostearate; hypromellose; hypromellose phthalate; lactose; methacrylic acid copolymer, type B; polyethylene glycols (PEG 400, PEG 8000); polyethylene oxides; polysorbate 80; propylene glycol; silicon dioxide; sodium chloride; sodium lauryl sulfate; synthetic black iron oxide; red iron oxide; talc; titanium dioxide and triacetin.
## Pharmacodynamics
Lovastatin, as well as some of its metabolites, are pharmacologically active in humans. The liver is the primary site of action and the principal site of cholesterol synthesis and LDL clearance.
The involvement of low-density lipoprotein cholesterol (LDL-C) in atherogenesis has been well documented in clinical and pathological studies, as well as in many animal experiments. Epidemiological and clinical studies have established that high LDL-C and low high-density lipoprotein cholesterol (HDL-C) levels are both associated with coronary heart disease. However, the risk of developing coronary heart disease is continuous and graded over the range of cholesterol levels and many coronary events do occur in patients with total cholesterol (Total-C) and LDL-C levels in the lower end of this range.
Lovastatin immediate-release tablets have been shown to reduce elevated LDL-C concentrations. LDL is formed from very low-density lipoprotein (VLDL) and is catabolized predominantly by the high-affinity LDL receptor. The mechanism of the LDL-lowering effect of lovastatin immediate-release may involve both reduction of VLDL-C concentration, and induction of the LDL receptor, leading to reduced production and/or increased catabolism of LDL-C. The independent effect of raising HDL or lowering TG on the risk of coronary and cardiovascular morbidity and mortality has not been determined. The effects of lovastatin immediate-release on lipoprotein (a) , fibrinogen, and certain other independent biochemical risk markers for coronary heart disease are unknown.
## Pharmacokinetics
- Absorption:
- The appearance of lovastatin in plasma from an lovastatin extended-release tablet is slower and more prolonged compared to the lovastatin immediate-release formulation.
- A pharmacokinetic study carried out with lovastatin involved measurement of the systemic concentrations of lovastatin (pro-drug), lovastatin acid (active-drug) and total and active inhibitors of HMG-CoA reductase. The pharmacokinetic parameters in 12 hypercholesterolemic subjects at steady state, after 28 days of treatment, comparing lovastatin 40 mg to lovastatin immediate-release 40 mg, are summarized in the table below.
- The mean plasma concentration-time profiles of lovastatin and lovastatin acid in patients after multiple doses of lovastatin immediate-release at day 28 are shown in the graph below.
- The extended-release properties of lovastatin are characterized by a prolonged absorptive phase, which results in a longer Tmax and lower Cmax for lovastatin (pro-drug) and its major metabolite, lovastatin acid, compared to lovastatin immediate-release.
- The bioavailability of lovastatin (pro-drug) as measured by the AUC0-24hr was greater for lovastatin compared to lovastatin immediate-release (as measured by a chemical assay), while the bioavailability of total and active inhibitors of HMG-CoA reductase were equivalent to lovastatin immediate-release (as measured by an enzymatic assay).
- With once-a-day dosing, mean values of AUCs of active and total inhibitors at steady state were about 1.8-1.9 times those following a single dose. Accumulation ratio of lovastatin exposure was 1.5 after multiple daily doses of lovastatin compared to that of a single dose measured using a chemical assay. lovastatin appears to have dose linearity for doses from 10 mg up to 60 mg per day.
- When lovastatin was given after a meal, plasma concentrations of lovastatin and lovastatin acid were about 0.5 - 0.6 times those found when lovastatin was administered in the fasting state, indicating that food decreases the bioavailability of lovastatin. There was an association between the bioavailability of lovastatin and dosing after mealtimes. Bioavailability was lowered under the following conditions, (from higher bioavailability to lower bioavailability) in the following order: under overnight fasting conditions, before bedtime, with dinner, and with a high fat breakfast. In a multicenter, randomized, parallel group study, patients were administered 40 mg of lovastatin at three different times; before breakfast, after dinner and at bedtime. Although there was no statistical difference in the extent of lipid change between the three groups, there was a numerically greater reduction in LDL-C and TG and an increase in HDL-C when lovastatin was administered at bedtime. Results of this study are displayed in the table below.
Lovastatin Immediate-Release
- Absorption of lovastatin, estimated relative to an intravenous reference dose in each of four animal species tested, averaged about 30% of an oral dose. Following an oral dose of 14C-labeled lovastatin in man, 10% of the dose was excreted in urine and 83% in feces. The latter represents absorbed drug equivalents excreted in bile, as well as any unabsorbed drug. In a single dose study in four hypercholesterolemic patients, it was estimated that less than 5% of an oral dose of lovastatin reaches the general circulation as active inhibitors.
- Distribution:
- Both lovastatin and its β-hydroxyacid metabolite are highly bound (>95%) to human plasma proteins. Animal studies demonstrated that lovastatin crosses the blood-brain and placental barriers.
- In animal studies, after oral dosing, lovastatin had high selectivity for the liver, where it achieved substantially higher concentrations than in non-target tissues.
- Lovastatin undergoes extensive first-pass extraction in the liver, its primary site of action, with subsequent excretion of drug equivalents in the bile. As a consequence of extensive hepatic extraction of lovastatin, the availability of drug to the general circulation is low and variable.
Metabolism: Metabolism studies with lovastatin have not been conducted.
Lovastatin
Lovastatin is a lactone that is readily hydrolyzed in vivo to the corresponding β-hydroxyacid, a strong inhibitor of HMG-CoA reductase. Inhibition of HMG-CoA reductase is the basis for an assay in pharmacokinetic studies of the β-hydroxyacid metabolites (active inhibitors) and, following base hydrolysis, active plus latent inhibitors (total inhibitors) in plasma following administration of lovastatin.
The major active metabolites present in human plasma are the β-hydroxyacid of lovastatin, its 6’-hydroxy derivative, and two additional metabolites. The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma. Strong inhibitors of CYP3A can raise the plasma levels of HMG-CoA reductase inhibitory activity and increase the risk of myopathy.
Lovastatin is a substrate for CYP3A4. Grapefruit juice contains one or more components that inhibit CYP3A and can increase the plasma concentrations of drugs metabolized by CYP3A4. In one study1, 10 subjects consumed 200 mL of double-strength grapefruit juice (one can of frozen concentrate diluted with one rather than 3 cans of water) three times daily for 2 days and an additional 200 mL double-strength grapefruit juice together with and 30 and 90 minutes following a single dose of 80 mg lovastatin on the third day. This regimen of grapefruit juice resulted in mean increases in the concentration of lovastatin and its beta-hydroxyacid metabolite (as measured by the area under the concentration-time curve) of 15-fold and 5-fold respectively (as measured using a chemical assay – liquid chromatography/tandem mass spectrometry). In a second study, 15 subjects consumed one 8 oz glass of single-strength grapefruit juice (one can of frozen concentrate diluted with 3 cans of water) with breakfast for 3 consecutive days and a single dose of 40 mg lovastatin in the evening of the third day. This regimen of grapefruit juice resulted in a mean increase in the plasma concentration (as measured by the area under the concentration-time curve) of active and total HMG-CoA reductase inhibitory activity of 1.34-fold and 1.36-fold, respectively, and of lovastatin and its β-hydroxyacid metabolite (measured using a chemical assay – liquid chromatography/tandem mass spectrometry) of 1.94-fold and 1.57-fold, respectively. The effect of amounts of grapefruit juice between those used in these two studies on lovastatin pharmacokinetics has not been studied.
- Digoxin: In patients with hypercholesterolemia, concomitant administration of lovastatin and digoxin resulted in no effect on digoxin plasma concentrations.
- Oral H=hypoglycemic agents: In pharmacokinetic studies of lovastatin immediate-release in hypercholesterolemic non-insulin dependent diabetic patients, there was no drug interaction with glipizide or with chlorpropamide.
- Excretion: In a single-dose study with lovastatin, the amounts of lovastatin and lovastatin acid excreted in the urine were below the lower limit of quantitation of the assay (1.0 ng/mL), indicating that negligible excretion of lovastatin occurs through the kidney.
- Lovastatin undergoes extensive first-pass extraction in the liver, its primary site of action, with subsequent excretion of drug equivalents in the bile.
### Specific Populations
- Geriatric: Lovastatin Immediate-Release
- In a study with lovastatin immediate-release which included 16 elderly patients between 70-78 years of age who received lovastatin immediate-release 80 mg/day, the mean plasma level of HMG-CoA reductase inhibitory activity was increased approximately 45% compared with 18 patients between 18-30 years of age.
- Pediatric: Pharmacokinetic data in the pediatric population are not available.
- Gender: In a single dose pharmacokinetic study with lovastatin, there were no statistically significant differences in pharmacokinetic parameters between men (n=12) and women (n=10), although exposure tended to be higher in men than women.
- In clinical studies with lovastatin, there was no clinically significant difference in LDL-C reduction between men and women.
- Renal Impairment: In a study of patients with severe renal impairment (creatinine clearance 10-30 mL/min), the plasma concentrations of total inhibitors after a single dose of lovastatin were approximately two-fold higher than those in healthy volunteers.
- Hemodialysis: The effect of hemodialysis on plasma levels of lovastatin and its metabolites have not been studied.
- Hepatic Impairment: No pharmacokinetic studies with lovastatin have been conducted in patients with hepatic impairment.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 21-month carcinogenic study in mice with lovastatin immediate-release, there was a statistically significant increase in the incidence of hepatocellular carcinomas and adenomas in both males and females at 500 mg/kg/day. This dose produced a total plasma drug exposure 3 to 4 times that of humans given the highest recommended dose of lovastatin (drug exposure was measured as total HMG-CoA reductase inhibitory activity in extracted plasma). Tumor increases were not seen at 20 and 100 mg/kg/day, doses that produced drug exposures of 0.3 to 2 times that of humans at the 80 mg/day lovastatin immediate-release dose. A statistically significant increase in pulmonary adenomas was seen in female mice at approximately 4 times the human drug exposure. .
There was an increase in incidence of papilloma in the non-glandular mucosa of the stomach of mice beginning at exposures of 1 to 2 times that of humans given lovastatin immediate-release. The glandular mucosa was not affected. The human stomach contains only glandular mucosa.
In a 24-month carcinogenicity study in rats, there was a positive dose response relationship for hepatocellular carcinogenicity in males at drug exposures between 2-7 times that of human exposure at 80 mg/day lovastatin immediate-release (doses in rats were 5, 30 and 180 mg/kg/day).
An increased incidence of thyroid neoplasms in rats appears to be a response that has been seen with other HMG-CoA reductase inhibitors.
A chemically similar drug in this class was administered to mice for 72 weeks at 25, 100, and 400 mg/kg body weight, which resulted in mean serum drug levels approximately 3, 15, and 33 times higher than the mean human serum drug concentration (as total inhibitory activity) after a 40 mg oral dose of lovastatin immediate-release. Liver carcinomas were significantly increased in high-dose females and mid- and high-dose males, with a maximum incidence of 90 percent in males. The incidence of adenomas of the liver was significantly increased in mid- and high-dose females. Drug treatment also significantly increased the incidence of lung adenomas in mid- and high-dose males and females. Adenomas of the Harderian gland (a gland of the eye of rodents) were significantly higher in high dose mice than in controls.
No evidence of mutagenicity was observed with lovastatin immediate-release in a microbial mutagen test using mutant strains of Salmonella typhimurium with or without rat or mouse liver metabolic activation. In addition, no evidence of damage to genetic material was noted in an in vitro alkaline elution assay using rat or mouse hepatocytes, a V-79 mammalian cell forward mutation study, an in vitro chromosome aberration study in CHO cells, or an in vivo chromosomal aberration assay in mouse bone marrow.
Drug-related testicular atrophy, decreased spermatogenesis, spermatocytic degeneration and giant cell formation were seen in dogs starting at 20 mg/kg/day with lovastatin immediate-release. Similar findings were seen with another drug in this class. No drug-related effects on fertility were found in studies with lovastatin in rats. However, in studies with a similar drug in this class, there was decreased fertility in male rats treated for 34 weeks at 25 mg/kg body weight, although this effect was not observed in a subsequent fertility study when this same dose was administered for 11 weeks (the entire cycle of spermatogenesis, including epididymal maturation). In rats treated with this same reductase inhibitor at 180 mg/kg/day, seminiferous tubule degeneration (necrosis and loss of spermatogenic epithelium) was observed. No microscopic changes were observed in the testes from rats of either study. The clinical significance of these findings is unclear.
# Clinical Studies
Lovastatin has been shown to reduce Total-C, LDL-C, and TG and increase HDL-C in patients with hypercholesterolemia. Near maximal response was observed after four weeks of treatment and the response was maintained with continuation of therapy for up to 6 months.
In a 12-week, multicenter, placebo-controlled, double-blind, dose-response study in adult men and women 21 to 70 years of age with primary hypercholesterolemia, once daily administration of lovastatin 10 to 60 mg in the evening was compared to placebo. Lovastatin produced dose related reductions in LDL-C and Total-C. Lovastatin produced mean reductions in TG across all doses that varied from approximately 10% to 25%. Lovastatin produced mean increases in HDL-C across all doses that varied from approximately 9% to 13%.
The lipid changes with lovastatin treatment in this study, from baseline to endpoint, are displayed in the table below.
The range of LDL-C responses is represented graphically in the following in the figure below:
The distribution of LDL-C responses is represented graphically by the boxplots in the figure above. The bottom line of the box represents the 25th percentile and the top line, the 75th percentile. The horizontal line in the box represents the median and the gray area is the 95% confidence interval for the median. The range of responses is depicted by the tails and outliers.
Expanded Clinical Evaluation of Lovastatin (EXCEL) Study
Lovastatin immediate-release was compared to placebo in 8,245 patients with hypercholesterolemia ] 240-300mg/dL (6.2 mmol/L-7.6 mmol/L), LDL-C >160 mg/dL (4.1 mmol/L)] in the randomized, double-blind, parallel, 48-week EXCEL study. All changes in the lipid measurements observed in lovastatin immediate-release-treated patients were dose-related and significantly different from placebo (p≤0.001). These results were sustained throughout the study.
Lovastatin Long-Term Study
A total of 365 patients were enrolled in an extension study in which all patients were administered lovastatin 40 mg or 60 mg once daily for up to 6 months of treatment. The lipid-altering effects of lovastatin were comparable to what was observed in the dose-response study, and were maintained for up to 6 months of treatment.
Specific Populations
In clinical studies with lovastatin, there were no statistically significant differences in LDL-C reduction in an older population (≥65 years old), compared to a younger population (<65 years old). There were also no statistically significant differences in LDL-C reduction between male and female patients.
Lovastatin Immediate-Release
Lovastatin immediate-release has been shown to be effective in reducing Total-C and LDL-C in heterozygous familial and non-familial forms of primary hypercholesterolemia and in mixed hyperlipidemia. A marked response was seen within 2 weeks, and the maximum therapeutic response occurred within 4-6 weeks. The response was maintained during continuation of therapy. Single daily doses given in the evening were more effective than the same dose given in the morning, perhaps because cholesterol is synthesized mainly at night.
Lovastatin immediate-release was studied in controlled trials in hypercholesterolemic patients with well-controlled non-insulin dependent diabetes mellitus with normal renal function. The effect of lovastatin immediate-release on lipids and lipoproteins and the safety profile of lovastatin immediate-release were similar to that demonstrated in studies in nondiabetics. Lovastatin immediate-release had no clinically important effect on glycemic control or on the dose requirement of oral hypoglycemic agents.
The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS), a double-blind, randomized, placebo-controlled, primary prevention study, demonstrated that treatment with lovastatin immediate-release decreased the rate of acute major coronary events (composite endpoint of myocardial infarction, unstable angina, and sudden cardiac death) compared with placebo during a median of 5.1 years of follow-up. Participants were middle-aged and elderly men (ages 45-73) and women (ages 55-73) without symptomatic cardiovascular disease with average to moderately elevated Total-C and LDL-C, below average HDL-C, and who were at high risk based on elevated Total-C/HDL-C. In addition to age, 63% of the participants had at least one other risk factor (baseline HDL-C <35 mg/dL, hypertension, family history, smoking and diabetes).
AFCAPS/TexCAPS enrolled 6,605 participants (5,608 men, 997 women) based on the following lipid entry criteria: Total-C range of 180-264 mg/dL, LDL-C range of 130-190 mg/dL, HDL-C of ≤45 mg/dL for men and ≤47 mg/dL for women, and TG of ≤400 mg/dL. Participants were treated with standard care, including diet, and either lovastatin immediate-release 20 mg - 40 mg daily (n= 3,304) or placebo (n= 3,301). Approximately 50% of the participants treated with lovastatin immediate-release were titrated to 40 mg daily when their LDL-C remained >110 mg/dL at the 20-mg starting dose.
Lovastatin immediate-release reduced the risk of a first acute major coronary event, the primary efficacy endpoint, by 37% (lovastatin immediate-release 3.5%, placebo 5.5%; p<0.001; Figure 3). A first acute major coronary event was defined as myocardial infarction (54 participants on lovastatin immediate-release, 94 on placebo) or unstable angina (54 vs. 80) or sudden cardiac death (8 vs. 9). Furthermore, among the secondary endpoints, lovastatin immediate-release reduced the risk of unstable angina by 32% (1.8% vs. 2.6%; p=0.023), of myocardial infarction by 40% (1.7% vs. 2.9%; p=0.002), and of undergoing coronary revascularization procedures (e.g., coronary artery bypass grafting or percutaneous transluminal coronary angioplasty) by 33% (3.2% vs. 4.8%; p=0.001). Trends in risk reduction associated with treatment with lovastatin immediate-release were consistent across men and women, smokers and non-smokers, hypertensives and non-hypertensives, and older and younger participants. Participants with ≥2 risk factors had risk reductions (RR) in both acute major coronary events (RR 43%) and coronary revascularization procedures (RR 37%). Because there were too few events among those participants with age as their only risk factor in this study, the effect of lovastatin immediate-release on outcomes could not be adequately assessed in this subgroup.
Atherosclerosis
In the Canadian Coronary Atherosclerosis Intervention Trial (CCAIT), the effect of therapy with lovastatin on coronary atherosclerosis was assessed by coronary angiography in hyperlipidemic patients. In this randomized, double-blind, controlled clinical trial, patients were treated with conventional measures (usually diet and 325 mg of aspirin every other day) and either lovastatin 20 mg - 80 mg daily or placebo. Angiograms were evaluated at baseline and at two years by computerized quantitative coronary angiography (QCA). Lovastatin significantly slowed the progression of lesions as measured by the mean change per-patient in minimum lumen diameter (the primary endpoint) and percent diameter stenosis, and decreased the proportions of patients categorized with disease progression (33% vs. 50%) and with new lesions (16% vs. 32%).
In a similarly designed trial, the Monitored Atherosclerosis Regression Study (MARS), patients were treated with diet and either lovastatin 80 mg daily or placebo. No statistically significant difference between lovastatin and placebo was seen for the primary endpoint (mean change per patient in percent diameter stenosis of all lesions), or for most secondary QCA endpoints. Visual assessment by angiographers who formed a consensus opinion of overall angiographic change (Global Change Score) was also a secondary endpoint. By this endpoint, significant slowing of disease was seen, with regression in 23% of patients treated with lovastatin compared to 11% of placebo patients.
The effect of lovastatin on the progression of atherosclerosis in the coronary arteries has been corroborated by similar findings in another vasculature. In the Asymptomatic Carotid Artery Progression Study (ACAPS), the effect of therapy with lovastatin on carotid atherosclerosis was assessed by B-mode ultrasonography in hyperlipidemic patients with early carotid lesions and without known coronary heart disease at baseline. In this double- blind, controlled clinical trial, 919 patients were randomized in a 2 x 2 factorial design to placebo, lovastatin 10-40 mg daily and/or warfarin. Ultrasonograms of the carotid walls were used to determine the change per patient from baseline to three years in mean maximum intimal-medial thickness (IMT) of 12 measured segments. There was a significant regression of carotid lesions in patients receiving lovastatin alone compared to those receiving placebo alone (p=0.001). The predictive value of changes in IMT for stroke has not yet been established. In the lovastatin group there was a significant reduction in the number of patients with major cardiovascular events relative to the placebo group (5 vs. 14) and a significant reduction in all-cause mortality (1 vs. 8).
Eye
There was a high prevalence of baseline lenticular opacities in the patient population included in the early clinical trials with lovastatin immediate-release. During these trials the appearance of new opacities was noted in both the lovastatin immediate-release and placebo groups. There was no clinically significant change in visual acuity in the patients who had new opacities reported nor was any patient, including those with opacities noted at baseline, discontinued from therapy because of a decrease in visual acuity.
A three-year, double-blind, placebo-controlled study in hypercholesterolemic patients to assess the effect of lovastatin immediate-release on the human lens demonstrated that there were no clinically or statistically significant differences between the lovastatin immediate-release and placebo groups in the incidence, type or progression of lenticular opacities. There are no controlled clinical data assessing the lens available for treatment beyond three years.
# How Supplied
Lovastatin extended-release tablets are supplied as round, convex shaped tablets containing 20 mg, 40 mg and 60 mg of lovastatin.
- NDC 59630-628-30: 20 mg extended-release orange-colored tablets imprinted with Andrx logo and 20 on one side, bottles of 30.
- NDC 59630-629-30: 40 mg extended-release peach-colored tablets imprinted with Andrx logo and 40 on one side, bottles of 30.
- NDC 59630-630-30: 60 mg extended-release light peach-colored tablets imprinted with Andrx logo and 60 on one side, bottles of 30.
## Storage
Store at 20º-25°C (68º-77°F) - Excursions Permitted to 15°-30°C (59° -86°F) . Avoid excessive heat and humidity.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Patients taking lovastatin should be advised that cholesterol is a chronic condition and they should adhere to their medication along with their National Cholesterol Education Program (NCEP)-recommended diet, a regular exercise program as appropriate, and periodic testing of a fasting lipid panel to determine goal attainment.
Patients should be advised about substances they should not take concomitantly with lovastatin. Patients should also be advised to inform other healthcare professionals prescribing a new medication that they are taking lovastatin.
### Muscle Pain
All patients starting therapy with lovastatin should be advised of the risk of myopathy, including rhabdomyolysis, and told to report promptly any unexplained muscle pain, tenderness, or weakness particularly if accompanied by malaise or fever or if these muscle signs or symptoms persist after discontinuing lovastatin. The risk of this occurring is increased when taking certain types of medication or consuming grapefruit juice. Patients should discuss all medication, both prescription and over the counter, with their healthcare professional.
### Liver Enzymes
It is recommended that liver enzyme tests be performed before the initiation of lovastatin and if signs or symptoms of liver injury occur. All patients treated with lovastatin should be advised to report promptly any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice.
### Pregnancy
Women of childbearing age should be advised to use an effective method of birth control to prevent pregnancy while using lovastatin. Discuss future pregnancy plans with your patients, and discuss when to stop lovastatin if they are trying to conceive. Patients should be advised that if they become pregnant, they should stop taking lovastatin and call their healthcare professional.
### Breastfeeding
Women who are breastfeeding should be advised to not use lovastatin. Patients, who have a lipid disorder and are breastfeeding, should be advised to discuss the options with their healthcare professional.
# Precautions with Alcohol
Alcohol-Lovastatin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Advicor
- Altoprev
# Look-Alike Drug Names
- Altocor - Advicor
- Mevacor - Benicar
# Drug Shortage Status
# Price | Lovastatin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alonso Alvarado, M.D. [2]
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# Overview
Lovastatin is a HMG-CoA Reductase Inhibitor that is FDA approved for the {{{indicationType}}} of prevention of coronary heart disease, hyperlipidemia, limitations of use. Common adverse reactions include abdominal pain, constipation, arthralgia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- 20-60 mg/day, in single doses taken in the evening at bedtime.
### Prevention of Coronary Heart Disease
- Dosing Information
- 20 to 60 mg rally once daily at bedtime; adjust dose at intervals of 4 weeks or more
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information about Off-Label Guideline-Supported Use of Lovastatin in adult patients.
### Non–Guideline-Supported Use
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Lovastatin FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information about Off-Label Guideline-Supported Use of Lovastatin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information about Off-Label Non–Guideline-Supported Use of Lovastatin in pediatric patients.
# Contraindications
- Concomitant administration of strong CYP3A inhibitors
- Concomitant administration of erythromycin.
- Hypersensitivity to any component of this product.
- Women who are pregnant or may become pregnant.
- Because HMG-CoA reductase inhibitors decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol. Additionally, there is no apparent benefit to therapy during pregnancy, and safety in pregnant women has not been established. If the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus and the lack of known clinical benefit with continued use during pregnancy.
- Nursing mothers.
- Because another drug in this class passes into breast milk, and because HMG-CoA reductase inhibitors have the potential to cause serious adverse reactions in nursing infants.
# Warnings
Cases of myopathy and rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with HMG-CoA reductase inhibitors, including lovastatin. These risks can occur at any dose level, but increase in a dose-dependent manner. Predisposing factors for myopathy include advanced age (≥65 years), female gender, renal impairment, and inadequately treated hypothyroidism. In a clinical study (EXCEL) in which patients were carefully monitored and some interacting drugs were excluded, there was one case of myopathy among 4933 patients randomized to lovastatin 20-40 mg daily for 48 weeks, and 4 among 1649 patients randomized to 80 mg daily.
There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation; improvement with immunosuppressive agents.
All patients starting therapy with lovastatin, or whose dose of lovastatin is being increased, should be advised of the risk of myopathy, including rhabdomyolysis, and told to report promptly any unexplained muscle pain, tenderness or weakness particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing lovastatin. Lovastatin therapy should be discontinued immediately if myopathy is diagnosed or suspected.
Lovastatin therapy should be discontinued if markedly elevated creatine kinase (CK) levels occur or myopathy is diagnosed or suspected. Lovastatin therapy should also be temporarily withheld in any patient experiencing an acute or serious condition predisposing to the development of renal failure secondary to rhabdomyolysis, e.g., sepsis; hypotension; dehydration; major surgery; trauma; severe metabolic, endocrine, and electrolyte disorders; or uncontrolled epilepsy.
Drug Interactions that can cause skeletal muscle effects
- Strong CYP3A Inhibitors
- The risk of myopathy and rhabdomyolysis is increased by high levels of statin activity in plasma. Lovastatin is metabolized by the cytochrome P450 isoform 3A4. Certain drugs which inhibit this metabolic pathway can raise the plasma levels of lovastatin and may increase the risk of myopathy. Co-administration of these drugs with lovastatin is contraindicated. If treatment with strong CYP3A inhibitors is unavoidable, therapy with lovastatin should be suspended during the course of treatment.
- Erythromycin
- Co-administration of erythromycin with lovastatin is contraindicated. If treatment with erythromycin is unavoidable, therapy with lovastatin should be suspended during the course of treatment.
- Gemfibrozil
- Avoid the combined use of lovastatin with gemfibrozil.
- Other lipid-lowering drugs (other fibrates, or lipid-lowering doses (≥ 1 g/day) of niacin
- Use caution when prescribing other fibrates or lipid-lowering doses (≥ 1 g/day) of niacin with lovastatin, as these agents can cause myopathy when given alone and the risk is increased when they are coadministered with lovastatin. Carefully weigh the expected benefit of further alterations in lipid levels by the combined use of lovastatin with other fibrates or niacin against the potential risks of these combinations.
- Cyclosporine
- Avoid the combined use of lovastatin with cyclosporine.
- Danazol, diltiazem, dronedarone or verapamil with higher doses of lovastatin
- Do not exceed 20 mg of lovastatin daily in patients receiving concomitant therapy with danazol, diltiazem, dronedarone or verapamil. Weigh carefully the benefits of the use of lovastatin in patients receiving danazol, diltiazem, dronedarone or verapamil against the risks of these combinations.
- Amiodarone
- Do not exceed 40 mg of lovastatin daily in patients receiving concomitant therapy with amiodarone. Avoid the combined use of lovastatin at doses exceeding 40 mg daily with amiodarone unless the clinical benefit is likely to outweigh the increased risk of myopathy. The concomitant use of higher doses of a closely related member of the HMG-CoA reductase inhibitor class with amiodarone increased the risk of myopathy/rhabdomyolysis.
- Colchicine
- There have been cases of myopathy, including rhabdomyolysis, reported in patients receiving lovastatin coadministered with colchicine. Use caution when prescribing lovastatin with colchicine.
- Ranolazine
- Concomitant use of ranolazine and lovastatin may increase the risk of myopathy, including rhabdomyolysis. Consider dose adjustment of lovastatin if coadministering with ranolazine.
Prescribing recommendations for interacting agents are summarized in the table below.
### Liver Enzyme Abnormalities
Increases in serum transaminases (aspartate aminotransferase [AST] or alanine aminotransferase [ALT]) have been reported with HMG-CoA reductase inhibitors, including lovastatin.
Persistent increases (to more than 3 times the upper limit of normal) in serum transaminases occurred in 1.9% of adult patients who received lovastatin for at least one year in early clinical trials. When the drug was interrupted or discontinued in these patients, the transaminase levels usually fell slowly to pretreatment levels.
It is recommended that liver enzyme tests be obtained prior to initiating therapy with lovastatin and repeated as clinically indicated. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including lovastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with lovastatin, promptly interrupt therapy. If an alternate etiology is not found, do not restart lovastatin.
The drug should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of chronic liver disease. Active liver disease or unexplained transaminase elevations are contraindications to the use of lovastatin.
In controlled clinical trials (467 patients treated with lovastatin and 329 patients treated with lovastatin immediate-release) no meaningful differences in transaminase elevations between the two treatments were observed.
Lovastatin
In the EXCEL study [see Clinical Studies (14)], the incidence of persistent increases in serum transaminases over 48 weeks was 0.1% for placebo, 0.1% at 20 mg/day, 0.9% at 40 mg/day, and 1.5% at 80 mg/day in patients on lovastatin. However, in post-marketing experience with lovastatin immediate-release, symptomatic liver disease has been reported rarely at all dosages.
In AFCAPS/TexCAPS, the number of participants with consecutive elevations of either alanine aminotransferase (ALT) or aspartate aminotransferase (AST) (>3 times the upper limit of normal), over a median of 5.1 years of follow-up, was not significantly different between the lovastatin immediate-release and placebo groups [18 (0.6%) vs. 11 (0.3%)]. Elevated transaminases resulted in discontinuation of 6 (0.2%) participants from therapy in the lovastatin immediate-release group (n=3,304) and 4 (0.1%) in the placebo group (n=3,301).
### Endocrine Effects
Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including lovastatin.
HMG-CoA reductase inhibitors interfere with cholesterol synthesis and as such might theoretically blunt adrenal and/or gonadal steroid production. Results of clinical trials with drugs in this class have been inconsistent with regard to drug effects on basal and reserve steroid levels. However, clinical studies have shown that lovastatin does not reduce basal plasma cortisol concentration or impair adrenal reserve, and does not reduce basal plasma testosterone concentration. Another HMG-CoA reductase inhibitor has been shown to reduce the plasma testosterone response to HCG. The effects of HMG-CoA reductase inhibitors on male fertility have not been studied in adequate numbers of male patients. The effects, if any, on the pituitary-gonadal axis in premenopausal women are unknown. Patients treated with lovastatin who develop clinical evidence of endocrine dysfunction should be evaluated appropriately. Caution should also be exercised if an HMG-CoA reductase inhibitor or other agent used to lower cholesterol levels is administered to patients also receiving other drugs (e.g., spironolactone, cimetidine) that may decrease the levels or activity of endogenous steroid hormones.
# Adverse Reactions
## Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
In controlled clinical trials with lovastatin, (467 patients with mean exposure to study drug of approximately 11.6 weeks), 3.2% of patients were discontinued due to adverse reactions. This was similar to the discontinuation rate in the placebo (2/34, 5.9%) and lovastatin immediate-release (3.3%) treatment groups.
Pooled results from clinical trials with v show that the most frequently reported adverse reactions in the lovastatin group were infection, headache and accidental injury. Similar incidences of these adverse reactions were seen in the lovastatin and placebo groups. In controlled clinical trials, clinical adverse reactions reported in >5% of patients in any treatment group are shown in the table below.
In AFCAPS/TexCAPS
involving 6,605 participants treated with 20-40 mg/day of lovastatin immediate-release (n=3,304) or placebo (n=3,301), the safety and tolerability profile of the group treated with lovastatin immediate-release was comparable to that of the group treated with placebo during a median of 5.1 years of follow-up.
AFCAPS/TexCAPS
The number of participants with consecutive elevations of either alanine aminotransferase (ALT) or aspartate aminotransferase (AST) (>3 times the upper limit of normal), over a median of 5.1 years of follow-up, was not significantly different between the lovastatin immediate-release and placebo groups [18 (0.6%) vs. 11 (0.3%)]. The starting dose of lovastatin immediate-release was 20 mg/day; 50% of the lovastatin immediate-release treated participants were titrated to 40 mg/day at Week 18. Of the 18 participants on lovastatin immediate-release with consecutive elevations of either ALT or AST, 11 (0.7%) elevations occurred in participants taking 20 mg/day, while 7 (0.4%) elevations occurred in participants titrated to 40 mg/day. Elevated transaminases resulted in discontinuation of 6 (0.2%) participants from therapy in the lovastatin immediate-release group (n=3,304) and 4 (0.1%) in the placebo group (n=3,301).
## Postmarketing Experience
The following adverse reactions have been identified during post-approval use of lovastatin and/or are class effects of HMG CoA reductase inhibitors (statins). 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.
- Skeletal: muscle cramps, myalgia, myopathy, rhabdomyolysis, arthralgias.
- There have been rare reports of immune-mediated necrotizing myopathy associated with statin use.
- Neurological: dysfunction of certain cranial nerves (including alteration of taste, impairment of extra-ocular movement, facial paresis), tremor, dizziness, vertigo, paresthesia, peripheral neuropathy, peripheral nerve palsy, psychic disturbances, anxiety, insomnia, depression.
- There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been reported for all statins. The reports are generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).
- Hypersensitivity Reactions: An apparent hypersensitivity syndrome has been reported rarely which has included one or more of the following features: anaphylaxis, angioedema, lupus erythematous-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, purpura, thrombocytopenia, leukopenia, hemolytic anemia, positive ANA, ESR increase, eosinophilia, arthritis, arthralgia, urticaria, asthenia, photosensitivity, fever, chills, flushing, malaise, dyspnea, toxic epidermal necrolysis, erythema multiforme, including Stevens-Johnson syndrome.
- Gastrointestinal: pancreatitis, hepatitis, including chronic active hepatitis, cholestatic jaundice, fatty change in liver; and rarely, cirrhosis, fulminant hepatic necrosis, and hepatoma; anorexia, vomiting, fatal and non-fatal hepatic failure.
- Skin: alopecia, pruritus. A variety of skin changes (e.g., nodules, discoloration, dryness of skin/mucous membranes, changes to hair/nails) have been reported.
- Reproductive: gynecomastia, loss of libido, erectile dysfunction.
- Eye: progression of cataracts (lens opacities), ophthalmoplegia.
- Laboratory Abnormalities: elevated transaminases, alkaline phosphatase, gamma-glutamyl transpeptidase, and bilirubin; thyroid function abnormalities.
# Drug Interactions
Drug interaction studies have not been performed with lovastatin. The types, frequencies and magnitude of drug interactions that may be encountered whenlovastatin is administered with other drugs may differ from the drug interactions encountered with the lovastatin immediate-release formulation. In addition, as the drug exposure with lovastatin 60 mg is greater than that with lovastatin immediate-release 80 mg (maximum recommended dose), the severity and magnitude of drug interactions that may be encountered with lovastatin 60 mg are not known. It is therefore recommended that the following precautions and recommendations for the concomitant administration of lovastatin immediate-release with other drugs be interpreted with caution, and that the monitoring of the pharmacologic effects of lovastatin and/or other concomitantly administered drugs be undertaken where appropriate.
- Strong CYP3A Inhibitors
- Lovastatin is metabolized by CYP3A4 but has no CYP3A inhibitory activity; therefore it is not expected to affect the plasma concentrations of other drugs metabolized by CYP3A. Strong inhibitors of CYP3A (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, and nefazodone), increase the risk of myopathy by reducing the elimination of lovastatin. The use of lovastatin with strong CYP3A inhibitors is contraindicated.
- Erythromycin
- Do not use lovastatin concomitantly with erythromycin.
- Interactions with lipid-lowering drugs that can cause myopathy when given alone
- The risk of myopathy is also increased by the following lipid-lowering drugs that are not strong CYP3A inhibitors, but which can cause myopathy when given alone.
- Gemfibrozil – Avoid the concomitant use of lovastatin with gemfibrozil.
- Other fibrates - Use caution when prescribing lovastatin with other fibrates.
- Niacin (nicotinic acid) (≥1 g/day)
- Use caution when prescribing lovastatin with lipid-modifying (≥1 g/day) doses of niacin.
- Cyclosporine
- Avoid the concomitant use of lovastatin with cyclosporine.
- Danazol, diltiazem, dronedarone or verapamil
- Do not exceed 20 mg of lovastatin daily in patients receiving concomitant therapy with danazol, diltiazem, dronedarone or verapamil.
- Amiodarone
- Do not exceed 40 mg of lovastatin daily in patients receiving concomitant therapy with amiodarone.
- Coumarin Anticoagulants
- In a small clinical trial in which lovastatin was administered to warfarin treated patients, no effect on prothrombin time was detected. However, another HMG-CoA reductase inhibitor has been found to produce a less than two second increase in prothrombin time in healthy volunteers receiving low doses of warfarin. Also, bleeding and/or increased prothrombin time has been reported in a few patients taking coumarin anticoagulants concomitantly with lovastatin. In patients taking anticoagulants, prothrombin time should be determined before starting lovastatin and frequently enough during early therapy to ensure that no significant alteration of prothrombin time occurs. Once a stable prothrombin time has been documented, prothrombin times can be monitored at the intervals usually recommended for patients on coumarin anticoagulants. If the dose of lovastatin is changed, the same procedure should be repeated. Lovastatin therapy has not been associated with bleeding or with changes in prothrombin time in patients not taking anticoagulants.
- Colchicine
- Cases of myopathy, including rhabdomyolysis have been reported with lovastatin coadministered with colchicine. Exercise caution when prescribing lovastatin with colchicine.
- Ranolazine
- The risk of myopathy, including rhabdomyolysis, may be increased by concomitant administration of ranolazine. Exercise caution when prescribing lovastatin with ranolazine. Dose adjustment of lovastatin may be necessary during coadministration with ranolazine.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): X
Safety in pregnant women has not been established. Lovastatin immediate-release has been shown to produce skeletal malformations at plasma levels 40 times the human exposure (for mouse fetus) and 80 times the human exposure (for rat fetus) based on mg/m2 surface area (doses were 800 mg/kg/day). No drug-induced changes were seen in either species at multiples of 8 times (rat) or 4 times (mouse) based on surface area. No evidence of malformations was noted in rabbits at exposures up to 3 times the human exposure (dose of 15 mg/kg/day, highest tolerated dose of lovastatin immediate-release).
Rare reports of congenital anomalies have been received following intrauterine exposure to HMG-CoA reductase inhibitors. In a review2 of approximately 100 prospectively followed pregnancies in women exposed to lovastatin immediate-release or another structurally related HMG-CoA reductase inhibitor, the incidences of congenital anomalies, spontaneous abortions and fetal deaths/stillbirths did not exceed what would be expected in the general population. The number of cases is adequate only to exclude a 3 to 4-fold increase in congenital anomalies over the background incidence. In 89% of the prospectively followed pregnancies, drug treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified. As safety in pregnant women has not been established and there is no apparent benefit to therapy with lovastatin during pregnancy, treatment should be immediately discontinued as soon as pregnancy is recognized. Lovastatin should be administered to women of child-bearing potential only when such patients are highly unlikely to conceive and have been informed of the potential hazard.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Lovastatin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Lovastatin during labor and delivery.
### Nursing Mothers
It is not known whether lovastatin is excreted in human milk. Because a small amount of another drug in this class is excreted in human breast milk and because of the potential for serious adverse reactions in nursing infants, women taking lovastatin should not nurse their infants.
### Pediatric Use
Safety and effectiveness in pediatric patients have not been established. Because pediatric patients are not likely to benefit from cholesterol lowering for at least a decade and because experience with this drug is limited (no studies in subjects below the age of 20 years), treatment of pediatric patients with lovastatin is not recommended at this time.
### Geriatic Use
Of the 467 patients who received lovastatin in controlled clinical studies, 18% were 65 years and older. Of the 297 patients who received lovastatin in uncontrolled clinical studies, 22% were 65 years and older. No overall differences in effectiveness or safety were observed between these patients and other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Thus, lower starting doses of lovastatin are recommended for elderly patients.
In pharmacokinetic studies with lovastatin immediate-release, the mean plasma level of HMG-CoA reductase inhibitory activity was shown to be approximately 45% higher in elderly patients between 70-78 years of age compared with patients between 18-30 years of age; however, clinical study experience in the elderly indicates that dosage adjustment based on this age-related pharmacokinetic difference is not needed. In the two large clinical studies conducted with lovastatin immediate-release (EXCEL and AFCAPS/TexCAPS), 21% (3094/14850) of patients were ≥65 years of age. Lipid-lowering efficacy with lovastatin was at least as great in elderly patients compared with younger patients, and there were no overall differences in safety over the 20 to 80 mg dosage range.
### Gender
There is no FDA guidance on the use of Lovastatin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Lovastatin with respect to specific racial populations.
### Renal Impairment
In a study of patients with severe renal impairment (creatinine clearance 10–30 mL/min), the plasma concentrations of total inhibitors after a single dose of lovastatin were approximately two-fold higher than those in healthy volunteers.
### Hepatic Impairment
There is no FDA guidance on the use of Lovastatin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Lovastatin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Lovastatin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Oral
### Monitoring
There is limited information regarding Lovastatin Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Lovastatin and IV administrations.
# Overdosage
- After oral administration of lovastatin immediate-release to mice the median lethal dose observed was >15 g/m2.
- Five healthy human volunteers have received up to 200 mg of lovastatin as a single dose without clinically significant adverse experiences. A few cases of accidental overdosage with lovastatin immediate-release have been reported; no patients had any specific symptoms, and all patients recovered without sequelae. The maximum dose taken was 5 g to 6 g.
- Until further experience is obtained, no specific treatment of overdosage with lovastatin can be recommended.
- The dialyzability of lovastatin and its metabolites in man is not known at present.
# Pharmacology
## Mechanism of Action
Lovastatin is a lactone that is readily hydrolyzed in vivo to the corresponding β-hydroxyacid, a strong inhibitor of HMG-CoA reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonate. The conversion of HMG-CoA to mevalonate is an early step in the biosynthetic pathway for cholesterol.
## Structure
Lovastatin tablets contain a cholesterol-lowering agent isolated from a strain of Aspergillus terreus. After oral ingestion, lovastatin, which is an inactive lactone, is hydrolyzed to the corresponding β-hydroxyacid form. This is a principal metabolite and inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, which is an early and rate limiting step in the biosynthesis of cholesterol.
Lovastatin is [1 S -[1α(R*),3α,7β,8β(2 S*,4 S*),8aβ]]-1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1-naphthalenyl 2-methylbutanoate. The empirical formula of lovastatin is C24H36O5 and its molecular weight is 404.55. Its structural formula is:
Lovastatin is a white, nonhygroscopic crystalline powder that is insoluble in water and sparingly soluble in ethanol, methanol, and acetonitrile.
Tablets are designed for once-a-day oral administration and deliver 20 mg, 40 mg, or 60 mg of lovastatin. In addition to the active ingredient lovastatin, each tablet contains the following inactive ingredients: acetyltributyl citrate; butylated hydroxy anisole; candellila wax; cellulose acetate; confectioner’s sugar (contains corn starch); F D & C yellow # 6; glyceryl monostearate; hypromellose; hypromellose phthalate; lactose; methacrylic acid copolymer, type B; polyethylene glycols (PEG 400, PEG 8000); polyethylene oxides; polysorbate 80; propylene glycol; silicon dioxide; sodium chloride; sodium lauryl sulfate; synthetic black iron oxide; red iron oxide; talc; titanium dioxide and triacetin.
## Pharmacodynamics
Lovastatin, as well as some of its metabolites, are pharmacologically active in humans. The liver is the primary site of action and the principal site of cholesterol synthesis and LDL clearance.
The involvement of low-density lipoprotein cholesterol (LDL-C) in atherogenesis has been well documented in clinical and pathological studies, as well as in many animal experiments. Epidemiological and clinical studies have established that high LDL-C and low high-density lipoprotein cholesterol (HDL-C) levels are both associated with coronary heart disease. However, the risk of developing coronary heart disease is continuous and graded over the range of cholesterol levels and many coronary events do occur in patients with total cholesterol (Total-C) and LDL-C levels in the lower end of this range.
Lovastatin immediate-release tablets have been shown to reduce elevated LDL-C concentrations. LDL is formed from very low-density lipoprotein (VLDL) and is catabolized predominantly by the high-affinity LDL receptor. The mechanism of the LDL-lowering effect of lovastatin immediate-release may involve both reduction of VLDL-C concentration, and induction of the LDL receptor, leading to reduced production and/or increased catabolism of LDL-C. The independent effect of raising HDL or lowering TG on the risk of coronary and cardiovascular morbidity and mortality has not been determined. The effects of lovastatin immediate-release on lipoprotein (a) [Lp(a)], fibrinogen, and certain other independent biochemical risk markers for coronary heart disease are unknown.
## Pharmacokinetics
- Absorption:
- The appearance of lovastatin in plasma from an lovastatin extended-release tablet is slower and more prolonged compared to the lovastatin immediate-release formulation.
- A pharmacokinetic study carried out with lovastatin involved measurement of the systemic concentrations of lovastatin (pro-drug), lovastatin acid (active-drug) and total and active inhibitors of HMG-CoA reductase. The pharmacokinetic parameters in 12 hypercholesterolemic subjects at steady state, after 28 days of treatment, comparing lovastatin 40 mg to lovastatin immediate-release 40 mg, are summarized in the table below.
- The mean plasma concentration-time profiles of lovastatin and lovastatin acid in patients after multiple doses of lovastatin immediate-release at day 28 are shown in the graph below.
- The extended-release properties of lovastatin are characterized by a prolonged absorptive phase, which results in a longer Tmax and lower Cmax for lovastatin (pro-drug) and its major metabolite, lovastatin acid, compared to lovastatin immediate-release.
- The bioavailability of lovastatin (pro-drug) as measured by the AUC0-24hr was greater for lovastatin compared to lovastatin immediate-release (as measured by a chemical assay), while the bioavailability of total and active inhibitors of HMG-CoA reductase were equivalent to lovastatin immediate-release (as measured by an enzymatic assay).
- With once-a-day dosing, mean values of AUCs of active and total inhibitors at steady state were about 1.8-1.9 times those following a single dose. Accumulation ratio of lovastatin exposure was 1.5 after multiple daily doses of lovastatin compared to that of a single dose measured using a chemical assay. lovastatin appears to have dose linearity for doses from 10 mg up to 60 mg per day.
- When lovastatin was given after a meal, plasma concentrations of lovastatin and lovastatin acid were about 0.5 - 0.6 times those found when lovastatin was administered in the fasting state, indicating that food decreases the bioavailability of lovastatin. There was an association between the bioavailability of lovastatin and dosing after mealtimes. Bioavailability was lowered under the following conditions, (from higher bioavailability to lower bioavailability) in the following order: under overnight fasting conditions, before bedtime, with dinner, and with a high fat breakfast. In a multicenter, randomized, parallel group study, patients were administered 40 mg of lovastatin at three different times; before breakfast, after dinner and at bedtime. Although there was no statistical difference in the extent of lipid change between the three groups, there was a numerically greater reduction in LDL-C and TG and an increase in HDL-C when lovastatin was administered at bedtime. Results of this study are displayed in the table below.
Lovastatin Immediate-Release
- Absorption of lovastatin, estimated relative to an intravenous reference dose in each of four animal species tested, averaged about 30% of an oral dose. Following an oral dose of 14C-labeled lovastatin in man, 10% of the dose was excreted in urine and 83% in feces. The latter represents absorbed drug equivalents excreted in bile, as well as any unabsorbed drug. In a single dose study in four hypercholesterolemic patients, it was estimated that less than 5% of an oral dose of lovastatin reaches the general circulation as active inhibitors.
- Distribution:
- Both lovastatin and its β-hydroxyacid metabolite are highly bound (>95%) to human plasma proteins. Animal studies demonstrated that lovastatin crosses the blood-brain and placental barriers.
- In animal studies, after oral dosing, lovastatin had high selectivity for the liver, where it achieved substantially higher concentrations than in non-target tissues.
- Lovastatin undergoes extensive first-pass extraction in the liver, its primary site of action, with subsequent excretion of drug equivalents in the bile. As a consequence of extensive hepatic extraction of lovastatin, the availability of drug to the general circulation is low and variable.
Metabolism: Metabolism studies with lovastatin have not been conducted.
Lovastatin
Lovastatin is a lactone that is readily hydrolyzed in vivo to the corresponding β-hydroxyacid, a strong inhibitor of HMG-CoA reductase. Inhibition of HMG-CoA reductase is the basis for an assay in pharmacokinetic studies of the β-hydroxyacid metabolites (active inhibitors) and, following base hydrolysis, active plus latent inhibitors (total inhibitors) in plasma following administration of lovastatin.
The major active metabolites present in human plasma are the β-hydroxyacid of lovastatin, its 6’-hydroxy derivative, and two additional metabolites. The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma. Strong inhibitors of CYP3A can raise the plasma levels of HMG-CoA reductase inhibitory activity and increase the risk of myopathy.
Lovastatin is a substrate for CYP3A4. Grapefruit juice contains one or more components that inhibit CYP3A and can increase the plasma concentrations of drugs metabolized by CYP3A4. In one study1, 10 subjects consumed 200 mL of double-strength grapefruit juice (one can of frozen concentrate diluted with one rather than 3 cans of water) three times daily for 2 days and an additional 200 mL double-strength grapefruit juice together with and 30 and 90 minutes following a single dose of 80 mg lovastatin on the third day. This regimen of grapefruit juice resulted in mean increases in the concentration of lovastatin and its beta-hydroxyacid metabolite (as measured by the area under the concentration-time curve) of 15-fold and 5-fold respectively (as measured using a chemical assay – liquid chromatography/tandem mass spectrometry). In a second study, 15 subjects consumed one 8 oz glass of single-strength grapefruit juice (one can of frozen concentrate diluted with 3 cans of water) with breakfast for 3 consecutive days and a single dose of 40 mg lovastatin in the evening of the third day. This regimen of grapefruit juice resulted in a mean increase in the plasma concentration (as measured by the area under the concentration-time curve) of active and total HMG-CoA reductase inhibitory activity [using a validated enzyme inhibition assay different from that used in the first study, both before (for active inhibitors) and after (for total inhibitors) base hydrolysis] of 1.34-fold and 1.36-fold, respectively, and of lovastatin and its β-hydroxyacid metabolite (measured using a chemical assay – liquid chromatography/tandem mass spectrometry) of 1.94-fold and 1.57-fold, respectively. The effect of amounts of grapefruit juice between those used in these two studies on lovastatin pharmacokinetics has not been studied.
- Digoxin: In patients with hypercholesterolemia, concomitant administration of lovastatin and digoxin resulted in no effect on digoxin plasma concentrations.
- Oral H=hypoglycemic agents: In pharmacokinetic studies of lovastatin immediate-release in hypercholesterolemic non-insulin dependent diabetic patients, there was no drug interaction with glipizide or with chlorpropamide.
- Excretion: In a single-dose study with lovastatin, the amounts of lovastatin and lovastatin acid excreted in the urine were below the lower limit of quantitation of the assay (1.0 ng/mL), indicating that negligible excretion of lovastatin occurs through the kidney.
- Lovastatin undergoes extensive first-pass extraction in the liver, its primary site of action, with subsequent excretion of drug equivalents in the bile.
### Specific Populations
- Geriatric: Lovastatin Immediate-Release
- In a study with lovastatin immediate-release which included 16 elderly patients between 70-78 years of age who received lovastatin immediate-release 80 mg/day, the mean plasma level of HMG-CoA reductase inhibitory activity was increased approximately 45% compared with 18 patients between 18-30 years of age.
- Pediatric: Pharmacokinetic data in the pediatric population are not available.
- Gender: In a single dose pharmacokinetic study with lovastatin, there were no statistically significant differences in pharmacokinetic parameters between men (n=12) and women (n=10), although exposure tended to be higher in men than women.
- In clinical studies with lovastatin, there was no clinically significant difference in LDL-C reduction between men and women.
- Renal Impairment: In a study of patients with severe renal impairment (creatinine clearance 10-30 mL/min), the plasma concentrations of total inhibitors after a single dose of lovastatin were approximately two-fold higher than those in healthy volunteers.
- Hemodialysis: The effect of hemodialysis on plasma levels of lovastatin and its metabolites have not been studied.
- Hepatic Impairment: No pharmacokinetic studies with lovastatin have been conducted in patients with hepatic impairment.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 21-month carcinogenic study in mice with lovastatin immediate-release, there was a statistically significant increase in the incidence of hepatocellular carcinomas and adenomas in both males and females at 500 mg/kg/day. This dose produced a total plasma drug exposure 3 to 4 times that of humans given the highest recommended dose of lovastatin (drug exposure was measured as total HMG-CoA reductase inhibitory activity in extracted plasma). Tumor increases were not seen at 20 and 100 mg/kg/day, doses that produced drug exposures of 0.3 to 2 times that of humans at the 80 mg/day lovastatin immediate-release dose. A statistically significant increase in pulmonary adenomas was seen in female mice at approximately 4 times the human drug exposure. [Although mice were given 300 times the human dose (HD) on a mg/kg body weight basis, plasma levels of total inhibitory activity were only 4 times higher in mice than in humans given 80 mg of lovastatin immediate-release].
There was an increase in incidence of papilloma in the non-glandular mucosa of the stomach of mice beginning at exposures of 1 to 2 times that of humans given lovastatin immediate-release. The glandular mucosa was not affected. The human stomach contains only glandular mucosa.
In a 24-month carcinogenicity study in rats, there was a positive dose response relationship for hepatocellular carcinogenicity in males at drug exposures between 2-7 times that of human exposure at 80 mg/day lovastatin immediate-release (doses in rats were 5, 30 and 180 mg/kg/day).
An increased incidence of thyroid neoplasms in rats appears to be a response that has been seen with other HMG-CoA reductase inhibitors.
A chemically similar drug in this class was administered to mice for 72 weeks at 25, 100, and 400 mg/kg body weight, which resulted in mean serum drug levels approximately 3, 15, and 33 times higher than the mean human serum drug concentration (as total inhibitory activity) after a 40 mg oral dose of lovastatin immediate-release. Liver carcinomas were significantly increased in high-dose females and mid- and high-dose males, with a maximum incidence of 90 percent in males. The incidence of adenomas of the liver was significantly increased in mid- and high-dose females. Drug treatment also significantly increased the incidence of lung adenomas in mid- and high-dose males and females. Adenomas of the Harderian gland (a gland of the eye of rodents) were significantly higher in high dose mice than in controls.
No evidence of mutagenicity was observed with lovastatin immediate-release in a microbial mutagen test using mutant strains of Salmonella typhimurium with or without rat or mouse liver metabolic activation. In addition, no evidence of damage to genetic material was noted in an in vitro alkaline elution assay using rat or mouse hepatocytes, a V-79 mammalian cell forward mutation study, an in vitro chromosome aberration study in CHO cells, or an in vivo chromosomal aberration assay in mouse bone marrow.
Drug-related testicular atrophy, decreased spermatogenesis, spermatocytic degeneration and giant cell formation were seen in dogs starting at 20 mg/kg/day with lovastatin immediate-release. Similar findings were seen with another drug in this class. No drug-related effects on fertility were found in studies with lovastatin in rats. However, in studies with a similar drug in this class, there was decreased fertility in male rats treated for 34 weeks at 25 mg/kg body weight, although this effect was not observed in a subsequent fertility study when this same dose was administered for 11 weeks (the entire cycle of spermatogenesis, including epididymal maturation). In rats treated with this same reductase inhibitor at 180 mg/kg/day, seminiferous tubule degeneration (necrosis and loss of spermatogenic epithelium) was observed. No microscopic changes were observed in the testes from rats of either study. The clinical significance of these findings is unclear.
# Clinical Studies
Lovastatin has been shown to reduce Total-C, LDL-C, and TG and increase HDL-C in patients with hypercholesterolemia. Near maximal response was observed after four weeks of treatment and the response was maintained with continuation of therapy for up to 6 months.
In a 12-week, multicenter, placebo-controlled, double-blind, dose-response study in adult men and women 21 to 70 years of age with primary hypercholesterolemia, once daily administration of lovastatin 10 to 60 mg in the evening was compared to placebo. Lovastatin produced dose related reductions in LDL-C and Total-C. Lovastatin produced mean reductions in TG across all doses that varied from approximately 10% to 25%. Lovastatin produced mean increases in HDL-C across all doses that varied from approximately 9% to 13%.
The lipid changes with lovastatin treatment in this study, from baseline to endpoint, are displayed in the table below.
The range of LDL-C responses is represented graphically in the following in the figure below:
The distribution of LDL-C responses is represented graphically by the boxplots in the figure above. The bottom line of the box represents the 25th percentile and the top line, the 75th percentile. The horizontal line in the box represents the median and the gray area is the 95% confidence interval for the median. The range of responses is depicted by the tails and outliers.
Expanded Clinical Evaluation of Lovastatin (EXCEL) Study
Lovastatin immediate-release was compared to placebo in 8,245 patients with hypercholesterolemia [[[Cholesterol|Total-C]] 240-300mg/dL (6.2 mmol/L-7.6 mmol/L), LDL-C >160 mg/dL (4.1 mmol/L)] in the randomized, double-blind, parallel, 48-week EXCEL study. All changes in the lipid measurements observed in lovastatin immediate-release-treated patients were dose-related and significantly different from placebo (p≤0.001). These results were sustained throughout the study.
Lovastatin Long-Term Study
A total of 365 patients were enrolled in an extension study in which all patients were administered lovastatin 40 mg or 60 mg once daily for up to 6 months of treatment. The lipid-altering effects of lovastatin were comparable to what was observed in the dose-response study, and were maintained for up to 6 months of treatment.
Specific Populations
In clinical studies with lovastatin, there were no statistically significant differences in LDL-C reduction in an older population (≥65 years old), compared to a younger population (<65 years old). There were also no statistically significant differences in LDL-C reduction between male and female patients.
Lovastatin Immediate-Release
Lovastatin immediate-release has been shown to be effective in reducing Total-C and LDL-C in heterozygous familial and non-familial forms of primary hypercholesterolemia and in mixed hyperlipidemia. A marked response was seen within 2 weeks, and the maximum therapeutic response occurred within 4-6 weeks. The response was maintained during continuation of therapy. Single daily doses given in the evening were more effective than the same dose given in the morning, perhaps because cholesterol is synthesized mainly at night.
Lovastatin immediate-release was studied in controlled trials in hypercholesterolemic patients with well-controlled non-insulin dependent diabetes mellitus with normal renal function. The effect of lovastatin immediate-release on lipids and lipoproteins and the safety profile of lovastatin immediate-release were similar to that demonstrated in studies in nondiabetics. Lovastatin immediate-release had no clinically important effect on glycemic control or on the dose requirement of oral hypoglycemic agents.
The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS), a double-blind, randomized, placebo-controlled, primary prevention study, demonstrated that treatment with lovastatin immediate-release decreased the rate of acute major coronary events (composite endpoint of myocardial infarction, unstable angina, and sudden cardiac death) compared with placebo during a median of 5.1 years of follow-up. Participants were middle-aged and elderly men (ages 45-73) and women (ages 55-73) without symptomatic cardiovascular disease with average to moderately elevated Total-C and LDL-C, below average HDL-C, and who were at high risk based on elevated Total-C/HDL-C. In addition to age, 63% of the participants had at least one other risk factor (baseline HDL-C <35 mg/dL, hypertension, family history, smoking and diabetes).
AFCAPS/TexCAPS enrolled 6,605 participants (5,608 men, 997 women) based on the following lipid entry criteria: Total-C range of 180-264 mg/dL, LDL-C range of 130-190 mg/dL, HDL-C of ≤45 mg/dL for men and ≤47 mg/dL for women, and TG of ≤400 mg/dL. Participants were treated with standard care, including diet, and either lovastatin immediate-release 20 mg - 40 mg daily (n= 3,304) or placebo (n= 3,301). Approximately 50% of the participants treated with lovastatin immediate-release were titrated to 40 mg daily when their LDL-C remained >110 mg/dL at the 20-mg starting dose.
Lovastatin immediate-release reduced the risk of a first acute major coronary event, the primary efficacy endpoint, by 37% (lovastatin immediate-release 3.5%, placebo 5.5%; p<0.001; Figure 3). A first acute major coronary event was defined as myocardial infarction (54 participants on lovastatin immediate-release, 94 on placebo) or unstable angina (54 vs. 80) or sudden cardiac death (8 vs. 9). Furthermore, among the secondary endpoints, lovastatin immediate-release reduced the risk of unstable angina by 32% (1.8% vs. 2.6%; p=0.023), of myocardial infarction by 40% (1.7% vs. 2.9%; p=0.002), and of undergoing coronary revascularization procedures (e.g., coronary artery bypass grafting or percutaneous transluminal coronary angioplasty) by 33% (3.2% vs. 4.8%; p=0.001). Trends in risk reduction associated with treatment with lovastatin immediate-release were consistent across men and women, smokers and non-smokers, hypertensives and non-hypertensives, and older and younger participants. Participants with ≥2 risk factors had risk reductions (RR) in both acute major coronary events (RR 43%) and coronary revascularization procedures (RR 37%). Because there were too few events among those participants with age as their only risk factor in this study, the effect of lovastatin immediate-release on outcomes could not be adequately assessed in this subgroup.
Atherosclerosis
In the Canadian Coronary Atherosclerosis Intervention Trial (CCAIT), the effect of therapy with lovastatin on coronary atherosclerosis was assessed by coronary angiography in hyperlipidemic patients. In this randomized, double-blind, controlled clinical trial, patients were treated with conventional measures (usually diet and 325 mg of aspirin every other day) and either lovastatin 20 mg - 80 mg daily or placebo. Angiograms were evaluated at baseline and at two years by computerized quantitative coronary angiography (QCA). Lovastatin significantly slowed the progression of lesions as measured by the mean change per-patient in minimum lumen diameter (the primary endpoint) and percent diameter stenosis, and decreased the proportions of patients categorized with disease progression (33% vs. 50%) and with new lesions (16% vs. 32%).
In a similarly designed trial, the Monitored Atherosclerosis Regression Study (MARS), patients were treated with diet and either lovastatin 80 mg daily or placebo. No statistically significant difference between lovastatin and placebo was seen for the primary endpoint (mean change per patient in percent diameter stenosis of all lesions), or for most secondary QCA endpoints. Visual assessment by angiographers who formed a consensus opinion of overall angiographic change (Global Change Score) was also a secondary endpoint. By this endpoint, significant slowing of disease was seen, with regression in 23% of patients treated with lovastatin compared to 11% of placebo patients.
The effect of lovastatin on the progression of atherosclerosis in the coronary arteries has been corroborated by similar findings in another vasculature. In the Asymptomatic Carotid Artery Progression Study (ACAPS), the effect of therapy with lovastatin on carotid atherosclerosis was assessed by B-mode ultrasonography in hyperlipidemic patients with early carotid lesions and without known coronary heart disease at baseline. In this double- blind, controlled clinical trial, 919 patients were randomized in a 2 x 2 factorial design to placebo, lovastatin 10-40 mg daily and/or warfarin. Ultrasonograms of the carotid walls were used to determine the change per patient from baseline to three years in mean maximum intimal-medial thickness (IMT) of 12 measured segments. There was a significant regression of carotid lesions in patients receiving lovastatin alone compared to those receiving placebo alone (p=0.001). The predictive value of changes in IMT for stroke has not yet been established. In the lovastatin group there was a significant reduction in the number of patients with major cardiovascular events relative to the placebo group (5 vs. 14) and a significant reduction in all-cause mortality (1 vs. 8).
Eye
There was a high prevalence of baseline lenticular opacities in the patient population included in the early clinical trials with lovastatin immediate-release. During these trials the appearance of new opacities was noted in both the lovastatin immediate-release and placebo groups. There was no clinically significant change in visual acuity in the patients who had new opacities reported nor was any patient, including those with opacities noted at baseline, discontinued from therapy because of a decrease in visual acuity.
A three-year, double-blind, placebo-controlled study in hypercholesterolemic patients to assess the effect of lovastatin immediate-release on the human lens demonstrated that there were no clinically or statistically significant differences between the lovastatin immediate-release and placebo groups in the incidence, type or progression of lenticular opacities. There are no controlled clinical data assessing the lens available for treatment beyond three years.
# How Supplied
Lovastatin extended-release tablets are supplied as round, convex shaped tablets containing 20 mg, 40 mg and 60 mg of lovastatin.
- NDC 59630-628-30: 20 mg extended-release orange-colored tablets imprinted with Andrx logo and 20 on one side, bottles of 30.
- NDC 59630-629-30: 40 mg extended-release peach-colored tablets imprinted with Andrx logo and 40 on one side, bottles of 30.
- NDC 59630-630-30: 60 mg extended-release light peach-colored tablets imprinted with Andrx logo and 60 on one side, bottles of 30.
## Storage
Store at 20º-25°C (68º-77°F) - Excursions Permitted to 15°-30°C (59° -86°F) [See USP Controlled Room Temperature]. Avoid excessive heat and humidity.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Patients taking lovastatin should be advised that cholesterol is a chronic condition and they should adhere to their medication along with their National Cholesterol Education Program (NCEP)-recommended diet, a regular exercise program as appropriate, and periodic testing of a fasting lipid panel to determine goal attainment.
Patients should be advised about substances they should not take concomitantly with lovastatin. Patients should also be advised to inform other healthcare professionals prescribing a new medication that they are taking lovastatin.
### Muscle Pain
All patients starting therapy with lovastatin should be advised of the risk of myopathy, including rhabdomyolysis, and told to report promptly any unexplained muscle pain, tenderness, or weakness particularly if accompanied by malaise or fever or if these muscle signs or symptoms persist after discontinuing lovastatin. The risk of this occurring is increased when taking certain types of medication or consuming grapefruit juice. Patients should discuss all medication, both prescription and over the counter, with their healthcare professional.
### Liver Enzymes
It is recommended that liver enzyme tests be performed before the initiation of lovastatin and if signs or symptoms of liver injury occur. All patients treated with lovastatin should be advised to report promptly any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice.
### Pregnancy
Women of childbearing age should be advised to use an effective method of birth control to prevent pregnancy while using lovastatin. Discuss future pregnancy plans with your patients, and discuss when to stop lovastatin if they are trying to conceive. Patients should be advised that if they become pregnant, they should stop taking lovastatin and call their healthcare professional.
### Breastfeeding
Women who are breastfeeding should be advised to not use lovastatin. Patients, who have a lipid disorder and are breastfeeding, should be advised to discuss the options with their healthcare professional.
# Precautions with Alcohol
Alcohol-Lovastatin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Advicor
- Altoprev
# Look-Alike Drug Names
- Altocor - Advicor
- Mevacor - Benicar
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Advicor | |
37b4130c062c7150181e9a09585bb4c85d8439b5 | wikidoc | Salmeterol | Salmeterol
- Because of this risk, use of SEREVENT DISKUS for the treatment of asthma without a concomitant long-term asthma control medication, such as an inhaled corticosteroid, is contraindicated. Use SEREVENT DISKUS only as additional therapy for patients with asthma who are currently taking but are inadequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue SEREVENT DISKUS) if possible without loss of asthma control and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do not use SEREVENT DISKUS for patients whose asthma is adequately controlled on low- or medium-dose inhaled corticosteroids.
- Pediatric and Adolescent Patients: Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. For pediatric and adolescent patients with asthma who require addition of a LABA to an inhaled corticosteroid, a fixed-dose combination product containing both an inhaled corticosteroid and a LABA should ordinarily be used to ensure adherence with both drugs. In cases where use of a separate long-term asthma control medication (e.g., inhaled corticosteroid) and a LABA is clinically indicated, appropriate steps must be taken to ensure adherence with both treatment components. If adherence cannot be assured, a fixed-dose combination product containing both an inhaled corticosteroid and a LABA is recommended.
- SEREVENT DISKUS is indicated for the treatment of asthma and in the prevention of bronchospasm only as concomitant therapy with a long-term asthma control medication, such as an inhaled corticosteroid, in patients aged 4 years and older with reversible obstructive airway disease, including patients with symptoms of nocturnal asthma. LABA, such as salmeterol, the active ingredient in SEREVENT DISKUS, increase the risk of asthma-related death . Use of SEREVENT DISKUS for the treatment of asthma without concomitant use of a long-term asthma control medication, such as an inhaled corticosteroid, is contraindicated . Use SEREVENT DISKUS only as additional therapy for patients with asthma who are currently taking but are inadequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue SEREVENT DISKUS) if possible without loss of asthma control and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do not use SEREVENT DISKUS for patients whose asthma is adequately controlled on low- or medium-dose inhaled corticosteroids.
Pediatric and Adolescent Patients: Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. For pediatric and adolescent patients with asthma who require addition of a LABA to an inhaled corticosteroid, a fixed-dose combination product containing both an inhaled corticosteroid and a LABA should ordinarily be used to ensure adherence with both drugs. In cases where use of a separate long-term asthma control medication (e.g., inhaled corticosteroid) and a LABA is clinically indicated, appropriate steps must be taken to ensure adherence with both treatment components. If adherence cannot be assured, a fixed-dose combination product containing both an inhaled corticosteroid and a LABA is recommended.
- SEREVENT DISKUS is NOT indicated for the relief of acute bronchospasm.
# Prevention of Exercise-Induced Bronchospasm
- SEREVENT DISKUS is also indicated for prevention of exercise-induced bronchospasm (EIB) in patients aged 4 years and older. Use of SEREVENT DISKUS as a single agent for the prevention of EIB may be clinically indicated in patients who do not have persistent asthma. In patients with persistent asthma, use of SEREVENT DISKUS for the prevention of EIB may be clinically indicated, but the treatment of asthma should include a long-term asthma control medication, such as an inhaled corticosteroid.
# Maintenance Treatment of Chronic Obstructive Pulmonary Disease
- SEREVENT DISKUS is indicated for the long-term twice-daily administration in the maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD) (including emphysema and chronic bronchitis).
- SEREVENT DISKUS is NOT indicated for the relief of acute bronchospasm.
# Dosing Information
- SEREVENT DISKUS should be administered by the orally inhaled route only.
- More frequent administration or a greater number of inhalations (more than 1 inhalation twice daily) is not recommended as some patients are more likely to experience adverse effects. Patients using SEREVENT DISKUS should not use additional LABA for any reason.
- LABA, such as salmeterol, the active ingredient in SEREVENT DISKUS, increase the risk of asthma-related death .
- Because of this risk, use of SEREVENT DISKUS for the treatment of asthma without concomitant use of a long-term asthma control medication, such as an inhaled corticosteroid is contraindicated. Use SEREVENT DISKUS only as additional therapy for patients with asthma who are currently taking but are inadequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue SEREVENT DISKUS) if possible without loss of asthma control and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do not use SEREVENT DISKUS for patients whose asthma is adequately controlled on low- or medium-dose inhaled corticosteroids.
- Pediatric and Adolescent Patients: Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. For patients with asthma younger than 18 years who require addition of a LABA to an inhaled corticosteroid, a fixed-dose combination product containing both an inhaled corticosteroid and a LABA should ordinarily be used to ensure adherence with both drugs. In cases where use of a separate long-term asthma control medication (e.g., inhaled corticosteroid) and a LABA is clinically indicated, appropriate steps must be taken to ensure adherence with both treatment components. If adherence cannot be assured, a fixed-dose combination product containing both an inhaled corticosteroid and a LABA is recommended.
- For bronchodilatation and prevention of symptoms of asthma, including the symptoms of nocturnal asthma, the usual dosage for adults and children aged 4 years and older is 1 inhalation (50 mcg) twice daily, approximately 12 hours apart. If a previously effective dosage regimen fails to provide the usual response, medical advice should be sought immediately as this is often a sign of destabilization of asthma. Under these circumstances, the therapeutic regimen should be reevaluated. If symptoms arise in the period between doses, an inhaled, short-acting beta2-agonist should be taken for immediate relief.
- Use of SEREVENT DISKUS as a single agent for the prevention of EIB may be clinically indicated in patients who do not have persistent asthma. In patients with persistent asthma, use of SEREVENT DISKUS for the prevention of EIB may be clinically indicated, but the treatment of asthma should include a long-term asthma control medication, such as an inhaled corticosteroid. One inhalation of SEREVENT DISKUS at least 30 minutes before exercise has been shown to protect patients against EIB. When used intermittently as needed for prevention of EIB, this protection may last up to 9 hours in adults and adolescents and up to 12 hours in patients aged 4 to 11 years. Additional doses of SEREVENT should not be used for 12 hours after the administration of this drug. Patients who are receiving SEREVENT DISKUS twice daily should not use additional SEREVENT for prevention of EIB.
- For maintenance treatment of bronchospasm associated with COPD (including chronic bronchitis and emphysema), the dosage for adults is 1 inhalation (50 mcg) twice daily approximately 12 hours apart.
- Cystic fibrosis
- High altitude pulmonary edema
- Occupational asthma
- The use of SEREVENT DISKUS is contraindicated in the following conditions:
- Primary treatment of status asthmaticus or other acute episodes of asthma or COPD where intensive measures are required.
- Severe hypersensitivity to milk proteins.
- LABA, such as salmeterol, the active ingredient in SEREVENT DISKUS, increase the risk of asthma-related death. Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA.
- Because of this risk, use of SEREVENT DISKUS for the treatment of asthma without concomitant use of a long-term asthma control medication, such as an inhaled corticosteroid, is contraindicated. Use SEREVENT DISKUS only as additional therapy for patients with asthma who are currently taking but are inadequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue SEREVENT DISKUS) if possible without loss of asthma control and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do not use SEREVENT DISKUS for patients whose asthma is adequately controlled on low- or medium-dose inhaled corticosteroids.
- Pediatric and Adolescent Patients:Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. For pediatric and adolescent patients with asthma who require addition of a LABA to an inhaled corticosteroid, a fixed-dose combination product containing both an inhaled corticosteroid and a LABA should ordinarily be used to ensure adherence with both drugs. In cases where use of a separate long-term asthma control medication (e.g., inhaled corticosteroid) and a LABA is clinically indicated, appropriate steps must be taken to ensure adherence with both treatment components. If adherence cannot be assured, a fixed-dose combination product containing both an inhaled corticosteroid and a LABA is recommended.
- The Salmeterol Multi-center Asthma Research Trial (SMART) was a large 28-week placebo-controlled US trial comparing the safety of salmeterol (SEREVENT® Inhalation Aerosol) with placebo, each added to usual asthma therapy, that showed an increase in asthma-related deaths in subjects receiving salmeterol . Given the similar basic mechanisms of action of beta2-agonists, the findings seen in the SMART trial are considered a class effect.
- A 16-week clinical trial performed in the United Kingdom, the Salmeterol Nationwide Surveillance (SNS) trial, showed results similar to the SMART trial. In the SNS trial, the rate of asthma-related death was numerically, though not statistically significantly, greater in subjects with asthma treated with salmeterol (42 mcg twice daily) than those treated with albuterol (180 mcg 4 times daily) added to usual asthma therapy.
- The SNS and SMART trials enrolled subjects with asthma. No trials have been conducted that were primarily designed to determine whether the rate of death in patients with COPD is increased by LABA.
- SEREVENT DISKUS should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of asthma or COPD. SEREVENT DISKUS has not been studied in subjects with acutely deteriorating asthma or COPD. The initiation of SEREVENT DISKUS in this setting is not appropriate.
- Serious acute respiratory events, including fatalities, have been reported when salmeterol has been initiated in patients with significantly worsening or acutely deteriorating asthma. In most cases, these have occurred in patients with severe asthma (e.g., patients with a history of corticosteroid dependence, low pulmonary function, intubation, mechanical ventilation, frequent hospitalizations, previous life-threatening acute asthma exacerbations) and in some patients with acutely deteriorating asthma (e.g., patients with significantly increasing symptoms; increasing need for inhaled, short-acting beta2-agonists; decreasing response to usual medications; increasing need for systemic corticosteroids; recent emergency room visits; deteriorating lung function). However, these events have occurred in a few patients with less severe asthma as well. It was not possible from these reports to determine whether salmeterol contributed to these events.
- Increasing use of inhaled, short-acting beta2-agonists is a marker of deteriorating asthma. In this situation, the patient requires immediate reevaluation with reassessment of the treatment regimen, giving special consideration to the possible need for adding additional inhaled corticosteroid or initiating systemic corticosteroids. Patients should not use more than 1 inhalation twice daily of SEREVENT DISKUS.
- SEREVENT DISKUS should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. An inhaled, short-acting beta2-agonist, not SEREVENT DISKUS, should be used to relieve acute symptoms such as shortness of breath. When prescribing SEREVENT DISKUS, the healthcare provider should also prescribe an inhaled, short-acting beta2-agonist (e.g., albuterol) for treatment of acute symptoms.
- When beginning treatment with SEREVENT DISKUS, patients who have been taking oral or inhaled, short-acting beta2-agonists on a regular basis (e.g., 4 times a day) should be instructed to discontinue the regular use of these drugs.
- There are no data demonstrating that SEREVENT DISKUS has a clinical anti-inflammatory effect such as that associated with corticosteroids. When initiating and throughout treatment with SEREVENT DISKUS in patients receiving oral or inhaled corticosteroids for treatment of asthma, patients must continue taking a suitable dosage of corticosteroids to maintain clinical stability even if they feel better as a result of initiating SEREVENT DISKUS. Any change in corticosteroid dosage should be made ONLY after clinical evaluation.
- SEREVENT DISKUS should not be used more often than recommended, at higher doses than recommended, or in conjunction with other medicines containing LABA, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Patients using SEREVENT DISKUS should not use another medicine containing a LABA (e.g., formoterol fumarate, arformoterol tartrate, indacaterol) for any reason.
- As with other inhaled medicines, SEREVENT DISKUS can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with SEREVENT DISKUS, it should be treated immediately with an inhaled, short-acting bronchodilator. SEREVENT DISKUS should be discontinued immediately, and alternative therapy should be instituted. Upper airway symptoms of laryngeal spasm, irritation, or swelling, such as stridor and choking, have been reported in patients receiving SEREVENT DISKUS.
- Excessive beta-adrenergic stimulation has been associated with seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min, arrhythmias, nervousness, headache, tremor, palpitation, nausea, dizziness, fatigue, malaise, and insomnia . Therefore, SEREVENT DISKUS, like all products containing sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.
- Salmeterol can produce a clinically significant cardiovascular effect in some patients as measured by pulse rate, blood pressure, and/or symptoms. Although such effects are uncommon after administration of salmeterol at recommended doses, if they occur, the drug may need to be discontinued. In addition, beta-agonists have been reported to produce electrocardiogram (ECG) changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression. The clinical significance of these findings is unknown. Large doses of inhaled or oral salmeterol (12 to 20 times the recommended dose) have been associated with clinically significant prolongation of the QTc interval, which has the potential for producing ventricular arrhythmias. Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs.
- Immediate hypersensitivity reactions (e.g., urticaria, angioedema, rash, bronchospasm, hypotension), including anaphylaxis, may occur after administration of SEREVENT DISKUS. There have been reports of anaphylactic reactions in patients with severe milk protein allergy after inhalation of powder products containing lactose; therefore, patients with severe milk protein allergy should not use SEREVENT DISKUS .
- The use of strong cytochrome P450 3A4 (CYP3A4) inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, ketoconazole, telithromycin) with SEREVENT DISKUS is not recommended because increased cardiovascular adverse effects may occur .
- SEREVENT DISKUS, like all medicines containing sympathomimetic amines, should be used with caution in patients with convulsive disorders or thyrotoxicosis and in those who are unusually responsive to sympathomimetic amines. Doses of the related beta2-adrenoceptor agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis.
- Beta-adrenergic agonist medicines may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects . The decrease in serum potassium is usually transient, not requiring supplementation. Clinically significant and dose-related changes in blood glucose and/or serum potassium were seen infrequently during clinical trials with SEREVENT DISKUS at recommended doses.
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- Adult and Adolescent Subjects Aged 12 Years and Older: Two multicenter, 12-week, placebo-controlled clinical trials evaluated twice-daily doses of SEREVENT DISKUS in subjects aged 12 years and older with asthma. Table 1 reports the incidence of adverse reactions in these 2 trials.
- Table 1 includes all events (whether considered drug-related or nondrug-related by the investigator) that occurred at a rate of ≥3% in the group treated with SEREVENT DISKUS and were more common than in the placebo group.
- Pharyngitis, sinusitis, upper respiratory tract infection, and cough occurred at ≥3% but were more common in the placebo group. However, throat irritation has been described at rates exceeding that of placebo in other controlled clinical trials.
- Additional Adverse Reactions:
- Other adverse reactions not previously listed, whether considered drug-related or not by the investigators, that were reported more frequently by subjects with asthma treated with SEREVENT DISKUS compared with subjects treated with placebo include the following: contact dermatitis, eczema, localized aches and pains, nausea, oral mucosal abnormality, pain in joint, paresthesia, pyrexia of unknown origin, sinus headache, and sleep disturbance.
- Pediatric Subjects Aged 4 to 11 Years:
- Two multicenter, 12-week, controlled trials have evaluated twice-daily doses of SEREVENT DISKUS in subjects aged 4 to 11 years with asthma. Table 2 includes all events (whether considered drug-related or nondrug-related by the investigator) that occurred at a rate of 3% or greater in the group receiving SEREVENT DISKUS and were more common than in the placebo group.
- The following events were reported at an incidence of >1% in the salmeterol group and with a higher incidence than in the albuterol and placebo groups: gastrointestinal signs and symptoms, lower respiratory signs and symptoms, photodermatitis, and arthralgia and articular rheumatism.
- In clinical trials evaluating concurrent therapy of salmeterol with inhaled corticosteroids, adverse events were consistent with those previously reported for salmeterol, or with events that would be expected with the use of inhaled corticosteroids.
- Laboratory Test Abnormalities:
- Elevation of hepatic enzymes was reported in ≥1% of subjects in clinical trials. The elevations were transient and did not lead to discontinuation from the trials. In addition, there were no clinically relevant changes noted in glucose or potassium.
- Two multicenter, 24-week, placebo-controlled US trials evaluated twice-daily doses of SEREVENT DISKUS in subjects with COPD. For presentation (Table 3), the placebo data from a third trial, identical in design, subject entrance criteria, and overall conduct but comparing fluticasone propionate with placebo, were integrated with the placebo data from these 2 trials (total N = 341 for salmeterol and 576 for placebo).
- aTable 3 includes all events (whether considered drug-related or nondrug-related by the investigator) that occurred at a rate of 3% or greater in the group receiving SEREVENT DISKUS and were more common in the group receiving SEREVENT DISKUS than in the placebo group.
- Additional Adverse Reactions:
- Other adverse reactions occurring in the group receiving SEREVENT DISKUS that occurred at a frequency of ≥1% and were more common than in the placebo group were as follows: anxiety; arthralgia and articular rheumatism; bone and skeletal pain; candidiasis mouth/throat; dental discomfort and pain; dyspeptic symptoms; edema and swelling; gastrointestinal infections; hyperglycemia; hyposalivation; keratitis and conjunctivitis; lower respiratory signs and symptoms; migraines; muscle pain; muscle stiffness, tightness, and rigidity; musculoskeletal inflammation; pain; and skin rashes.
- Adverse reactions to salmeterol are similar in nature to those seen with other selective beta2-adrenoceptor agonists, e.g., tachycardia; palpitations; immediate hypersensitivity reactions, including urticaria, angioedema, rash, bronchospasm; headache; tremor; nervousness; and paradoxical bronchospasm.
- Laboratory Abnormalities:
- There were no clinically relevant changes in these trials. Specifically, no changes in potassium were noted.
- In extensive US and worldwide postmarketing experience with salmeterol, serious exacerbations of asthma, including some that have been fatal, have been reported. In most cases, these have occurred in patients with severe asthma and/or in some patients in whom asthma has been acutely deteriorating , but they have also occurred in a few patients with less severe asthma. It was not possible from these reports to determine whether salmeterol contributed to these events.
- Arrhythmias (including atrial fibrillation, supraventricular tachycardia, extrasystoles) and anaphylaxis.
- Very rare anaphylactic reaction in patients with severe milk protein allergy.
- Reports of upper airway symptoms of laryngeal spasm, irritation, or swelling such as stridor or choking; oropharyngeal irritation.
- Salmeterol is a substrate of CYP3A4. The use of strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, ketoconazole, telithromycin) with SEREVENT DISKUS is not recommended because increased cardiovascular adverse effects may occur.
- In a drug interaction trial in 20 healthy subjects, coadministration of inhaled salmeterol (50 mcg twice daily) and oral ketoconazole (400 mg once daily) for 7 days resulted in greater systemic exposure to salmeterol (AUC increased 16-fold and Cmax increased 1.4-fold). Three (3) subjects were withdrawn due to beta2-agonist side effects (2 with prolonged QTc and 1 with palpitations and sinus tachycardia). Although there was no statistical effect on the mean QTc, coadministration of salmeterol and ketoconazole was associated with more frequent increases in QTc duration compared with salmeterol and placebo administration.
- SEREVENT DISKUS should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants, or within 2 weeks of discontinuation of such agents, because the action of salmeterol on the vascular system may be potentiated by these agents.
- Beta-blockers not only block the pulmonary effect of beta-agonists, such as SEREVENT DISKUS, but may also produce severe bronchospasm in patients with asthma or COPD. Therefore, patients with asthma or COPD should not normally be treated with beta-blockers. However, under certain circumstances, there may be no acceptable alternatives to the use of beta-adrenergic blocking agents for these patients; cardioselective beta-blockers could be considered, although they should be administered with caution.
- The ECG changes and/or hypokalemia that may result from the administration of non–potassium-sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is not known, caution is advised in the coadministration of SEREVENT DISKUS with non–potassium-sparing diuretics.
- No teratogenic effects occurred in rats at salmeterol doses approximately 160 times the maximum recommended daily inhalation dose (MRHDID) (on a mg/m2 basis at maternal oral doses up to 2 mg/kg/day). In pregnant Dutch rabbits administered oral doses approximately 50 times the MRHDID (on an AUC basis at maternal oral doses of 1 mg/kg/day and higher), fetal toxic effects were observed characteristically resulting from beta-adrenoceptor stimulation. These included precocious eyelid openings, cleft palate, sternebral fusion, limb and paw flexures, and delayed ossification of the frontal cranial bones. No such effects occurred at a salmeterol dose approximately 20 times the MRHDID (on an AUC basis at a maternal oral dose of 0.6 mg/kg/day).
- New Zealand White rabbits were less sensitive since only delayed ossification of the frontal cranial bones was seen at an oral dose approximately 1,600 times the MRHDID (on n mg/m2 basis at a maternal oral dose of 10 mg/kg/day).
- Salmeterol crossed the placenta following oral administration to mice and rats.
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Salmeterol in women who are pregnant.
- The safety and efficacy of SEREVENT DISKUS in adolescents (aged 12 years and older) have been established based on adequate and well-controlled trials conducted in adults and adolescents . A large 28-week placebo-controlled US trial comparing salmeterol (SEREVENT Inhalation Aerosol) and placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in subjects receiving salmeterol . Post-hoc analyses in pediatric subjects aged 12 to 18 years were also performed. Pediatric subjects accounted for approximately 12% of subjects in each treatment arm. Respiratory-related death or life-threatening experience occurred at a similar rate in the salmeterol group (0.12% ) and the placebo group (0.12% ; relative risk: 1.0 ). All-cause hospitalization, however, was increased in the salmeterol group (2% ) versus the placebo group (<1% ; relative risk: 2.1 ).
- The safety and efficacy of SEREVENT DISKUS have been evaluated in over 2,500 subjects aged 4 to 11 years with asthma, 346 of whom were administered SEREVENT DISKUS for 1 year. Based on available data, no adjustment of dosage of SEREVENT DISKUS in pediatric patients is warranted for either asthma or EIB.
- In 2 randomized, double-blind, controlled clinical trials of 12 weeks’ duration, SEREVENT DISKUS 50 mcg was administered to 211 pediatric subjects with asthma who did and who did not receive concurrent inhaled corticosteroids. The efficacy of SEREVENT DISKUS was demonstrated over the 12-week treatment period with respect to peak expiratory flow (PEF) and forced expiratory volume in 1 second (FEV1). SEREVENT DISKUS was effective in demographic subgroups (gender and age) of the population.
- In 2 randomized trials in children aged 4 to 11 years with asthma and EIB, a single 50-mcg dose of SEREVENT DISKUS prevented EIB when dosed 30 minutes prior to exercise, with protection lasting up to 11.5 hours in repeat testing following this single dose in many subjects.
- Description
- As with all inhaled sympathomimetic medicines, cardiac arrest and even death may be associated with an overdose of SEREVENT DISKUS.
- Treatment consists of discontinuation of SEREVENT DISKUS together with appropriate symptomatic therapy. The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medication can produce bronchospasm. There is insufficient evidence to determine if dialysis is beneficial for overdosage of SEREVENT DISKUS. Cardiac monitoring is recommended in cases of overdosage.
- The pharmacologic effects of beta2-adrenoceptor agonist drugs, including salmeterol, are at least in part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3′,5′-adenosine monophosphate (cyclic AMP). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells.
- In vitro tests show that salmeterol is a potent and long-lasting inhibitor of the release of mast cell mediators, such as histamine, leukotrienes, and prostaglandin D2, from human lung. Salmeterol inhibits histamine-induced plasma protein extravasation and inhibits platelet-activating factor–induced eosinophil accumulation in the lungs of guinea pigs when administered by the inhaled route. In humans, single doses of salmeterol administered via inhalation aerosol attenuate allergen-induced bronchial hyper-responsiveness.
- The effects of rising inhaled doses of salmeterol and standard inhaled doses of albuterol were studied in volunteers and in subjects with asthma. Salmeterol doses up to 84 mcg administered as inhalation aerosol resulted in heart rate increases of 3 to 16 beats/min, about the same as albuterol dosed at 180 mcg by inhalation aerosol (4 to 10 beats/min). Adult and adolescent subjects receiving 50-mcg doses of salmeterol inhalation powder (n = 60) underwent continuous electrocardiographic monitoring during two 12-hour periods after the first dose and after 1 month of therapy, and no clinically significant dysrhythmias were noted. Also, pediatric patients receiving 50-mcg doses of salmeterol inhalation powder (n = 67) underwent continuous electrocardiographic monitoring during two 12-hour periods after the first dose and after 3 months of therapy, and no clinically significant dysrhythmias were noted.
- In 24-week clinical studies in patients with COPD, the incidence of clinically significant abnormalities on the predose ECGs at Weeks 12 and 24 in patients who received salmeterol 50 mcg was not different compared with placebo.
- No effect of treatment with salmeterol 50 mcg was observed on pulse rate and systolic and diastolic blood pressure in a subset of patients with COPD who underwent 12-hour serial vital sign measurements after the first dose (n = 91) and after 12 weeks of therapy (n = 74). Median changes from baseline in pulse rate and systolic and diastolic blood pressure were similar for patients receiving either salmeterol or placebo .
- Short-Acting Beta2-Agonists: In two 12-week repetitive-dose clinical trials in adult and adolescent subjects with asthma (N = 149), the mean daily need for additional beta2-agonist in subjects using SEREVENT DISKUS was approximately 1½ inhalations/day. Twenty-six percent (26%) of the subjects in these trials used between 8 and 24 inhalations of short-acting beta-agonist per day on 1 or more occasions. Nine percent (9%) of the subjects in these trials averaged over 4 inhalations/day over the course of the 12-week trials. No increase in frequency of cardiovascular events was observed among the 3 subjects who averaged 8 to 11 inhalations/day; however, the safety of concomitant use of more than 8 inhalations/day of short-acting beta2-agonist with SEREVENT DISKUS has not been established. In 29 subjects who experienced worsening of asthma while receiving SEREVENT DISKUS during these trials, albuterol therapy administered via either nebulizer or inhalation aerosol (1 dose in most cases) led to improvement in FEV1 and no increase in occurrence of cardiovascular adverse events.
- In 2 clinical trials in subjects with COPD, the mean daily need for additional beta2-agonist for subjects using SEREVENT DISKUS was approximately 4 inhalations/day. Twenty-four percent (24%) of subjects using SEREVENT DISKUS averaged 6 or more inhalations of albuterol per day over the course of the 24-week trials. No increase in frequency of cardiovascular adverse reactions was observed among subjects who averaged 6 or more inhalations per day.
- The concurrent use of intravenously or orally administered methylxanthines (e.g., aminophylline, theophylline) by subjects receiving salmeterol has not been completely evaluated. In 1 clinical trial in subjects with asthma, 87 subjects receiving SEREVENT Inhalation Aerosol 42 mcg twice daily concurrently with a theophylline product had adverse event rates similar to those in 71 subjects receiving SEREVENT Inhalation Aerosol without theophylline. Resting heart rates were slightly higher in the subjects on theophylline but were little affected by therapy with SEREVENT Inhalation Aerosol.
- In 2 clinical trials in subjects with COPD, 39 subjects receiving SEREVENT DISKUS concurrently with a theophylline product had adverse event rates similar to those in 302 subjects receiving SEREVENT DISKUS without theophylline. Based on the available data, the concomitant administration of methylxanthines with SEREVENT DISKUS did not alter the observed adverse event profile.
- In clinical trials, inhaled cromolyn sodium did not alter the safety profile of salmeterol when administered concurrently.
- Because of the small therapeutic dose, systemic levels of salmeterol are low or undetectable after inhalation of recommended doses (50 mcg of salmeterol inhalation powder twice daily). Following chronic administration of an inhaled dose of 50 mcg of salmeterol inhalation powder twice daily, salmeterol was detected in plasma within 5 to 45 minutes in 7 subjects with asthma; plasma concentrations were very low, with mean peak concentrations of 167 pg/mL at 20 minutes and no accumulation with repeated doses.
- The percentage of salmeterol bound to human plasma proteins averages 96% in vitro over the concentration range of 8 to 7,722 ng of salmeterol base per milliliter, much higher concentrations than those achieved following therapeutic doses of salmeterol.
- Salmeterol base is extensively metabolized by hydroxylation, with subsequent elimination predominantly in the feces. No significant amount of unchanged salmeterol base was detected in either urine or feces.
- An in vitro study using human liver microsomes showed that salmeterol is extensively metabolized to α-hydroxysalmeterol (aliphatic oxidation) by CYP3A4. Ketoconazole, a strong inhibitor of CYP3A4, essentially completely inhibited the formation of α-hydroxysalmeterol in vitro.
- In 2 healthy adult subjects who received 1 mg of radiolabeled salmeterol (as salmeterol xinafoate) orally, approximately 25% and 60% of the radiolabeled salmeterol was eliminated in urine and feces, respectively, over a period of 7 days. The terminal elimination half-life was about 5.5 hours (1 volunteer only).
- The xinafoate moiety has no apparent pharmacologic activity. The xinafoate moiety is highly protein bound (>99%) and has a long elimination half-life of 11 days.
# Drug Interactions
- Ketoconazole:
- In a placebo-controlled crossover drug interaction trial in 20 healthy male and female subjects, coadministration of salmeterol (50 mcg twice daily) and the strong CYP3A4 inhibitor ketoconazole (400 mg once daily) for 7 days resulted in a significant increase in plasma salmeterol exposure as determined by a 16-fold increase in AUC (ratio with and without ketoconazole 15.76 ) mainly due to increased bioavailability of the swallowed portion of the dose. Peak plasma salmeterol concentrations were increased by 1.4-fold (90% CI: 1.23, 1.68). Three (3) out of 20 subjects (15%) were withdrawn from salmeterol and ketoconazole coadministration due to beta-agonist–mediated systemic effects (2 with QTc prolongation and 1 with palpitations and sinus tachycardia). Coadministration of salmeterol and ketoconazole did not result in a clinically significant effect on mean heart rate, mean blood potassium, or mean blood glucose. Although there was no statistical effect on the mean QTc, coadministration of salmeterol and ketoconazole was associated with more frequent increases in QTc duration compared with salmeterol and placebo administration.
- Erythromycin:
- In a repeat-dose trial in 13 healthy subjects, concomitant administration of erythromycin (a moderate CYP3A4 inhibitor) and salmeterol inhalation aerosol resulted in a 40% increase in salmeterol Cmax at steady state (ratio with and without erythromycin 1.4 , P = 0.12), a 3.6-beat/min increase in heart rate (, P <0.04), a 5.8-msec increase in QTc interval (, P = 0.34), and no change in plasma potassium.
- In an 18-month carcinogenicity study in CD-mice, salmeterol at oral doses of 1.4 mg/kg and above (approximately 20 times the MRHDID for adults and children based on comparison of the plasma AUCs) caused a dose-related increase in the incidence of smooth muscle hyperplasia, cystic glandular hyperplasia, leiomyomas of the uterus, and ovarian cysts. No tumors were seen at 0.2 mg/kg (approximately 3 times the MRHDID for adults and children based on comparison of the AUCs).
- In a 24-month oral and inhalation carcinogenicity study in Sprague Dawley rats, salmeterol caused a dose-related increase in the incidence of mesovarian leiomyomas and ovarian cysts at doses of 0.68 mg/kg and above (approximately 55 and 25 times the MRHDID for adults and children, respectively, on a mg/m2 basis). No tumors were seen at 0.21 mg/kg (approximately 15 and 8 times the MRHDID for adults and children, respectively, on a mg/m2 basis). These findings in rodents are similar to those reported previously for other beta-adrenergic agonist drugs. The relevance of these findings to human use is unknown.
- Salmeterol produced no detectable or reproducible increases in microbial and mammalian gene mutation in vitro. No clastogenic activity occurred in vitro in human lymphocytes or in vivo in a rat micronucleus test. No effects on fertility were identified in rats treated with salmeterol at oral doses up to 2 mg/kg (approximately 160 times the MRHDID for adults on a mg/m2 basis).
- Preclinical: Studies in laboratory animals (minipigs, rodents, and dogs) have demonstrated the occurrence of cardiac arrhythmias and sudden death (with histologic evidence of myocardial necrosis) when beta-agonists and methylxanthines are administered concurrently. The clinical relevance of these findings is unknown.
- The initial trials supporting the approval of SEREVENT DISKUS for the treatment of asthma did not require the regular use of inhaled corticosteroids. However, for the treatment of asthma, SEREVENT DISKUS is currently indicated only as concomitant therapy with an inhaled corticosteroid .
- Adult and Adolescent Subjects Aged 12 Years and Older: In 2 randomized double-blind trials, SEREVENT DISKUS was compared with albuterol inhalation aerosol and placebo in adolescent and adult subjects with mild-to-moderate asthma (protocol defined as 50% to 80% predicted FEV1, actual mean of 67.7% at baseline), including subjects who did and who did not receive concurrent inhaled corticosteroids. The efficacy of SEREVENT DISKUS was demonstrated over the 12-week period with no change in effectiveness over this time period (see Figure 1). There were no gender- or age-related differences in safety or efficacy. No development of tachyphylaxis to the bronchodilator effect was noted in these trials. FEV1 measurements (mean change from baseline) from these two 12-week trials are shown in Figure 1 for both the first and last treatment days.
- Table 4 shows the treatment effects seen during daily treatment with SEREVENT DISKUS for 12 weeks in adolescent and adult subjects with mild-to-moderate asthma.
- aStatistically superior to placebo and albuterol (P<0.001).
- bStatistically superior to placebo (P<0.001).
- Maintenance of efficacy for periods up to 1 year has been documented.
- SEREVENT DISKUS and SEREVENT Inhalation Aerosol were compared with placebo in 2 additional randomized double-blind clinical trials in adolescent and adult subjects with mild-to-moderate asthma. SEREVENT DISKUS 50 mcg and SEREVENT Inhalation Aerosol 42 mcg, both administered twice daily, produced significant improvements in pulmonary function compared with placebo over the 12-week period. While no statistically significant differences were observed between the active treatments for any of the efficacy assessments or safety evaluations performed, there were some efficacy measures on which the metered-dose inhaler appeared to provide better results. Similar findings were noted in 2 randomized, single-dose, crossover comparisons of SEREVENT DISKUS and SEREVENT Inhalation Aerosol for the prevention of EIB. Therefore, while SEREVENT DISKUS was comparable to SEREVENT Inhalation Aerosol in clinical trials in mild-to-moderate subjects with asthma, it should not be assumed that they will produce clinically equivalent outcomes in all subjects.
- In 4 clinical trials in adult and adolescent subjects with asthma (N = 1,922), the effect of adding SEREVENT Inhalation Aerosol to inhaled corticosteroid therapy was evaluated over a 24-week treatment period. The trials compared the addition of salmeterol therapy to an increase (at least doubling) of the inhaled corticosteroid dose.
- Two randomized, double-blind, controlled, parallel-group clinical trials (N = 997) enrolled subjects (aged 18 to 82 years) with persistent asthma who were previously maintained but not adequately controlled on inhaled corticosteroid therapy. During the 2-week run-in period, all subjects were switched to beclomethasone dipropionate (BDP) 168 mcg twice daily. Subjects still not adequately controlled were randomized to either the addition of SEREVENT Inhalation Aerosol 42 mcg twice daily or an increase of BDP to 336 mcg twice daily. As compared with the doubled dose of BDP, the addition of SEREVENT Inhalation Aerosol resulted in statistically significantly greater improvements in pulmonary function and asthma symptoms, and statistically significantly greater reduction in supplemental albuterol use. The percent of subjects who experienced asthma exacerbations overall was not different between groups (i.e., 16.2% in the group receiving SEREVENT Inhalation Aerosol versus 17.9% in the higher-dose beclomethasone dipropionate group).
- Two randomized, double-blind, controlled, parallel-group clinical trials (N = 925) enrolled subjects (aged 12 to 78 years) with persistent asthma who were previously maintained but not adequately controlled on prior asthma therapy. During the 2- to 4-week run-in period, all subjects were switched to fluticasone propionate 88 mcg twice daily. Subjects still not adequately controlled were randomized to either the addition of SEREVENT Inhalation Aerosol 42 mcg twice daily or an increase of fluticasone propionate to 220 mcg twice daily. As compared with the increased (2.5 times) dose of fluticasone propionate, the addition of SEREVENT Inhalation Aerosol resulted in statistically significantly greater improvements in pulmonary function and asthma symptoms, and statistically significantly greater reductions in supplemental albuterol use. Fewer subjects receiving SEREVENT Inhalation Aerosol experienced asthma exacerbations than those receiving the higher dose of fluticasone propionate (8.8% versus 13.8%).
- Table 5 shows the treatment effects seen during daily treatment with SEREVENT Inhalation Aerosol for 24 weeks in adolescent and adult subjects with mild-to-moderate asthma.
- During the initial treatment day in several multiple-dose clinical trials with SEREVENT DISKUS in subjects with asthma, the median time to onset of clinically significant bronchodilatation (≥15% improvement in FEV1) ranged from 30 to 48 minutes after a 50-mcg dose.
- One hour after a single dose of 50 mcg of SEREVENT DISKUS, the majority of subjects had ≥15% improvement in FEV1. Maximum improvement in FEV1 generally occurred within 180 minutes, and clinically significant improvement continued for 12 hours in most subjects.
- In a randomized, double-blind, controlled trial (N = 449), 50 mcg of SEREVENT DISKUS was administered twice daily to pediatric subjects with asthma who did and who did not receive concurrent inhaled corticosteroids. The efficacy of salmeterol inhalation powder was demonstrated over the 12-week treatment period with respect to periodic serial PEF (36% to 39% postdose increase from baseline) and FEV1 (32% to 33% postdose increase from baseline). Salmeterol was effective in demographic subgroup analyses (gender and age) and was effective when coadministered with other inhaled asthma medications such as short-acting bronchodilators and inhaled corticosteroids. A second randomized, double-blind, placebo-controlled trial (N = 207) with 50 mcg of salmeterol inhalation powder via an alternate device supported the findings of the trial with the DISKUS.
- The SMART trial was a randomized double-blind trial that enrolled LABA-naive subjects with asthma (average age of 39 years; 71% Caucasian, 18% African American, 8% Hispanic) to assess the safety of salmeterol (SEREVENT Inhalation Aerosol) 42 mcg twice daily over 28 weeks compared with placebo when added to usual asthma therapy.
- A planned interim analysis was conducted when approximately half of the intended number of subjects had been enrolled (N = 26,355), which led to premature termination of the trial. The results of the interim analysis showed that subjects receiving salmeterol were at increased risk for fatal asthma events (see Table 5 and Figure 2). In the total population, a higher rate of asthma-related death occurred in subjects treated with salmeterol than those treated with placebo (0.10% versus 0.02%, relative risk: 4.37 ).
- Post-hoc subpopulation analyses were performed. In Caucasians, asthma-related death occurred at a higher rate in subjects treated with salmeterol than in subjects treated with placebo (0.07% versus 0.01%, relative risk: 5.82 ). In African Americans also, asthma-related death occurred at a higher rate in subjects treated with salmeterol than those treated with placebo (0.31% versus 0.04%, relative risk: 7.26 ). Although the relative risks of asthma-related death were similar in Caucasians and African Americans, the estimate of excess deaths in subjects treated with salmeterol was greater in African Americans because there was a higher overall rate of asthma-related death in African American subjects (see Table 5).
- Post-hoc analyses in pediatric subjects aged 12 to 18 years were also performed. Pediatric subjects accounted for approximately 12% of subjects in each treatment arm. Respiratory-related death or life-threatening experience occurred at a similar rate in the salmeterol group (0.12% ) and the placebo group (0.12% ; relative risk: 1.0 ). All-cause hospitalization, however, was increased in the salmeterol group (2% ) versus the placebo group (<1% ; relative risk: 2.1 ).
- The data from the SMART trial are not adequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma control therapy mitigates the risk of asthma-related death.
- aLife-table 28-week estimate, adjusted according to the subjects’ actual lengths of exposure to study treatment to account for early withdrawal of subjects from the study.
- bRelative risk is the ratio of the rate of asthma-related death in the salmeterol group and the rate in the placebo group. The relative risk indicates how many more times likely an asthma-related death occurred in the salmeterol group than in the placebo group in a 28-week treatment period.
- cEstimate of the number of additional asthma-related deaths in subjects treated with salmeterol in SMART, assuming 10,000 subjects received salmeterol for a 28-week treatment period. Estimate calculated as the difference between the salmeterol and placebo groups in the rates of asthma-related death multiplied by 10,000.
- dThe Total Population includes the following ethnic origins listed on the case report form: Caucasian, African American, Hispanic, Asian, and “Other.” In addition, the Total Population includes those subjects whose ethnic origin was not reported. The results for Caucasian and African American subpopulations are shown above. No asthma-related deaths occurred in the Hispanic (salmeterol n = 996, placebo n = 999), Asian (salmeterol n = 173, placebo n = 149), or “Other” (salmeterol n = 230, placebo n = 224) subpopulations. One asthma-related death occurred in the placebo group in the subpopulation whose ethnic origin was not reported (salmeterol n = 130, placebo n = 127).
- In 2 randomized, single-dose, crossover trials in adolescents and adults with EIB (N = 52), 50 mcg of SEREVENT DISKUS prevented EIB when dosed 30 minutes prior to exercise. For some subjects, this protective effect against EIB was still apparent up to 8.5 hours following a single dose (see Table 6).
- In 2 randomized trials in children aged 4 to 11 years with asthma and EIB (N = 50), a single 50-mcg dose of SEREVENT DISKUS prevented EIB when dosed 30 minutes prior to exercise, with protection lasting up to 11.5 hours in repeat testing following this single dose in many subjects.
- In 2 clinical trials evaluating twice-daily treatment with SEREVENT DISKUS 50 mcg (n = 336) compared with placebo (n = 366) in subjects with chronic bronchitis with airflow limitation, with or without emphysema, improvements in pulmonary function endpoints were greater with salmeterol 50 mcg than with placebo. Treatment with SEREVENT DISKUS did not result in significant improvements in secondary endpoints assessing COPD symptoms in either clinical trial. Both trials were randomized, double-blind, parallel-group trials of 24 weeks’ duration and were identical in design, subject entrance criteria, and overall conduct.
- Figure 3 displays the integrated 2-hour postdose FEV1 results from the 2 clinical trials. The percent change in FEV1 refers to the change from baseline, defined as the predose value on Treatment Day 1. To account for subject withdrawals during the trial, Endpoint (last evaluable FEV1) data are provided. Subjects receiving SEREVENT DISKUS 50 mcg had significantly greater improvements in 2-hour postdose FEV1 at Endpoint (216 mL, 20%) compared with placebo (43 mL, 5%). Improvement was apparent on the first day of treatment and maintained throughout the 24 weeks of treatment.
- Onset of Action and Duration of Effect:
- The onset of action and duration of effect of SEREVENT DISKUS were evaluated in a subset of subjects (n = 87) from 1 of the 2 clinical trials discussed above. Following the first 50-mcg dose, significant improvement in pulmonary function (mean FEV1 increase of 12% or more and at least 200 mL) occurred at 2 hours. The mean time to peak bronchodilator effect was 4.75 hours. As seen in Figure 4, evidence of bronchodilatation was seen throughout the 12-hour period. Figure 4 also demonstrates that the bronchodilating effect after 12 weeks of treatment was similar to that observed after the first dose. The mean time to peak bronchodilator effect after 12 weeks of treatment was 3.27 hours.
- Serevent Diskus is also supplied in an institutional pack containing 28 blisters (NDC 0173-0520-00).
- Store in a dry place away from direct heat or sunlight.
- Keep out of reach of children.
- SEREVENT DISKUS should be stored inside the unopened moisture-protective foil pouch and only removed from the pouch immediately before initial use. Discard SEREVENT DISKUS 6 weeks after opening the foil pouch or when the counter reads “0” (after all blisters have been used), whichever comes first. The inhaler is not reusable. Do not attempt to take the inhaler apart.
NDC 0173-0521-00
Serevent®Diskus®
(salmeterol xinafoate inhalation powder)
50 mcg
FOR ORAL INHALATION ONLY
Each blister contains 50 mcg of salmeterol base with lactose monohydrate.
Federal Law requires the dispensing of SEREVENT DISKUS with the Medication Guide inside the carton.
See prescribing information for dosing information.
Rx only
1 DISKUS® Inhalation Device Containing 1 Foil Strip of 60 Blisters
Made in Singapore
©2013, GlaxoSmithKline
10000000117746 Rev. 8/13
NDC 0173-0520-00
Serevent®Diskus®
(salmeterol xinafoate inhalation powder)
INSTITUTIONAL PACK
50 mcg
FOR ORAL INHALATION ONLY
Each blister contains 50 mcg of salmeterol base with lactose monohydrate.
Federal Law requires the dispensing of SEREVENT DISKUS with the Medication Guide inside the carton.
See prescribing information for dosing information.
Rx only
1 DISKUS® Inhalation Device Containing 1 Foil Strip of 28 Blisters
Made in Singapore
©2013, GlaxoSmithKline
10000000117744 Rev. 8/13
- Inform patients that salmeterol increases the risk of asthma-related death and may increase the risk of asthma-related hospitalization in pediatric and adolescent patients. Inform patients that SEREVENT DISKUS should not be the only therapy for the treatment of asthma and must only be used as additional therapy when long-term asthma control medications (e.g., inhaled corticosteroids) do not adequately control asthma symptoms. Also inform them that currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA.Inform patients that when SEREVENT DISKUS is added to their treatment regimen they must continue to use their long-term asthma control medication.
- Inform patients that SEREVENT DISKUS is not meant to relieve acute asthma symptoms or exacerbations of COPD and extra doses should not be used for that purpose. Advise patients to treat acute symptoms with an inhaled, short-acting beta2-agonist such as albuterol. Provide patients with such medication and instruct them in how it should be used.
- Instruct patients to seek medical attention immediately if they experience any of the following:
- Decreasing effectiveness of inhaled, short-acting beta 2-agonists
- Need for more inhalations than usual of inhaled, short-acting beta 2-agonists
- Significant decrease in lung function as outlined by the physician
- Tell patients they should not stop therapy with SEREVENT DISKUS without physician/provider guidance since symptoms may recur after discontinuation.
- Advise all patients with asthma that they must also continue regular maintenance treatment with an inhaled corticosteroid if they are taking SEREVENT DISKUS.
- SEREVENT DISKUS should not be used as a substitute for oral or inhaled corticosteroids. The dosage of these medications should not be changed and they should not be stopped without consulting the physician, even if the patient feels better after initiating treatment with SEREVENT DISKUS.
- Instruct patients not to use other LABA.
- Advise patients that immediate hypersensitivity reactions (e.g., urticaria, angioedema, rash, bronchospasm, hypotension), including anaphylaxis, may occur after administration of SEREVENT DISKUS. Patients should discontinue SEREVENT DISKUS if such reactions occur. There have been reports of anaphylactic reactions in patients with severe milk protein allergy after inhalation of powder products containing lactose; therefore, patients with severe milk protein allergy should not take SEREVENT DISKUS.
- Inform patients of adverse effects associated with beta2-agonists, such as palpitations, chest pain, rapid heart rate, tremor, or nervousness.
- Patients using SEREVENT DISKUS for the treatment of EIB should not use additional doses for 12 hours. Patients who are receiving SEREVENT DISKUS twice daily should not use additional SEREVENT for prevention of EIB.
- SEREVENT and DISKUS are registered trademarks of the GSK group of companies.
GlaxoSmithKline
Research Triangle Park, NC 27709
©2014, the GSK group of companies. All rights reserved.
SRD:10PI
# MEDICATION GUIDE | Salmeterol
- Because of this risk, use of SEREVENT DISKUS for the treatment of asthma without a concomitant long-term asthma control medication, such as an inhaled corticosteroid, is contraindicated. Use SEREVENT DISKUS only as additional therapy for patients with asthma who are currently taking but are inadequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue SEREVENT DISKUS) if possible without loss of asthma control and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do not use SEREVENT DISKUS for patients whose asthma is adequately controlled on low- or medium-dose inhaled corticosteroids.
- Pediatric and Adolescent Patients: Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. For pediatric and adolescent patients with asthma who require addition of a LABA to an inhaled corticosteroid, a fixed-dose combination product containing both an inhaled corticosteroid and a LABA should ordinarily be used to ensure adherence with both drugs. In cases where use of a separate long-term asthma control medication (e.g., inhaled corticosteroid) and a LABA is clinically indicated, appropriate steps must be taken to ensure adherence with both treatment components. If adherence cannot be assured, a fixed-dose combination product containing both an inhaled corticosteroid and a LABA is recommended.
- SEREVENT DISKUS is indicated for the treatment of asthma and in the prevention of bronchospasm only as concomitant therapy with a long-term asthma control medication, such as an inhaled corticosteroid, in patients aged 4 years and older with reversible obstructive airway disease, including patients with symptoms of nocturnal asthma. LABA, such as salmeterol, the active ingredient in SEREVENT DISKUS, increase the risk of asthma-related death [see Warnings and Precautions (5.1)]. Use of SEREVENT DISKUS for the treatment of asthma without concomitant use of a long-term asthma control medication, such as an inhaled corticosteroid, is contraindicated [see Contraindications (4)]. Use SEREVENT DISKUS only as additional therapy for patients with asthma who are currently taking but are inadequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue SEREVENT DISKUS) if possible without loss of asthma control and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do not use SEREVENT DISKUS for patients whose asthma is adequately controlled on low- or medium-dose inhaled corticosteroids.
Pediatric and Adolescent Patients: Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. For pediatric and adolescent patients with asthma who require addition of a LABA to an inhaled corticosteroid, a fixed-dose combination product containing both an inhaled corticosteroid and a LABA should ordinarily be used to ensure adherence with both drugs. In cases where use of a separate long-term asthma control medication (e.g., inhaled corticosteroid) and a LABA is clinically indicated, appropriate steps must be taken to ensure adherence with both treatment components. If adherence cannot be assured, a fixed-dose combination product containing both an inhaled corticosteroid and a LABA is recommended.
- SEREVENT DISKUS is NOT indicated for the relief of acute bronchospasm.
### Prevention of Exercise-Induced Bronchospasm
- SEREVENT DISKUS is also indicated for prevention of exercise-induced bronchospasm (EIB) in patients aged 4 years and older. Use of SEREVENT DISKUS as a single agent for the prevention of EIB may be clinically indicated in patients who do not have persistent asthma. In patients with persistent asthma, use of SEREVENT DISKUS for the prevention of EIB may be clinically indicated, but the treatment of asthma should include a long-term asthma control medication, such as an inhaled corticosteroid.
### Maintenance Treatment of Chronic Obstructive Pulmonary Disease
- SEREVENT DISKUS is indicated for the long-term twice-daily administration in the maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD) (including emphysema and chronic bronchitis).
- SEREVENT DISKUS is NOT indicated for the relief of acute bronchospasm.
### Dosing Information
- SEREVENT DISKUS should be administered by the orally inhaled route only.
- More frequent administration or a greater number of inhalations (more than 1 inhalation twice daily) is not recommended as some patients are more likely to experience adverse effects. Patients using SEREVENT DISKUS should not use additional LABA for any reason.
- LABA, such as salmeterol, the active ingredient in SEREVENT DISKUS, increase the risk of asthma-related death [see Warnings and Precautions (5.1)].
- Because of this risk, use of SEREVENT DISKUS for the treatment of asthma without concomitant use of a long-term asthma control medication, such as an inhaled corticosteroid is contraindicated. Use SEREVENT DISKUS only as additional therapy for patients with asthma who are currently taking but are inadequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue SEREVENT DISKUS) if possible without loss of asthma control and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do not use SEREVENT DISKUS for patients whose asthma is adequately controlled on low- or medium-dose inhaled corticosteroids.
- Pediatric and Adolescent Patients: Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. For patients with asthma younger than 18 years who require addition of a LABA to an inhaled corticosteroid, a fixed-dose combination product containing both an inhaled corticosteroid and a LABA should ordinarily be used to ensure adherence with both drugs. In cases where use of a separate long-term asthma control medication (e.g., inhaled corticosteroid) and a LABA is clinically indicated, appropriate steps must be taken to ensure adherence with both treatment components. If adherence cannot be assured, a fixed-dose combination product containing both an inhaled corticosteroid and a LABA is recommended.
- For bronchodilatation and prevention of symptoms of asthma, including the symptoms of nocturnal asthma, the usual dosage for adults and children aged 4 years and older is 1 inhalation (50 mcg) twice daily, approximately 12 hours apart. If a previously effective dosage regimen fails to provide the usual response, medical advice should be sought immediately as this is often a sign of destabilization of asthma. Under these circumstances, the therapeutic regimen should be reevaluated. If symptoms arise in the period between doses, an inhaled, short-acting beta2-agonist should be taken for immediate relief.
- Use of SEREVENT DISKUS as a single agent for the prevention of EIB may be clinically indicated in patients who do not have persistent asthma. In patients with persistent asthma, use of SEREVENT DISKUS for the prevention of EIB may be clinically indicated, but the treatment of asthma should include a long-term asthma control medication, such as an inhaled corticosteroid. One inhalation of SEREVENT DISKUS at least 30 minutes before exercise has been shown to protect patients against EIB. When used intermittently as needed for prevention of EIB, this protection may last up to 9 hours in adults and adolescents and up to 12 hours in patients aged 4 to 11 years. Additional doses of SEREVENT should not be used for 12 hours after the administration of this drug. Patients who are receiving SEREVENT DISKUS twice daily should not use additional SEREVENT for prevention of EIB.
- For maintenance treatment of bronchospasm associated with COPD (including chronic bronchitis and emphysema), the dosage for adults is 1 inhalation (50 mcg) twice daily approximately 12 hours apart.
- Cystic fibrosis
- High altitude pulmonary edema
- Occupational asthma
- The use of SEREVENT DISKUS is contraindicated in the following conditions:
- Primary treatment of status asthmaticus or other acute episodes of asthma or COPD where intensive measures are required.
- Severe hypersensitivity to milk proteins.
- LABA, such as salmeterol, the active ingredient in SEREVENT DISKUS, increase the risk of asthma-related death. Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA.
- Because of this risk, use of SEREVENT DISKUS for the treatment of asthma without concomitant use of a long-term asthma control medication, such as an inhaled corticosteroid, is contraindicated. Use SEREVENT DISKUS only as additional therapy for patients with asthma who are currently taking but are inadequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue SEREVENT DISKUS) if possible without loss of asthma control and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do not use SEREVENT DISKUS for patients whose asthma is adequately controlled on low- or medium-dose inhaled corticosteroids.
- Pediatric and Adolescent Patients:Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. For pediatric and adolescent patients with asthma who require addition of a LABA to an inhaled corticosteroid, a fixed-dose combination product containing both an inhaled corticosteroid and a LABA should ordinarily be used to ensure adherence with both drugs. In cases where use of a separate long-term asthma control medication (e.g., inhaled corticosteroid) and a LABA is clinically indicated, appropriate steps must be taken to ensure adherence with both treatment components. If adherence cannot be assured, a fixed-dose combination product containing both an inhaled corticosteroid and a LABA is recommended.
- The Salmeterol Multi-center Asthma Research Trial (SMART) was a large 28-week placebo-controlled US trial comparing the safety of salmeterol (SEREVENT® Inhalation Aerosol) with placebo, each added to usual asthma therapy, that showed an increase in asthma-related deaths in subjects receiving salmeterol [see Clinical Studies (14.1)]. Given the similar basic mechanisms of action of beta2-agonists, the findings seen in the SMART trial are considered a class effect.
- A 16-week clinical trial performed in the United Kingdom, the Salmeterol Nationwide Surveillance (SNS) trial, showed results similar to the SMART trial. In the SNS trial, the rate of asthma-related death was numerically, though not statistically significantly, greater in subjects with asthma treated with salmeterol (42 mcg twice daily) than those treated with albuterol (180 mcg 4 times daily) added to usual asthma therapy.
- The SNS and SMART trials enrolled subjects with asthma. No trials have been conducted that were primarily designed to determine whether the rate of death in patients with COPD is increased by LABA.
- SEREVENT DISKUS should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of asthma or COPD. SEREVENT DISKUS has not been studied in subjects with acutely deteriorating asthma or COPD. The initiation of SEREVENT DISKUS in this setting is not appropriate.
- Serious acute respiratory events, including fatalities, have been reported when salmeterol has been initiated in patients with significantly worsening or acutely deteriorating asthma. In most cases, these have occurred in patients with severe asthma (e.g., patients with a history of corticosteroid dependence, low pulmonary function, intubation, mechanical ventilation, frequent hospitalizations, previous life-threatening acute asthma exacerbations) and in some patients with acutely deteriorating asthma (e.g., patients with significantly increasing symptoms; increasing need for inhaled, short-acting beta2-agonists; decreasing response to usual medications; increasing need for systemic corticosteroids; recent emergency room visits; deteriorating lung function). However, these events have occurred in a few patients with less severe asthma as well. It was not possible from these reports to determine whether salmeterol contributed to these events.
- Increasing use of inhaled, short-acting beta2-agonists is a marker of deteriorating asthma. In this situation, the patient requires immediate reevaluation with reassessment of the treatment regimen, giving special consideration to the possible need for adding additional inhaled corticosteroid or initiating systemic corticosteroids. Patients should not use more than 1 inhalation twice daily of SEREVENT DISKUS.
- SEREVENT DISKUS should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. An inhaled, short-acting beta2-agonist, not SEREVENT DISKUS, should be used to relieve acute symptoms such as shortness of breath. When prescribing SEREVENT DISKUS, the healthcare provider should also prescribe an inhaled, short-acting beta2-agonist (e.g., albuterol) for treatment of acute symptoms.
- When beginning treatment with SEREVENT DISKUS, patients who have been taking oral or inhaled, short-acting beta2-agonists on a regular basis (e.g., 4 times a day) should be instructed to discontinue the regular use of these drugs.
- There are no data demonstrating that SEREVENT DISKUS has a clinical anti-inflammatory effect such as that associated with corticosteroids. When initiating and throughout treatment with SEREVENT DISKUS in patients receiving oral or inhaled corticosteroids for treatment of asthma, patients must continue taking a suitable dosage of corticosteroids to maintain clinical stability even if they feel better as a result of initiating SEREVENT DISKUS. Any change in corticosteroid dosage should be made ONLY after clinical evaluation.
- SEREVENT DISKUS should not be used more often than recommended, at higher doses than recommended, or in conjunction with other medicines containing LABA, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Patients using SEREVENT DISKUS should not use another medicine containing a LABA (e.g., formoterol fumarate, arformoterol tartrate, indacaterol) for any reason.
- As with other inhaled medicines, SEREVENT DISKUS can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with SEREVENT DISKUS, it should be treated immediately with an inhaled, short-acting bronchodilator. SEREVENT DISKUS should be discontinued immediately, and alternative therapy should be instituted. Upper airway symptoms of laryngeal spasm, irritation, or swelling, such as stridor and choking, have been reported in patients receiving SEREVENT DISKUS.
- Excessive beta-adrenergic stimulation has been associated with seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min, arrhythmias, nervousness, headache, tremor, palpitation, nausea, dizziness, fatigue, malaise, and insomnia [see Overdosage (10)]. Therefore, SEREVENT DISKUS, like all products containing sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.
- Salmeterol can produce a clinically significant cardiovascular effect in some patients as measured by pulse rate, blood pressure, and/or symptoms. Although such effects are uncommon after administration of salmeterol at recommended doses, if they occur, the drug may need to be discontinued. In addition, beta-agonists have been reported to produce electrocardiogram (ECG) changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression. The clinical significance of these findings is unknown. Large doses of inhaled or oral salmeterol (12 to 20 times the recommended dose) have been associated with clinically significant prolongation of the QTc interval, which has the potential for producing ventricular arrhythmias. Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs.
- Immediate hypersensitivity reactions (e.g., urticaria, angioedema, rash, bronchospasm, hypotension), including anaphylaxis, may occur after administration of SEREVENT DISKUS. There have been reports of anaphylactic reactions in patients with severe milk protein allergy after inhalation of powder products containing lactose; therefore, patients with severe milk protein allergy should not use SEREVENT DISKUS [see Contraindications (4)].
- The use of strong cytochrome P450 3A4 (CYP3A4) inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, ketoconazole, telithromycin) with SEREVENT DISKUS is not recommended because increased cardiovascular adverse effects may occur [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].
- SEREVENT DISKUS, like all medicines containing sympathomimetic amines, should be used with caution in patients with convulsive disorders or thyrotoxicosis and in those who are unusually responsive to sympathomimetic amines. Doses of the related beta2-adrenoceptor agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis.
- Beta-adrenergic agonist medicines may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects [see Clinical Pharmacology (12.2)]. The decrease in serum potassium is usually transient, not requiring supplementation. Clinically significant and dose-related changes in blood glucose and/or serum potassium were seen infrequently during clinical trials with SEREVENT DISKUS at recommended doses.
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- Adult and Adolescent Subjects Aged 12 Years and Older: Two multicenter, 12-week, placebo-controlled clinical trials evaluated twice-daily doses of SEREVENT DISKUS in subjects aged 12 years and older with asthma. Table 1 reports the incidence of adverse reactions in these 2 trials.
- Table 1 includes all events (whether considered drug-related or nondrug-related by the investigator) that occurred at a rate of ≥3% in the group treated with SEREVENT DISKUS and were more common than in the placebo group.
- Pharyngitis, sinusitis, upper respiratory tract infection, and cough occurred at ≥3% but were more common in the placebo group. However, throat irritation has been described at rates exceeding that of placebo in other controlled clinical trials.
- Additional Adverse Reactions:
- Other adverse reactions not previously listed, whether considered drug-related or not by the investigators, that were reported more frequently by subjects with asthma treated with SEREVENT DISKUS compared with subjects treated with placebo include the following: contact dermatitis, eczema, localized aches and pains, nausea, oral mucosal abnormality, pain in joint, paresthesia, pyrexia of unknown origin, sinus headache, and sleep disturbance.
- Pediatric Subjects Aged 4 to 11 Years:
- Two multicenter, 12-week, controlled trials have evaluated twice-daily doses of SEREVENT DISKUS in subjects aged 4 to 11 years with asthma. Table 2 includes all events (whether considered drug-related or nondrug-related by the investigator) that occurred at a rate of 3% or greater in the group receiving SEREVENT DISKUS and were more common than in the placebo group.
- The following events were reported at an incidence of >1% in the salmeterol group and with a higher incidence than in the albuterol and placebo groups: gastrointestinal signs and symptoms, lower respiratory signs and symptoms, photodermatitis, and arthralgia and articular rheumatism.
- In clinical trials evaluating concurrent therapy of salmeterol with inhaled corticosteroids, adverse events were consistent with those previously reported for salmeterol, or with events that would be expected with the use of inhaled corticosteroids.
- Laboratory Test Abnormalities:
- Elevation of hepatic enzymes was reported in ≥1% of subjects in clinical trials. The elevations were transient and did not lead to discontinuation from the trials. In addition, there were no clinically relevant changes noted in glucose or potassium.
- Two multicenter, 24-week, placebo-controlled US trials evaluated twice-daily doses of SEREVENT DISKUS in subjects with COPD. For presentation (Table 3), the placebo data from a third trial, identical in design, subject entrance criteria, and overall conduct but comparing fluticasone propionate with placebo, were integrated with the placebo data from these 2 trials (total N = 341 for salmeterol and 576 for placebo).
- aTable 3 includes all events (whether considered drug-related or nondrug-related by the investigator) that occurred at a rate of 3% or greater in the group receiving SEREVENT DISKUS and were more common in the group receiving SEREVENT DISKUS than in the placebo group.
- Additional Adverse Reactions:
- Other adverse reactions occurring in the group receiving SEREVENT DISKUS that occurred at a frequency of ≥1% and were more common than in the placebo group were as follows: anxiety; arthralgia and articular rheumatism; bone and skeletal pain; candidiasis mouth/throat; dental discomfort and pain; dyspeptic symptoms; edema and swelling; gastrointestinal infections; hyperglycemia; hyposalivation; keratitis and conjunctivitis; lower respiratory signs and symptoms; migraines; muscle pain; muscle stiffness, tightness, and rigidity; musculoskeletal inflammation; pain; and skin rashes.
- Adverse reactions to salmeterol are similar in nature to those seen with other selective beta2-adrenoceptor agonists, e.g., tachycardia; palpitations; immediate hypersensitivity reactions, including urticaria, angioedema, rash, bronchospasm; headache; tremor; nervousness; and paradoxical bronchospasm.
- Laboratory Abnormalities:
- There were no clinically relevant changes in these trials. Specifically, no changes in potassium were noted.
- In extensive US and worldwide postmarketing experience with salmeterol, serious exacerbations of asthma, including some that have been fatal, have been reported. In most cases, these have occurred in patients with severe asthma and/or in some patients in whom asthma has been acutely deteriorating [see Warnings and Precautions (5.2)], but they have also occurred in a few patients with less severe asthma. It was not possible from these reports to determine whether salmeterol contributed to these events.
- Arrhythmias (including atrial fibrillation, supraventricular tachycardia, extrasystoles) and anaphylaxis.
- Very rare anaphylactic reaction in patients with severe milk protein allergy.
- Reports of upper airway symptoms of laryngeal spasm, irritation, or swelling such as stridor or choking; oropharyngeal irritation.
- Salmeterol is a substrate of CYP3A4. The use of strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, ketoconazole, telithromycin) with SEREVENT DISKUS is not recommended because increased cardiovascular adverse effects may occur.
- In a drug interaction trial in 20 healthy subjects, coadministration of inhaled salmeterol (50 mcg twice daily) and oral ketoconazole (400 mg once daily) for 7 days resulted in greater systemic exposure to salmeterol (AUC increased 16-fold and Cmax increased 1.4-fold). Three (3) subjects were withdrawn due to beta2-agonist side effects (2 with prolonged QTc and 1 with palpitations and sinus tachycardia). Although there was no statistical effect on the mean QTc, coadministration of salmeterol and ketoconazole was associated with more frequent increases in QTc duration compared with salmeterol and placebo administration.
- SEREVENT DISKUS should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants, or within 2 weeks of discontinuation of such agents, because the action of salmeterol on the vascular system may be potentiated by these agents.
- Beta-blockers not only block the pulmonary effect of beta-agonists, such as SEREVENT DISKUS, but may also produce severe bronchospasm in patients with asthma or COPD. Therefore, patients with asthma or COPD should not normally be treated with beta-blockers. However, under certain circumstances, there may be no acceptable alternatives to the use of beta-adrenergic blocking agents for these patients; cardioselective beta-blockers could be considered, although they should be administered with caution.
- The ECG changes and/or hypokalemia that may result from the administration of non–potassium-sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is not known, caution is advised in the coadministration of SEREVENT DISKUS with non–potassium-sparing diuretics.
- No teratogenic effects occurred in rats at salmeterol doses approximately 160 times the maximum recommended daily inhalation dose (MRHDID) (on a mg/m2 basis at maternal oral doses up to 2 mg/kg/day). In pregnant Dutch rabbits administered oral doses approximately 50 times the MRHDID (on an AUC basis at maternal oral doses of 1 mg/kg/day and higher), fetal toxic effects were observed characteristically resulting from beta-adrenoceptor stimulation. These included precocious eyelid openings, cleft palate, sternebral fusion, limb and paw flexures, and delayed ossification of the frontal cranial bones. No such effects occurred at a salmeterol dose approximately 20 times the MRHDID (on an AUC basis at a maternal oral dose of 0.6 mg/kg/day).
- New Zealand White rabbits were less sensitive since only delayed ossification of the frontal cranial bones was seen at an oral dose approximately 1,600 times the MRHDID (on n mg/m2 basis at a maternal oral dose of 10 mg/kg/day).
- Salmeterol crossed the placenta following oral administration to mice and rats.
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Salmeterol in women who are pregnant.
- The safety and efficacy of SEREVENT DISKUS in adolescents (aged 12 years and older) have been established based on adequate and well-controlled trials conducted in adults and adolescents [see Clinical Studies (14.1)]. A large 28-week placebo-controlled US trial comparing salmeterol (SEREVENT Inhalation Aerosol) and placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in subjects receiving salmeterol [see Clinical Studies (14.1)]. Post-hoc analyses in pediatric subjects aged 12 to 18 years were also performed. Pediatric subjects accounted for approximately 12% of subjects in each treatment arm. Respiratory-related death or life-threatening experience occurred at a similar rate in the salmeterol group (0.12% [2/1,653]) and the placebo group (0.12% [2/1,622]; relative risk: 1.0 [95% CI: 0.1, 7.2]). All-cause hospitalization, however, was increased in the salmeterol group (2% [35/1,653]) versus the placebo group (<1% [16/1,622]; relative risk: 2.1 [95% CI: 1.1, 3.7]).
- The safety and efficacy of SEREVENT DISKUS have been evaluated in over 2,500 subjects aged 4 to 11 years with asthma, 346 of whom were administered SEREVENT DISKUS for 1 year. Based on available data, no adjustment of dosage of SEREVENT DISKUS in pediatric patients is warranted for either asthma or EIB.
- In 2 randomized, double-blind, controlled clinical trials of 12 weeks’ duration, SEREVENT DISKUS 50 mcg was administered to 211 pediatric subjects with asthma who did and who did not receive concurrent inhaled corticosteroids. The efficacy of SEREVENT DISKUS was demonstrated over the 12-week treatment period with respect to peak expiratory flow (PEF) and forced expiratory volume in 1 second (FEV1). SEREVENT DISKUS was effective in demographic subgroups (gender and age) of the population.
- In 2 randomized trials in children aged 4 to 11 years with asthma and EIB, a single 50-mcg dose of SEREVENT DISKUS prevented EIB when dosed 30 minutes prior to exercise, with protection lasting up to 11.5 hours in repeat testing following this single dose in many subjects.
- Description
- As with all inhaled sympathomimetic medicines, cardiac arrest and even death may be associated with an overdose of SEREVENT DISKUS.
- Treatment consists of discontinuation of SEREVENT DISKUS together with appropriate symptomatic therapy. The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medication can produce bronchospasm. There is insufficient evidence to determine if dialysis is beneficial for overdosage of SEREVENT DISKUS. Cardiac monitoring is recommended in cases of overdosage.
- The pharmacologic effects of beta2-adrenoceptor agonist drugs, including salmeterol, are at least in part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3′,5′-adenosine monophosphate (cyclic AMP). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells.
- In vitro tests show that salmeterol is a potent and long-lasting inhibitor of the release of mast cell mediators, such as histamine, leukotrienes, and prostaglandin D2, from human lung. Salmeterol inhibits histamine-induced plasma protein extravasation and inhibits platelet-activating factor–induced eosinophil accumulation in the lungs of guinea pigs when administered by the inhaled route. In humans, single doses of salmeterol administered via inhalation aerosol attenuate allergen-induced bronchial hyper-responsiveness.
- The effects of rising inhaled doses of salmeterol and standard inhaled doses of albuterol were studied in volunteers and in subjects with asthma. Salmeterol doses up to 84 mcg administered as inhalation aerosol resulted in heart rate increases of 3 to 16 beats/min, about the same as albuterol dosed at 180 mcg by inhalation aerosol (4 to 10 beats/min). Adult and adolescent subjects receiving 50-mcg doses of salmeterol inhalation powder (n = 60) underwent continuous electrocardiographic monitoring during two 12-hour periods after the first dose and after 1 month of therapy, and no clinically significant dysrhythmias were noted. Also, pediatric patients receiving 50-mcg doses of salmeterol inhalation powder (n = 67) underwent continuous electrocardiographic monitoring during two 12-hour periods after the first dose and after 3 months of therapy, and no clinically significant dysrhythmias were noted.
- In 24-week clinical studies in patients with COPD, the incidence of clinically significant abnormalities on the predose ECGs at Weeks 12 and 24 in patients who received salmeterol 50 mcg was not different compared with placebo.
- No effect of treatment with salmeterol 50 mcg was observed on pulse rate and systolic and diastolic blood pressure in a subset of patients with COPD who underwent 12-hour serial vital sign measurements after the first dose (n = 91) and after 12 weeks of therapy (n = 74). Median changes from baseline in pulse rate and systolic and diastolic blood pressure were similar for patients receiving either salmeterol or placebo [see Adverse Reactions (6.1)].
- Short-Acting Beta2-Agonists: In two 12-week repetitive-dose clinical trials in adult and adolescent subjects with asthma (N = 149), the mean daily need for additional beta2-agonist in subjects using SEREVENT DISKUS was approximately 1½ inhalations/day. Twenty-six percent (26%) of the subjects in these trials used between 8 and 24 inhalations of short-acting beta-agonist per day on 1 or more occasions. Nine percent (9%) of the subjects in these trials averaged over 4 inhalations/day over the course of the 12-week trials. No increase in frequency of cardiovascular events was observed among the 3 subjects who averaged 8 to 11 inhalations/day; however, the safety of concomitant use of more than 8 inhalations/day of short-acting beta2-agonist with SEREVENT DISKUS has not been established. In 29 subjects who experienced worsening of asthma while receiving SEREVENT DISKUS during these trials, albuterol therapy administered via either nebulizer or inhalation aerosol (1 dose in most cases) led to improvement in FEV1 and no increase in occurrence of cardiovascular adverse events.
- In 2 clinical trials in subjects with COPD, the mean daily need for additional beta2-agonist for subjects using SEREVENT DISKUS was approximately 4 inhalations/day. Twenty-four percent (24%) of subjects using SEREVENT DISKUS averaged 6 or more inhalations of albuterol per day over the course of the 24-week trials. No increase in frequency of cardiovascular adverse reactions was observed among subjects who averaged 6 or more inhalations per day.
- The concurrent use of intravenously or orally administered methylxanthines (e.g., aminophylline, theophylline) by subjects receiving salmeterol has not been completely evaluated. In 1 clinical trial in subjects with asthma, 87 subjects receiving SEREVENT Inhalation Aerosol 42 mcg twice daily concurrently with a theophylline product had adverse event rates similar to those in 71 subjects receiving SEREVENT Inhalation Aerosol without theophylline. Resting heart rates were slightly higher in the subjects on theophylline but were little affected by therapy with SEREVENT Inhalation Aerosol.
- In 2 clinical trials in subjects with COPD, 39 subjects receiving SEREVENT DISKUS concurrently with a theophylline product had adverse event rates similar to those in 302 subjects receiving SEREVENT DISKUS without theophylline. Based on the available data, the concomitant administration of methylxanthines with SEREVENT DISKUS did not alter the observed adverse event profile.
- In clinical trials, inhaled cromolyn sodium did not alter the safety profile of salmeterol when administered concurrently.
- Because of the small therapeutic dose, systemic levels of salmeterol are low or undetectable after inhalation of recommended doses (50 mcg of salmeterol inhalation powder twice daily). Following chronic administration of an inhaled dose of 50 mcg of salmeterol inhalation powder twice daily, salmeterol was detected in plasma within 5 to 45 minutes in 7 subjects with asthma; plasma concentrations were very low, with mean peak concentrations of 167 pg/mL at 20 minutes and no accumulation with repeated doses.
- The percentage of salmeterol bound to human plasma proteins averages 96% in vitro over the concentration range of 8 to 7,722 ng of salmeterol base per milliliter, much higher concentrations than those achieved following therapeutic doses of salmeterol.
- Salmeterol base is extensively metabolized by hydroxylation, with subsequent elimination predominantly in the feces. No significant amount of unchanged salmeterol base was detected in either urine or feces.
- An in vitro study using human liver microsomes showed that salmeterol is extensively metabolized to α-hydroxysalmeterol (aliphatic oxidation) by CYP3A4. Ketoconazole, a strong inhibitor of CYP3A4, essentially completely inhibited the formation of α-hydroxysalmeterol in vitro.
- In 2 healthy adult subjects who received 1 mg of radiolabeled salmeterol (as salmeterol xinafoate) orally, approximately 25% and 60% of the radiolabeled salmeterol was eliminated in urine and feces, respectively, over a period of 7 days. The terminal elimination half-life was about 5.5 hours (1 volunteer only).
- The xinafoate moiety has no apparent pharmacologic activity. The xinafoate moiety is highly protein bound (>99%) and has a long elimination half-life of 11 days.
### Drug Interactions
- Ketoconazole:
- In a placebo-controlled crossover drug interaction trial in 20 healthy male and female subjects, coadministration of salmeterol (50 mcg twice daily) and the strong CYP3A4 inhibitor ketoconazole (400 mg once daily) for 7 days resulted in a significant increase in plasma salmeterol exposure as determined by a 16-fold increase in AUC (ratio with and without ketoconazole 15.76 [90% CI: 10.66, 23.31]) mainly due to increased bioavailability of the swallowed portion of the dose. Peak plasma salmeterol concentrations were increased by 1.4-fold (90% CI: 1.23, 1.68). Three (3) out of 20 subjects (15%) were withdrawn from salmeterol and ketoconazole coadministration due to beta-agonist–mediated systemic effects (2 with QTc prolongation and 1 with palpitations and sinus tachycardia). Coadministration of salmeterol and ketoconazole did not result in a clinically significant effect on mean heart rate, mean blood potassium, or mean blood glucose. Although there was no statistical effect on the mean QTc, coadministration of salmeterol and ketoconazole was associated with more frequent increases in QTc duration compared with salmeterol and placebo administration.
- Erythromycin:
- In a repeat-dose trial in 13 healthy subjects, concomitant administration of erythromycin (a moderate CYP3A4 inhibitor) and salmeterol inhalation aerosol resulted in a 40% increase in salmeterol Cmax at steady state (ratio with and without erythromycin 1.4 [90% CI: 0.96, 2.03], P = 0.12), a 3.6-beat/min increase in heart rate ([95% CI: 0.19, 7.03], P <0.04), a 5.8-msec increase in QTc interval ([95% CI: -6.14, 17.77], P = 0.34), and no change in plasma potassium.
- In an 18-month carcinogenicity study in CD-mice, salmeterol at oral doses of 1.4 mg/kg and above (approximately 20 times the MRHDID for adults and children based on comparison of the plasma AUCs) caused a dose-related increase in the incidence of smooth muscle hyperplasia, cystic glandular hyperplasia, leiomyomas of the uterus, and ovarian cysts. No tumors were seen at 0.2 mg/kg (approximately 3 times the MRHDID for adults and children based on comparison of the AUCs).
- In a 24-month oral and inhalation carcinogenicity study in Sprague Dawley rats, salmeterol caused a dose-related increase in the incidence of mesovarian leiomyomas and ovarian cysts at doses of 0.68 mg/kg and above (approximately 55 and 25 times the MRHDID for adults and children, respectively, on a mg/m2 basis). No tumors were seen at 0.21 mg/kg (approximately 15 and 8 times the MRHDID for adults and children, respectively, on a mg/m2 basis). These findings in rodents are similar to those reported previously for other beta-adrenergic agonist drugs. The relevance of these findings to human use is unknown.
- Salmeterol produced no detectable or reproducible increases in microbial and mammalian gene mutation in vitro. No clastogenic activity occurred in vitro in human lymphocytes or in vivo in a rat micronucleus test. No effects on fertility were identified in rats treated with salmeterol at oral doses up to 2 mg/kg (approximately 160 times the MRHDID for adults on a mg/m2 basis).
- Preclinical: Studies in laboratory animals (minipigs, rodents, and dogs) have demonstrated the occurrence of cardiac arrhythmias and sudden death (with histologic evidence of myocardial necrosis) when beta-agonists and methylxanthines are administered concurrently. The clinical relevance of these findings is unknown.
- The initial trials supporting the approval of SEREVENT DISKUS for the treatment of asthma did not require the regular use of inhaled corticosteroids. However, for the treatment of asthma, SEREVENT DISKUS is currently indicated only as concomitant therapy with an inhaled corticosteroid [see Indications and Usage (1.1)].
- Adult and Adolescent Subjects Aged 12 Years and Older: In 2 randomized double-blind trials, SEREVENT DISKUS was compared with albuterol inhalation aerosol and placebo in adolescent and adult subjects with mild-to-moderate asthma (protocol defined as 50% to 80% predicted FEV1, actual mean of 67.7% at baseline), including subjects who did and who did not receive concurrent inhaled corticosteroids. The efficacy of SEREVENT DISKUS was demonstrated over the 12-week period with no change in effectiveness over this time period (see Figure 1). There were no gender- or age-related differences in safety or efficacy. No development of tachyphylaxis to the bronchodilator effect was noted in these trials. FEV1 measurements (mean change from baseline) from these two 12-week trials are shown in Figure 1 for both the first and last treatment days.
- Table 4 shows the treatment effects seen during daily treatment with SEREVENT DISKUS for 12 weeks in adolescent and adult subjects with mild-to-moderate asthma.
- aStatistically superior to placebo and albuterol (P<0.001).
- bStatistically superior to placebo (P<0.001).
- Maintenance of efficacy for periods up to 1 year has been documented.
- SEREVENT DISKUS and SEREVENT Inhalation Aerosol were compared with placebo in 2 additional randomized double-blind clinical trials in adolescent and adult subjects with mild-to-moderate asthma. SEREVENT DISKUS 50 mcg and SEREVENT Inhalation Aerosol 42 mcg, both administered twice daily, produced significant improvements in pulmonary function compared with placebo over the 12-week period. While no statistically significant differences were observed between the active treatments for any of the efficacy assessments or safety evaluations performed, there were some efficacy measures on which the metered-dose inhaler appeared to provide better results. Similar findings were noted in 2 randomized, single-dose, crossover comparisons of SEREVENT DISKUS and SEREVENT Inhalation Aerosol for the prevention of EIB. Therefore, while SEREVENT DISKUS was comparable to SEREVENT Inhalation Aerosol in clinical trials in mild-to-moderate subjects with asthma, it should not be assumed that they will produce clinically equivalent outcomes in all subjects.
- In 4 clinical trials in adult and adolescent subjects with asthma (N = 1,922), the effect of adding SEREVENT Inhalation Aerosol to inhaled corticosteroid therapy was evaluated over a 24-week treatment period. The trials compared the addition of salmeterol therapy to an increase (at least doubling) of the inhaled corticosteroid dose.
- Two randomized, double-blind, controlled, parallel-group clinical trials (N = 997) enrolled subjects (aged 18 to 82 years) with persistent asthma who were previously maintained but not adequately controlled on inhaled corticosteroid therapy. During the 2-week run-in period, all subjects were switched to beclomethasone dipropionate (BDP) 168 mcg twice daily. Subjects still not adequately controlled were randomized to either the addition of SEREVENT Inhalation Aerosol 42 mcg twice daily or an increase of BDP to 336 mcg twice daily. As compared with the doubled dose of BDP, the addition of SEREVENT Inhalation Aerosol resulted in statistically significantly greater improvements in pulmonary function and asthma symptoms, and statistically significantly greater reduction in supplemental albuterol use. The percent of subjects who experienced asthma exacerbations overall was not different between groups (i.e., 16.2% in the group receiving SEREVENT Inhalation Aerosol versus 17.9% in the higher-dose beclomethasone dipropionate group).
- Two randomized, double-blind, controlled, parallel-group clinical trials (N = 925) enrolled subjects (aged 12 to 78 years) with persistent asthma who were previously maintained but not adequately controlled on prior asthma therapy. During the 2- to 4-week run-in period, all subjects were switched to fluticasone propionate 88 mcg twice daily. Subjects still not adequately controlled were randomized to either the addition of SEREVENT Inhalation Aerosol 42 mcg twice daily or an increase of fluticasone propionate to 220 mcg twice daily. As compared with the increased (2.5 times) dose of fluticasone propionate, the addition of SEREVENT Inhalation Aerosol resulted in statistically significantly greater improvements in pulmonary function and asthma symptoms, and statistically significantly greater reductions in supplemental albuterol use. Fewer subjects receiving SEREVENT Inhalation Aerosol experienced asthma exacerbations than those receiving the higher dose of fluticasone propionate (8.8% versus 13.8%).
- Table 5 shows the treatment effects seen during daily treatment with SEREVENT Inhalation Aerosol for 24 weeks in adolescent and adult subjects with mild-to-moderate asthma.
- During the initial treatment day in several multiple-dose clinical trials with SEREVENT DISKUS in subjects with asthma, the median time to onset of clinically significant bronchodilatation (≥15% improvement in FEV1) ranged from 30 to 48 minutes after a 50-mcg dose.
- One hour after a single dose of 50 mcg of SEREVENT DISKUS, the majority of subjects had ≥15% improvement in FEV1. Maximum improvement in FEV1 generally occurred within 180 minutes, and clinically significant improvement continued for 12 hours in most subjects.
- In a randomized, double-blind, controlled trial (N = 449), 50 mcg of SEREVENT DISKUS was administered twice daily to pediatric subjects with asthma who did and who did not receive concurrent inhaled corticosteroids. The efficacy of salmeterol inhalation powder was demonstrated over the 12-week treatment period with respect to periodic serial PEF (36% to 39% postdose increase from baseline) and FEV1 (32% to 33% postdose increase from baseline). Salmeterol was effective in demographic subgroup analyses (gender and age) and was effective when coadministered with other inhaled asthma medications such as short-acting bronchodilators and inhaled corticosteroids. A second randomized, double-blind, placebo-controlled trial (N = 207) with 50 mcg of salmeterol inhalation powder via an alternate device supported the findings of the trial with the DISKUS.
- The SMART trial was a randomized double-blind trial that enrolled LABA-naive subjects with asthma (average age of 39 years; 71% Caucasian, 18% African American, 8% Hispanic) to assess the safety of salmeterol (SEREVENT Inhalation Aerosol) 42 mcg twice daily over 28 weeks compared with placebo when added to usual asthma therapy.
- A planned interim analysis was conducted when approximately half of the intended number of subjects had been enrolled (N = 26,355), which led to premature termination of the trial. The results of the interim analysis showed that subjects receiving salmeterol were at increased risk for fatal asthma events (see Table 5 and Figure 2). In the total population, a higher rate of asthma-related death occurred in subjects treated with salmeterol than those treated with placebo (0.10% versus 0.02%, relative risk: 4.37 [95% CI: 1.25, 15.34]).
- Post-hoc subpopulation analyses were performed. In Caucasians, asthma-related death occurred at a higher rate in subjects treated with salmeterol than in subjects treated with placebo (0.07% versus 0.01%, relative risk: 5.82 [95% CI: 0.70, 48.37]). In African Americans also, asthma-related death occurred at a higher rate in subjects treated with salmeterol than those treated with placebo (0.31% versus 0.04%, relative risk: 7.26 [95% CI: 0.89, 58.94]). Although the relative risks of asthma-related death were similar in Caucasians and African Americans, the estimate of excess deaths in subjects treated with salmeterol was greater in African Americans because there was a higher overall rate of asthma-related death in African American subjects (see Table 5).
- Post-hoc analyses in pediatric subjects aged 12 to 18 years were also performed. Pediatric subjects accounted for approximately 12% of subjects in each treatment arm. Respiratory-related death or life-threatening experience occurred at a similar rate in the salmeterol group (0.12% [2/1,653]) and the placebo group (0.12% [2/1,622]; relative risk: 1.0 [95% CI: 0.1, 7.2]). All-cause hospitalization, however, was increased in the salmeterol group (2% [35/1,653]) versus the placebo group (<1% [16/1,622]; relative risk: 2.1 [95% CI: 1.1, 3.7]).
- The data from the SMART trial are not adequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma control therapy mitigates the risk of asthma-related death.
- aLife-table 28-week estimate, adjusted according to the subjects’ actual lengths of exposure to study treatment to account for early withdrawal of subjects from the study.
- bRelative risk is the ratio of the rate of asthma-related death in the salmeterol group and the rate in the placebo group. The relative risk indicates how many more times likely an asthma-related death occurred in the salmeterol group than in the placebo group in a 28-week treatment period.
- cEstimate of the number of additional asthma-related deaths in subjects treated with salmeterol in SMART, assuming 10,000 subjects received salmeterol for a 28-week treatment period. Estimate calculated as the difference between the salmeterol and placebo groups in the rates of asthma-related death multiplied by 10,000.
- dThe Total Population includes the following ethnic origins listed on the case report form: Caucasian, African American, Hispanic, Asian, and “Other.” In addition, the Total Population includes those subjects whose ethnic origin was not reported. The results for Caucasian and African American subpopulations are shown above. No asthma-related deaths occurred in the Hispanic (salmeterol n = 996, placebo n = 999), Asian (salmeterol n = 173, placebo n = 149), or “Other” (salmeterol n = 230, placebo n = 224) subpopulations. One asthma-related death occurred in the placebo group in the subpopulation whose ethnic origin was not reported (salmeterol n = 130, placebo n = 127).
- In 2 randomized, single-dose, crossover trials in adolescents and adults with EIB (N = 52), 50 mcg of SEREVENT DISKUS prevented EIB when dosed 30 minutes prior to exercise. For some subjects, this protective effect against EIB was still apparent up to 8.5 hours following a single dose (see Table 6).
- In 2 randomized trials in children aged 4 to 11 years with asthma and EIB (N = 50), a single 50-mcg dose of SEREVENT DISKUS prevented EIB when dosed 30 minutes prior to exercise, with protection lasting up to 11.5 hours in repeat testing following this single dose in many subjects.
- In 2 clinical trials evaluating twice-daily treatment with SEREVENT DISKUS 50 mcg (n = 336) compared with placebo (n = 366) in subjects with chronic bronchitis with airflow limitation, with or without emphysema, improvements in pulmonary function endpoints were greater with salmeterol 50 mcg than with placebo. Treatment with SEREVENT DISKUS did not result in significant improvements in secondary endpoints assessing COPD symptoms in either clinical trial. Both trials were randomized, double-blind, parallel-group trials of 24 weeks’ duration and were identical in design, subject entrance criteria, and overall conduct.
- Figure 3 displays the integrated 2-hour postdose FEV1 results from the 2 clinical trials. The percent change in FEV1 refers to the change from baseline, defined as the predose value on Treatment Day 1. To account for subject withdrawals during the trial, Endpoint (last evaluable FEV1) data are provided. Subjects receiving SEREVENT DISKUS 50 mcg had significantly greater improvements in 2-hour postdose FEV1 at Endpoint (216 mL, 20%) compared with placebo (43 mL, 5%). Improvement was apparent on the first day of treatment and maintained throughout the 24 weeks of treatment.
- Onset of Action and Duration of Effect:
- The onset of action and duration of effect of SEREVENT DISKUS were evaluated in a subset of subjects (n = 87) from 1 of the 2 clinical trials discussed above. Following the first 50-mcg dose, significant improvement in pulmonary function (mean FEV1 increase of 12% or more and at least 200 mL) occurred at 2 hours. The mean time to peak bronchodilator effect was 4.75 hours. As seen in Figure 4, evidence of bronchodilatation was seen throughout the 12-hour period. Figure 4 also demonstrates that the bronchodilating effect after 12 weeks of treatment was similar to that observed after the first dose. The mean time to peak bronchodilator effect after 12 weeks of treatment was 3.27 hours.
- Serevent Diskus is also supplied in an institutional pack containing 28 blisters (NDC 0173-0520-00).
- Store in a dry place away from direct heat or sunlight.
- Keep out of reach of children.
- SEREVENT DISKUS should be stored inside the unopened moisture-protective foil pouch and only removed from the pouch immediately before initial use. Discard SEREVENT DISKUS 6 weeks after opening the foil pouch or when the counter reads “0” (after all blisters have been used), whichever comes first. The inhaler is not reusable. Do not attempt to take the inhaler apart.
NDC 0173-0521-00
Serevent®Diskus®
(salmeterol xinafoate inhalation powder)
50 mcg
FOR ORAL INHALATION ONLY
Each blister contains 50 mcg of salmeterol base with lactose monohydrate.
Federal Law requires the dispensing of SEREVENT DISKUS with the Medication Guide inside the carton.
See prescribing information for dosing information.
Rx only
1 DISKUS® Inhalation Device Containing 1 Foil Strip of 60 Blisters
Made in Singapore
©2013, GlaxoSmithKline
10000000117746 Rev. 8/13
NDC 0173-0520-00
Serevent®Diskus®
(salmeterol xinafoate inhalation powder)
INSTITUTIONAL PACK
50 mcg
FOR ORAL INHALATION ONLY
Each blister contains 50 mcg of salmeterol base with lactose monohydrate.
Federal Law requires the dispensing of SEREVENT DISKUS with the Medication Guide inside the carton.
See prescribing information for dosing information.
Rx only
1 DISKUS® Inhalation Device Containing 1 Foil Strip of 28 Blisters
Made in Singapore
©2013, GlaxoSmithKline
10000000117744 Rev. 8/13
- Inform patients that salmeterol increases the risk of asthma-related death and may increase the risk of asthma-related hospitalization in pediatric and adolescent patients. Inform patients that SEREVENT DISKUS should not be the only therapy for the treatment of asthma and must only be used as additional therapy when long-term asthma control medications (e.g., inhaled corticosteroids) do not adequately control asthma symptoms. Also inform them that currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA.Inform patients that when SEREVENT DISKUS is added to their treatment regimen they must continue to use their long-term asthma control medication.
- Inform patients that SEREVENT DISKUS is not meant to relieve acute asthma symptoms or exacerbations of COPD and extra doses should not be used for that purpose. Advise patients to treat acute symptoms with an inhaled, short-acting beta2-agonist such as albuterol. Provide patients with such medication and instruct them in how it should be used.
- Instruct patients to seek medical attention immediately if they experience any of the following:
- Decreasing effectiveness of inhaled, short-acting beta 2-agonists
- Need for more inhalations than usual of inhaled, short-acting beta 2-agonists
- Significant decrease in lung function as outlined by the physician
- Tell patients they should not stop therapy with SEREVENT DISKUS without physician/provider guidance since symptoms may recur after discontinuation.
- Advise all patients with asthma that they must also continue regular maintenance treatment with an inhaled corticosteroid if they are taking SEREVENT DISKUS.
- SEREVENT DISKUS should not be used as a substitute for oral or inhaled corticosteroids. The dosage of these medications should not be changed and they should not be stopped without consulting the physician, even if the patient feels better after initiating treatment with SEREVENT DISKUS.
- Instruct patients not to use other LABA.
- Advise patients that immediate hypersensitivity reactions (e.g., urticaria, angioedema, rash, bronchospasm, hypotension), including anaphylaxis, may occur after administration of SEREVENT DISKUS. Patients should discontinue SEREVENT DISKUS if such reactions occur. There have been reports of anaphylactic reactions in patients with severe milk protein allergy after inhalation of powder products containing lactose; therefore, patients with severe milk protein allergy should not take SEREVENT DISKUS.
- Inform patients of adverse effects associated with beta2-agonists, such as palpitations, chest pain, rapid heart rate, tremor, or nervousness.
- Patients using SEREVENT DISKUS for the treatment of EIB should not use additional doses for 12 hours. Patients who are receiving SEREVENT DISKUS twice daily should not use additional SEREVENT for prevention of EIB.
- SEREVENT and DISKUS are registered trademarks of the GSK group of companies.
GlaxoSmithKline
Research Triangle Park, NC 27709
©2014, the GSK group of companies. All rights reserved.
SRD:10PI
### MEDICATION GUIDE | https://www.wikidoc.org/index.php/Aeromax | |
a2671a06d306866f938a9752f8043ffb3dd58883 | wikidoc | Aerophagia | Aerophagia
Synonyms and keywords: aerophagy
# Overview
Aerophagia is a condition that occurs when a person swallows too much air, which goes to the stomach.
# Pathophysiology
Aerophagia can occur without any act of swallowing. A Ukrainian study showed that in people with cervical disease, inhaling also caused air to go down into the esophagus and stomach. The study recommends cervical spine therapy as a method of treatment. Aerophagia is not uncommon in psychiatric disorders. In one case , aerophagia was successfully treated with thorazine, a typical antipsychotic sometimes used to treat hiccups.
# Causes
- Anxiety
- Carbonated drinks
- Cervical spine disease
- Psychiatric conditions
# Diagnosis
## Symptoms
It causes gas bloating of the abdomen and frequent belching. It may cause pain, too, which sometimes is difficult to diagnose. | Aerophagia
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Synonyms and keywords: aerophagy
# Overview
Aerophagia is a condition that occurs when a person swallows too much air, which goes to the stomach.
# Pathophysiology
Aerophagia can occur without any act of swallowing. A Ukrainian study[2] showed that in people with cervical disease, inhaling also caused air to go down into the esophagus and stomach. The study recommends cervical spine therapy as a method of treatment. Aerophagia is not uncommon in psychiatric disorders. In one case [3], aerophagia was successfully treated with thorazine, a typical antipsychotic sometimes used to treat hiccups.
# Causes
- Anxiety
- Carbonated drinks
- Cervical spine disease
- Psychiatric conditions
# Diagnosis
## Symptoms
It causes gas bloating of the abdomen and frequent belching. It may cause pain, too, which sometimes is difficult to diagnose. | https://www.wikidoc.org/index.php/Aerophagia | |
656c4eaa849fb1bea968f0a57381d4d37a6d1577 | wikidoc | Affymetrix | Affymetrix
Affymetrix (Template:NASDAQ) is a manufacturer of DNA microarrays, based in Santa Clara, California, United States. The company was co-founded by Dr. Stephen Fodor in 1992. The company was begun as a unit in Affymax N.V. in 1991 by Fodor's group, which had in the late 1980's developed methods for fabricating DNA microarrays, called "GeneChips" according to the Affymetrix trademark, using semiconductor manufacturing techniques. The company's first product, an HIV genotyping GeneChip, was introduced in 1994 and the company went public in 1996. As a result of their pioneering work and the ensuing popularity of microrarray products, Affymetrix derives significant benefit from its patent portfolio in this area.
Acquisitions have included Genetic MicroSystems for slide-based microarrays and scanners and Neomorphic for bioinformatics. In 2000 Perlegen Sciences was spun out to focus on wafer-scale genomics for massive data creation and collection required for characterizing population variance of genomic markers and expression for the drug discovery process.
# Description of Product
Affymetrix makes quartz chips for analysis of DNA Microarrays. These chips are sold under the trademarked name GeneChip. Affymetrix's GeneChips assist researchers in quickly scanning for the presence of particular genes in a biological sample. Within this area, Affymetrix is focused on oligonucleotide microarrays. These microarrays are used to determine which genes exist in a sample by detecting specific pieces of mRNA. A single chip can be used to do thousands of experiments in parallel. Chips can be used only once.
Affymetrix sells both mass produced GeneChips intended to match scientifically important parts of human and other animal genomes. It also operates the Affymetrix Made-to-Order Program which makes custom chips available to researchers.
Affymetrix manufactures its GeneChips using photolithography. Glass chips are relatively expensive; list prices range from $50-$500 depending on the capabilities of the single-use chip.
Competitors in the DNA Microarray business include Illumina, GE Healthcare, Ocimum Biosolutions, Applied Biosystems, Beckman Coulter, Eppendorf Biochip Systems, and Agilent. There are also various inexpensive plastic-based technologies under development in small companies and laboratories around the world. It has been widely speculated that mass-produced plastic chips can be produced at lower prices than Affymetrix's quartz chips.
The company also manufactures machinery for high speed analysis of biological samples. List prices for the newest DNA arrayers, which prepare and place samples onto chips, are around $250,000 each. Scanners which read the results from the chip list from $150,000 for complete starter systems to $325,000 for high-throughput systems. Substantially lower retail prices have been seen in the market.
The business model of Affymetrix is based on these sources for revenue: consumables; instruments; subscription, service, license; royalty; and sales to Perlegen Sciences. Affymetrix currently controls 82% of the DNA microarray market in terms of sales.
Affymetrix has established a licensing program to make its intellectual property accessible to stimulate the broad commercialization of genome analysis technologies. Licensing fees have offset weak product sales in Q3-2006. They have several collaboration relationships with other companies that utilize their patented GeneChip technology.
Currently Affymetrix is fighting a patent infringement lawsuit against Illumina, alleging the infringement of six Affymetrix patents. A pre-trial hearing favors Affymetrix, but the trial is not until May 2007. | Affymetrix
Template:Infobox Company
Affymetrix (Template:NASDAQ) is a manufacturer of DNA microarrays, based in Santa Clara, California, United States. The company was co-founded by Dr. Stephen Fodor in 1992. The company was begun as a unit in Affymax N.V. in 1991 by Fodor's group, which had in the late 1980's developed methods for fabricating DNA microarrays, called "GeneChips" according to the Affymetrix trademark, using semiconductor manufacturing techniques. The company's first product, an HIV genotyping GeneChip, was introduced in 1994 and the company went public in 1996. As a result of their pioneering work and the ensuing popularity of microrarray products, Affymetrix derives significant benefit from its patent portfolio in this area.
Acquisitions have included Genetic MicroSystems for slide-based microarrays and scanners and Neomorphic for bioinformatics. In 2000 Perlegen Sciences was spun out to focus on wafer-scale genomics for massive data creation and collection required for characterizing population variance of genomic markers and expression for the drug discovery process.
# Description of Product
Affymetrix makes quartz chips for analysis of DNA Microarrays. These chips are sold under the trademarked name GeneChip. Affymetrix's GeneChips assist researchers in quickly scanning for the presence of particular genes in a biological sample. Within this area, Affymetrix is focused on oligonucleotide microarrays. These microarrays are used to determine which genes exist in a sample by detecting specific pieces of mRNA. A single chip can be used to do thousands of experiments in parallel. Chips can be used only once.
Affymetrix sells both mass produced GeneChips intended to match scientifically important parts of human and other animal genomes. It also operates the Affymetrix Made-to-Order Program which makes custom chips available to researchers.
Affymetrix manufactures its GeneChips using photolithography. Glass chips are relatively expensive; list prices range from $50-$500 depending on the capabilities of the single-use chip.
Competitors in the DNA Microarray business include Illumina, GE Healthcare, Ocimum Biosolutions, Applied Biosystems, Beckman Coulter, Eppendorf Biochip Systems[1], and Agilent. There are also various inexpensive plastic-based technologies under development in small companies and laboratories around the world. It has been widely speculated that mass-produced plastic chips can be produced at lower prices than Affymetrix's quartz chips.
The company also manufactures machinery for high speed analysis of biological samples. List prices for the newest DNA arrayers, which prepare and place samples onto chips, are around $250,000 each. Scanners which read the results from the chip list from $150,000 for complete starter systems to $325,000 for high-throughput systems. Substantially lower retail prices have been seen in the market.
The business model of Affymetrix is based on these sources for revenue: consumables; instruments; subscription, service, license; royalty; and sales to Perlegen Sciences. Affymetrix currently controls 82% of the DNA microarray market[citation needed] in terms of sales.
Affymetrix has established a licensing program to make its intellectual property accessible to stimulate the broad commercialization of genome analysis technologies. Licensing fees have offset weak product sales in Q3-2006. They have several collaboration relationships with other companies that utilize their patented GeneChip technology.
Currently Affymetrix is fighting a patent infringement lawsuit against Illumina, alleging the infringement of six Affymetrix patents. A pre-trial hearing favors Affymetrix, but the trial is not until May 2007.
# External links
- Affymetrix Homepage
- Perlegen Sciences Homepage
- DNAVision - Affymetrix official service provider.
- Genevestigator - Web-based database and analysis tool to study gene expression across many tissues, developmental stages, drugs, stimuli, and genetic modifications. The database contains data from thousands of Affymetrix microarrays. | https://www.wikidoc.org/index.php/Affymetrix | |
7bfc923d4675f2106ae01c722964a0f60402a420 | wikidoc | Afrotheria | Afrotheria
Afrotheria is a clade of mammals with the rank of superorder or cohort, containing (among others) the golden moles, elephant shrews, tenrecs, aardvarks, hyraxes, elephants and manatees.
# Evolutionary relationships
Afrotheria has been proposed based solely on molecular & DNA analyses. Genetic analyses since the 1990s have identified Afrotheria as one of four major groups within the infraclass Eutheria (containing placental mammals). Exact relations among the four cohorts, Afrotheria, Xenarthra, Laurasiatheria, and Euarchontoglires (aka Supraprimates) remain somewhat controversial. One reconstruction proposes that the oldest split was between Afrotheria and the other three some 105 million years ago when the African continent was separated from other major landmasses. (The name Afrotheria was coined from two roots, Afro- for 'Africa' and -theria meaning 'animal' in Greek.) Genetic analysis and the fossil record suggests that Xenarthra developed in South America and diverged from the remaining two somewhat later. Laurasiatheria and Euarchontoglires are more closely related than the other two cohorts and may be grouped together within the taxon Boreoeutheria.
Some researchers consider these classifications based on recent comparative DNA analysis to be preliminary or controversial, as they often cut across previous groupings of mammalian relationships that were based on morphological considerations. For example, the order Insectivora, which comprised many genera and species of mostly small, insect-eating mammals, now appear to be only distantly related, and apparently share similar anatomy and behaviors primarily as the result of convergent evolution. As another example, distinctive morphological features of the Xenarthra (which includes anteaters, sloths, and armadillos) previously led taxonomists group all other Eutherian mammals into the taxon Epitheria, with Xenarthra as the most distantly related grouping. Yet another reconstruction would place Xenarthra and Afrotheria together within the clade Atlantogenata as a sister clade to the Boreoeutheria.
# Current status
Many members of Afrotheria appear to be at high risk of extinction; if the grouping is accurate, this would be a particularly devastating loss of genetic and evolutionary diversity. The Afrotheria Specialist Group notes that Afrotheria as currently reconstructed includes nearly a third of all mammalian orders currently found in Africa and Madagascar, but only 75 out of more than 1200 mammalian species in those areas. While most extant species assigned to the cohort Afrotheria are found in Africa, some (such as the Indian elephant and the three species of manatee) are found elsewhere; many of these are endangered as well.
# Organization
Afrotheria is a division of the infraclass Eutheria or Placentalia and groups together six living orders of mammals:
- INFRACLASS EUTHERIA: placental mammals
Superorder Afrotheria
Order Afrosoricida
Suborder Chrysochloridea: golden moles (21 species)
Suborder: Tenrecomorpha: tenrecs and otter shrews (32 species)
Order Macroscelidea: elephant shrews or sengis (15 species)
Order Tubulidentata: aardvark (1 species)
Clade Paenungulata
Order Hyracoidea: hyraxes (4-6 species, depending on classification of subspecies)
Order Proboscidea: elephants (3 species)
Order Sirenia: manatees (3 species) dugong (1 species) and several extinct species of sea cow
Order Embrithopoda: extinct
Order Desmostylia: extinct
Superorder Xenarthra
taxon Boreoeutheria
Superorder Laurasiatheria
Superorder Euarchontoglires (Supraprimates)
- Superorder Afrotheria
Order Afrosoricida
Suborder Chrysochloridea: golden moles (21 species)
Suborder: Tenrecomorpha: tenrecs and otter shrews (32 species)
Order Macroscelidea: elephant shrews or sengis (15 species)
Order Tubulidentata: aardvark (1 species)
Clade Paenungulata
Order Hyracoidea: hyraxes (4-6 species, depending on classification of subspecies)
Order Proboscidea: elephants (3 species)
Order Sirenia: manatees (3 species) dugong (1 species) and several extinct species of sea cow
Order Embrithopoda: extinct
Order Desmostylia: extinct
- Order Afrosoricida
Suborder Chrysochloridea: golden moles (21 species)
Suborder: Tenrecomorpha: tenrecs and otter shrews (32 species)
Order Macroscelidea: elephant shrews or sengis (15 species)
Order Tubulidentata: aardvark (1 species)
- Order Afrosoricida
Suborder Chrysochloridea: golden moles (21 species)
Suborder: Tenrecomorpha: tenrecs and otter shrews (32 species)
- Suborder Chrysochloridea: golden moles (21 species)
- Suborder: Tenrecomorpha: tenrecs and otter shrews (32 species)
- Order Macroscelidea: elephant shrews or sengis (15 species)
- Order Tubulidentata: aardvark (1 species)
- Clade Paenungulata
Order Hyracoidea: hyraxes (4-6 species, depending on classification of subspecies)
Order Proboscidea: elephants (3 species)
Order Sirenia: manatees (3 species) dugong (1 species) and several extinct species of sea cow
Order Embrithopoda: extinct
Order Desmostylia: extinct
- Order Hyracoidea: hyraxes (4-6 species, depending on classification of subspecies)
- Order Proboscidea: elephants (3 species)
- Order Sirenia: manatees (3 species) dugong (1 species) and several extinct species of sea cow
- Order Embrithopoda: extinct
- Order Desmostylia: extinct
- Superorder Xenarthra
- taxon Boreoeutheria
Superorder Laurasiatheria
Superorder Euarchontoglires (Supraprimates)
- Superorder Laurasiatheria
- Superorder Euarchontoglires (Supraprimates)
# Classification problems
Afrotheria are believed to have originated in Africa at a time when the continent was isolated from other continents. Their only externally visible common characteristic is the movable snout, although there is no convincing evidence that this structure is in fact homologous across all members of this group.
The biggest problem with considering Afrotherians as an originally African clade is the fossil record. The earliest fossil evidence for African ungulates and elephant shrews are found outside Africa. The Afrotheres are part of the proposed clade Atlantogenata.
Afrotherian monophyly is not universally accepted, and morphological evidence places the elephants and their relatives as true ungulates. This may also be the case for the aardvarks and the elephant shrews, although not the tenrecs and golden moles, and the elephant shrews may be related to gnawing mammals (within Glires). A mammal known from Madagascar (Plesiorycteropus) is of unknown affinities but may also be an ungulate perhaps related to the mainland aardvark. Some morphological evidence does support the affinity of the tenrecs and golden moles to other Lipotyphlan insectivores, especially to Solenodon in the Caribbean region. This is a more traditional interpretation of Tenrecomorph relationships. | Afrotheria
Afrotheria is a clade of mammals with the rank of superorder or cohort, containing (among others) the golden moles, elephant shrews, tenrecs, aardvarks, hyraxes, elephants and manatees.
# Evolutionary relationships
Afrotheria has been proposed based solely on molecular & DNA analyses. Genetic analyses since the 1990s have identified Afrotheria as one of four major groups within the infraclass Eutheria (containing placental mammals). Exact relations among the four cohorts, Afrotheria, Xenarthra, Laurasiatheria, and Euarchontoglires (aka Supraprimates) remain somewhat controversial. One reconstruction proposes that the oldest split was between Afrotheria and the other three some 105 million years ago when the African continent was separated from other major landmasses. (The name Afrotheria was coined from two roots, Afro- for 'Africa' and -theria meaning 'animal' in Greek.) Genetic analysis and the fossil record suggests that Xenarthra developed in South America and diverged from the remaining two somewhat later. Laurasiatheria and Euarchontoglires are more closely related than the other two cohorts and may be grouped together within the taxon Boreoeutheria.
Some researchers consider these classifications based on recent comparative DNA analysis to be preliminary or controversial, as they often cut across previous groupings of mammalian relationships that were based on morphological considerations. For example, the order Insectivora, which comprised many genera and species of mostly small, insect-eating mammals, now appear to be only distantly related, and apparently share similar anatomy and behaviors primarily as the result of convergent evolution. [1] As another example, distinctive morphological features of the Xenarthra (which includes anteaters, sloths, and armadillos) previously led taxonomists group all other Eutherian mammals into the taxon Epitheria, with Xenarthra as the most distantly related grouping. Yet another reconstruction would place Xenarthra and Afrotheria together within the clade Atlantogenata as a sister clade to the Boreoeutheria.
# Current status
Many members of Afrotheria appear to be at high risk of extinction; if the grouping is accurate, this would be a particularly devastating loss of genetic and evolutionary diversity. The Afrotheria Specialist Group notes that Afrotheria as currently reconstructed includes nearly a third of all mammalian orders currently found in Africa and Madagascar, but only 75 out of more than 1200 mammalian species in those areas. While most extant species assigned to the cohort Afrotheria are found in Africa, some (such as the Indian elephant and the three species of manatee) are found elsewhere; many of these are endangered as well.
# Organization
Afrotheria is a division of the infraclass Eutheria or Placentalia and groups together six living orders of mammals:
- INFRACLASS EUTHERIA: placental mammals
Superorder Afrotheria[2]
Order Afrosoricida
Suborder Chrysochloridea: golden moles (21 species)
Suborder: Tenrecomorpha: tenrecs and otter shrews (32 species)
Order Macroscelidea: elephant shrews or sengis (15 species)
Order Tubulidentata: aardvark (1 species)
Clade Paenungulata
Order Hyracoidea: hyraxes (4-6 species, depending on classification of subspecies)
Order Proboscidea: elephants (3 species)
Order Sirenia: manatees (3 species) dugong (1 species) and several extinct species of sea cow
Order Embrithopoda: extinct
Order Desmostylia: extinct
Superorder Xenarthra
taxon Boreoeutheria
Superorder Laurasiatheria
Superorder Euarchontoglires (Supraprimates)
- Superorder Afrotheria[2]
Order Afrosoricida
Suborder Chrysochloridea: golden moles (21 species)
Suborder: Tenrecomorpha: tenrecs and otter shrews (32 species)
Order Macroscelidea: elephant shrews or sengis (15 species)
Order Tubulidentata: aardvark (1 species)
Clade Paenungulata
Order Hyracoidea: hyraxes (4-6 species, depending on classification of subspecies)
Order Proboscidea: elephants (3 species)
Order Sirenia: manatees (3 species) dugong (1 species) and several extinct species of sea cow
Order Embrithopoda: extinct
Order Desmostylia: extinct
- Order Afrosoricida
Suborder Chrysochloridea: golden moles (21 species)
Suborder: Tenrecomorpha: tenrecs and otter shrews (32 species)
Order Macroscelidea: elephant shrews or sengis (15 species)
Order Tubulidentata: aardvark (1 species)
- Order Afrosoricida
Suborder Chrysochloridea: golden moles (21 species)
Suborder: Tenrecomorpha: tenrecs and otter shrews (32 species)
- Suborder Chrysochloridea: golden moles (21 species)
- Suborder: Tenrecomorpha: tenrecs and otter shrews (32 species)
- Order Macroscelidea: elephant shrews or sengis (15 species)
- Order Tubulidentata: aardvark (1 species)
- Clade Paenungulata
Order Hyracoidea: hyraxes (4-6 species, depending on classification of subspecies)
Order Proboscidea: elephants (3 species)
Order Sirenia: manatees (3 species) dugong (1 species) and several extinct species of sea cow
Order Embrithopoda: extinct
Order Desmostylia: extinct
- Order Hyracoidea: hyraxes (4-6 species, depending on classification of subspecies)
- Order Proboscidea: elephants (3 species)
- Order Sirenia: manatees (3 species) dugong (1 species) and several extinct species of sea cow
- Order Embrithopoda: extinct
- Order Desmostylia: extinct
- Superorder Xenarthra
- taxon Boreoeutheria
Superorder Laurasiatheria
Superorder Euarchontoglires (Supraprimates)
- Superorder Laurasiatheria
- Superorder Euarchontoglires (Supraprimates)
# Classification problems
Afrotheria are believed to have originated in Africa at a time when the continent was isolated from other continents. Their only externally visible common characteristic is the movable snout, although there is no convincing evidence that this structure is in fact homologous across all members of this group.
The biggest problem with considering Afrotherians as an originally African clade is the fossil record. The earliest fossil evidence for African ungulates and elephant shrews are found outside Africa. The Afrotheres are part of the proposed clade Atlantogenata.
Afrotherian monophyly is not universally accepted, and morphological evidence places the elephants and their relatives as true ungulates. This may also be the case for the aardvarks and the elephant shrews, although not the tenrecs and golden moles, and the elephant shrews may be related to gnawing mammals (within Glires). A mammal known from Madagascar (Plesiorycteropus) is of unknown affinities but may also be an ungulate perhaps related to the mainland aardvark. Some morphological evidence does support the affinity of the tenrecs and golden moles to other Lipotyphlan insectivores, especially to Solenodon in the Caribbean region. This is a more traditional interpretation of Tenrecomorph relationships. | https://www.wikidoc.org/index.php/Afrotheria | |
106408d79fc601b3ecc2fd225ff5486cb3175cf5 | wikidoc | Aftershave | Aftershave
Aftershave is a lotion, gel, or liquid used mainly by men after they have finished shaving. It may contain an antiseptic agent such as alcohol to prevent infection from cuts as well as numb damaged skin, a perfume to enhance scent, and a moisturizer to soften the skin. An alcohol-based, fragrance-free astringent can be used as an aftershave. It is said that the alcohol in the aftershave closes pores in the skin and prevents irritation ("razor burn").
Aftershaves are also sometimes mistakenly referred to as Eau de Cologne.
Noted brands include Brut, Global Gillette, Lynx, Adidas, Crabtree & Evelyn and Old Spice. Many fashion designer houses lend their names to brands of aftershave, including Hugo Boss, Comme des Garçons, Tommy Hilfiger, Marc Jacobs, Calvin Klein, Lacoste, Jil Sander, and Vera Wang.
Aftershave-like substances were used in ancient Egyptian times to clean and deodorize a dead body before it was soaked in natron and wrapped in linen bandages.
# Other brands
- Hai Karate
de:Rasierwasser
it:Dopobarba
he:אפטר שייב
nl:Aftershave
fi:Partavesi
sv:Rakvatten | Aftershave
Aftershave is a lotion, gel, or liquid used mainly by men after they have finished shaving. It may contain an antiseptic agent such as alcohol to prevent infection from cuts as well as numb damaged skin, a perfume to enhance scent, and a moisturizer to soften the skin. An alcohol-based, fragrance-free astringent can be used as an aftershave. It is said that the alcohol in the aftershave closes pores in the skin and prevents irritation ("razor burn").
Aftershaves are also sometimes mistakenly referred to as Eau de Cologne.
Noted brands include Brut, Global Gillette, Lynx, Adidas, Crabtree & Evelyn and Old Spice. Many fashion designer houses lend their names to brands of aftershave, including Hugo Boss, Comme des Garçons, Tommy Hilfiger, Marc Jacobs, Calvin Klein, Lacoste, Jil Sander, and Vera Wang.
Aftershave-like substances were used in ancient Egyptian times to clean and deodorize a dead body before it was soaked in natron and wrapped in linen bandages.
# Other brands
- Hai Karate
Template:Material-stub
de:Rasierwasser
it:Dopobarba
he:אפטר שייב
nl:Aftershave
fi:Partavesi
sv:Rakvatten | https://www.wikidoc.org/index.php/Aftershave | |
eb1a1453a603c30cd62d56c410139d6882c4a4be | wikidoc | Agar plate | Agar plate
# Overview
An agar plate is a sterile Petri dish that contains a growth medium (typically agar plus nutrients) used to culture microorganisms. Selective growth compounds may also be added to the media, such as antibiotics.
Individual microorganisms placed on the plate will grow into individual colonies, each a clone genetically identical to the individual ancestor organism (except for the low, unavoidable rate of mutation). Thus, the plate can be used either to estimate the concentration of organisms in a liquid culture or a suitable dilution of that culture, using a colony counter, or to generate genetically pure cultures from a mixed culture of genetically different organisms, using a technique known as streaking. In this technique, a drop of the culture on the end of a thin, sterile loop of wire is "streaked" across the surface of the agar leaving organisms behind, a higher number at the beginning of the streak and a lower number at the end. At some point during a successful "streak", the number of organisms deposited will be such that distinct individual colonies will grow in that area which may be removed for further culturing, using another sterile loop.
For information on agar plate preparation, please visit the Wikibooks Agar Plate page.
# Types of agar plates
Like other growth medium, the formulations of agar used in plates may be classified as either defined or undefined; defined medium being synthesized from the individual chemicals as required by the organism so that the exact molecular composition is known, while undefined medium is made up of natural products such as yeast extract, where the precise composition is unknown.
Agar plates may be formulated as either permissive, with the intent of allowing the growth of whatever organisms are present, or restrictive or selective, with the intent of only selecting for growth a particular subset of those organisms. This may take the form of a nutritional requirement, for instance providing a particular compound such as lactose as the only source of carbon for energy and material and thereby selecting only organisms which can metabolize that compound, or by including a particular antibiotic or other substance in order to select only organisms which are resistant to that substance. This correlates to some degree with defined and undefined media; undefined media, made from natural products and containing an unknown combination of very many organic molecules, is typically more permissive in terms of supplying the needs of a wider variety of organisms, while defined media can be precisely tailored to select organisms with very specific properties.
Agar plates may also be indicator plates, where the organisms are not selected on the basis of growth, but a compound in the agar is altered by an enzyme or similar in some colonies so as to change color and identify them from those lacking the enzyme.
Some commonly used agar plate types are:
## Blood agar types
- Blood agar plate (BAP)
- Chocolate agar (CHOC)
- Thayer-Martin agar (TM)
## General bacterial media
- Bile Esculin Agar (BEA)
- Cysteine Lactose Electrolyte Deficient agar (CLED)
- Hektoen Enteric (HE)
- MacConkey agar (MAC)
- Mannitol Salt Agar (MSA)
- Mueller Hinton agar
- Nutrient agar
- Önöz agar
- Phenylethyl Alcohol Agar (PEA)
- Tryptic (Trypticase) Soy Agar (TSA)
- Xylose-Lysine-Deoxycholate agar (XLD)
## Fungal media
- Sabouraud agar
- Hay Infusion agar
- Potato dextrose agar | Agar plate
Template:Infobox laboratory equipment
# Overview
An agar plate is a sterile Petri dish that contains a growth medium (typically agar plus nutrients) used to culture microorganisms. Selective growth compounds may also be added to the media, such as antibiotics.[1]
Individual microorganisms placed on the plate will grow into individual colonies, each a clone genetically identical to the individual ancestor organism (except for the low, unavoidable rate of mutation). Thus, the plate can be used either to estimate the concentration of organisms in a liquid culture or a suitable dilution of that culture, using a colony counter, or to generate genetically pure cultures from a mixed culture of genetically different organisms, using a technique known as streaking. In this technique, a drop of the culture on the end of a thin, sterile loop of wire is "streaked" across the surface of the agar leaving organisms behind, a higher number at the beginning of the streak and a lower number at the end. At some point during a successful "streak", the number of organisms deposited will be such that distinct individual colonies will grow in that area which may be removed for further culturing, using another sterile loop.[1]
For information on agar plate preparation, please visit the Wikibooks Agar Plate page.
# Types of agar plates
Like other growth medium, the formulations of agar used in plates may be classified as either defined or undefined; defined medium being synthesized from the individual chemicals as required by the organism so that the exact molecular composition is known, while undefined medium is made up of natural products such as yeast extract, where the precise composition is unknown.[2]
Agar plates may be formulated as either permissive, with the intent of allowing the growth of whatever organisms are present, or restrictive or selective, with the intent of only selecting for growth a particular subset of those organisms.[3] This may take the form of a nutritional requirement, for instance providing a particular compound such as lactose as the only source of carbon for energy and material and thereby selecting only organisms which can metabolize that compound, or by including a particular antibiotic or other substance in order to select only organisms which are resistant to that substance. This correlates to some degree with defined and undefined media; undefined media, made from natural products and containing an unknown combination of very many organic molecules, is typically more permissive in terms of supplying the needs of a wider variety of organisms, while defined media can be precisely tailored to select organisms with very specific properties.
Agar plates may also be indicator plates, where the organisms are not selected on the basis of growth, but a compound in the agar is altered by an enzyme or similar in some colonies so as to change color and identify them from those lacking the enzyme.
Some commonly used agar plate types are:
## Blood agar types
- Blood agar plate (BAP)
- Chocolate agar (CHOC)
- Thayer-Martin agar (TM)
## General bacterial media
- Bile Esculin Agar (BEA)
- Cysteine Lactose Electrolyte Deficient agar (CLED)
- Hektoen Enteric (HE)
- MacConkey agar (MAC)
- Mannitol Salt Agar (MSA)
- Mueller Hinton agar
- Nutrient agar
- Önöz agar
- Phenylethyl Alcohol Agar (PEA)
- Tryptic (Trypticase) Soy Agar (TSA)
- Xylose-Lysine-Deoxycholate agar (XLD)
## Fungal media
- Sabouraud agar
- Hay Infusion agar
- Potato dextrose agar | https://www.wikidoc.org/index.php/Agar_plate | |
58bae486d71465c8b70195291f2018f5dd21188a | wikidoc | Agaricales | Agaricales
The order Agaricales, also known as gilled mushrooms (for their distinctive gills), or euagarics, contains some of the most familiar types of mushrooms. The order has about 4,000 identified species, or one quarter of all known homobasidiomycetes. They range from the ubiquitous common mushroom to the deadly destroying angel and the hallucinogenic fly agaric to the bioluminescent jack-o-lantern mushroom.
# Classification
Some notable fungi with gill-like structures, such as chanterelles, have long been recognised as being substantially different from usual Agaricales. Interestingly, molecular studies are showing other groups as being more divergent than previously thought, such as the genera Russula and Lactarius belonging to a separate order Russulales, and other gilled fungi, including such species as Paxillus involutus and Hygrophoropsis aurantiaca showing a closer affinity with Boletes in the order Boletales.
Also, some other quite distinctive fungi, the puffballs and the Beefsteak fungus have been recently been shown lie within the Agaricales.
The term agaric had traditionally referred to Agaricales, which were defined as exactly those fungi with gills. Given the discoveries described above, those two categories are not synonymous (although there is a very large overlap between the two groups).
# Distribution and habitat
Agarics are ubiquitous, being found across all continents. Although all are terrestrial, their habitats include all types of woodland and grassland, varying largely from one species to another.
# Characteristics
Basidiocarps of the agarics are typically fleshy, with a stipe, often called a stem or stalk, a pileus (or cap) and lamellae (or gills), where basidiospores are stored. This is indeed the stereotyped structure of what we would call a mushroom or toadstool.
# Life cycle
The agarics' life cycle is very much representative of the basidiomycetes. Clamp connections are present in the dikaryons of several species, but that is not always the case. The agarics always have their basidiospores ejected from the basidium into the area between gill edges. The spores are then let fall to the ground or carried by the wind. | Agaricales
Template:Wikispecies
The order Agaricales, also known as gilled mushrooms (for their distinctive gills), or euagarics, contains some of the most familiar types of mushrooms. The order has about 4,000 identified species, or one quarter of all known homobasidiomycetes. They range from the ubiquitous common mushroom to the deadly destroying angel and the hallucinogenic fly agaric to the bioluminescent jack-o-lantern mushroom.
# Classification
Some notable fungi with gill-like structures, such as chanterelles, have long been recognised as being substantially different from usual Agaricales. Interestingly, molecular studies are showing other groups as being more divergent than previously thought, such as the genera Russula and Lactarius belonging to a separate order Russulales, and other gilled fungi, including such species as Paxillus involutus and Hygrophoropsis aurantiaca showing a closer affinity with Boletes in the order Boletales.
Also, some other quite distinctive fungi, the puffballs and the Beefsteak fungus have been recently been shown lie within the Agaricales.
The term agaric had traditionally referred to Agaricales, which were defined as exactly those fungi with gills. Given the discoveries described above, those two categories are not synonymous (although there is a very large overlap between the two groups).
# Distribution and habitat
Agarics are ubiquitous, being found across all continents. Although all are terrestrial, their habitats include all types of woodland and grassland, varying largely from one species to another.
# Characteristics
Basidiocarps of the agarics are typically fleshy, with a stipe, often called a stem or stalk, a pileus (or cap) and lamellae (or gills), where basidiospores are stored. This is indeed the stereotyped structure of what we would call a mushroom or toadstool.
# Life cycle
The agarics' life cycle is very much representative of the basidiomycetes. Clamp connections are present in the dikaryons of several species, but that is not always the case. The agarics always have their basidiospores ejected from the basidium into the area between gill edges. The spores are then let fall to the ground or carried by the wind. | https://www.wikidoc.org/index.php/Agaricales | |
460d57d898fad94afbe067e2f1011ec66520525c | wikidoc | Liver spot | Liver spot
# Overview
Liver spots are blemishes on the skin associated with aging and exposure to ultra-violet radiation from the sun. They are also known as age spots, sun spots, lentigos, or senile/solar lentigines. They range in color from light brown to black and are located in areas most often exposed to the sun, particularly the hands, face, shoulders, arms and forehead. In spite of their name, liver spots are not related to the liver, rather to the liver colouration of the spots.
From the age of 40 onwards, the skin is less able to regenerate from sun exposure and liver spots are very common in this older age group, particularly in those who enjoy being out in the sunshine. They have been known to proliferate in some individuals under emotional distress.
In the vast majority of cases, liver spots pose no threat and no treatment is necessary. In a very small number of cases, they have been known to obscure the detection of skin cancer.
Some people consider these spots unsightly and wish to have them removed for cosmetic reasons. This can be done by cryotherapy or laser treatment.
# Diagnosis
## Physical Examination
### Skin
- Liver spot. Adapted from Dermatology Atlas.
- Liver spot. Adapted from Dermatology Atlas.
- Liver spot. Adapted from Dermatology Atlas. | Liver spot
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2]
# Overview
Liver spots are blemishes on the skin associated with aging and exposure to ultra-violet radiation from the sun. They are also known as age spots, sun spots, lentigos, or senile/solar lentigines. They range in color from light brown to black and are located in areas most often exposed to the sun, particularly the hands, face, shoulders, arms and forehead. In spite of their name, liver spots are not related to the liver, rather to the liver colouration of the spots.
From the age of 40 onwards, the skin is less able to regenerate from sun exposure and liver spots are very common in this older age group, particularly in those who enjoy being out in the sunshine. They have been known to proliferate in some individuals under emotional distress.
In the vast majority of cases, liver spots pose no threat and no treatment is necessary. In a very small number of cases, they have been known to obscure the detection of skin cancer.
Some people consider these spots unsightly and wish to have them removed for cosmetic reasons. This can be done by cryotherapy or laser treatment.
# Diagnosis
## Physical Examination
### Skin
- Liver spot. Adapted from Dermatology Atlas.[1]
- Liver spot. Adapted from Dermatology Atlas.[1]
- Liver spot. Adapted from Dermatology Atlas.[1] | https://www.wikidoc.org/index.php/Age_spots | |
3e1a81a7785d8a962453ba895245c1539558d68c | wikidoc | Senescence | Senescence
Senescence refers to the biological processes of a living organism approaching an advanced age (i.e., the combination of processes of deterioration which follow the period of development of an organism). The word senescence is derived from the Latin word senex, meaning "old man" or "old age" or "advanced in age".
For the science of the care of the elderly, see gerontology; for experimental gerontology, see life extension.
# Cellular senescence
Cellular senescence is the phenomenon where normal diploid differentiated cells lose the ability to divide. This phenomenon is also known as "replicative senescence", the "Hayflick phenomenon", or the Hayflick limit in honour of Dr. Leonard Hayflick who was the first to publish it in 1965. In response to DNA damage (including shortened telomeres) cells either senesce or self-destruct (apoptosis, programmed cell death) if the damage cannot be repaired. In this 'cellular suicide', the death of one, or more, cells may benefit the organism as a whole. For example, in plants the death of the water-conducting xylem cells (tracheids and vessel elements) allows the cells to function more efficiently and so deliver water to the upper parts of a plant.
# Aging of the whole organism
Organismal senescence is the aging of whole organisms. The term aging has become so commonly equated with senescence that the terms will be used interchangeably in this article.
Aging is generally characterized by the declining ability to respond to stress, increasing homeostatic imbalance and increased risk of aging-associated diseases. Because of this, death is the ultimate consequence of aging. Differences in maximum life span between species correspond to different "rates of aging". For example, inherited differences in the rate of aging make a mouse elderly at 3 years and a human elderly at 90 years. These genetic differences affect a variety of physiological processes, including the efficiency of DNA repair, antioxidant enzymes, and rates of free radical production.
Senescence of the organism gives rise to the Gompertz-Makeham law of mortality, which says that mortality rate rises rapidly with age.
Some animals, such as some reptiles and fish, age slowly. Some even exhibit "negative senescence", in which mortality falls with age, in disagreement with the Gompertz-Makeham "law".
# Theories of aging
The process of senescence is complex, and may derive from a variety of different mechanisms and exist for a variety of different reasons. However, senescence is not universal, and scientific evidence suggests that cellular senescence evolved in certain species as a mechanism to prevent the onset of cancer. In a few simple species, senescence is negligible and cannot be detected. All such species have no "post-mitotic" cells; they reduce the effect of damaging free radicals by cell division and dilution. Such species are not immortal, however, as they will eventually fall prey to trauma or disease. Moreover, average lifespans can vary greatly within and between species. This suggests that both genetic and environmental factors contribute to aging.
Traditionally, theories that explain senescence have generally been divided between the programmed and stochastic theories of aging. Programmed theories imply that aging is regulated by biological clocks operating throughout the life span. This regulation would depend on changes in gene expression that affect the systems responsible for maintenance, repair and defense responses. Stochastic theories blame environmental impacts on living organisms that induce cumulative damage at various levels as the cause of aging, examples which range from damage to deoxyribonucleic acid (DNA), damage to tissues and cells by oxygen radicals (widely known as free radicals countered by the even more well known antioxidants), and cross-linking.
The above categorisation of theories of aging is obsolete and no serious biogerontologist follows that division anymore. Instead, aging is seen as a progressive failure of homeodynamics (homeostasis) involving genes for the maintenance and repair, stochastic events leading to molecular damage and molecular heterogeneity, and chance events determining the probability of death. Since complex and interacting systems of maintenance and repair comprise the homeodynamic (old term, homeostasis) space of a biological system, aging is considered to be a progressive shrinkage of homeodynamic space mainly due to increased molecular heterogeneity.
## Evolutionary theories
Ageing is believed to have evolved because of the increasingly smaller probability of an organism still being alive at older age, due to predation and accidents, both of which may be random and age-invariant. It is thought that strategies which result in a higher reproductive rate at a young age, but shorter overall lifespan, result in a higher lifetime reproductive success and are therefore favoured by natural selection. Essentially, ageing is therefore the result of investing resources in reproduction, rather than maintenance of the body (the "Disposable Soma" theory), in light of the fact that accidents, predation and disease will eventually kill the organism no matter how much energy is devoted to repair of the body. Various other, or more specific, theories of ageing exist, and are not necessarily mutually exclusive.
The geneticist J. B. S. Haldane wondered why the dominant mutation which causes Huntington's disease remained in the population, why natural selection had not eliminated it. The onset of this neurological disease is (on average) at age 45 and is invariably fatal within 10-20 years. Haldane assumed, probably reasonably, that in human prehistory, few survived until age 45. Since few were alive at older ages and their contribution to the next generation was therefore small relative to the large cohorts of younger age groups, the force of selection against such late-acting deleterious mutations was correspondingly small. However if a mutation affected younger individuals, selection against it would be strong. Therefore, late-acting deleterious mutations could accumulate in populations over evolutionary time through genetic drift. This principle has been proven correct. And it is these later-acting deleterious mutations which are believed to cause, or perhaps more correctly allow, age-related mortality.
Peter Medawar formalised this observation in his mutation accumulation theory of ageing. "The force of natural selection weakens with increasing age — even in a theoretically immortal population, provided only that it is exposed to real hazards of mortality. If a genetic disaster... happens late enough in individual life, its consequences may be completely unimportant". The 'real hazards of mortality' are typically predation, disease and accidents. So, even an immortal population, whose fertility does not decline with time, will have fewer individuals alive in older age groups. This is called 'extrinsic mortality.' Young cohorts, not depleted in numbers yet by extrinsic mortality, contribute far more to the next generation than the few remaining older cohorts, so the force of selection against late-acting deleterious mutations, which only affect these few older individuals, is very weak. The mutations may not be selected against, therefore, and may spread over evolutionary time into the population.
The major testable prediction made by this model is that species which have high extrinsic mortality in nature will age more quickly and have shorter intrinsic life spans. This is because there is too little time before death occurs by extrinsic causes for the effects of deleterious mutations to be expressed and, therefore, selected against. This is borne out among mammals, the most well studied in terms of life history. There is a correlation among mammals between body size and lifespan, such that larger species live longer than smaller species in controlled/optimum conditions, but there are notable exceptions. For instance, many bats and rodents are similarly sized, yet bats live much, much longer. For instance, the little brown bat, half the size of a mouse, can live 30 years in the wild. A mouse will live 2–3 years even with optimum conditions. The explanation is that bats have fewer predators, and have lower overall metabolic activity, due to lengthier periods of dormancy, so therefore low extrinsic mortality. Thus more individuals survive to later ages so the force of selection against late-acting deleterious mutations is stronger. Fewer late-acting deleterious mutations = slower ageing = longer lifespan. Birds are also warm-blooded and similarly sized to many small mammals, yet live often 5–10 times as long. They clearly have fewer predation pressures compared with ground-dwelling mammals. And seabirds, which generally have the fewest predators of all birds, live longest.
Also, when examining the body-size vs. lifespan relationship, predator mammals tend to have longer lifespans than prey animals in a controlled environment such as a zoo or nature reserve. The explanation for the long lifespans of primates (such as humans, monkeys and apes) relative to body size is that their intelligence and often sociality helps them avoid becoming prey. Being a predator, being smart and working together all reduce extrinsic mortality.
Another evolutionary theory of ageing was proposed by George C. Williams (Williams 1957) and involves antagonistic pleiotropy. A single gene may affect multiple traits. Some traits that increase fitness early in life may also have negative effects later in life. But because many more individuals are alive at young ages than at old ages, even small positive effects early can be strongly selected for, and large negative effects later may be very weakly selected against. Williams suggested the following example: perhaps a gene codes for calcium deposition in bones which promotes juvenile survival and will therefore be favored by natural selection; however this same gene promotes calcium deposition in the arteries, causing negative effects in old age. Therefore negative effects in old age may reflect the result of natural selection for pleiotropic genes which are beneficial early in life. In this case, fitness is relatively high when Fisher's reproductive value is high and relatively low when Fisher's reproductive value is low.
## Gene regulation
A number of genetic components of aging have been identified using model organisms, ranging from the simple budding yeast Saccharomyces cerevisiae to worms such as Caenorhabditis elegans and fruit flies (Drosophila melanogaster). Study of these organisms has revealed the presence of at least two conserved aging pathways.
One of these pathways involves the gene Sir2, a NAD+-dependent histone deacetylase. In yeast, Sir2 is required for genomic silencing at three loci: the yeast mating loci, the telomeres and the ribosomal DNA (rDNA). In some species of yeast replicative aging may be partially caused by homologous recombination between rDNA repeats; excision of rDNA repeats results in the formation of extrachromosomal rDNA circles (ERCs). These ERCs replicate and preferentially segregate to the mother cell during cell division, and are believed to result in cellular senescence by titrating away (competing for) essential nuclear factors. ERCs have not been observed in other species of yeast (which also display replicative senescence), and ERCs are not believed to contribute to aging in higher organisms such as humans. Extrachromosomal circular DNA (eccDNA) has been found in worms, flies and humans. The role of eccDNA in aging, if any, is unknown.
Despite the lack of a connection between circular DNA and aging in higher organisms, extra copies of Sir2 are capable of extending the lifespan of both worms and flies. The mechanisms by which Sir2 homologues in higher organisms regulate lifespan is unclear, but the human SIRT1 protein has been demonstrated to deacetylate p53, Ku70, and the forkhead family of transcription factors. SIRT1 can also regulate acetylates such as CBP/p300, and has been shown to deacetylate specific histone residues.
RAS1 and RAS2 also affect aging in yeast and have a human homologue. RAS2 overexpression has been shown to extend lifespan in yeast.
Other genes regulate aging in yeast by increasing the resistance to oxidative stress. Superoxide dismutase, a protein that protects against the effects of mitochondrial free radicals, can extend yeast lifespan in stationary phase when overexpressed.
In higher organisms, aging is likely to be regulated in part through the insulin/IGF-1 pathway. Mutations that affect insulin-like signaling in worms, flies and mice are associated with extended lifespan. In yeast, Sir2 activity is regulated by the nicotinamidase PNC1. PNC1 is transcriptionally upregulated under stressful conditions such as caloric restriction, heat shock, and osmotic shock. By converting nicotinamide to niacin, it removes nicotinamide, which inhibits the activity of Sir2. A nicotinamidase found in humans, known as PBEF, may serve a similar function, and a secreted form of PBEF known as visfatin may help to regulate serum insulin levels. It is not known, however, whether these mechanisms also exist in humans since there are obvious differences in biology between humans and model organisms.
Sir2 activity has been shown to increase under calorie restriction. Due to the lack of available glucose in the cells more NAD+ is available and can activate Sir2. Resveratrol, a polyphenol found in the skin of red grapes, was reported to extend the lifespan of yeast, worms, and flies. It has been shown to activate Sir2 activity and therefore mimics the effects of calorie restriction.
Gene expression is imperfectly controlled, and it is possible that random fluctuations in the expression levels of many genes contribute to the aging process (Ryley, J. 2006). Individual cells, which are genetically identical, none-the-less can have substantially different responses to outside stimuli, and markedly different lifespans, indicating the epigenetic factors play an important role in gene expression and aging as well as genetic factors.
This is a list of confirmed longevity genes from model animals.
The major genetic model organisms used in aging research are the filamentous fungus (Podospora anserina), bakers' yeast (Saccharomyces cerevisiae), the soil roundworm (Caenorhabditis elegans), the fruit fly (Drosophila melanogaster), and the mouse (Mus musculus).
## Cellular senescence
As noted above, senescence is not universal, and senescence is not observed in single-celled organisms that reproduce through the process of cellular mitosis. Moreover, cellular senescence is not observed in many organisms, including sponges, corals, and lobsters. In those species where cellular senescence is observed, cells eventually become post-mitotic when they can no longer replicate themselves through the process of cellular mitosis -- i.e., cells experience replicative senescence. How and why some cells become post-mitotic in some species has been the subject of much research and speculation, but (as noted above) it is widely believed that cellular senescence evolved as a way to prevent the onset and spread of cancer. Somatic cells that have divided many times will have accumulated DNA mutations and would therefore be in danger of becoming cancerous if cell division continued.
Lately the role of telomeres in cellular senescence has aroused general interest, especially with a view to the possible genetically adverse effects of cloning. The successive shortening of the chromosomal telomeres with each cell cycle is also believed to limit the number of divisions of the cell, thus contributing to aging. There have, on the other hand, also been reports that cloning could alter the shortening of telomeres. Some cells do not age and are therefore described as being "biologically immortal." It is theorized by some that when it is discovered exactly what allows these cells, whether it be the result of telomere lengthening or not, to divide without limit that it will be possible to genetically alter other cells to have the same capability. It is further theorized that it will eventually be possible to genetically engineer all cells in the human body to have this capability by employing gene therapy and thereby stop or reverse ageing, effectively making the entire organism potentially immortal.
## Chemical damage
The earliest aging theory was the Rate of Living Hypothesis described by Raymond Pearl in 1928, based on the idea that fast basal metabolic rate corresponds to short maximum life span (much as a rapidly running machine will experience more damage from wear). (The idea had been posited earlier by Max Rubner).
While there is likely some validity to this theory, in the form of various types of specific damage detailed below which, all other things being equal may reduce lifespan, in general this theory does not adequately explain the differences in lifespan either within, or between, species. Calorically-restricted animals process as much, or more, calories per gram of body mass, as their ad libitum fed counterparts, yet exhibit substantially longer lifespans. Similarly, metabolic rate is a poor predictor of lifespan for birds, bats and other species which presumably have reduced mortality from predation, and therefore have evolved long lifespans even in the presence of very high metabolic rates.
With respect to specific types of chemical damage caused by metabolism, it is suggested that damage to long-lived biopolymers, such as structural proteins or DNA, caused by ubiquitous chemical agents in the body such as oxygen and sugars, are in part responsible for aging. The damage can include breakage of biopolymer chains, cross-linking of biopolymers, or chemical attachment of unnatural substituents (haptens) to biopolymers.
Under normal aerobic conditions, approximately 4% of the oxygen metabolized by mitochondria is converted to superoxide ion which can subsequently be converted to hydrogen peroxide, hydroxyl radical and eventually other reactive species including other peroxides and singlet oxygen, which can in turn generate free radicals capable of damaging structural proteins and DNA. Certain metal ions found in the body, such as copper and iron, may participate in the process. (In Wilson's disease, a hereditary defect which causes the body to retain copper, some of the symptoms resemble accelerated senescence.) These processes are termed oxidative damage and are linked to the benefits of nutritionally derived polyphenol antioxidants.
Sugars such as glucose and fructose can react with certain amino acids such as lysine and arginine and certain DNA bases such as guanine to produce sugar adducts, in a process called glycation. These adducts can further rearrange to form reactive species which can then cross-link the structural proteins or DNA to similar biopolymers or other biomolecules such as non-structural proteins. People with diabetes, who have elevated blood sugar, develop senescence-associated disorders much earlier than the general population, but can delay such disorders by rigorous control of their blood sugar levels. There is evidence that sugar damage is linked to oxidant damage in a process termed glycoxidation.
Free radicals can damage proteins, lipids or DNA. Glycation mainly damages proteins. Damaged proteins and lipids accumulate in lysosomes as lipofuscin. Chemical damage to structural proteins can lead to loss of function; for example, damage to collagen of blood vessel walls can lead to vessel-wall stiffness and thus hypertension, and vessel wall thickening and reactive tissue formation (atherosclerosis); similar processes in the kidney can lead to renal failure. Damage to enzymes reduces cellular functionality. Lipid peroxidation of the inner mitochondrial membrane reduces the electric potential and the ability to generate energy. It is probably no accident that nearly all of the so-called "accelerated aging diseases" are due to defective DNA repair enzymes.
## Reliability theory
Reliability theory suggests that biological systems start their adult life with a high load of initial damage. Reliability theory is a general theory about systems failure. It allows researchers to predict the age-related failure kinetics for a system of given architecture (reliability structure) and given reliability of its components. Reliability theory predicts that even those systems that are entirely composed of non-aging elements (with a constant failure rate) will nevertheless deteriorate (fail more often) with age, if these systems are redundant in irreplaceable elements. Aging, therefore, is a direct consequence of systems redundancy.
Reliability theory also predicts the late-life mortality deceleration with subsequent leveling-off, as well as the late-life mortality plateaus, as an inevitable consequence of redundancy exhaustion at extreme old ages. The theory explains why mortality rates increase exponentially with age (the Gompertz law) in many species, by taking into account the initial flaws (defects) in newly formed systems. It also explains why organisms "prefer" to die according to the Gompertz law, while technical devices usually fail according to the Weibull (power) law. Reliability theory allows to specify conditions when organisms die according to the Weibull law: organisms should be relatively free of initial flaws and defects. The theory makes it possible to find a general failure law applicable to all adult and extreme old ages, where the Gompertz and the Weibull laws are just special cases of this more general failure law. The theory explains why relative differences in mortality rates of compared populations (within a given species) vanish with age (compensation law of mortality), and mortality convergence is observed due to the exhaustion of initial differences in redundancy levels.
## Neuro-endocrine-immunological theories
Senescence may also simply be a result of wear and tear overwhelming repair mechanisms. It is also possible that senescence is a mechanism to control the development and spread of cancer; if cells have built-in limits to how many times they can replicate, they must somehow overcome this before they can spread indefinitely.
# Miscellaneous
Recently, early senescence has been alleged to be a possible unintended outcome of early cloning experiments. Most notably, the issue was raised in the case of Dolly the sheep, following her death from a contagious lung disease. The claim that Dolly's early death involved premature senescence has been vigorously contested (e.g. by Kerry Lynn Macintosh in her book, Illegal Beings: Human Clones and the Law), and Dolly's creator, Dr. Ian Wilmut has expressed the view that her illness and death were probably unrelated to the fact that she was a clone.
A set of rare hereditary (genetic) disorders, each called progeria, has been known for some time. Sufferers exhibit symptoms resembling accelerated aging, including wrinkled skin. The cause of Hutchinson–Gilford progeria syndrome was reported in the journal Nature in May 2003. This report suggests that DNA damage, not oxidative stress, is the cause of this form of accelerated aging. | Senescence
Template:Tooshort
Senescence refers to the biological processes of a living organism approaching an advanced age (i.e., the combination of processes of deterioration which follow the period of development of an organism). The word senescence is derived from the Latin word senex, meaning "old man" or "old age" or "advanced in age".
For the science of the care of the elderly, see gerontology; for experimental gerontology, see life extension.
# Cellular senescence
Cellular senescence is the phenomenon where normal diploid differentiated cells lose the ability to divide. This phenomenon is also known as "replicative senescence", the "Hayflick phenomenon", or the Hayflick limit in honour of Dr. Leonard Hayflick who was the first to publish it in 1965. In response to DNA damage (including shortened telomeres) cells either senesce or self-destruct (apoptosis, programmed cell death) if the damage cannot be repaired. In this 'cellular suicide', the death of one, or more, cells may benefit the organism as a whole. For example, in plants the death of the water-conducting xylem cells (tracheids and vessel elements) allows the cells to function more efficiently and so deliver water to the upper parts of a plant.
# Aging of the whole organism
Organismal senescence is the aging of whole organisms. The term aging has become so commonly equated with senescence that the terms will be used interchangeably in this article.
Aging is generally characterized by the declining ability to respond to stress, increasing homeostatic imbalance and increased risk of aging-associated diseases. Because of this, death is the ultimate consequence of aging. Differences in maximum life span between species correspond to different "rates of aging". For example, inherited differences in the rate of aging make a mouse elderly at 3 years and a human elderly at 90 years. These genetic differences affect a variety of physiological processes, including the efficiency of DNA repair, antioxidant enzymes, and rates of free radical production.
Senescence of the organism gives rise to the Gompertz-Makeham law of mortality, which says that mortality rate rises rapidly with age.
Some animals, such as some reptiles and fish, age slowly. Some even exhibit "negative senescence", in which mortality falls with age, in disagreement with the Gompertz-Makeham "law".[1]
# Theories of aging
The process of senescence is complex, and may derive from a variety of different mechanisms and exist for a variety of different reasons. However, senescence is not universal, and scientific evidence suggests that cellular senescence evolved in certain species as a mechanism to prevent the onset of cancer. In a few simple species, senescence is negligible and cannot be detected. All such species have no "post-mitotic" cells; they reduce the effect of damaging free radicals by cell division and dilution. Such species are not immortal, however, as they will eventually fall prey to trauma or disease. Moreover, average lifespans can vary greatly within and between species. This suggests that both genetic and environmental factors contribute to aging.
Traditionally, theories that explain senescence have generally been divided between the programmed and stochastic theories of aging. Programmed theories imply that aging is regulated by biological clocks operating throughout the life span. This regulation would depend on changes in gene expression that affect the systems responsible for maintenance, repair and defense responses. Stochastic theories blame environmental impacts on living organisms that induce cumulative damage at various levels as the cause of aging, examples which range from damage to deoxyribonucleic acid (DNA), damage to tissues and cells by oxygen radicals (widely known as free radicals countered by the even more well known antioxidants), and cross-linking.
The above categorisation of theories of aging is obsolete and no serious biogerontologist follows that division anymore. Instead, aging is seen as a progressive failure of homeodynamics (homeostasis) involving genes for the maintenance and repair, stochastic events leading to molecular damage and molecular heterogeneity, and chance events determining the probability of death. Since complex and interacting systems of maintenance and repair comprise the homeodynamic (old term, homeostasis) space of a biological system, aging is considered to be a progressive shrinkage of homeodynamic space mainly due to increased molecular heterogeneity.[citation needed]
## Evolutionary theories
Ageing is believed to have evolved because of the increasingly smaller probability of an organism still being alive at older age, due to predation and accidents, both of which may be random and age-invariant. It is thought that strategies which result in a higher reproductive rate at a young age, but shorter overall lifespan, result in a higher lifetime reproductive success and are therefore favoured by natural selection. Essentially, ageing is therefore the result of investing resources in reproduction, rather than maintenance of the body (the "Disposable Soma" theory), in light of the fact that accidents, predation and disease will eventually kill the organism no matter how much energy is devoted to repair of the body. Various other, or more specific, theories of ageing exist, and are not necessarily mutually exclusive.
The geneticist J. B. S. Haldane wondered why the dominant mutation which causes Huntington's disease remained in the population, why natural selection had not eliminated it. The onset of this neurological disease is (on average) at age 45 and is invariably fatal within 10-20 years. Haldane assumed, probably reasonably, that in human prehistory, few survived until age 45. Since few were alive at older ages and their contribution to the next generation was therefore small relative to the large cohorts of younger age groups, the force of selection against such late-acting deleterious mutations was correspondingly small. However if a mutation affected younger individuals, selection against it would be strong. Therefore, late-acting deleterious mutations could accumulate in populations over evolutionary time through genetic drift. This principle has been proven correct. And it is these later-acting deleterious mutations which are believed to cause, or perhaps more correctly allow, age-related mortality.
Peter Medawar formalised this observation in his mutation accumulation theory of ageing[2]. "The force of natural selection weakens with increasing age — even in a theoretically immortal population, provided only that it is exposed to real hazards of mortality. If a genetic disaster... happens late enough in individual life, its consequences may be completely unimportant". The 'real hazards of mortality' are typically predation, disease and accidents. So, even an immortal population, whose fertility does not decline with time, will have fewer individuals alive in older age groups. This is called 'extrinsic mortality.' Young cohorts, not depleted in numbers yet by extrinsic mortality, contribute far more to the next generation than the few remaining older cohorts, so the force of selection against late-acting deleterious mutations, which only affect these few older individuals, is very weak. The mutations may not be selected against, therefore, and may spread over evolutionary time into the population.
The major testable prediction made by this model is that species which have high extrinsic mortality in nature will age more quickly and have shorter intrinsic life spans. This is because there is too little time before death occurs by extrinsic causes for the effects of deleterious mutations to be expressed and, therefore, selected against. This is borne out among mammals, the most well studied in terms of life history. There is a correlation among mammals between body size and lifespan, such that larger species live longer than smaller species in controlled/optimum conditions, but there are notable exceptions. For instance, many bats and rodents are similarly sized, yet bats live much, much longer. For instance, the little brown bat, half the size of a mouse, can live 30 years in the wild. A mouse will live 2–3 years even with optimum conditions. The explanation is that bats have fewer predators, and have lower overall metabolic activity, due to lengthier periods of dormancy, so therefore low extrinsic mortality. Thus more individuals survive to later ages so the force of selection against late-acting deleterious mutations is stronger. Fewer late-acting deleterious mutations = slower ageing = longer lifespan. Birds are also warm-blooded and similarly sized to many small mammals, yet live often 5–10 times as long. They clearly have fewer predation pressures compared with ground-dwelling mammals. And seabirds, which generally have the fewest predators of all birds, live longest.
Also, when examining the body-size vs. lifespan relationship, predator mammals tend to have longer lifespans than prey animals in a controlled environment such as a zoo or nature reserve. The explanation for the long lifespans of primates (such as humans, monkeys and apes) relative to body size is that their intelligence and often sociality helps them avoid becoming prey. Being a predator, being smart and working together all reduce extrinsic mortality.
Another evolutionary theory of ageing was proposed by George C. Williams (Williams 1957) and involves antagonistic pleiotropy. A single gene may affect multiple traits. Some traits that increase fitness early in life may also have negative effects later in life. But because many more individuals are alive at young ages than at old ages, even small positive effects early can be strongly selected for, and large negative effects later may be very weakly selected against. Williams suggested the following example: perhaps a gene codes for calcium deposition in bones which promotes juvenile survival and will therefore be favored by natural selection; however this same gene promotes calcium deposition in the arteries, causing negative effects in old age. Therefore negative effects in old age may reflect the result of natural selection for pleiotropic genes which are beneficial early in life. In this case, fitness is relatively high when Fisher's reproductive value is high and relatively low when Fisher's reproductive value is low.
## Gene regulation
A number of genetic components of aging have been identified using model organisms, ranging from the simple budding yeast Saccharomyces cerevisiae to worms such as Caenorhabditis elegans and fruit flies (Drosophila melanogaster). Study of these organisms has revealed the presence of at least two conserved aging pathways.
One of these pathways involves the gene Sir2, a NAD+-dependent histone deacetylase. In yeast, Sir2 is required for genomic silencing at three loci: the yeast mating loci, the telomeres and the ribosomal DNA (rDNA). In some species of yeast replicative aging may be partially caused by homologous recombination between rDNA repeats; excision of rDNA repeats results in the formation of extrachromosomal rDNA circles (ERCs). These ERCs replicate and preferentially segregate to the mother cell during cell division, and are believed to result in cellular senescence by titrating away (competing for) essential nuclear factors. ERCs have not been observed in other species of yeast (which also display replicative senescence), and ERCs are not believed to contribute to aging in higher organisms such as humans. Extrachromosomal circular DNA (eccDNA) has been found in worms, flies and humans. The role of eccDNA in aging, if any, is unknown.
Despite the lack of a connection between circular DNA and aging in higher organisms, extra copies of Sir2 are capable of extending the lifespan of both worms and flies. The mechanisms by which Sir2 homologues in higher organisms regulate lifespan is unclear, but the human SIRT1 protein has been demonstrated to deacetylate p53, Ku70, and the forkhead family of transcription factors. SIRT1 can also regulate acetylates such as CBP/p300, and has been shown to deacetylate specific histone residues.
RAS1 and RAS2 also affect aging in yeast and have a human homologue. RAS2 overexpression has been shown to extend lifespan in yeast.
Other genes regulate aging in yeast by increasing the resistance to oxidative stress. Superoxide dismutase, a protein that protects against the effects of mitochondrial free radicals, can extend yeast lifespan in stationary phase when overexpressed.
In higher organisms, aging is likely to be regulated in part through the insulin/IGF-1 pathway. Mutations that affect insulin-like signaling in worms, flies and mice are associated with extended lifespan. In yeast, Sir2 activity is regulated by the nicotinamidase PNC1. PNC1 is transcriptionally upregulated under stressful conditions such as caloric restriction, heat shock, and osmotic shock. By converting nicotinamide to niacin, it removes nicotinamide, which inhibits the activity of Sir2. A nicotinamidase found in humans, known as PBEF, may serve a similar function, and a secreted form of PBEF known as visfatin may help to regulate serum insulin levels. It is not known, however, whether these mechanisms also exist in humans since there are obvious differences in biology between humans and model organisms.
Sir2 activity has been shown to increase under calorie restriction. Due to the lack of available glucose in the cells more NAD+ is available and can activate Sir2. Resveratrol, a polyphenol found in the skin of red grapes, was reported to extend the lifespan of yeast, worms, and flies. It has been shown to activate Sir2 activity and therefore mimics the effects of calorie restriction.
Gene expression is imperfectly controlled, and it is possible that random fluctuations in the expression levels of many genes contribute to the aging process (Ryley, J. 2006). Individual cells, which are genetically identical, none-the-less can have substantially different responses to outside stimuli, and markedly different lifespans, indicating the epigenetic factors play an important role in gene expression and aging as well as genetic factors.
This is a list of confirmed longevity genes from model animals.
The major genetic model organisms used in aging research are the filamentous fungus (Podospora anserina), bakers' yeast (Saccharomyces cerevisiae), the soil roundworm (Caenorhabditis elegans), the fruit fly (Drosophila melanogaster), and the mouse (Mus musculus).
## Cellular senescence
As noted above, senescence is not universal, and senescence is not observed in single-celled organisms that reproduce through the process of cellular mitosis. Moreover, cellular senescence is not observed in many organisms, including sponges, corals, and lobsters. In those species where cellular senescence is observed, cells eventually become post-mitotic when they can no longer replicate themselves through the process of cellular mitosis -- i.e., cells experience replicative senescence. How and why some cells become post-mitotic in some species has been the subject of much research and speculation, but (as noted above) it is widely believed that cellular senescence evolved as a way to prevent the onset and spread of cancer. Somatic cells that have divided many times will have accumulated DNA mutations and would therefore be in danger of becoming cancerous if cell division continued.
Lately the role of telomeres in cellular senescence has aroused general interest, especially with a view to the possible genetically adverse effects of cloning. The successive shortening of the chromosomal telomeres with each cell cycle is also believed to limit the number of divisions of the cell, thus contributing to aging. There have, on the other hand, also been reports that cloning could alter the shortening of telomeres. Some cells do not age and are therefore described as being "biologically immortal." It is theorized by some that when it is discovered exactly what allows these cells, whether it be the result of telomere lengthening or not, to divide without limit that it will be possible to genetically alter other cells to have the same capability. It is further theorized that it will eventually be possible to genetically engineer all cells in the human body to have this capability by employing gene therapy and thereby stop or reverse ageing, effectively making the entire organism potentially immortal.
## Chemical damage
The earliest aging theory was the Rate of Living Hypothesis described by Raymond Pearl in 1928[3], based on the idea that fast basal metabolic rate corresponds to short maximum life span (much as a rapidly running machine will experience more damage from wear). (The idea had been posited earlier by Max Rubner).
While there is likely some validity to this theory, in the form of various types of specific damage detailed below which, all other things being equal may reduce lifespan, in general this theory does not adequately explain the differences in lifespan either within, or between, species. Calorically-restricted animals process as much, or more, calories per gram of body mass, as their ad libitum fed counterparts, yet exhibit substantially longer lifespans. Similarly, metabolic rate is a poor predictor of lifespan for birds, bats and other species which presumably have reduced mortality from predation, and therefore have evolved long lifespans even in the presence of very high metabolic rates.
With respect to specific types of chemical damage caused by metabolism, it is suggested that damage to long-lived biopolymers, such as structural proteins or DNA, caused by ubiquitous chemical agents in the body such as oxygen and sugars, are in part responsible for aging. The damage can include breakage of biopolymer chains, cross-linking of biopolymers, or chemical attachment of unnatural substituents (haptens) to biopolymers.
Under normal aerobic conditions, approximately 4% of the oxygen metabolized by mitochondria is converted to superoxide ion which can subsequently be converted to hydrogen peroxide, hydroxyl radical and eventually other reactive species including other peroxides and singlet oxygen, which can in turn generate free radicals capable of damaging structural proteins and DNA. Certain metal ions found in the body, such as copper and iron, may participate in the process. (In Wilson's disease, a hereditary defect which causes the body to retain copper, some of the symptoms resemble accelerated senescence.) These processes are termed oxidative damage and are linked to the benefits of nutritionally derived polyphenol antioxidants[citation needed].
Sugars such as glucose and fructose can react with certain amino acids such as lysine and arginine and certain DNA bases such as guanine to produce sugar adducts, in a process called glycation. These adducts can further rearrange to form reactive species which can then cross-link the structural proteins or DNA to similar biopolymers or other biomolecules such as non-structural proteins. People with diabetes, who have elevated blood sugar, develop senescence-associated disorders much earlier than the general population, but can delay such disorders by rigorous control of their blood sugar levels. There is evidence that sugar damage is linked to oxidant damage in a process termed glycoxidation.
Free radicals can damage proteins, lipids or DNA. Glycation mainly damages proteins. Damaged proteins and lipids accumulate in lysosomes as lipofuscin. Chemical damage to structural proteins can lead to loss of function; for example, damage to collagen of blood vessel walls can lead to vessel-wall stiffness and thus hypertension, and vessel wall thickening and reactive tissue formation (atherosclerosis); similar processes in the kidney can lead to renal failure. Damage to enzymes reduces cellular functionality. Lipid peroxidation of the inner mitochondrial membrane reduces the electric potential and the ability to generate energy. It is probably no accident that nearly all of the so-called "accelerated aging diseases" are due to defective DNA repair enzymes.
## Reliability theory
Reliability theory suggests that biological systems start their adult life with a high load of initial damage. Reliability theory is a general theory about systems failure. It allows researchers to predict the age-related failure kinetics for a system of given architecture (reliability structure) and given reliability of its components. Reliability theory predicts that even those systems that are entirely composed of non-aging elements (with a constant failure rate) will nevertheless deteriorate (fail more often) with age, if these systems are redundant in irreplaceable elements. Aging, therefore, is a direct consequence of systems redundancy.
Reliability theory also predicts the late-life mortality deceleration with subsequent leveling-off, as well as the late-life mortality plateaus, as an inevitable consequence of redundancy exhaustion at extreme old ages. The theory explains why mortality rates increase exponentially with age (the Gompertz law) in many species, by taking into account the initial flaws (defects) in newly formed systems. It also explains why organisms "prefer" to die according to the Gompertz law, while technical devices usually fail according to the Weibull (power) law. Reliability theory allows to specify conditions when organisms die according to the Weibull law: organisms should be relatively free of initial flaws and defects. The theory makes it possible to find a general failure law applicable to all adult and extreme old ages, where the Gompertz and the Weibull laws are just special cases of this more general failure law. The theory explains why relative differences in mortality rates of compared populations (within a given species) vanish with age (compensation law of mortality), and mortality convergence is observed due to the exhaustion of initial differences in redundancy levels.
## Neuro-endocrine-immunological theories
Senescence may also simply be a result of wear and tear overwhelming repair mechanisms. It is also possible that senescence is a mechanism to control the development and spread of cancer; if cells have built-in limits to how many times they can replicate, they must somehow overcome this before they can spread indefinitely.
# Miscellaneous
Recently, early senescence has been alleged to be a possible unintended outcome of early cloning experiments. Most notably, the issue was raised in the case of Dolly the sheep, following her death from a contagious lung disease. The claim that Dolly's early death involved premature senescence has been vigorously contested (e.g. by Kerry Lynn Macintosh in her book, Illegal Beings: Human Clones and the Law), and Dolly's creator, Dr. Ian Wilmut has expressed the view that her illness and death were probably unrelated to the fact that she was a clone.
A set of rare hereditary (genetic) disorders, each called progeria, has been known for some time. Sufferers exhibit symptoms resembling accelerated aging, including wrinkled skin. The cause of Hutchinson–Gilford progeria syndrome was reported in the journal Nature in May 2003. This report suggests that DNA damage, not oxidative stress, is the cause of this form of accelerated aging. | https://www.wikidoc.org/index.php/Aging_DNA | |
16319fc2dc021e804eeb94856b49dbb69172820b | wikidoc | Agmatinase | Agmatinase
In enzymology, an agmatinase (EC 3.5.3.11) is an enzyme that catalyzes the chemical reaction
Thus, the two substrates of this enzyme are agmatine and H2O, whereas its two products are putrescine and urea.
This enzyme belongs to the family of hydrolases, those acting on carbon-nitrogen bonds other than peptide bonds, specifically in linear amidines. The systematic name of this enzyme class is agmatine amidinohydrolase. Other names in common use include agmatine ureohydrolase, and SpeB. This enzyme participates in urea cycle and metabolism of amino groups.
# Genetics
In humans, the enzyme is encoded by the AGMAT gene.
# Structural studies
As of late 2007, 5 structures have been solved for this class of enzymes, with PDB accession codes 1GQ6, 1GQ7, 1WOG, 1WOH, and 1WOI.
# Inhibitors
- Piperazine-1-carboxamidine | Agmatinase
In enzymology, an agmatinase (EC 3.5.3.11) is an enzyme that catalyzes the chemical reaction
Thus, the two substrates of this enzyme are agmatine and H2O, whereas its two products are putrescine and urea.
This enzyme belongs to the family of hydrolases, those acting on carbon-nitrogen bonds other than peptide bonds, specifically in linear amidines. The systematic name of this enzyme class is agmatine amidinohydrolase. Other names in common use include agmatine ureohydrolase, and SpeB. This enzyme participates in urea cycle and metabolism of amino groups.
# Genetics
In humans, the enzyme is encoded by the AGMAT gene.[1][2][3][4]
# Structural studies
As of late 2007, 5 structures have been solved for this class of enzymes, with PDB accession codes 1GQ6, 1GQ7, 1WOG, 1WOH, and 1WOI.
# Inhibitors
- Piperazine-1-carboxamidine | https://www.wikidoc.org/index.php/Agmatinase | |
28c1a25ae870ec137fe0e0c52161fdf066dead63 | wikidoc | Dysgraphia | Dysgraphia
# Overview
Dysgraphia (or agraphia) is a deficiency in the ability to write, regardless of the ability to read, not due to intellectual impairment. People with dysgraphia often can write on some level, but often lack co-ordination, and may find other fine motor tasks such as tying shoes difficult. It often does not affect all fine motor skills. They can also lack basic spelling skills (having difficulties with p,q,b,d), and often will write the wrong word when trying to formulate thoughts (on paper). In childhood, the disorder generally emerges when they are first introduced to writing. They make inappropriately sized and spaced letters, or write wrong or misspelled words despite thorough instruction. Children with the disorder may have other learning disabilities; however, they usually have no social or other academic problems. Cases of dysgraphia in adults generally occur after some neurological trauma or it might be diagnosed in a person with Tourette syndrome, ADHD or an autism spectrum disorder such as Asperger's. The DSM IV identifies dysgraphia as a "Disorder of Written Expression" as "writing skills (that) ...are substantially below those expected given the person's ...age, measured intelligence, and age-appropriate education."
## The Cause
The cause of dysgraphia is unknown but whenever it occurs in an adult, it is usually caused by head trauma, some types of diseases or brain damage. When it is found in children there is a tendency for there to be multiple dysgraphics in his or her family. A parent or close relative of the child tend to also show signs of dysgraphia.
There have been few studies on Dysgraphia.
# Types of dysgraphia
## Dyslexic dysgraphia
With dyslexic dysgraphia, spontaneously written work is illegible, copied work is fairly good, and spelling is bad. Finger tapping speed (a method for identifying fine motor problems) is normal, indicating the deficit does not likely stem from cerebellar damage. A dyslexic dysgraphic does not necessarily have dyslexia. (Dyslexia and dysgraphia appear to be unrelated but are often comorbid.)
## Motor dysgraphia
Motor dysgraphia is due to deficient fine motor skills, poor dexterity, poor muscle tone, and/or unspecified motor clumsiness. Generally, written work is poor to illegible, even if copied by sight from another document. Letter formation may be acceptable in very short samples of writing, but this requires extreme effort and an unreasonable amount of time to accomplish, and cannot be sustained for a significant length of time. Writing is often slanted due to holding a pen or pencil incorrectly. Spelling skills are not impaired. Finger tapping speed results are below normal.
## Spatial dysgraphia
Dysgraphia due to a defect in the understanding of space has illegible spontaneously written work, illegible copied work, but normal spelling and normal tapping speed.
Some children may have a combination of any two or all three of these. Symptoms in actuality may vary in presentation from what is listed here.
# Symptoms of dysgraphia
A mixture of upper/lower case letters, irregular letter sizes and shapes, unfinished letters, struggle to use writing as a communications tool, odd writing grip, many spelling mistakes (sometimes), pain when writing, decreased or increased speed of writing and copying, talks to self while writing, muscle spasms in the arm and shoulder(sometimes in the rest of the body), inability to flex(sometimes move) the arm (creating an L like shape), and general illegibility. Reluctance or refusal to complete writing tasks.
## Lesser known symptoms of dysgraphia
### Pain while writing
Many people who are dysgraphic will experience pain while writing. The pain usually starts in the center of the forearm and then spreads along the nervous system to the entire body. This pain can get worse or even appear when a dysgraphic is stressed. Few people who do not have dysgraphia know about this, because many with dysgraphia will not mention it to anyone. There are a few reasons why pain while writing is rarely mentioned:
- Sufferers do not know that it is unusual to experience this type of pain with writing.
- If they know that it is different from how others experience writing, they know that few will believe them.
- Those who do believe that the pain while writing is real will often not understand it. It will usually be attributed to muscle ache or cramping, and it will often be considered only a minor inconvenience.
# Common problems that are often associated with dysgraphia
### Stress
There are some common problems not related to dysgraphia but often associated with dysgraphia, the most common of which is stress. Often children (and adults) with dysgraphia will become extremely frustrated with the task of writing (and spelling); younger children may cry or refuse to complete written assignments. This frustration can cause the child (or adult) a great deal of stress and can lead to stress related illnesses. Other common environmental sources of stress in the classroom setting are (a) high levels of environmental noise, and (b) over-illumination. This can be a result of any symptom of dysgraphia.
# Treatment
Treatment for dysgraphia varies and may include treatment for motor disorders to help control writing movements. Other treatments may address impaired memory or other neurological problems. Some physicians recommend that individuals with dysgraphia use computers to avoid the problems of handwriting.
Occupational therapy could be considered to strengthen muscle tone, improve dexterity, and evaluate eye-hand coordination. Dysgraphic children should also be evaluated for ambidexterity, which can delay fine motor skills in early childhood.
Often small things can help a student with dysgraphia, such as allowing them to use a preferred writing utensil or allowing them to submit typed work instead of hand written documents.
Suggestions for teachers and parents:
- Use jumbo pencils (and grips for new writers)
- Use pre-lined paper that has yellow highlighting where the words are supposed to go
- Allow students extra time to complete in-class assignments; otherwise they won't get the benefit of the instructional practice
- Get students keyboarding early on; they can start on an Alphasmart word processor
- Allow children to dictate to an adult; they can then recopy if necessary
- Allow children to dictate into a tape recorder; they or an adult can transcribe later. This allows the creative output process to occur without being stopped by the execution problem.
- Have compassion and know that this issue has nothing to do with intelligence or behavior. | Dysgraphia
Template:DiseaseDisorder infobox
# Overview
Dysgraphia (or agraphia) is a deficiency in the ability to write, regardless of the ability to read, not due to intellectual impairment. People with dysgraphia often can write on some level, but often lack co-ordination, and may find other fine motor tasks such as tying shoes difficult. It often does not affect all fine motor skills. They can also lack basic spelling skills (having difficulties with p,q,b,d), and often will write the wrong word when trying to formulate thoughts (on paper). In childhood, the disorder generally emerges when they are first introduced to writing. They make inappropriately sized and spaced letters, or write wrong or misspelled words despite thorough instruction. Children with the disorder may have other learning disabilities; however, they usually have no social or other academic problems. Cases of dysgraphia in adults generally occur after some neurological trauma or it might be diagnosed in a person with Tourette syndrome, ADHD or an autism spectrum disorder such as Asperger's. The DSM IV identifies dysgraphia as a "Disorder of Written Expression" as "writing skills (that) ...are substantially below those expected given the person's ...age, measured intelligence, and age-appropriate education."
## The Cause
The cause of dysgraphia is unknown but whenever it occurs in an adult, it is usually caused by head trauma, some types of diseases or brain damage. When it is found in children there is a tendency for there to be multiple dysgraphics in his or her family. A parent or close relative of the child tend to also show signs of dysgraphia.
There have been few studies on Dysgraphia.
# Types of dysgraphia
## Dyslexic dysgraphia
With dyslexic dysgraphia, spontaneously written work is illegible, copied work is fairly good, and spelling is bad. Finger tapping speed (a method for identifying fine motor problems) is normal, indicating the deficit does not likely stem from cerebellar damage. A dyslexic dysgraphic does not necessarily have dyslexia. (Dyslexia and dysgraphia appear to be unrelated but are often comorbid.)[citation needed]
## Motor dysgraphia
Motor dysgraphia is due to deficient fine motor skills, poor dexterity, poor muscle tone, and/or unspecified motor clumsiness. Generally, written work is poor to illegible, even if copied by sight from another document. Letter formation may be acceptable in very short samples of writing, but this requires extreme effort and an unreasonable amount of time to accomplish, and cannot be sustained for a significant length of time. Writing is often slanted due to holding a pen or pencil incorrectly. Spelling skills are not impaired. Finger tapping speed results are below normal.
## Spatial dysgraphia
Dysgraphia due to a defect in the understanding of space has illegible spontaneously written work, illegible copied work, but normal spelling and normal tapping speed.
Some children may have a combination of any two or all three of these. Symptoms in actuality may vary in presentation from what is listed here.
# Symptoms of dysgraphia
A mixture of upper/lower case letters, irregular letter sizes and shapes, unfinished letters, struggle to use writing as a communications tool, odd writing grip, many spelling mistakes (sometimes), pain when writing, decreased or increased speed of writing and copying, talks to self while writing, muscle spasms in the arm and shoulder(sometimes in the rest of the body), inability to flex(sometimes move) the arm (creating an L like shape), and general illegibility. Reluctance or refusal to complete writing tasks.
## Lesser known symptoms of dysgraphia
### Pain while writing
Many people who are dysgraphic will experience pain while writing. The pain usually starts in the center of the forearm and then spreads along the nervous system to the entire body. This pain can get worse or even appear when a dysgraphic is stressed. Few people who do not have dysgraphia know about this, because many with dysgraphia will not mention it to anyone. There are a few reasons why pain while writing is rarely mentioned:
- Sufferers do not know that it is unusual to experience this type of pain with writing.
- If they know that it is different from how others experience writing, they know that few will believe them.
- Those who do believe that the pain while writing is real will often not understand it. It will usually be attributed to muscle ache or cramping, and it will often be considered only a minor inconvenience.
# Common problems that are often associated with dysgraphia
### Stress
There are some common problems not related to dysgraphia but often associated with dysgraphia, the most common of which is stress. Often children (and adults) with dysgraphia will become extremely frustrated with the task of writing (and spelling); younger children may cry or refuse to complete written assignments. This frustration can cause the child (or adult) a great deal of stress and can lead to stress related illnesses. Other common environmental sources of stress in the classroom setting are (a) high levels of environmental noise, and (b) over-illumination. This can be a result of any symptom of dysgraphia.
# Treatment
Treatment for dysgraphia varies and may include treatment for motor disorders to help control writing movements. Other treatments may address impaired memory or other neurological problems. Some physicians recommend that individuals with dysgraphia use computers to avoid the problems of handwriting.
Occupational therapy could be considered to strengthen muscle tone, improve dexterity, and evaluate eye-hand coordination. Dysgraphic children should also be evaluated for ambidexterity, which can delay fine motor skills in early childhood.
Often small things can help a student with dysgraphia, such as allowing them to use a preferred writing utensil or allowing them to submit typed work instead of hand written documents.
Suggestions for teachers and parents:
- Use jumbo pencils (and grips for new writers)
- Use pre-lined paper that has yellow highlighting where the words are supposed to go
- Allow students extra time to complete in-class assignments; otherwise they won't get the benefit of the instructional practice
- Get students keyboarding early on; they can start on an Alphasmart word processor
- Allow children to dictate to an adult; they can then recopy if necessary
- Allow children to dictate into a tape recorder; they or an adult can transcribe later. This allows the creative output process to occur without being stopped by the execution problem.
- Have compassion and know that this issue has nothing to do with intelligence or behavior. | https://www.wikidoc.org/index.php/Agraphia | |
d787a01589937eda8ac3740c92949aa6c3a40aaa | wikidoc | Ahmad Tibi | Ahmad Tibi
Dr. Ahmad Tibi (Template:Lang-ar, Template:Lang-he, sometimes spelt Ahmed Tibi, born 19 December 1958) is an Israeli Arab politician and leader of the Arab nationalist party, Ta'al (the Arab Movement for Renewal). He was elected on a joint ticket with the United Arab List to serve in Israel's parliament, the Knesset. He describes himself as Arab-Palestinian in nationality, but has called Israel his "homeland" and vowed to stay in Israel regardless of the fate of the Palestinian territories.
Tibi is from Taibeh, in the Center District of Israel. He is a trained physician and graduate of the Hebrew University of Jerusalem.
# Early controversy
Tibi worked as a resident at Hadassah Hospital, noted for its warm Jewish-Arab relations. Those relations were challenged when he swung his briefcase into a security guard's head (eventually requiring stitches), and stalked away while the guard bled on the floor. He was dismissed a few hours later, but raised a political brouhaha over his dismissal, attempting to get reinstated. He argued that the dismissal was related to the fact that he was Arab, and asserting the guard should have had shown more respect for a doctor. The hospital maintained that Tibi had refused to allow his briefcase to be searched, and the guard was merely doing his job.
# Political career
## Early career
Tibi served as a political advisor to the late Palestinian Authority Chairman Yasser Arafat for several years, even representing the Palestinians at the 1998 Wye River negotiations. Tibi resigned from the post in 1999, upon deciding to run for the Knesset. Tibi has described his relationship with Arafat as "close" and "extremely interesting and important to ." He was first elected to the Knesset in the 1999 elections as a member of Azmi Bishara's Balad party, but broke away and formed his own party Ta'al during the Knesset session.
## Travel restrictions conflict
In 2002 right-wing MK Michael Kleiner initiated actions in the Knesset to restrict movements by Tibi inside the Gaza Strip and the West Bank. Kleiner claimed that Tibi was assisting the Palestinians in their war against Israel. Tibi protested the Knesset's decision as unconstitutional and illegal under Israeli law and appealed to the Supreme Court of Israel, which deferred a decision on the case .
## 2003 elections
Ahead of Israel's 2003 elections, several right-wing politicians, including the heads of the National Union and National Religious Party, sought to have Tibi banned from holding Knesset office; the official motion to disqualify Tibi's candidacy was filed by Likud MK Michael Eitan and passed the Israeli Central Elections Committee by one vote.
Eitan argued that Tibi has supported Palestinian terror throughout the intifada and served as an adviser to Yasser Arafat. He additionally asserted that since being elected to the Knesset, Tibi exploited his immunity to promote Palestinian and Arafat's interests. He further maintained that throughout his Knesset career, Tibi was involved in anti-Israeli activities, including the expression of solidarity with Israel's enemies, incitement and sedition.
However, the Supreme Court of Israel rejected the Committee's arguments and overturned the ban unanimously, and Tibi was elected as part of a joint list of Ta'al and Hadash.
## 2006 elections
Before the 2006 elections, Tibi took his Ta'al party out of the Hadash coalition and joined the United Arab List. He is currently a Deputy Speaker of the Knesset. | Ahmad Tibi
Template:MKs
Dr. Ahmad Tibi (Template:Lang-ar, Template:Lang-he, sometimes spelt Ahmed Tibi, born 19 December 1958) is an Israeli Arab politician and leader of the Arab nationalist party, Ta'al (the Arab Movement for Renewal). He was elected on a joint ticket with the United Arab List to serve in Israel's parliament, the Knesset. He describes himself as Arab-Palestinian in nationality, but has called Israel his "homeland" and vowed to stay in Israel regardless of the fate of the Palestinian territories.
Tibi is from Taibeh, in the Center District of Israel. He is a trained physician and graduate of the Hebrew University of Jerusalem.
# Early controversy
Tibi worked as a resident at Hadassah Hospital, noted for its warm Jewish-Arab relations. Those relations were challenged when he swung his briefcase into a security guard's head (eventually requiring stitches), and stalked away while the guard bled on the floor. He was dismissed a few hours later, but raised a political brouhaha over his dismissal, attempting to get reinstated. He argued that the dismissal was related to the fact that he was Arab, and asserting the guard should have had shown more respect for a doctor. The hospital maintained that Tibi had refused to allow his briefcase to be searched, and the guard was merely doing his job.
# Political career
## Early career
Tibi served as a political advisor to the late Palestinian Authority Chairman Yasser Arafat for several years, even representing the Palestinians at the 1998 Wye River negotiations. Tibi resigned from the post in 1999, upon deciding to run for the Knesset. Tibi has described his relationship with Arafat as "close" and "extremely interesting and important to [him]." He was first elected to the Knesset in the 1999 elections as a member of Azmi Bishara's Balad party, but broke away and formed his own party Ta'al during the Knesset session.
## Travel restrictions conflict
In 2002 right-wing MK Michael Kleiner initiated actions in the Knesset to restrict movements by Tibi inside the Gaza Strip and the West Bank. Kleiner claimed that Tibi was assisting the Palestinians in their war against Israel. Tibi protested the Knesset's decision as unconstitutional and illegal under Israeli law [1] and appealed to the Supreme Court of Israel, which deferred a decision on the case [2].
## 2003 elections
Ahead of Israel's 2003 elections, several right-wing politicians, including the heads of the National Union and National Religious Party, sought to have Tibi banned from holding Knesset office; the official motion to disqualify Tibi's candidacy was filed by Likud MK Michael Eitan and passed the Israeli Central Elections Committee by one vote.
Eitan argued that Tibi has supported Palestinian terror throughout the intifada and served as an adviser to [PA Chairman] Yasser Arafat. He additionally asserted that since being elected to the Knesset, Tibi exploited his immunity to promote Palestinian and Arafat's interests. He further maintained that throughout his Knesset career, Tibi was involved in anti-Israeli activities, including the expression of solidarity with Israel's enemies, incitement and sedition.[3]
However, the Supreme Court of Israel rejected the Committee's arguments and overturned the ban unanimously,[4] and Tibi was elected as part of a joint list of Ta'al and Hadash.
## 2006 elections
Before the 2006 elections, Tibi took his Ta'al party out of the Hadash coalition and joined the United Arab List. He is currently a Deputy Speaker of the Knesset. | https://www.wikidoc.org/index.php/Ahmad_Tibi | |
3f76084cd74ed55e2411f8dd6435f36fec3561c2 | wikidoc | Ajmalicine | Ajmalicine
Ajmaline is a class Ia antiarrhythmic agent. It is often used to bring out typical findings of ST elevations in patients suspected of having Brugada syndrome.
The compound was first isolated by Salimuzzaman Siddiqui in 1931 from the roots of Rauwolfia serpentina. He named it Ajmaline, after Hakim Ajmal Khan, one of the most illustrious practitioners of Unani medicine in South Asia.
# Notes
- ↑ Siddiqui, S.; Siddiqui, R. H. (1931). J. Indian Chem. Soc. 8: 667–80.
- ↑ Ahmed Nasim Sandilvi (2003), Salimuzzaman Siddiqui: pioneer of scientific research in Pakistan. Daily Dawn. 12 April, 2003. Retrieved on 19 July 2007.
de:Ajmalin | Ajmalicine
Ajmaline is a class Ia antiarrhythmic agent. It is often used to bring out typical findings of ST elevations in patients suspected of having Brugada syndrome.
The compound was first isolated by Salimuzzaman Siddiqui in 1931 [1] from the roots of Rauwolfia serpentina. He named it Ajmaline, after Hakim Ajmal Khan, one of the most illustrious practitioners of Unani medicine in South Asia.[2]
# Notes
- ↑ Siddiqui, S.; Siddiqui, R. H. (1931). J. Indian Chem. Soc. 8: 667–80.
- ↑ Ahmed Nasim Sandilvi (2003), Salimuzzaman Siddiqui: pioneer of scientific research in Pakistan. Daily Dawn. 12 April, 2003. Retrieved on 19 July 2007.
Template:Antiarrhythmic agents
Template:Drug-stub
de:Ajmalin
Template:WS | https://www.wikidoc.org/index.php/Ajmalicine | |
8d42e22af3c4cd09a95f0ec5b3a89c6e44b970c0 | wikidoc | Alagebrium | Alagebrium
Alagebrium (formerly known as ALT-711; chemical name 4,5-dimethyl-3-(2-oxo-2-phenylethyl)-thiazolium chloride) is a drug produced by Synvista Therapeutics Inc., which is currently being evaluated in clinical trials. It is the first drug to be clinically tested for the purpose of breaking the crosslinks caused by advanced glycation endproducts (A.G.E.s), thereby reversing one of the main mechanisms of aging. Through this effect alagebrium is designed to increase cardiac and vascular compliance cardiovascular disease, as well as many other forms of degradation associated with protein crosslinking, such as diabetic nephropathy, a form of kidney disease.
A.G.E.s are permanent carbohydrate structures that form when carbohydrates bind to proteins, lipids and DNA. Many proteins, including structural proteins such as collagen and elastin, play an integral role in the architecture of tissues and organs and maintenance of cardiovascular elasticity and vascular wall integrity. Diabetic individuals form excessive amounts of A.G.E.s earlier in life than non-diabetic individuals. This process can impair the normal function of organs that depend on flexibility for normal function, such as blood vessels and cardiac muscle. The formation of A.G.E. crosslinks leads to increased stiffness and loss of function of tissues and organs, and abnormal protein accumulation, which together cause many of the complications of aging and diabetes. A.G.E.s are also known to induce oxidative stress, in which reactive molecules provoke the underlying component of inflammation.
Pharmacologic intervention with alagebrium directly targets the biochemical pathway leading to the stiffness of the cardiovascular system. Removal of the A.G.E.s by cleavage of the abnormal crosslinking bonds has been associated with diminished inflammatory and sclerotic signaling pathways. These pathways are responsible for the deposition of abnormal amounts of matrix proteins that physically stiffen tissues. The presence of A.G.E. crosslinks also renders tissues and organs less susceptible to normal turnover thus enhancing the presence of these abnormal bonds on various molecules. Importantly, alagebrium does not disrupt the natural carbohydrate modification to proteins, intra-molecular crosslinking or peptide bonds that are responsible for maintaining the normal integrity of the collagen chain. Thus, normal structure and function is preserved while abnormal crosslinking is reduced. | Alagebrium
Alagebrium (formerly known as ALT-711; chemical name 4,5-dimethyl-3-(2-oxo-2-phenylethyl)-thiazolium chloride) is a drug produced by Synvista Therapeutics Inc., which is currently being evaluated in clinical trials. It is the first drug to be clinically tested for the purpose of breaking the crosslinks caused by advanced glycation endproducts (A.G.E.s), thereby reversing one of the main mechanisms of aging.[1] Through this effect alagebrium is designed to increase cardiac and vascular compliance cardiovascular disease, as well as many other forms of degradation associated with protein crosslinking, such as diabetic nephropathy, a form of kidney disease.[2][3][4]
A.G.E.s are permanent carbohydrate structures that form when carbohydrates bind to proteins, lipids and DNA. Many proteins, including structural proteins such as collagen and elastin, play an integral role in the architecture of tissues and organs and maintenance of cardiovascular elasticity and vascular wall integrity. Diabetic individuals form excessive amounts of A.G.E.s earlier in life than non-diabetic individuals. This process can impair the normal function of organs that depend on flexibility for normal function, such as blood vessels and cardiac muscle. The formation of A.G.E. crosslinks leads to increased stiffness and loss of function of tissues and organs, and abnormal protein accumulation, which together cause many of the complications of aging and diabetes. A.G.E.s are also known to induce oxidative stress, in which reactive molecules provoke the underlying component of inflammation.
Pharmacologic intervention with alagebrium directly targets the biochemical pathway leading to the stiffness of the cardiovascular system. Removal of the A.G.E.s by cleavage of the abnormal crosslinking bonds has been associated with diminished inflammatory and sclerotic signaling pathways. These pathways are responsible for the deposition of abnormal amounts of matrix proteins that physically stiffen tissues. The presence of A.G.E. crosslinks also renders tissues and organs less susceptible to normal turnover thus enhancing the presence of these abnormal bonds on various molecules. Importantly, alagebrium does not disrupt the natural carbohydrate modification to proteins, intra-molecular crosslinking or peptide bonds that are responsible for maintaining the normal integrity of the collagen chain. Thus, normal structure and function is preserved while abnormal crosslinking is reduced. | https://www.wikidoc.org/index.php/Alagebrium | |
d6c63a6964edc8e028a2b535a89674c668a24577 | wikidoc | Loratadine | Loratadine
# 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
Loratadine is an antihistamine that is FDA approved for the treatment of runny nose, sneezing, itchy, watery eyes, itching of the nose or throat. Common adverse reactions include xerostomia, headache, somnolence and fatigue.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Seasonal allergic rhinitis
- Dose: 10 mg PO daily
### Idiopathic urticaria
- Dose: 10 mg PO daily
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Loratadine in adult patients.
### Non–Guideline-Supported Use
### Asthma
- 10-20 mg PO daily up to 8 weeks
### Eosinophilic nonallergic rhinitis
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
### Seasonal allergic rhinitis
- Dose (2-5 years): 5 mg PO daily
- Dose (>6 years): 10 mg PO daily
### Idiopathic urticaria
- Dose 2-5 years: 5 mg PO daily
- Dose >6 years: 10 mg PO daily
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Loratadine in pediatric patients.
### Non–Guideline-Supported Use
### Asthma
- <30 kg: 10 mg PO daily
- >30 kg: 20 mg PO daily
# Contraindications
- Hypersensitivity to loratadine
# Warnings
- Do not use if you have ever had an allergic reaction to this product or any of its ingredients
- Ask a doctor before use if you have liver or kidney disease. Your doctor should determine if you need a different dose.
- When using this product do not take more than directed. Taking more than directed may cause drowsiness.
- Stop use and ask a doctor is an allergic reaction to this product occurs. Seek medical help right away.
- If pregnant or breast-feeding, ask a health professional before use.
- Keep out of reach of children.
- In case of overdose, get medical help or contact a Poison Control Center right away.
# Adverse Reactions
## Clinical Trials Experience
### Dermatologic
- Rash
### Gastrointestinal
- Abdominal pain
- Diarrhea
- Stomatitis
- Xerostomia
### Hepatic
- Hepatic necrosis
- Hepatitis
- Jaundice
### Neurologic
- Anxiety
- Headache
- Hyperactivity
- Somnolence
### Respiratory
- Epistaxis
- Pharyngitis
- Upper respiratory infections
- Viral disease
- Wheezing
### Other
- Dysphonia
- Fatigue
- Influenza-like symptoms
- Malaise
- Somnolence
- Tooth disorder
## Postmarketing Experience
There is limited information regarding Loratadine Postmarketing Experience in the drug label.
# Drug Interactions
- Amiodarone: QT interval prolongation and Torsade de Pointes have been reported with the co-administration of loratadine and amiodarone.
- Carbamazepine: Loratadine increase plasma concentration of carbamazepine.
- Cimetidine: increases plasma concentrations of loratadine
- Ketoconazole: increases plasma concentrations of loratadine
- Mepenzolate
- Morphine: increases risk of paralytic ileus
- Morphine sulfate liposome: increases risk of paralytic ileus
- Oximorphone
- Umeclidinium
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
- Ask a health professional before use.
Pregnancy Category (AUS): B1
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Loratadine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Loratadine during labor and delivery.
### Nursing Mothers
- Ask a health professional before use.
### Pediatric Use
- In case of overdose, get medical help or contact a Poison Control Center right away. (1-800-222-1222)
### Geriatic Use
There is no FDA guidance on the use of Loratadine in geriatric settings.
### Gender
There is no FDA guidance on the use of Loratadine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Loratadine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Loratadine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Loratadine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Loratadine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Loratadine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Oral
### Monitoring
There is limited information regarding Loratadine Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Loratadine and IV administrations.
# Overdosage
There is limited information regarding Loratadine overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
Loratadine is a tricyclic antihistamine, which acts as a selective inverse agonist of peripheral histamine H1-receptors.
## Structure
There is limited information regarding Loratadine Structure in the drug label.
## Pharmacodynamics
There is limited information regarding Loratadine Pharmacodynamics in the drug label.
## Pharmacokinetics
Loratadine is given orally, is well absorbed from the gastrointestinal tract, and has rapid first-pass hepatic metabolism; it is metabolized by isoenzymes of the cytochrome P450 system, including CYP3A4, CYP2D6, and, to a lesser extent, several others. Loratadine is almost totally (97–99%) bound to plasma proteins. Its metabolite desloratadine, which is largely responsible for the antihistaminergic effects, binds to plasma proteins by 73–76%.
## Nonclinical Toxicology
There is limited information regarding Loratadine Nonclinical Toxicology in the drug label.
# Clinical Studies
There is limited information regarding Loratadine Clinical Studies in the drug label.
# How Supplied
- Supplied as tablets of 10 mg in 30 tablet carton and 40 tablet bottle carton.
## Storage
- Store at 20°-25°C (68°-77°F)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Loratadine Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Loratadine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Alavert
- Claritin
- Claritin Reditabs
- Clearatadine
- Triaminic Allerchews
- Children's Clear-Atadine
- Children's Dimetapp ND Allergy
- Children's Claritin
# Look-Alike Drug Names
There is limited information regarding Loratadine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Loratadine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alberto Plate [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Loratadine is an antihistamine that is FDA approved for the treatment of runny nose, sneezing, itchy, watery eyes, itching of the nose or throat. Common adverse reactions include xerostomia, headache, somnolence and fatigue.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Seasonal allergic rhinitis
- Dose: 10 mg PO daily
### Idiopathic urticaria
- Dose: 10 mg PO daily
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Loratadine in adult patients.
### Non–Guideline-Supported Use
### Asthma
- 10-20 mg PO daily up to 8 weeks [1][2]
### Eosinophilic nonallergic rhinitis
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
### Seasonal allergic rhinitis
- Dose (2-5 years): 5 mg PO daily
- Dose (>6 years): 10 mg PO daily
### Idiopathic urticaria
- Dose 2-5 years: 5 mg PO daily
- Dose >6 years: 10 mg PO daily
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Loratadine in pediatric patients.
### Non–Guideline-Supported Use
### Asthma
- <30 kg: 10 mg PO daily
- >30 kg: 20 mg PO daily
# Contraindications
- Hypersensitivity to loratadine
# Warnings
- Do not use if you have ever had an allergic reaction to this product or any of its ingredients
- Ask a doctor before use if you have liver or kidney disease. Your doctor should determine if you need a different dose.
- When using this product do not take more than directed. Taking more than directed may cause drowsiness.
- Stop use and ask a doctor is an allergic reaction to this product occurs. Seek medical help right away.
- If pregnant or breast-feeding, ask a health professional before use.
- Keep out of reach of children.
- In case of overdose, get medical help or contact a Poison Control Center right away.
# Adverse Reactions
## Clinical Trials Experience
### Dermatologic
- Rash
### Gastrointestinal
- Abdominal pain
- Diarrhea
- Stomatitis
- Xerostomia
### Hepatic
- Hepatic necrosis
- Hepatitis
- Jaundice
### Neurologic
- Anxiety
- Headache
- Hyperactivity
- Somnolence
### Respiratory
- Epistaxis
- Pharyngitis
- Upper respiratory infections
- Viral disease
- Wheezing
### Other
- Dysphonia
- Fatigue
- Influenza-like symptoms
- Malaise
- Somnolence
- Tooth disorder
## Postmarketing Experience
There is limited information regarding Loratadine Postmarketing Experience in the drug label.
# Drug Interactions
- Amiodarone: QT interval prolongation and Torsade de Pointes have been reported with the co-administration of loratadine and amiodarone.
- Carbamazepine: Loratadine increase plasma concentration of carbamazepine.
- Cimetidine: increases plasma concentrations of loratadine
- Ketoconazole: increases plasma concentrations of loratadine
- Mepenzolate
- Morphine: increases risk of paralytic ileus
- Morphine sulfate liposome: increases risk of paralytic ileus
- Oximorphone
- Umeclidinium
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
- Ask a health professional before use.
Pregnancy Category (AUS): B1
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Loratadine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Loratadine during labor and delivery.
### Nursing Mothers
- Ask a health professional before use.
### Pediatric Use
- In case of overdose, get medical help or contact a Poison Control Center right away. (1-800-222-1222)
### Geriatic Use
There is no FDA guidance on the use of Loratadine in geriatric settings.
### Gender
There is no FDA guidance on the use of Loratadine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Loratadine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Loratadine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Loratadine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Loratadine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Loratadine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Oral
### Monitoring
There is limited information regarding Loratadine Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Loratadine and IV administrations.
# Overdosage
There is limited information regarding Loratadine overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
Loratadine is a tricyclic antihistamine, which acts as a selective inverse agonist of peripheral histamine H1-receptors.
## Structure
There is limited information regarding Loratadine Structure in the drug label.
## Pharmacodynamics
There is limited information regarding Loratadine Pharmacodynamics in the drug label.
## Pharmacokinetics
Loratadine is given orally, is well absorbed from the gastrointestinal tract, and has rapid first-pass hepatic metabolism; it is metabolized by isoenzymes of the cytochrome P450 system, including CYP3A4, CYP2D6, and, to a lesser extent, several others.[3][4] Loratadine is almost totally (97–99%) bound to plasma proteins. Its metabolite desloratadine, which is largely responsible for the antihistaminergic effects, binds to plasma proteins by 73–76%.
## Nonclinical Toxicology
There is limited information regarding Loratadine Nonclinical Toxicology in the drug label.
# Clinical Studies
There is limited information regarding Loratadine Clinical Studies in the drug label.
# How Supplied
- Supplied as tablets of 10 mg in 30 tablet carton and 40 tablet bottle carton.
## Storage
- Store at 20°-25°C (68°-77°F)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Loratadine Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Loratadine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Alavert
- Claritin
- Claritin Reditabs
- Clearatadine
- Triaminic Allerchews
- Children's Clear-Atadine
- Children's Dimetapp ND Allergy
- Children's Claritin
# Look-Alike Drug Names
There is limited information regarding Loratadine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Alavert | |
b7870d704df08e3ce399ae772d421b5d6838f4ab | wikidoc | Alcuronium | Alcuronium
# Overview
Alcuronium is a neuromuscular blocking (NMB) agent, alternatively referred to as a skeletal muscle relaxant. It is a semi-synthetic substance prepared from C-toxiferine I, a bis-quaternary alkaloid obtained from Strychnos toxifera. C-toxiferine I itself has been tested for its pharmacological action and noted to be a very long acting neuromuscular blocking agent For a formal definition of the durations of actions associated with NMB agents, see page for gantacurium. The replacement of both the N-methyl groups with N-allyl moieties yielded N,N-diallyl-bis-nortoxiferine, now recognized as alcuornium (and at one time marketed as the proprietary agent called Alloferin).
Inclusion of the allylic functions presented an enhanced potential area of biotransformation, and thus alcuronium is observed to have a much shorter duration of neuromuscular blocking action than its parent C-toxiferine I. It also has a more rapid onset of action, and is ~1.5 times as potent as tubocurarine. The pharmacological action of alcuronium is readily reversed by neostigmine, and it produced little histamine release. The major disadvantage of alcuronium is that it elicits a vagolytic effect produced by a selective atropoine-like blockade of cardiac muscarinic receptors.
# Effects
- Cardiovascular system: histamine release and blockage of the sympathetic ganglia including adrenal medulla could cause hypotension
- Respiratory: apnea due to phrenic blockage but bronchoconstriction can occur from the histamine release
- Central nervous system: no effect on intraoccular pressure
- Autonomic ganglion blockade can cause decrease in gut motility
# Special points
- Duration of action prolonged in states of low potassium, calcium and protein, also in states of high magnesium and acidosis.
- Pharmaceutically incompatible with thiopentone
- Infusion can cause fixed dilated pupils | Alcuronium
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Alcuronium is a neuromuscular blocking (NMB) agent, alternatively referred to as a skeletal muscle relaxant. It is a semi-synthetic substance prepared from C-toxiferine I,[1] a bis-quaternary alkaloid obtained from Strychnos toxifera. C-toxiferine I itself has been tested for its pharmacological action and noted to be a very long acting neuromuscular blocking agent[2] For a formal definition of the durations of actions associated with NMB agents, see page for gantacurium. The replacement of both the N-methyl groups with N-allyl moieties yielded N,N-diallyl-bis-nortoxiferine, now recognized as alcuornium (and at one time marketed as the proprietary agent called Alloferin).
Inclusion of the allylic functions presented an enhanced potential area of biotransformation, and thus alcuronium is observed to have a much shorter duration of neuromuscular blocking action than its parent C-toxiferine I.[3] It also has a more rapid onset of action, and is ~1.5 times as potent as tubocurarine.[4] The pharmacological action of alcuronium is readily reversed by neostigmine, and it produced little histamine release.[5] The major disadvantage of alcuronium is that it elicits a vagolytic effect produced by a selective atropoine-like blockade of cardiac muscarinic receptors.[4][6][7]
# Effects
- Cardiovascular system: histamine release and blockage of the sympathetic ganglia including adrenal medulla could cause hypotension
- Respiratory: apnea due to phrenic blockage but bronchoconstriction can occur from the histamine release
- Central nervous system: no effect on intraoccular pressure
- Autonomic ganglion blockade can cause decrease in gut motility
# Special points
- Duration of action prolonged in states of low potassium, calcium and protein, also in states of high magnesium and acidosis.
- Pharmaceutically incompatible with thiopentone
- Infusion can cause fixed dilated pupils | https://www.wikidoc.org/index.php/Alcuronium | |
7fad3cf97d6ed18e2c2362c71a4af5eb829ccdfe | wikidoc | Aldolase A | Aldolase A
Aldolase A (ALDOA, or ALDA), also known as fructose-bisphosphate aldolase, is an enzyme that in humans is encoded by the ALDOA gene on chromosome 16.
The protein encoded by this gene is a glycolytic enzyme that catalyzes the reversible conversion of fructose-1,6-bisphosphate to glyceraldehyde 3-phosphate and dihydroxyacetone phosphate. Three aldolase isozymes (A, B, and C), encoded by three different genes, are differentially expressed during development. Aldolase A is found in the developing embryo and is produced in even greater amounts in adult muscle. Aldolase A expression is repressed in adult liver, kidney and intestine and similar to aldolase C levels in brain and other nervous tissue. Aldolase A deficiency has been associated with myopathy and hemolytic anemia. Alternative splicing and alternative promoter usage results in multiple transcript variants. Related pseudogenes have been identified on chromosomes 3 and 10.
# Structure
ALDOA is a homotetramer and one of the three aldolase isozymes (A, B, and C), encoded by three different genes. The ALDOA gene contains 8 exons and the 5' UTR IB. Key amino acids responsible for its catalytic function have been identified. The residue Tyr363 functions as the acid–base catalyst for protonating C3 of the substrate, while Lys146 is proposed to stabilize the negative charge of the resulting conjugate base of Tyr363 and the strained configuration of the C-terminal. Residue Glu187 participates in multiple functions, including FBP aldolase catalysis, acid–base catalysis during substrate binding, dehydration, and substrate cleavage. Though ALDOA localizes to the nucleus, it lacks any known nuclear localization signals (NLS).
# Mechanism
In mammalian aldolase, the key catalytic amino acid residues involved in the reaction are lysine and tyrosine. The tyrosine acts as an efficient hydrogen acceptor while the lysine covalently binds and stabilizes the intermediates. Many bacteria use two magnesium ions in place of the lysine.
Compound C05378 at KEGG Pathway Database. Enzyme 4.1.2.13 at KEGG Pathway Database. Compound C00111 at KEGG Pathway Database. Compound C00118 at KEGG Pathway Database.
The numbering of the carbon atoms indicates the fate of the carbons according to their position in fructose 6-phosphate.
# Function
ALDOA is a key enzyme in the fourth step of glycolysis, as well as in the reverse pathway gluconeogenesis. It catalyzes the reversible conversion of fructose-1,6-bisphosphate to glyceraldehydes-3-phosphate and dihydroxyacetone phosphate by aldol cleavage of the C3–C4 bond. As a result, it is a crucial player in ATP biosynthesis. ALDOA also contributes to other "moonlighting" functions such as muscle maintenance, regulation of cell shape and motility, striated muscle contraction, actin cytoskeleton organization, and regulation of cell proliferation. ALDOA likely regulates actin cytoskeleton remodeling through interacting with cytohesin-2 (ARNO) and Arf6.
ALDOA is ubiquitously expressed in most tissues, though it is predominantly expressed in developing embryo and adult muscle. In lymphocytes, ALDOA is the predominant aldolase isoform. Within the cell, ALDOA typically localizes to the cytoplasm, but it can localize to the nucleus during DNA synthesis of the cell cycle S phase. This nuclear localization is regulated by the protein kinases AKT and p38. It is suggested that the nucleus serves as a reservoir for ALDOA in low glucose conditions. ALDOA has also been found in mitochondria.
ALDOA is regulated by the energy metabolism substrates glucose, lactate, and glutamine. In human mast cells (MCs), ALDOA has been observed to undergo post-translational regulation by protein tyrosine nitration, which may alter its relative affinity for FBP and/or IP3. This change then affects IP3 and PLC signaling cascades in IgE-dependent responses.
# Clinical significance
Aldolase A (ALDOA) is a highly expressed in multiple cancers, including lung squamous cell carcinoma (LSCC), renal cancer, and hepatocellular carcinoma. It is proposed that ALDOA overexpression enhances glycolysis in these tumor cells, promoting their growth. In LSCC, its upregulation correlates with metastasis and poor prognosis, while its downregulation reduces tumor cell motility and tumorigenesis. Thus, ALDOA could be a potential LSCC biomarker and therapeutic drug target.
Aldolase A deficiency is a rare, autosomal recessive disorder that is linked to hemolysis and accompanied by weakness, muscle pain, and myopathy.
# Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles.
- ↑ The interactive pathway map can be edited at WikiPathways: "GlycolysisGluconeogenesis_WP534"..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}
# Interactions
Aldolase A has been shown to interact with:
- PLD2,
- actin,
- GLUT4,
- phospholipase D2,
- light chain 8 of dynein,
- erythrocyte anion exchanger Band 3 protein,
- ryanodine receptor,
- Cytohesin-2, and
- V-ATPase (vacuolar-type H+-ATPase). | Aldolase A
Aldolase A (ALDOA, or ALDA), also known as fructose-bisphosphate aldolase, is an enzyme that in humans is encoded by the ALDOA gene on chromosome 16.
The protein encoded by this gene is a glycolytic enzyme that catalyzes the reversible conversion of fructose-1,6-bisphosphate to glyceraldehyde 3-phosphate and dihydroxyacetone phosphate. Three aldolase isozymes (A, B, and C), encoded by three different genes, are differentially expressed during development. Aldolase A is found in the developing embryo and is produced in even greater amounts in adult muscle. Aldolase A expression is repressed in adult liver, kidney and intestine and similar to aldolase C levels in brain and other nervous tissue. Aldolase A deficiency has been associated with myopathy and hemolytic anemia. Alternative splicing and alternative promoter usage results in multiple transcript variants. Related pseudogenes have been identified on chromosomes 3 and 10. [provided by RefSeq, Aug 2011][1]
# Structure
ALDOA is a homotetramer and one of the three aldolase isozymes (A, B, and C), encoded by three different genes.[2][3] The ALDOA gene contains 8 exons and the 5' UTR IB.[3] Key amino acids responsible for its catalytic function have been identified. The residue Tyr363 functions as the acid–base catalyst for protonating C3 of the substrate, while Lys146 is proposed to stabilize the negative charge of the resulting conjugate base of Tyr363 and the strained configuration of the C-terminal. Residue Glu187 participates in multiple functions, including FBP aldolase catalysis, acid–base catalysis during substrate binding, dehydration, and substrate cleavage.[4] Though ALDOA localizes to the nucleus, it lacks any known nuclear localization signals (NLS).[5]
# Mechanism
In mammalian aldolase, the key catalytic amino acid residues involved in the reaction are lysine and tyrosine. The tyrosine acts as an efficient hydrogen acceptor while the lysine covalently binds and stabilizes the intermediates. Many bacteria use two magnesium ions in place of the lysine.
Compound C05378 at KEGG Pathway Database. Enzyme 4.1.2.13 at KEGG Pathway Database. Compound C00111 at KEGG Pathway Database. Compound C00118 at KEGG Pathway Database.
The numbering of the carbon atoms indicates the fate of the carbons according to their position in fructose 6-phosphate.
# Function
ALDOA is a key enzyme in the fourth step of glycolysis, as well as in the reverse pathway gluconeogenesis. It catalyzes the reversible conversion of fructose-1,6-bisphosphate to glyceraldehydes-3-phosphate and dihydroxyacetone phosphate by aldol cleavage of the C3–C4 bond. As a result, it is a crucial player in ATP biosynthesis.[2][4][5][6][7] ALDOA also contributes to other "moonlighting" functions such as muscle maintenance, regulation of cell shape and motility, striated muscle contraction, actin cytoskeleton organization, and regulation of cell proliferation.[2][5][6] ALDOA likely regulates actin cytoskeleton remodeling through interacting with cytohesin-2 (ARNO) and Arf6.[6]
ALDOA is ubiquitously expressed in most tissues, though it is predominantly expressed in developing embryo and adult muscle.[2][7] In lymphocytes, ALDOA is the predominant aldolase isoform.[7] Within the cell, ALDOA typically localizes to the cytoplasm, but it can localize to the nucleus during DNA synthesis of the cell cycle S phase. This nuclear localization is regulated by the protein kinases AKT and p38. It is suggested that the nucleus serves as a reservoir for ALDOA in low glucose conditions.[5] ALDOA has also been found in mitochondria.[7]
ALDOA is regulated by the energy metabolism substrates glucose, lactate, and glutamine.[5] In human mast cells (MCs), ALDOA has been observed to undergo post-translational regulation by protein tyrosine nitration, which may alter its relative affinity for FBP and/or IP3. This change then affects IP3 and PLC signaling cascades in IgE-dependent responses.[7]
# Clinical significance
Aldolase A (ALDOA) is a highly expressed in multiple cancers, including lung squamous cell carcinoma (LSCC), renal cancer, and hepatocellular carcinoma. It is proposed that ALDOA overexpression enhances glycolysis in these tumor cells, promoting their growth. In LSCC, its upregulation correlates with metastasis and poor prognosis, while its downregulation reduces tumor cell motility and tumorigenesis. Thus, ALDOA could be a potential LSCC biomarker and therapeutic drug target.[2]
Aldolase A deficiency is a rare, autosomal recessive disorder that is linked to hemolysis and accompanied by weakness, muscle pain, and myopathy.[3]
# Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles. [§ 1]
- ↑ The interactive pathway map can be edited at WikiPathways: "GlycolysisGluconeogenesis_WP534"..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}
# Interactions
Aldolase A has been shown to interact with:
- PLD2,[8]
- actin,[7]
- GLUT4,[9]
- phospholipase D2,[9]
- light chain 8 of dynein,[9]
- erythrocyte anion exchanger Band 3 protein,[9]
- ryanodine receptor,[7]
- Cytohesin-2,[6] and
- V-ATPase (vacuolar-type H+-ATPase).[6] | https://www.wikidoc.org/index.php/Aldolase_A | |
c330013995f563ad3a6834a46ea3bc46e1afda2a | wikidoc | Aldolase B | Aldolase B
Aldolase B also known as fructose-bisphosphate aldolase B or liver-type aldolase is one of three isoenzymes (A, B, and C) of the class I fructose 1,6-bisphosphate aldolase enzyme (EC 4.1.2.13), and plays a key role in both glycolysis and gluconeogenesis. The generic fructose 1,6-bisphosphate aldolase enzyme catalyzes the reversible cleavage of fructose 1,6-bisphosphate (FBP) into glyceraldehyde 3-phosphate and dihydroxyacetone phosphate (DHAP) as well as the reversible cleavage of fructose 1-phosphate (F1P) into glyceraldehyde and dihydroxyacetone phosphate. In mammals, aldolase B is preferentially expressed in the liver, while aldolase A is expressed in muscle and erythrocytes and aldolase C is expressed in the brain. Slight differences in isozyme structure result in different activities for the two substrate molecules: FBP and fructose 1-phosphate. Aldolase B exhibits no preference and thus catalyzes both reactions, while aldolases A and C prefer FBP.
In humans, aldolase B is encoded by the ALDOB gene located on chromosome 9. The gene is 14,500 base pairs long and contains 9 exons. Defects in this gene have been identified as the cause of hereditary fructose intolerance (HFI).
# Mechanism
The generic fructose bisphosphate aldolase enzyme cleaves a 6-carbon fructose sugar into two 3-carbon products in a reverse aldol reaction. This reaction is typified by the formation of a Schiff base intermediate with a lysine residue (lysine 229) in the active site of the enzyme; the formation of a Schiff base is the key differentiator between Class I (produced by animals) and Class II (produced by fungi and bacteria) aldolases. After Schiff base formation, the fourth hydroxyl group on the fructose backbone is then deprotonated by an aspartate residue (aspartate 33), which results in an aldol cleavage. Schiff base hydrolysis yields two 3-carbon products. Depending on the reactant, F1P or FBP, the products are DHAP and glyceraldehyde or glyceraldehyde 3-phosphate, respectively.
The ΔG°’ of this reaction is +23.9 kJ/mol. Though the reaction may seem too uphill to occur, it is of note that under physiological conditions, the ΔG of the reaction falls to close to or below zero. For example, the ΔG of this reaction under physiological conditions in erythrocytes is -0.23 kJ/mol.
# Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles.
- ↑ The interactive pathway map can be edited at WikiPathways: "GlycolysisGluconeogenesis_WP534"..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}
# Structure
Aldolase B is a homotetrameric enzyme, composed of four subunits with molecular weights of 36 kDa with local 222 symmetry. Each subunit has a molecular weight of 36 kDa and contains an eight-stranded α/β barrel, which encloses lysine 229 (the Schiff-base forming amino acid that is key for catalysis).
## Isozyme specific regions
Though the majority of the overall structure of the aldolase enzyme is conserved amongst the three isozymes, four regions of the generic aldolase enzyme have been identified to be highly variable among isozymes. Such regions have been denoted isozyme-specific regions (ISR1-4). These regions are thought to give isozymes their specificities and structural differences. ISRs 1-3 are all found in exon 3 of the ALDOB gene. ISR 4 is the most variable of the four and is found at the c-terminal end of the protein.
ISRs 1-3 are found predominantly in patches on the surface of the enzyme. These patches do not overlap with the active site, indicating that ISRs may change specific isozyme substrate specificity from a distance or cause the C-terminus interactions with the active site. A recent theory suggests that ISRs may allow for different conformational dynamics in the aldolase enzyme that account for its specificity.
# Physiology
Aldolase B plays a key role in carbohydrate metabolism as it catalyzes one of the major steps of the glycolytic-gluconeogenic pathway. Though it does catalyze the breakdown of glucose, it plays a particularly important role in fructose metabolism, which occurs mostly in the liver, renal cortex, and small intestinal mucosa. When fructose is absorbed, it is phosphorylated by fructokinase to form fructose 1-phosphate. Aldolase B then catalyzes F1P breakdown into glyceraldehyde and DHAP. After glyceraldehyde is phosphorylated by triose kinase to form G3P, both products can be used in the glycolytic-gluconeogenic pathway, that is, they can be modified to become either glucose or pyruvate.
Though the mechanism aldolase B regulation is unknown, increased ALDOB gene transcription in the liver has been noticed with an increase in dietary carbohydrates and decrease in glucagon concentration.
# Pathology
Genetic mutations leading to defects in aldolase B result in a condition called hereditary fructose intolerance. Due to the lack of functional aldolase B, organisms with HFI cannot properly process F1P, which leads to an accumulation of F1P in bodily tissues. In addition to being toxic to cellular tissues, high levels of F1P traps phosphate in an unusable form that does not return to the general phosphate pool, resulting in depletion of both phosphate and ATP stores. The lack of readily available phosphate causes the cessation of glycogenolysis in the liver, which results in hypoglycemia. This accumulation also inhibits gluconeogenesis, further reducing the amount of readily available glucose. The loss of ATP leads to a multitude of problems including inhibition of protein synthesis and hepatic and renal dysfunction. Patient prognosis, however, is good in cases of hereditary fructose intolerance. By avoiding foods containing fructose, sucrose, and sorbitol, patients can live symptom-free lives.
HFI is recessively inherited autosomal disorder. Approximately 30 mutations that cause HFI have been identified, and these combined mutations result in a HFI frequency of 1 in every 20,000 births. Mutant alleles are a result of a number different types of mutations including base pair substitutions and small deletions. The most common mutation is A149P, which is a guanine to cytosine transversion in exon 5, resulting in the replacement of alanine at position 149 with proline. This specific mutant allele is estimated to account for 53% of HFI alleles. Other mutations resulting in HFI are less frequent and often correlated with ancestral origins. | Aldolase B
Aldolase B also known as fructose-bisphosphate aldolase B or liver-type aldolase is one of three isoenzymes (A, B, and C) of the class I fructose 1,6-bisphosphate aldolase enzyme (EC 4.1.2.13), and plays a key role in both glycolysis and gluconeogenesis. The generic fructose 1,6-bisphosphate aldolase enzyme catalyzes the reversible cleavage of fructose 1,6-bisphosphate (FBP) into glyceraldehyde 3-phosphate and dihydroxyacetone phosphate (DHAP) as well as the reversible cleavage of fructose 1-phosphate (F1P) into glyceraldehyde and dihydroxyacetone phosphate. In mammals, aldolase B is preferentially expressed in the liver, while aldolase A is expressed in muscle and erythrocytes and aldolase C is expressed in the brain. Slight differences in isozyme structure result in different activities for the two substrate molecules: FBP and fructose 1-phosphate. Aldolase B exhibits no preference and thus catalyzes both reactions, while aldolases A and C prefer FBP.[1]
In humans, aldolase B is encoded by the ALDOB gene located on chromosome 9. The gene is 14,500 base pairs long and contains 9 exons.[2][3][4] Defects in this gene have been identified as the cause of hereditary fructose intolerance (HFI).[5]
# Mechanism
The generic fructose bisphosphate aldolase enzyme cleaves a 6-carbon fructose sugar into two 3-carbon products in a reverse aldol reaction. This reaction is typified by the formation of a Schiff base intermediate with a lysine residue (lysine 229) in the active site of the enzyme; the formation of a Schiff base is the key differentiator between Class I (produced by animals) and Class II (produced by fungi and bacteria) aldolases. After Schiff base formation, the fourth hydroxyl group on the fructose backbone is then deprotonated by an aspartate residue (aspartate 33), which results in an aldol cleavage. Schiff base hydrolysis yields two 3-carbon products. Depending on the reactant, F1P or FBP, the products are DHAP and glyceraldehyde or glyceraldehyde 3-phosphate, respectively.[6]
The ΔG°’ of this reaction is +23.9 kJ/mol. Though the reaction may seem too uphill to occur, it is of note that under physiological conditions, the ΔG of the reaction falls to close to or below zero. For example, the ΔG of this reaction under physiological conditions in erythrocytes is -0.23 kJ/mol.[6]
# Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles. [§ 1]
- ↑ The interactive pathway map can be edited at WikiPathways: "GlycolysisGluconeogenesis_WP534"..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}
# Structure
Aldolase B is a homotetrameric enzyme, composed of four subunits with molecular weights of 36 kDa with local 222 symmetry. Each subunit has a molecular weight of 36 kDa and contains an eight-stranded α/β barrel, which encloses lysine 229 (the Schiff-base forming amino acid that is key for catalysis).[7][8]
## Isozyme specific regions
Though the majority of the overall structure of the aldolase enzyme is conserved amongst the three isozymes, four regions of the generic aldolase enzyme have been identified to be highly variable among isozymes. Such regions have been denoted isozyme-specific regions (ISR1-4). These regions are thought to give isozymes their specificities and structural differences. ISRs 1-3 are all found in exon 3 of the ALDOB gene. ISR 4 is the most variable of the four and is found at the c-terminal end of the protein.[1]
ISRs 1-3 are found predominantly in patches on the surface of the enzyme. These patches do not overlap with the active site, indicating that ISRs may change specific isozyme substrate specificity from a distance or cause the C-terminus interactions with the active site.[8] A recent theory suggests that ISRs may allow for different conformational dynamics in the aldolase enzyme that account for its specificity.[9]
# Physiology
Aldolase B plays a key role in carbohydrate metabolism as it catalyzes one of the major steps of the glycolytic-gluconeogenic pathway. Though it does catalyze the breakdown of glucose, it plays a particularly important role in fructose metabolism, which occurs mostly in the liver, renal cortex, and small intestinal mucosa. When fructose is absorbed, it is phosphorylated by fructokinase to form fructose 1-phosphate. Aldolase B then catalyzes F1P breakdown into glyceraldehyde and DHAP. After glyceraldehyde is phosphorylated by triose kinase to form G3P, both products can be used in the glycolytic-gluconeogenic pathway, that is, they can be modified to become either glucose or pyruvate.[10]
Though the mechanism aldolase B regulation is unknown, increased ALDOB gene transcription in the liver has been noticed with an increase in dietary carbohydrates and decrease in glucagon concentration.[11][12]
# Pathology
Genetic mutations leading to defects in aldolase B result in a condition called hereditary fructose intolerance. Due to the lack of functional aldolase B, organisms with HFI cannot properly process F1P, which leads to an accumulation of F1P in bodily tissues. In addition to being toxic to cellular tissues, high levels of F1P traps phosphate in an unusable form that does not return to the general phosphate pool, resulting in depletion of both phosphate and ATP stores. The lack of readily available phosphate causes the cessation of glycogenolysis in the liver, which results in hypoglycemia.[13] This accumulation also inhibits gluconeogenesis, further reducing the amount of readily available glucose. The loss of ATP leads to a multitude of problems including inhibition of protein synthesis and hepatic and renal dysfunction. Patient prognosis, however, is good in cases of hereditary fructose intolerance. By avoiding foods containing fructose, sucrose, and sorbitol, patients can live symptom-free lives.[10]
HFI is recessively inherited autosomal disorder. Approximately 30 mutations that cause HFI have been identified, and these combined mutations result in a HFI frequency of 1 in every 20,000 births.[10][14] Mutant alleles are a result of a number different types of mutations including base pair substitutions and small deletions. The most common mutation is A149P, which is a guanine to cytosine transversion in exon 5, resulting in the replacement of alanine at position 149 with proline. This specific mutant allele is estimated to account for 53% of HFI alleles.[15] Other mutations resulting in HFI are less frequent and often correlated with ancestral origins.[16] | https://www.wikidoc.org/index.php/Aldolase_B | |
572e7dbeaf9e8177ee64dfedc7f095d3fdf74c76 | wikidoc | Aldolase C | Aldolase C
Aldolase C, fructose-bisphosphate (ALDOC, or ALDC), is an enzyme that, in humans, is encoded by the ALDOC gene on chromosome 17. This gene encodes a member of the class I fructose-bisphosphate aldolase gene family. Expressed specifically in the hippocampus and Purkinje cells of the brain, the encoded protein is a glycolytic enzyme that catalyzes the reversible aldol cleavage of fructose 1,6-bisphosphate and fructose-1-phosphate to dihydroxyacetone phosphate and either glyceraldehyde 3-phosphate or glyceraldehyde, respectively.
# Structure
ALDOC is one of the three aldolase isozymes (A, B, and C), encoded by three different genes. The amino acid sequence of ALDOC is highly similar to those of the other isozymes, sharing a 68% identity with ALDOB and 78% identity with ALDOA. In particular, the residues Asp33, Arg42, Lys107, Lys146, Glu187, Ser271, Arg303, and Lys229 are all conserved in the active sites of the three isozymes. This active site is located in the center of the homotetrameric αβ-barrel structure of these aldolases. However, several structural details set ALDOC apart. For instance, the Arg303 residue in ALDOC adopts an intermediate conformation between the liganded and unliganded structures observed in the other isozymes. Also, the C-terminal region between Glu332 and Lys71 forms a salt bridge with the barrel region that is absent in the A and B isoforms. Moreover, the electrostatic surface of ALDOC is more negatively charged, which may serve as an acidic binding site or as a docking site to accommodate the C-terminal conformations. Four ALDOC-specific residues (N90, V92, R96 and D100) may be key for ALDOC-specific functions.
# Function
ALDOC is a key enzyme in the fourth step of glycolysis, as well as in the reverse pathway gluconeogenesis. It catalyzes the reversible conversion of fructose-1,6-bisphosphate to glyceraldehydes-3-phosphate (G3P), or glyceraldehyde, and dihydroxyacetone phosphate (DHAP) by aldol cleavage. As a result, it is a crucial player in ATP biosynthesis. As an aldolase, ALDOC putatively also contributes to other "moonlighting" functions, though its exact involvements remain unclear. For instance, it binds less tightly to the cytoskeleton than the other isozymes do, likely due to its more acidic pI. In addition, ALDOC participates in the stress-response pathway for lung epithelial cell function during hypoxia and in the resistance of cerebellar Purkinje cells against excitotoxic insult.
ALDOC is ubiquitously expressed in most tissues, though it is predominantly expressed in brain, smooth muscle, and neuronal tissue. However, since the ALDOA isoform is co-expressed with ALDOC in the central nervous system (CS), it is suggested that ALDOC contributes to CNS function outside of glycolysis. Moreover, its presence within other cell types, such as platelets and mast cells (MCs), may serve as a failsafe in the case that the other predominant aldolase isozymes become inactivated. Within cells, it localizes to the cytoplasm.
# Clinical significance
This aldolase has been associated with cancer.
ALDOC is found to be upregulated in the brains of schizophrenia (SCZ) patients. Notably, while ALDOC is differentially expressed in the anterior cingulate cortex (ACC) of male SCZ patients, it displays no significant changes in female SCZ patients, indicating that different regulatory mechanisms may be involved in male versus female SCZ patients. It is likely that ALDOC is involved in SCZ through its role in glycolysis, which is a central biochemical pathway in SCZ.
Furthermore, ALDOC is reported to undergo oxidation in brains affected by mild cognitive impairment (MCI) and Alzheimer's disease (AD). This oxidative modification inhibits ALDOC activity, causing the accumulation of fructose 1,6- bisphosphate and driving the reverse reaction, in the direction of gluconeogenesis rather than glycolysis, thus halting ATP production.
# Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles.
- ↑ The interactive pathway map can be edited at WikiPathways: "GlycolysisGluconeogenesis_WP534"..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} | Aldolase C
Aldolase C, fructose-bisphosphate (ALDOC, or ALDC), is an enzyme that, in humans, is encoded by the ALDOC gene on chromosome 17. This gene encodes a member of the class I fructose-bisphosphate aldolase gene family. Expressed specifically in the hippocampus and Purkinje cells of the brain, the encoded protein is a glycolytic enzyme that catalyzes the reversible aldol cleavage of fructose 1,6-bisphosphate and fructose-1-phosphate to dihydroxyacetone phosphate and either glyceraldehyde 3-phosphate or glyceraldehyde, respectively.[provided by RefSeq, Jul 2008][1][2]
# Structure
ALDOC is one of the three aldolase isozymes (A, B, and C), encoded by three different genes.[3][4] The amino acid sequence of ALDOC is highly similar to those of the other isozymes, sharing a 68% identity with ALDOB and 78% identity with ALDOA. In particular, the residues Asp33, Arg42, Lys107, Lys146, Glu187, Ser271, Arg303, and Lys229 are all conserved in the active sites of the three isozymes. This active site is located in the center of the homotetrameric αβ-barrel structure of these aldolases. However, several structural details set ALDOC apart. For instance, the Arg303 residue in ALDOC adopts an intermediate conformation between the liganded and unliganded structures observed in the other isozymes. Also, the C-terminal region between Glu332 and Lys71 forms a salt bridge with the barrel region that is absent in the A and B isoforms. Moreover, the electrostatic surface of ALDOC is more negatively charged, which may serve as an acidic binding site or as a docking site to accommodate the C-terminal conformations.[4] Four ALDOC-specific residues (N90, V92, R96 and D100) may be key for ALDOC-specific functions.[5]
# Function
ALDOC is a key enzyme in the fourth step of glycolysis, as well as in the reverse pathway gluconeogenesis. It catalyzes the reversible conversion of fructose-1,6-bisphosphate to glyceraldehydes-3-phosphate (G3P), or glyceraldehyde, and dihydroxyacetone phosphate (DHAP) by aldol cleavage. As a result, it is a crucial player in ATP biosynthesis.[4][5] As an aldolase, ALDOC putatively also contributes to other "moonlighting" functions, though its exact involvements remain unclear.[4][5] For instance, it binds less tightly to the cytoskeleton than the other isozymes do, likely due to its more acidic pI.[4] In addition, ALDOC participates in the stress-response pathway for lung epithelial cell function during hypoxia and in the resistance of cerebellar Purkinje cells against excitotoxic insult.[6]
ALDOC is ubiquitously expressed in most tissues, though it is predominantly expressed in brain, smooth muscle, and neuronal tissue.[4][5][7][8] However, since the ALDOA isoform is co-expressed with ALDOC in the central nervous system (CS), it is suggested that ALDOC contributes to CNS function outside of glycolysis.[5] Moreover, its presence within other cell types, such as platelets and mast cells (MCs), may serve as a failsafe in the case that the other predominant aldolase isozymes become inactivated.[7] Within cells, it localizes to the cytoplasm.[8]
# Clinical significance
This aldolase has been associated with cancer.[4]
ALDOC is found to be upregulated in the brains of schizophrenia (SCZ) patients.[9] Notably, while ALDOC is differentially expressed in the anterior cingulate cortex (ACC) of male SCZ patients, it displays no significant changes in female SCZ patients, indicating that different regulatory mechanisms may be involved in male versus female SCZ patients. It is likely that ALDOC is involved in SCZ through its role in glycolysis, which is a central biochemical pathway in SCZ.[10]
Furthermore, ALDOC is reported to undergo oxidation in brains affected by mild cognitive impairment (MCI) and Alzheimer's disease (AD). This oxidative modification inhibits ALDOC activity, causing the accumulation of fructose 1,6- bisphosphate and driving the reverse reaction, in the direction of gluconeogenesis rather than glycolysis, thus halting ATP production.[11]
# Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles. [§ 1]
- ↑ The interactive pathway map can be edited at WikiPathways: "GlycolysisGluconeogenesis_WP534"..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} | https://www.wikidoc.org/index.php/Aldolase_C | |
fa29592fdb7a7e34b3119aeb6dc45839f13345dd | wikidoc | Methyldopa | Methyldopa
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# Overview
Methyldopa is an alpha-adrenergic blocker that is FDA approved for the treatment of hypertension. Common adverse reactions include asthenia, dizziness, headache, sedated, disorder of ejaculation , impotence, reduced libido, drug fever.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Initiation of Therapy
- The usual starting dosage of methyldopa tablet is 250 mg two to three times a day in the first 48 hours. The daily dosage then may be increased or decreased, preferably at intervals of not less than two days, until an adequate response is achieved. To minimize the sedation, start dosage increases in the evening. By adjustment of dosage, morning hypotension may be prevented without sacrificing control of afternoon blood pressure.
- When methyldopa is given to patients on other antihypertensives, the dose of these agents may need to be adjusted to effect a smooth transition. When methyldopa is given with anti-hypertensives other than thiazides, the initial dosage of methyldopa should be limited to 500 mg daily in divided doses; when methyldopa is added to a thiazide, the dosage of thiazide need not be changed.
- Maintenance of Therapy
- The usual daily dosage of methyldopa is 500 mg to 2 g in two to four doses. Although occasional patients have responded to higher doses, the maximum recommended daily dosage is 3 g. Once an effective dosage range is attained, a smooth blood pressure response occurs in most patients in 12 to 24 hours. Since methyldopa has a relatively short duration of action, withdrawal is followed by return of hypertension usually within 48 hours. This is not complicated by an overshoot of blood pressure.
- Occasionally tolerance may occur, usually between the second and third month of therapy. Adding a diuretic or increasing the dosage of methyldopa frequently will restore effective control of blood pressure. A thiazide may be added at any time during methyldopa therapy and is recommended if therapy has not been started with a thiazide or if effective control of blood pressure cannot be maintained on 2 g of methyldopa daily.
- Methyldopa is largely excreted by the kidney and patients with impaired renal function may respond to smaller doses. Syncope in older patients may be related to an increased sensitivity and advanced arteriosclerotic vascular disease. This may be avoided by lower doses.
- The usual adult dosage intravenously is 250 mg to 500 mg at six hour intervals as required. The maximum recommended intravenous dose is 1 gram every six hours.
- When control has been obtained, oral therapy with tablets may be substituted for intravenous therapy, starting with the same dosage schedule used for the parenteral route. The effectiveness and anticipated responses are described in the circular for tablets.
- Since methyldopate has a relatively short duration of action, withdrawal is followed by return of hypertension usually within 48 hours. This is not complicated by an overshoot of blood pressure.
- Occasionally tolerance may occur, usually between the second and third month of therapy. Adding a diuretic or increasing the dosage of methyldopa frequently will restore effective control of blood pressure. A thiazide may be added at any time during methyldopa therapy and is recommended if therapy has not been started with a thiazide or if effective control of blood pressure cannot be maintained on 2 grams of methyldopa daily.
- Methyldopa is largely excreted by the kidney and patients with impaired renal function may respond to smaller doses. Syncope in older patients may be related to an increased sensitivity and advanced arteriosclerotic vascular disease. This may be avoided by lower doses.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- Developed by: American College of Obstetricians and Gynecologists
- Class of Recommendation: Strong recommendation
- Strength of Evidence: Moderate
- Dosing Information/Recommendation
- 250-1500 mg PO q8-12h (maximum dose: 3g).
### Non–Guideline-Supported Use
- Dosing Information
- 250-500 mg PO q12h.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Initial dosage is based on 10 mg/kg of body weight daily in two to four doses. The daily dosage then is increased or decreased until an adequate response is achieved. The maximum dosage is 65 mg/kg or 3 g daily, whichever is less.
- The recommended daily dosage is 20 to 40 mg/kg of body weight in divided doses every six hours. The maximum dosage is 65 mg/kg or 3 grams daily, whichever is less. When the blood pressure is under control, continue with oral therapy using tablets in the same dosage as for the parenteral route
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Methyldopa in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Methyldopa in pediatric patients.
# Contraindications
- Patients with active hepatic disease, such as acute hepatitis and active cirrhosis.
- Patients with liver disorders previously associated with methyldopa therapy.
- Patients with hypersensitivity to any component of this product.
- Patients on therapy with monoamine oxidase inhibitors (MAO).
# Warnings
It is important to recognize that a positive Coombs test, hemolytic anemia, and liver disorders may occur with methyldopa therapy. The rare occurrences of hemolytic anemia or liver disorders could lead to potentially fatal complications unless properly recognized and managed. Read this section carefully to understand these reactions.
With prolonged methyldopa therapy, 10 to 20 percent of patients develop a positive direct Coombs test which usually occurs between 6 and 12 months of methyldopa therapy. Lowest incidence is at daily dosage of 1 g or less. This on rare occasions may be associated with hemolytic anemia, which could lead to potentially fatal complications. One cannot predict which patients with a positive direct Coombs test may develop hemolytic anemia.
Prior existence or development of a positive direct Coombs test is not in itself a contraindication to use of methyldopa. If a positive Coombs test develops during methyldopa therapy, the physician should determine whether hemolytic anemia exists and whether the positive Coombs test may be a problem. For example, in addition to a positive direct Coombs test there is less often a positive indirect Coombs test which may interfere with cross matching of blood.
Before treatment is started, it is desirable to do a blood count (hematocrit, hemoglobin, or red cell count) for a baseline or to establish whether there is anemia. Periodic blood counts should be done during therapy to detect hemolytic anemia. It may be useful to do a direct Coombs test before therapy and at 6 and 12 months after the start of therapy.
If Coombs-positive hemolytic anemia occurs, the cause may be methyldopa and the drug should be discontinued. Usually the anemia remits promptly. If not, corticosteroids may be given and other causes of anemia should be considered. If the hemolytic anemia is related to methyldopa, the drug should not be reinstituted.
When methyldopa causes Coombs positivity alone or with hemolytic anemia, the red cell is usually coated with gamma globulin of the lgG (gamma G) class only. The positive Coombs test may not revert to normal until weeks to months after methyldopa is stopped.
Should the need for transfusion arise in a patient receiving methyldopa, both a direct and an indirect Coombs test should be performed. In the absence of hemolytic anemia, usually only the direct Coombs test will be positive. A positive direct Coombs test alone will not interfere with typing or cross matching. If the indirect Coombs test is also positive, problems may arise in the major cross match and the assistance of a hematologist or transfusion expert will be needed.
Occasionally, fever has occurred within the first three weeks of methyldopa therapy, associated in some cases with eosinophilia or abnormalities in one or more liver function tests, such as serum alkaline phosphatase, serum transaminases (SGOT, SGPT), bilirubin, and prothrombin time. Jaundice, with or without fever, may occur with onset usually within the first two to three months of therapy. In some patients the findings are consistent with those of cholestasis. In others the findings are consistent with hepatitis and hepatocellular injury.
Rarely, fatal hepatic necrosis has been reported after use of methyldopa. These hepatic changes may represent hypersensitivity reactions. Periodic determinations of hepatic function should be done particularly during the first 6 to 12 weeks of therapy or whenever an unexplained fever occurs. If fever, abnormalities in liver function tests, or jaundice appear, stop therapy with methyldopa. If caused by methyldopa, the temperature and abnormalities in liver function characteristically have reverted to normal when the drug was discontinued. Methyldopa should not be reinstituted in such patients.
Rarely, a reversible reduction of the white blood cell count with a primary effect on the granulocytes has been seen. The granulocyte count returned promptly to normal on discontinuance of the drug. Rare cases of granulocytopenia have been reported. In each instance, upon stopping the drug, the white cell count returned to normal. Reversible thrombocytopenia has occurred rarely.
### PRECAUTIONS
- Methyldopa should be used with caution in patients with a history of previous liver disease or liver dysfunction.
- Some patients taking methyldopa experience clinical edema or weight gain which may be controlled by use of a diuretic. Methyldopa should not be continued if edema progresses or signs of heart failure appear.
- Hypertension has recurred occasionally after dialysis in patients given methyldopa because the drug is removed by this procedure.
- Rarely, involuntary choreoathetotic movements have been observed during therapy with methyldopa in patients with severe bilateral cerebrovascular disease. Should these movements occur, stop therapy.
Blood count, Coombs test and liver function tests are recommended before initiating therapy and at periodic intervals
# Adverse Reactions
## Clinical Trials Experience
Sedation, usually transient, may occur during the initial period of therapy or whenever the dose is increased. Headache, asthenia, or weakness may be noted as early and transient symptoms. However, significant adverse effects due to methyldopa have been infrequent and this agent usually is well tolerated.
The following adverse reactions have been reported and, within each category, are listed in order of decreasing severity.
- Cardiovascular: Aggravation of angina pectoris, congestive heart failure, prolonged carotid sinus hypersensitivity, orthostatic hypotension (decrease daily dosage), edema or weight gain, bradycardia.
- Digestive: Pancreatitis, colitis, vomiting, diarrhea, sialadenitis, sore or black tongue, nausea, constipation, distension, flatus, dryness of mouth.
- Endocrine: Hyperprolactinemia.
- Hematologic: Bone marrow depression, leukopenia, granulocytopenia, thrombocytopenia, hemolytic anemia; positive tests for antinuclear antibody, LE cells, and rheumatoid factor, positive Coombs test.
- Hepatic: Liver disorders including hepatitis, jaundice, abnormal liver function tests (see WARNINGS).
- Hypersensitivity: Myocarditis, pericarditis, vasculitis, lupus-like syndrome, drug-related fever, eosinophilia.
- Nervous System/Psychiatric: Parkinsonism, Bell's palsy, decreased mental acuity, involuntary choreoathetotic movements, symptoms of cerebrovascular insufficiency, psychic disturbances including nightmares and reversible mild psychoses or depression, headache, sedation, asthenia or weakness, dizziness, light-headedness, paresthesias.
- Metabolic: Rise in BUN.
- Musculoskeletal: Arthralgia, with or without joint swelling; myalgia.
- Respiratory: Nasal stuffiness.
- Skin: Toxic epidermal necrolysis, rash.
- Urogenital: Amenorrhea, breast enlargement, gynecomastia, lactation, impotence, decreased libido.
## Postmarketing Experience
There is limited information regarding Methyldopa Postmarketing Experience in the drug label.
# Drug Interactions
- When methyldopa is used with other antihypertensive drugs, potentiation of antihypertensive effect may occur. Patients should be followed carefully to detect side reactions or unusual manifestations of drug idiosyncrasy.
- Patients may require reduced doses of anesthetics when on methyldopa. If hypotension does occur during anesthesia, it usually can be controlled by vasopressors. The adrenergic receptors remain sensitive during treatment with methyldopa.
- When methyldopa and lithium are given concomitantly, the patient should be carefully monitored for symptoms of lithium toxicity. Read the circular for lithium preparations.
- Several studies demonstrate a decrease in the bioavailability of methyldopa when it is ingested with ferrous sulfate or ferrous gluconate. This may adversely affect blood pressure control in patients treated with methyldopa. Coadministration of methyldopa with ferrous sulfate or ferrous gluconate is not recommended.
- Monoamine oxidase (MAO) inhibitors
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
Reproduction studies performed with methyldopa at oral doses up to 1000 mg/kg in mice, 200 mg/kg in rabbits and 100 mg/kg in rats revealed no evidence of harm to the fetus. These doses are 16.6 times, 3.3 times and 1.7 times, respectively, the maximum daily human dose when compared on the basis of body weight; 1.4 times, 1.1 times and 0.2 times, respectively, when compared on the basis of body surface area; calculations assume a patient weight of 50 kg. There are, however, no adequate and well-controlled studies in pregnant women in the first trimester of pregnancy. Because animal reproduction studies are not always predictive of human response, methyldopa should be used during pregnancy only if clearly needed.
Published reports of the use of methyldopa during all trimesters indicate that if this drug is used during pregnancy the possibility of fetal harm appears remote. In five studies, three of which were controlled, involving 332 pregnant hypertensive women, treatment with methyldopa was associated with an improved fetal outcome. The majority of these women were in the third trimester when methyldopa therapy was begun.
In one study, women who had begun methyldopa treatment between weeks 16 and 20 of pregnancy gave birth to infants whose average head circumference was reduced by a small amount (34.2 ± 1.7 cm vs. 34.6 ± 1.3 cm ). Long-term follow-up of 195 (97.5%) of the children born to methyldopa-treated pregnant women (including those who began treatment between weeks 16 and 20) failed to uncover any significant adverse effect on the children. At four years of age, the developmental delay commonly seen in children born to hypertensive mothers was less evident in those whose mothers were treated with methyldopa during pregnancy than those whose mothers were untreated. The children of the treated group scored consistently higher than the children of the untreated group on five major indices of intellectual and motor development. At age 7 and one-half developmental scores and intelligence indices showed no significant differences in children of treated or untreated hypertensive women.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Methyldopa in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Methyldopa during labor and delivery.
### Nursing Mothers
Methyldopa appears in breast milk. Therefore, caution should be exercised when methyldopa is given to a nursing woman.
### Pediatric Use
There are no well-controlled clinical trials in pediatric patients. Information on dosing in pediatric patients is supported by evidence from published literature regarding the treatment of hypertension in pediatric patients.
### Geriatic Use
Of the total number of subjects (1685) in clinical studies of methyldopa, 223 patients were 65 years of age and over while 33 patients were 75 years of age 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.
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 Methyldopa with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Methyldopa with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Methyldopa in patients with renal impairment.
### Hepatic Impairment
Periodic determinations of hepatic function should be done particularly during the first 6 to 12 weeks of therapy or whenever an unexplained fever occurs. If fever, abnormalities in liver function tests, or jaundice appear, stop therapy with methyldopa. If caused by methyldopa, the temperature and abnormalities in liver function characteristically have reverted to normal when the drug was discontinued. Methyldopa should not be reinstituted in such patients.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Methyldopa in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Methyldopa in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Oral/Intravenous
### Monitoring
There is limited information regarding Methyldopa Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Methyldopa and IV administrations.
# Overdosage
There is limited information regarding Methyldopa overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
Methyldopa is an aromatic-aminoacid decarboxylase inhibitor in animals and in man. Although the mechanism of action has yet to be conclusively demonstrated, the antihypertensive effect of methyldopa probably is due to its metabolism to alpha-methylnorepinephrine, which then lowers arterial pressure by stimulation of central inhibitory alpha-adrenergic receptors, false neurotransmission, and/or reduction of plasma renin activity. Methyldopa has been shown to cause a net reduction in the tissue concentration of serotonin, dopamine, norepinephrine, and epinephrine.
## Structure
Methyldopa is an antihypertensive and is the L-isomer of alpha-methyldopa. It is levo-3-(3,4-dihydroxyphenyl)-2-methylalanine sesquihydrate. Methyldopa is supplied as tablets for oral administration, containing 250 mg and 500 mg of methyldopa. The amount of methyldopa is calculated on the anhydrous basis. Its molecular formula is C10H13NO41 1/2 H2O, with a molecular weight of 238.24, and its structural formula is:
Methyldopa is a white to yellowish white, odorless fine powder and is sparingly soluble in water.
The tablets contain the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol, sodium lauryl sulfate, titanium dioxide, triacetin, FD&C yellow #6 aluminum lake and FD&C blue #2 aluminum lake.
## Pharmacodynamics
Only methyldopa, the L-isomer of alpha-methyldopa, has the ability to inhibit dopa decarboxylase and to deplete animal tissues of norepinephrine. In man, the antihypertensive activity appears to be due solely to the L-isomer. About twice the dose of the racemate (DL-alpha-methyldopa) is required for equal antihypertensive effect.
Methyldopa has no direct effect on cardiac function and usually does not reduce glomerular filtration rate, renal blood flow, or filtration fraction. Cardiac output usually is maintained without cardiac acceleration. In some patients the heart rate is slowed.
Normal or elevated plasma renin activity may decrease in the course of methyldopa therapy.
Methyldopa reduces both supine and standing blood pressure. It usually produces highly effective lowering of the supine pressure with infrequent symptomatic orthostatic hypotension. Exercise hypotension and diurnal blood pressure variations rarely occur.
## Pharmacokinetics
The maximum decrease in blood pressure occurs four to six hours after oral dosage. Once an effective dosage level is attained, a smooth blood pressure response occurs in most patients in 12 to 24 hours. After withdrawal, blood pressure usually returns to pretreatment levels within 24–48 hours.
Methyldopa is extensively metabolized. The known urinary metabolites are: α-methyldopa mono-O-sulfate; 3-0-methyl-α-methyldopa; 3,4-dihydroxyphenylacetone; α-methyldopamine; 3-0-methyl-α-methyldopamine and their conjugates.
Approximately 70 percent of the drug which is absorbed is excreted in the urine as methyldopa and its mono-O-sulfate conjugate. The renal clearance is about 130 mL/min in normal subjects and is diminished in renal insufficiency. The plasma half-life of methyldopa is 105 minutes. After oral doses, excretion is essentially complete in 36 hours.
Methyldopa crosses the placental barrier, appears in cord blood, and appears in breast milk.
## Nonclinical Toxicology
No evidence of a tumorigenic effect was seen when methyldopa was given for two years to mice at doses up to 1800 mg/kg/day or to rats at doses up to 240 mg/kg/day (30 and 4 times the maximum recommended human dose in mice and rats, respectively, when compared on the basis of body weight; 2.5 and 0.6 times the maximum recommended human dose in mice and rats, respectively, when compared on the basis of body surface area; calculations assume a patient weight of 50 kg).
Methyldopa was not mutagenic in the Ames Test and did not increase chromosomal aberration or sister chromatid exchanges in Chinese hamster ovary cells. These in vitro studies were carried out both with and without exogenous metabolic activation.
Fertility was unaffected when methyldopa was given to male and female rats at 100 mg/kg/day (1.7 times the maximum daily human dose when compared on the basis of body weight; 0.2 times the maximum daily human dose when compared on the basis of body surface area). Methyldopa decreased sperm count, sperm motility, the number of late spermatids and the male fertility index when given to male rats at 200 and 400 mg/kg/day (3.3 and 6.7 times the maximum daily human dose when compared on the basis of body weight; 0.5 and 1 times the maximum daily human dose when compared on the basis of body surface area).
# Clinical Studies
There is limited information regarding Methyldopa Clinical Studies in the drug label.
# How Supplied
- The 250 mg tablets are beige, film-coated, round, unscored tablets debossed with MYLAN on one side of the tablet and 611 on the other side. They are available as follows: NDC 51079-200-20 - Unit dose blister packages of 100 (10 cards of 10 tablets each).
- The 500 mg tablets are beige, film-coated, capsule-shaped, unscored tablets debossed with MYLAN on one side of the tablet and 421 on the other side. They are available as follows: NDC 51079-201-20 - Unit dose blister packages of 100 (10 cards of 10 tablets each).
- Methyldopate HCl Injection, USP 250 mg/5 mL (50 mg/mL): NDC 0517-8905-10 - 5 mL Single Dose Vial (Boxes of 10)
## Storage
- Store at 20° to 25°C (68° to 77°F).
- Protect from light.
- Store at 20°-25°C (68°-77°F); excursions permitted to 15°-30°C (59°-86°F) .
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Methyldopa Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Methyldopa 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 Methyldopa Brand Names in the drug label.
# Look-Alike Drug Names
There is limited information regarding Methyldopa Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Methyldopa
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alonso Alvarado, 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
Methyldopa is an alpha-adrenergic blocker that is FDA approved for the treatment of hypertension. Common adverse reactions include asthenia, dizziness, headache, sedated, disorder of ejaculation , impotence, reduced libido, drug fever.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Initiation of Therapy
- The usual starting dosage of methyldopa tablet is 250 mg two to three times a day in the first 48 hours. The daily dosage then may be increased or decreased, preferably at intervals of not less than two days, until an adequate response is achieved. To minimize the sedation, start dosage increases in the evening. By adjustment of dosage, morning hypotension may be prevented without sacrificing control of afternoon blood pressure.
- When methyldopa is given to patients on other antihypertensives, the dose of these agents may need to be adjusted to effect a smooth transition. When methyldopa is given with anti-hypertensives other than thiazides, the initial dosage of methyldopa should be limited to 500 mg daily in divided doses; when methyldopa is added to a thiazide, the dosage of thiazide need not be changed.
- Maintenance of Therapy
- The usual daily dosage of methyldopa is 500 mg to 2 g in two to four doses. Although occasional patients have responded to higher doses, the maximum recommended daily dosage is 3 g. Once an effective dosage range is attained, a smooth blood pressure response occurs in most patients in 12 to 24 hours. Since methyldopa has a relatively short duration of action, withdrawal is followed by return of hypertension usually within 48 hours. This is not complicated by an overshoot of blood pressure.
- Occasionally tolerance may occur, usually between the second and third month of therapy. Adding a diuretic or increasing the dosage of methyldopa frequently will restore effective control of blood pressure. A thiazide may be added at any time during methyldopa therapy and is recommended if therapy has not been started with a thiazide or if effective control of blood pressure cannot be maintained on 2 g of methyldopa daily.
- Methyldopa is largely excreted by the kidney and patients with impaired renal function may respond to smaller doses. Syncope in older patients may be related to an increased sensitivity and advanced arteriosclerotic vascular disease. This may be avoided by lower doses.
- The usual adult dosage intravenously is 250 mg to 500 mg at six hour intervals as required. The maximum recommended intravenous dose is 1 gram every six hours.
- When control has been obtained, oral therapy with tablets may be substituted for intravenous therapy, starting with the same dosage schedule used for the parenteral route. The effectiveness and anticipated responses are described in the circular for tablets.
- Since methyldopate has a relatively short duration of action, withdrawal is followed by return of hypertension usually within 48 hours. This is not complicated by an overshoot of blood pressure.
- Occasionally tolerance may occur, usually between the second and third month of therapy. Adding a diuretic or increasing the dosage of methyldopa frequently will restore effective control of blood pressure. A thiazide may be added at any time during methyldopa therapy and is recommended if therapy has not been started with a thiazide or if effective control of blood pressure cannot be maintained on 2 grams of methyldopa daily.
- Methyldopa is largely excreted by the kidney and patients with impaired renal function may respond to smaller doses. Syncope in older patients may be related to an increased sensitivity and advanced arteriosclerotic vascular disease. This may be avoided by lower doses.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- Developed by: American College of Obstetricians and Gynecologists
- Class of Recommendation: Strong recommendation
- Strength of Evidence: Moderate
- Dosing Information/Recommendation
- 250-1500 mg PO q8-12h (maximum dose: 3g).[1]
### Non–Guideline-Supported Use
- Dosing Information
- 250-500 mg PO q12h.[2]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Initial dosage is based on 10 mg/kg of body weight daily in two to four doses. The daily dosage then is increased or decreased until an adequate response is achieved. The maximum dosage is 65 mg/kg or 3 g daily, whichever is less.
- The recommended daily dosage is 20 to 40 mg/kg of body weight in divided doses every six hours. The maximum dosage is 65 mg/kg or 3 grams daily, whichever is less. When the blood pressure is under control, continue with oral therapy using tablets in the same dosage as for the parenteral route
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Methyldopa in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Methyldopa in pediatric patients.
# Contraindications
- Patients with active hepatic disease, such as acute hepatitis and active cirrhosis.
- Patients with liver disorders previously associated with methyldopa therapy.
- Patients with hypersensitivity to any component of this product.
- Patients on therapy with monoamine oxidase inhibitors (MAO).
# Warnings
It is important to recognize that a positive Coombs test, hemolytic anemia, and liver disorders may occur with methyldopa therapy. The rare occurrences of hemolytic anemia or liver disorders could lead to potentially fatal complications unless properly recognized and managed. Read this section carefully to understand these reactions.
With prolonged methyldopa therapy, 10 to 20 percent of patients develop a positive direct Coombs test which usually occurs between 6 and 12 months of methyldopa therapy. Lowest incidence is at daily dosage of 1 g or less. This on rare occasions may be associated with hemolytic anemia, which could lead to potentially fatal complications. One cannot predict which patients with a positive direct Coombs test may develop hemolytic anemia.
Prior existence or development of a positive direct Coombs test is not in itself a contraindication to use of methyldopa. If a positive Coombs test develops during methyldopa therapy, the physician should determine whether hemolytic anemia exists and whether the positive Coombs test may be a problem. For example, in addition to a positive direct Coombs test there is less often a positive indirect Coombs test which may interfere with cross matching of blood.
Before treatment is started, it is desirable to do a blood count (hematocrit, hemoglobin, or red cell count) for a baseline or to establish whether there is anemia. Periodic blood counts should be done during therapy to detect hemolytic anemia. It may be useful to do a direct Coombs test before therapy and at 6 and 12 months after the start of therapy.
If Coombs-positive hemolytic anemia occurs, the cause may be methyldopa and the drug should be discontinued. Usually the anemia remits promptly. If not, corticosteroids may be given and other causes of anemia should be considered. If the hemolytic anemia is related to methyldopa, the drug should not be reinstituted.
When methyldopa causes Coombs positivity alone or with hemolytic anemia, the red cell is usually coated with gamma globulin of the lgG (gamma G) class only. The positive Coombs test may not revert to normal until weeks to months after methyldopa is stopped.
Should the need for transfusion arise in a patient receiving methyldopa, both a direct and an indirect Coombs test should be performed. In the absence of hemolytic anemia, usually only the direct Coombs test will be positive. A positive direct Coombs test alone will not interfere with typing or cross matching. If the indirect Coombs test is also positive, problems may arise in the major cross match and the assistance of a hematologist or transfusion expert will be needed.
Occasionally, fever has occurred within the first three weeks of methyldopa therapy, associated in some cases with eosinophilia or abnormalities in one or more liver function tests, such as serum alkaline phosphatase, serum transaminases (SGOT, SGPT), bilirubin, and prothrombin time. Jaundice, with or without fever, may occur with onset usually within the first two to three months of therapy. In some patients the findings are consistent with those of cholestasis. In others the findings are consistent with hepatitis and hepatocellular injury.
Rarely, fatal hepatic necrosis has been reported after use of methyldopa. These hepatic changes may represent hypersensitivity reactions. Periodic determinations of hepatic function should be done particularly during the first 6 to 12 weeks of therapy or whenever an unexplained fever occurs. If fever, abnormalities in liver function tests, or jaundice appear, stop therapy with methyldopa. If caused by methyldopa, the temperature and abnormalities in liver function characteristically have reverted to normal when the drug was discontinued. Methyldopa should not be reinstituted in such patients.
Rarely, a reversible reduction of the white blood cell count with a primary effect on the granulocytes has been seen. The granulocyte count returned promptly to normal on discontinuance of the drug. Rare cases of granulocytopenia have been reported. In each instance, upon stopping the drug, the white cell count returned to normal. Reversible thrombocytopenia has occurred rarely.
### PRECAUTIONS
- Methyldopa should be used with caution in patients with a history of previous liver disease or liver dysfunction.
- Some patients taking methyldopa experience clinical edema or weight gain which may be controlled by use of a diuretic. Methyldopa should not be continued if edema progresses or signs of heart failure appear.
- Hypertension has recurred occasionally after dialysis in patients given methyldopa because the drug is removed by this procedure.
- Rarely, involuntary choreoathetotic movements have been observed during therapy with methyldopa in patients with severe bilateral cerebrovascular disease. Should these movements occur, stop therapy.
Blood count, Coombs test and liver function tests are recommended before initiating therapy and at periodic intervals
# Adverse Reactions
## Clinical Trials Experience
Sedation, usually transient, may occur during the initial period of therapy or whenever the dose is increased. Headache, asthenia, or weakness may be noted as early and transient symptoms. However, significant adverse effects due to methyldopa have been infrequent and this agent usually is well tolerated.
The following adverse reactions have been reported and, within each category, are listed in order of decreasing severity.
- Cardiovascular: Aggravation of angina pectoris, congestive heart failure, prolonged carotid sinus hypersensitivity, orthostatic hypotension (decrease daily dosage), edema or weight gain, bradycardia.
- Digestive: Pancreatitis, colitis, vomiting, diarrhea, sialadenitis, sore or black tongue, nausea, constipation, distension, flatus, dryness of mouth.
- Endocrine: Hyperprolactinemia.
- Hematologic: Bone marrow depression, leukopenia, granulocytopenia, thrombocytopenia, hemolytic anemia; positive tests for antinuclear antibody, LE cells, and rheumatoid factor, positive Coombs test.
- Hepatic: Liver disorders including hepatitis, jaundice, abnormal liver function tests (see WARNINGS).
- Hypersensitivity: Myocarditis, pericarditis, vasculitis, lupus-like syndrome, drug-related fever, eosinophilia.
- Nervous System/Psychiatric: Parkinsonism, Bell's palsy, decreased mental acuity, involuntary choreoathetotic movements, symptoms of cerebrovascular insufficiency, psychic disturbances including nightmares and reversible mild psychoses or depression, headache, sedation, asthenia or weakness, dizziness, light-headedness, paresthesias.
- Metabolic: Rise in BUN.
- Musculoskeletal: Arthralgia, with or without joint swelling; myalgia.
- Respiratory: Nasal stuffiness.
- Skin: Toxic epidermal necrolysis, rash.
- Urogenital: Amenorrhea, breast enlargement, gynecomastia, lactation, impotence, decreased libido.
## Postmarketing Experience
There is limited information regarding Methyldopa Postmarketing Experience in the drug label.
# Drug Interactions
- When methyldopa is used with other antihypertensive drugs, potentiation of antihypertensive effect may occur. Patients should be followed carefully to detect side reactions or unusual manifestations of drug idiosyncrasy.
- Patients may require reduced doses of anesthetics when on methyldopa. If hypotension does occur during anesthesia, it usually can be controlled by vasopressors. The adrenergic receptors remain sensitive during treatment with methyldopa.
- When methyldopa and lithium are given concomitantly, the patient should be carefully monitored for symptoms of lithium toxicity. Read the circular for lithium preparations.
- Several studies demonstrate a decrease in the bioavailability of methyldopa when it is ingested with ferrous sulfate or ferrous gluconate. This may adversely affect blood pressure control in patients treated with methyldopa. Coadministration of methyldopa with ferrous sulfate or ferrous gluconate is not recommended.
- Monoamine oxidase (MAO) inhibitors
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
Reproduction studies performed with methyldopa at oral doses up to 1000 mg/kg in mice, 200 mg/kg in rabbits and 100 mg/kg in rats revealed no evidence of harm to the fetus. These doses are 16.6 times, 3.3 times and 1.7 times, respectively, the maximum daily human dose when compared on the basis of body weight; 1.4 times, 1.1 times and 0.2 times, respectively, when compared on the basis of body surface area; calculations assume a patient weight of 50 kg. There are, however, no adequate and well-controlled studies in pregnant women in the first trimester of pregnancy. Because animal reproduction studies are not always predictive of human response, methyldopa should be used during pregnancy only if clearly needed.
Published reports of the use of methyldopa during all trimesters indicate that if this drug is used during pregnancy the possibility of fetal harm appears remote. In five studies, three of which were controlled, involving 332 pregnant hypertensive women, treatment with methyldopa was associated with an improved fetal outcome. The majority of these women were in the third trimester when methyldopa therapy was begun.
In one study, women who had begun methyldopa treatment between weeks 16 and 20 of pregnancy gave birth to infants whose average head circumference was reduced by a small amount (34.2 ± 1.7 cm vs. 34.6 ± 1.3 cm [mean ± 1 S.D.]). Long-term follow-up of 195 (97.5%) of the children born to methyldopa-treated pregnant women (including those who began treatment between weeks 16 and 20) failed to uncover any significant adverse effect on the children. At four years of age, the developmental delay commonly seen in children born to hypertensive mothers was less evident in those whose mothers were treated with methyldopa during pregnancy than those whose mothers were untreated. The children of the treated group scored consistently higher than the children of the untreated group on five major indices of intellectual and motor development. At age 7 and one-half developmental scores and intelligence indices showed no significant differences in children of treated or untreated hypertensive women.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Methyldopa in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Methyldopa during labor and delivery.
### Nursing Mothers
Methyldopa appears in breast milk. Therefore, caution should be exercised when methyldopa is given to a nursing woman.
### Pediatric Use
There are no well-controlled clinical trials in pediatric patients. Information on dosing in pediatric patients is supported by evidence from published literature regarding the treatment of hypertension in pediatric patients.
### Geriatic Use
Of the total number of subjects (1685) in clinical studies of methyldopa, 223 patients were 65 years of age and over while 33 patients were 75 years of age 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.
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 Methyldopa with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Methyldopa with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Methyldopa in patients with renal impairment.
### Hepatic Impairment
Periodic determinations of hepatic function should be done particularly during the first 6 to 12 weeks of therapy or whenever an unexplained fever occurs. If fever, abnormalities in liver function tests, or jaundice appear, stop therapy with methyldopa. If caused by methyldopa, the temperature and abnormalities in liver function characteristically have reverted to normal when the drug was discontinued. Methyldopa should not be reinstituted in such patients.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Methyldopa in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Methyldopa in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Oral/Intravenous
### Monitoring
There is limited information regarding Methyldopa Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Methyldopa and IV administrations.
# Overdosage
There is limited information regarding Methyldopa overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
Methyldopa is an aromatic-aminoacid decarboxylase inhibitor in animals and in man. Although the mechanism of action has yet to be conclusively demonstrated, the antihypertensive effect of methyldopa probably is due to its metabolism to alpha-methylnorepinephrine, which then lowers arterial pressure by stimulation of central inhibitory alpha-adrenergic receptors, false neurotransmission, and/or reduction of plasma renin activity. Methyldopa has been shown to cause a net reduction in the tissue concentration of serotonin, dopamine, norepinephrine, and epinephrine.
## Structure
Methyldopa is an antihypertensive and is the L-isomer of alpha-methyldopa. It is levo-3-(3,4-dihydroxyphenyl)-2-methylalanine sesquihydrate. Methyldopa is supplied as tablets for oral administration, containing 250 mg and 500 mg of methyldopa. The amount of methyldopa is calculated on the anhydrous basis. Its molecular formula is C10H13NO4•1 1/2 H2O, with a molecular weight of 238.24, and its structural formula is:
Methyldopa is a white to yellowish white, odorless fine powder and is sparingly soluble in water.
The tablets contain the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol, sodium lauryl sulfate, titanium dioxide, triacetin, FD&C yellow #6 aluminum lake and FD&C blue #2 aluminum lake.
## Pharmacodynamics
Only methyldopa, the L-isomer of alpha-methyldopa, has the ability to inhibit dopa decarboxylase and to deplete animal tissues of norepinephrine. In man, the antihypertensive activity appears to be due solely to the L-isomer. About twice the dose of the racemate (DL-alpha-methyldopa) is required for equal antihypertensive effect.
Methyldopa has no direct effect on cardiac function and usually does not reduce glomerular filtration rate, renal blood flow, or filtration fraction. Cardiac output usually is maintained without cardiac acceleration. In some patients the heart rate is slowed.
Normal or elevated plasma renin activity may decrease in the course of methyldopa therapy.
Methyldopa reduces both supine and standing blood pressure. It usually produces highly effective lowering of the supine pressure with infrequent symptomatic orthostatic hypotension. Exercise hypotension and diurnal blood pressure variations rarely occur.
## Pharmacokinetics
The maximum decrease in blood pressure occurs four to six hours after oral dosage. Once an effective dosage level is attained, a smooth blood pressure response occurs in most patients in 12 to 24 hours. After withdrawal, blood pressure usually returns to pretreatment levels within 24–48 hours.
Methyldopa is extensively metabolized. The known urinary metabolites are: α-methyldopa mono-O-sulfate; 3-0-methyl-α-methyldopa; 3,4-dihydroxyphenylacetone; α-methyldopamine; 3-0-methyl-α-methyldopamine and their conjugates.
Approximately 70 percent of the drug which is absorbed is excreted in the urine as methyldopa and its mono-O-sulfate conjugate. The renal clearance is about 130 mL/min in normal subjects and is diminished in renal insufficiency. The plasma half-life of methyldopa is 105 minutes. After oral doses, excretion is essentially complete in 36 hours.
Methyldopa crosses the placental barrier, appears in cord blood, and appears in breast milk.
## Nonclinical Toxicology
No evidence of a tumorigenic effect was seen when methyldopa was given for two years to mice at doses up to 1800 mg/kg/day or to rats at doses up to 240 mg/kg/day (30 and 4 times the maximum recommended human dose in mice and rats, respectively, when compared on the basis of body weight; 2.5 and 0.6 times the maximum recommended human dose in mice and rats, respectively, when compared on the basis of body surface area; calculations assume a patient weight of 50 kg).
Methyldopa was not mutagenic in the Ames Test and did not increase chromosomal aberration or sister chromatid exchanges in Chinese hamster ovary cells. These in vitro studies were carried out both with and without exogenous metabolic activation.
Fertility was unaffected when methyldopa was given to male and female rats at 100 mg/kg/day (1.7 times the maximum daily human dose when compared on the basis of body weight; 0.2 times the maximum daily human dose when compared on the basis of body surface area). Methyldopa decreased sperm count, sperm motility, the number of late spermatids and the male fertility index when given to male rats at 200 and 400 mg/kg/day (3.3 and 6.7 times the maximum daily human dose when compared on the basis of body weight; 0.5 and 1 times the maximum daily human dose when compared on the basis of body surface area).
# Clinical Studies
There is limited information regarding Methyldopa Clinical Studies in the drug label.
# How Supplied
- The 250 mg tablets are beige, film-coated, round, unscored tablets debossed with MYLAN on one side of the tablet and 611 on the other side. They are available as follows: NDC 51079-200-20 - Unit dose blister packages of 100 (10 cards of 10 tablets each).
- The 500 mg tablets are beige, film-coated, capsule-shaped, unscored tablets debossed with MYLAN on one side of the tablet and 421 on the other side. They are available as follows: NDC 51079-201-20 - Unit dose blister packages of 100 (10 cards of 10 tablets each).
- Methyldopate HCl Injection, USP 250 mg/5 mL (50 mg/mL): NDC 0517-8905-10 - 5 mL Single Dose Vial (Boxes of 10)
## Storage
- Store at 20° to 25°C (68° to 77°F).
- Protect from light.
- Store at 20°-25°C (68°-77°F); excursions permitted to 15°-30°C (59°-86°F) .
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Methyldopa Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Methyldopa 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 Methyldopa Brand Names in the drug label.
# Look-Alike Drug Names
There is limited information regarding Methyldopa Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Aldomet | |
8443f00045c142dea362f250e3dc58c1968811a0 | wikidoc | Alfaxalone | Alfaxalone
# Overview
Alfaxalone (INN, JAN), also known as alphaxalone or alphaxolone (BAN), is a neuroactive steroid and general anaesthetic. It is used in veterinary practice under the trade name Alfaxan, and is licensed for use in both dogs and cats. Along with alfadolone, it is also one of the constituents of anesthetic drug mixture althesin.
Unlike some of its predecessors alfaxalone is not associated with histamine release and anaphylaxis.
A study 1987 found the primary mechanism for the anaesthetic action of alfaxalone to be modulation of neuronal cell membrane chloride ion transport, induced by binding of alfaxalone to GABAA cell surface receptors.
A 1994 study found that alfaxalone binds to a different region of this receptor than the benzodiazepines.
. These benzodiazepine-insensitive GABAA receptors are located extrasynaptically and are responsible for tonic inhibition. The occurrence of tonic GABAA inhibition coincides with the expression of relatively rare receptor subunits, particularly the α4, α6, and δ subunits, and as a general rule-of-thumb, δ subunit-containing receptors are extrasynaptic.
Alfaxalone is metabolised rapidly in the liver. It has a very short plasma elimination half-life in dogs and cats. | Alfaxalone
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Alfaxalone (INN, JAN), also known as alphaxalone or alphaxolone (BAN), is a neuroactive steroid and general anaesthetic.[1] It is used in veterinary practice under the trade name Alfaxan,[2] and is licensed for use in both dogs and cats.[citation needed] Along with alfadolone, it is also one of the constituents of anesthetic drug mixture althesin.
Unlike some of its predecessors alfaxalone is not associated with histamine release and anaphylaxis.[citation needed]
A study 1987 found the primary mechanism for the anaesthetic action of alfaxalone to be modulation of neuronal cell membrane chloride ion transport, induced by binding of alfaxalone to GABAA cell surface receptors.
[3]
A 1994 study found that alfaxalone binds to a different region of this receptor than the benzodiazepines.
.[4] These benzodiazepine-insensitive GABAA receptors are located extrasynaptically and are responsible for tonic inhibition. The occurrence of tonic GABAA inhibition coincides with the expression of relatively rare receptor subunits, particularly the α4, α6, and δ subunits, and as a general rule-of-thumb, δ subunit-containing receptors are extrasynaptic.[5]
Alfaxalone is metabolised rapidly in the liver. It has a very short plasma elimination half-life in dogs and cats.[citation needed] | https://www.wikidoc.org/index.php/Alfaxalone | |
480b4d8b9c73c1239763600193e8a945f36b4907 | wikidoc | Alfentanil | Alfentanil
# 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
Alfentanil is an analgesic opioid that is FDA approved for the {{{indicationType}}} of adjunct surgical procedures and anesthesia. Common adverse reactions include cardiovascular: bradyarrhythmia (14% ), hypertension (18% ), hypotension (10% ), tachycardia (12% ), gastrointestinal: nausea (28% ), vomiting (18% ).
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Administration of analgesic; Adjunct - Surgical procedure
- Surgery duration 30 min or less; 8-20 mcg/kg IV, then continuous IV infusion of 0.5-1 mcg/kg/min; total dose 8-40 mcg/kg
- Surgery duration 30-60 min; 20-50 mcg/kg IV, then maintenance IV injections of 5-15 mcg/kg every 5-20 min; total dose up to 75 mcg/kg
- Surgery duration longer than 45 min; 50-75 mcg/kg IV, then continuous IV infusion of 0.5-3 mcg/kg/min
- Anesthesia
- Individualized according to type and duration of surgical procedure/anesthesia
- When used as primary anesthetic agent; 130-245 mcg/kg induction dose followed by continuous IV infusion of 0.5-1.5 mcg/kg/min
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information about Off-Label Guideline-Supported Use of Alfentanil in adult patients.
### Non–Guideline-Supported Use
There is limited information about Off-Label Non–Guideline-Supported Use of Alfentanil in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Alfentanil is not recommended for children less than 12 years of age
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information about Off-Label Guideline-Supported Use of Alfentanil in pediatric patients.
### Non–Guideline-Supported Use
There is limited information about Off-Label Non–Guideline-Supported Use of Alfentanil in pediatric patients.
# Contraindications
Alfentanil is contraindicated in patients with known hypersensitivity to the drug or known intolerance to other opioid agonists.
# Warnings
- Alfentanil should be administered only by persons specifically trained in the use of intravenous and general anesthetic agents and in the management of respiratory effects of potent opioids.
- An opioid antagonist, resuscitative and intubation equipment and oxygen should be readily available.
- Because of the possibility of delayed respiratory depression, monitoring of the patient must continue well after surgery.
- Alfentanil administered in initial dosages up to 20 mcg/kg may cause skeletal muscle rigidity, particularly of the truncal muscles. The incidence and severity of muscle rigidity is usually dose-related. Administration of alfentanil at anesthetic induction dosages (above 130 mcg/kg) will consistently produce muscular rigidity with an immediate onset. The onset of muscular rigidity occurs earlier than with other opioids. Alfentanil may produce muscular rigidity that involves all skeletal muscles, including those of the neck and extremities. The incidence may be reduced by: 1) routine methods of administration of neuromuscular blocking agents for balanced opioid anesthesia; 2) administration of up to 1/4 of the full paralyzing dose of a neuromuscular blocking agent just prior to administration of alfentanil at dosages up to 130 mcg/kg; following loss of consciousness, a full paralyzing dose of a neuromuscular blocking agent should be administered; or 3) simultaneous administration of alfentanil and a full paralyzing dose of a neuromuscular blocking agent when alfentanil is used in rapidly administered anesthetic dosages (above 130 mcg/kg).
- The neuromuscular blocking agent used should be appropriate for the patient's cardiovascular status. Adequate facilities should be available for postoperative monitoring and ventilation of patients administered alfentanil. It is essential that these facilities be fully equipped to handle all degrees of respiratory depression.
- Patients receiving monitored anesthesia care (mac) should be continuously monitored by persons not involved in the conduct of the surgical or diagnostic procedure; oxygen supplementation should be immediately available and provided where clinically indicated; oxygen saturation should be continuously monitored; the patient should be observed for early signs of hypotension, apnea, upper airway obstruction and/or oxygen desaturation.
- Severe and unpredictable potentiation of monoamine oxidase (MAO) inhibitors has been reported for other opioid analgesics, and rarely with alfentanil. Therefore when alfentanil is administered to patients who have received MAO inhibitors within 14 days, appropriate monitoring and ready availability of vasodilators and betablockers for the treatment of hypertension is recommended.
# Adverse Reactions
## Clinical Trials Experience
- The most common adverse reactions of opioids are respiratory depression and skeletal muscle rigidity, particularly of the truncal muscles. Alfentanil may produce muscular rigidity that involves the skeletal muscles of the neck and extremities. See Clinical pharmacology, warnings, and precautions on the management of respiratory depression and skeletal muscle rigidity.
- The adverse experience profile from 696 patients receiving alfentanil for Monitored Anesthesia Care (MAC) is similar to the profile established with alfentanil during general anesthesia. Respiratory events reported during MAC included hypoxia, apnea, and bradypnea. Other adverse events reported by patients receiving alfentanil for MAC, in order of decreasing frequency, were nausea, hypotension, vomiting, pruritus, confusion, somnolence and agitation.
- The following adverse reaction information is derived from controlled and open clinical trials in 785 patients who received intravenous alfentanil during induction and maintenance of general anesthesia. The controlled trials included treatment comparisons with fentanyl, thiopental sodium, enflurane, saline placebo and halothane. The incidence of certain side effects is influenced by the type of use, e.g., chest wall rigidity has a higher reported incidence in clinical trials of alfentanil induction, and by the type of surgery, e.g., nausea and vomiting have a higher reported incidence in patients undergoing gynecologic surgery. The overall reports of nausea and vomiting with alfentanil were comparable to fentanyl.
Incidence Greater than 1% - Probably Causally Related (Derived from clinical trials)
## Postmarketing Experience
# Drug Interactions
There is limited information regarding Alfentanil Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Alfentanil has been shown to have an embryocidal effect in rats and rabbits when given in doses 2.5 times the upper human dose for a period of 10 days to over 30 days. These effects could have been due to maternal toxicity (decreased food consumption with increased mortality) following prolonged administration of the drug.
- No evidence of teratogenic effects has been observed after administration of alfentanil in rats or rabbits.
- There are no adequate and well-controlled studies in pregnant women. Alfentanil should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Alfentanil in women who are pregnant.
### Labor and Delivery
There are insufficient data to support the use of alfentanil in labor and delivery. Placental transfer of the drug has been reported; therefore, use in labor and delivery is not recommended.
### Nursing Mothers
In one study of nine women undergoing postpartum tubal ligation, significant levels of alfentanil were detected in colostrum four hours after administration of 60 mcg/kg of alfentanil, with no detectable levels present after 28 hours. Caution should be exercised when alfentanil is administered to a nursing woman.
### Pediatric Use
Adequate data to support the use of alfentanil in children under 12 years of age are not presently available.
### Geriatic Use
There is no FDA guidance on the use of Alfentanil in geriatric settings.
### Gender
There is no FDA guidance on the use of Alfentanil with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Alfentanil with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Alfentanil in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Alfentanil in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Alfentanil in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Alfentanil in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Alfentanil Administration in the drug label.
### Monitoring
There is limited information regarding Alfentanil Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Alfentanil and IV administrations.
# Overdosage
- Overdosage would be manifested by extension of the pharmacological actions of alfentanil (see Clinical pharmacology) as with other potent opioid analgesics. No experience of overdosage with alfentanil was reported during clinical trials. The intravenous LD50 of alfentanil is 43 to 51 mg/kg in rats, 72 to 74 mg/kg in mice, 72 to 82 mg/kg in guinea pigs and 60 to 88 mg/kg in dogs. Intravenous administration of an opioid antagonist such as naloxone should be employed as a specific antidote to manage respiratory depression.
- The duration of respiratory depression following overdosage with alfentanil may be longer than the duration of action of the opioid antagonist. Administration of an opioid antagonist should not preclude immediate establishment of a patent airway, administration of oxygen, and assisted or controlled ventilation as indicated for hypoventilation or apnea. If respiratory depression is associated with muscular rigidity, a neuromuscular blocking agent may be required to facilitate assisted or controlled ventilation. Intravenous fluids and vasoactive agents may be required to manage hemodynamic instability.
# Pharmacology
## Mechanism of Action
There is limited information about the mechanism of action of Alfentanil.
## Structure
- Alfentanil HCl Injection, USP is an opioid analgesic chemically designated as N--4-(methoxymethyl)-4- piperidinyl]-N-phenylpropanamide monohydrochloride (1:1) with a molecular weight of 452.98 and an n-octanol:water partition coefficient of 128:1 at pH 7.4. The structural formula of Alfentanil hydrochloride is:
- Alfentanil HCl Injection, USP is a sterile, non-pyrogenic, preservative free aqueous solution containing alfentanil hydrochloride equivalent to 500 μg per mL of alfentanil base for intravenous injection. The solution, which contains sodium chloride for isotonicity, has a pH range of 4 to 6. Each mL contains: Active: Alfentanil base 500 mcg. Inactives: Sodium Chloride 9 mg and Water for Injection q.s.
## Pharmacodynamics
There is limited information regarding Alfentanil Pharmacodynamics in the drug label.
## Pharmacokinetics
- Alfentanil is an opioid analgesic with a rapid onset of action.
- At doses of 8 to 40 mcg/kg for surgical procedures lasting up to 30 minutes, alfentanil provides analgesic protection against hemodynamic responses to surgical stress with recovery times generally comparable to those seen with equipotent fentanyl dosages.
- For longer procedures, doses of up to 75 mcg/kg attenuate hemodynamic responses to laryngoscopy, intubation and incision, with recovery time comparable to fentanyl. At doses of 50 to 75 mcg/kg followed by a continuous infusion of 0.5 to 3 mcg/kg/min, alfentanil attenuates the catecholamine response with more rapid recovery and reduced need for postoperative analgesics as compared to patients administered enflurane. At doses of 5 mcg/kg, alfentanil provides analgesia for the conscious but sedated patient. Based on patient response, doses higher than 5 mcg/kg may be needed. Elderly or debilitated patients may require lower doses. High intrasubject and intersubject variability in the pharmacokinetic disposition of alfentanil has been reported.
- The pharmacokinetics of alfentanil can be described as a three-compartment model with sequential distribution half-lives of 1 and 14 minutes; and a terminal elimination half-life of 90 to 111 minutes (as compared to a terminal elimination half-life of approximately 475 minutes for fentanyl and approximately 265 minutes for sufentanil at doses of 250 mcg). The liver is the major site of biotransformation.
- Alfentanil has an apparent volume of distribution of 0.4 to 1 L/kg, which is approximately one-fourth to one-tenth that of fentanyl, with an average plasma clearance of 5 mL/kg/min as compared to approximately 8 mL/kg/min for fentanyl.
- Only 1% of the dose is excreted as unchanged drug; urinary excretion is the major route of elimination of metabolites. Plasma protein binding of alfentanil is approximately 92%.
- In one study involving 15 patients administered alfentanil with nitrous oxide/oxygen, a narrow range of plasma alfentanil concentrations, approximately 310 to 340 ng/mL, was shown to provide adequate anesthesia for intra-abdominal surgery, while lower concentrations, approximately 190 ng/mL, blocked responses to skin closure. Plasma concentrations between 100 to 200 ng/mL provided adequate anesthesia for superficial surgery.
- Alfentanil has an immediate onset of action. At dosages of approximately 105 mcg/kg, alfentanil produces hypnosis as determined by EEG patterns; an anesthetic ED90 of 182 mcg/kg for alfentanil in unpremedicated patients has been determined, based upon the ability to block response to placement of a nasopharyngeal airway. Based on clinical trials, induction dosage requirements range from 130 to 245 mcg/kg. For procedures lasting 30 to 60 minutes, loading dosages of up to 50 mcg/kg produce the hemodynamic response to endotracheal intubation and skin incision as comparable to those from fentanyl. A pre-intubation loading dose of 50 to 75 mcg/kg prior to a continuous infusion attenuates the response to laryngoscopy, intubation and incision. Subsequent administration of alfentanil infusion administered at a rate of 0.5 to 3 mcg/kg/min with nitrous oxide/oxygen attenuates sympathetic responses to surgical stress with more rapid recovery than enflurane.
- Requirements for volatile inhalation anesthetics were reduced by thirty to fifty percent during the first 60 minutes of maintenance in patients administered anesthetic doses (above 130 mcg/kg) of alfentanil as compared to patients given doses of 4 to 5 mg/kg thiopental for anesthetic induction. At anesthetic induction dosages, alfentanil provides a deep level of anesthesia during the first hour of anesthetic maintenance and provides attenuation of the hemodynamic response during intubation and incision.
- Following an anesthetic induction dose of alfentanil, requirements for alfentanil infusion are reduced by 30 to 50% for the first hour of maintenance.
- Patients with compromised liver function and those over 65 years of age have been found to have reduced plasma clearance and extended terminal elimination for alfentanil, which may prolong postoperative recovery. Repeated or continuous administration of alfentanil produces increasing plasma concentrations and an accumulation of the drug, particularly in patients with reduced plasma clearance.
- Bradycardia may be seen in patients administered alfentanil. The incidence and degree of bradycardia may be more pronounced when alfentanil is administered in conjunction with non-vagolytic neuromuscular blocking agents or in the absence of anticholinergic agents such as atropine.
- Administration of intravenous diazepam immediately prior to or following high doses of alfentanil has been shown to produce decreases in blood pressure that may be secondary to vasodilation; recovery may also be prolonged.
- Patients administered doses up to 200 mcg/kg of alfentanil have shown no significant increase in histamine levels and no clinical evidence of histamine release.
- Skeletal muscle rigidity is related to the dose and speed of administration of alfentanil. Muscular rigidity will occur with an immediate onset following anesthetic induction dosages. Preventative measures (see Warnings) may reduce the rate and severity.
- The duration and degree of respiratory depression and increased airway resistance usually increase with dose, but have also been observed at lower doses. Although higher doses may produce apnea and a longer duration of respiratory depression, apnea may also occur at low doses.
- During monitored anesthesia care (MAC), attention must be given to the respiratory effects of alfentanil. Decreased oxygen saturation, apnea, decreased respiratory rate, and upper airway obstruction can occur. (See Warnings)
## Nonclinical Toxicology
There is limited information regarding Alfentanil Nonclinical Toxicology in the drug label.
# Clinical Studies
There is limited information regarding Alfentanil Clinical Studies in the drug label.
# How Supplied
- Alfentanil HCl Injection, USP for intravenous use. Each mL contains: Active: Alfentanil base 500 mcg. Inactives: Sodium Chloride 9 mg and WFI q.s. Alfentanil HCl Injection, USP is available as:
- NDC 17478-841-02, 2 mL Ampule in packages of 10
- NDC 17478-841-05, 5 mL Ampule in packages of 10
- NDC 17478-841-10, 10 mL Ampule in packages of 5
- NDC 17478-841-20, 20 mL Ampule in packages of 5
U.S. Patent No. 4,167,574
May 1995, November 1995
Premier Pro™ Rx
Manufactured by: Akorn, Inc.
Lake Forest, IL 60045
PREMIERPro™Rx is a trademark of Premier Inc., used under license.
PAFA0N Rev. 04/13
Principal Display Panel Text for Container Label:
NDC 17478-841-02 2 mL Ampule
Alfentanil HCl
Injection, USP CII
500 mcg/mL
Alfentanil base
Rx only
May be habit forming.
Premier Logo
## Storage
Store at 20° to 25°C (68° to 77°F) . Protect from light.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Alfentanil Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Alfentanil 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 Alfentanil Brand Names in the drug label.
# Look-Alike Drug Names
There is limited information regarding Alfentanil Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Alfentanil
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Chetan Lokhande, M.B.B.S [2]
# Disclaimer
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# Overview
Alfentanil is an analgesic opioid that is FDA approved for the {{{indicationType}}} of adjunct surgical procedures and anesthesia. Common adverse reactions include cardiovascular: bradyarrhythmia (14% ), hypertension (18% ), hypotension (10% ), tachycardia (12% ), gastrointestinal: nausea (28% ), vomiting (18% ).
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Administration of analgesic; Adjunct - Surgical procedure
- Surgery duration 30 min or less; 8-20 mcg/kg IV, then continuous IV infusion of 0.5-1 mcg/kg/min; total dose 8-40 mcg/kg
- Surgery duration 30-60 min; 20-50 mcg/kg IV, then maintenance IV injections of 5-15 mcg/kg every 5-20 min; total dose up to 75 mcg/kg
- Surgery duration longer than 45 min; 50-75 mcg/kg IV, then continuous IV infusion of 0.5-3 mcg/kg/min
- Anesthesia
- Individualized according to type and duration of surgical procedure/anesthesia
- When used as primary anesthetic agent; 130-245 mcg/kg induction dose followed by continuous IV infusion of 0.5-1.5 mcg/kg/min
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information about Off-Label Guideline-Supported Use of Alfentanil in adult patients.
### Non–Guideline-Supported Use
There is limited information about Off-Label Non–Guideline-Supported Use of Alfentanil in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Alfentanil is not recommended for children less than 12 years of age
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information about Off-Label Guideline-Supported Use of Alfentanil in pediatric patients.
### Non–Guideline-Supported Use
There is limited information about Off-Label Non–Guideline-Supported Use of Alfentanil in pediatric patients.
# Contraindications
Alfentanil is contraindicated in patients with known hypersensitivity to the drug or known intolerance to other opioid agonists.
# Warnings
- Alfentanil should be administered only by persons specifically trained in the use of intravenous and general anesthetic agents and in the management of respiratory effects of potent opioids.
- An opioid antagonist, resuscitative and intubation equipment and oxygen should be readily available.
- Because of the possibility of delayed respiratory depression, monitoring of the patient must continue well after surgery.
- Alfentanil administered in initial dosages up to 20 mcg/kg may cause skeletal muscle rigidity, particularly of the truncal muscles. The incidence and severity of muscle rigidity is usually dose-related. Administration of alfentanil at anesthetic induction dosages (above 130 mcg/kg) will consistently produce muscular rigidity with an immediate onset. The onset of muscular rigidity occurs earlier than with other opioids. Alfentanil may produce muscular rigidity that involves all skeletal muscles, including those of the neck and extremities. The incidence may be reduced by: 1) routine methods of administration of neuromuscular blocking agents for balanced opioid anesthesia; 2) administration of up to 1/4 of the full paralyzing dose of a neuromuscular blocking agent just prior to administration of alfentanil at dosages up to 130 mcg/kg; following loss of consciousness, a full paralyzing dose of a neuromuscular blocking agent should be administered; or 3) simultaneous administration of alfentanil and a full paralyzing dose of a neuromuscular blocking agent when alfentanil is used in rapidly administered anesthetic dosages (above 130 mcg/kg).
- The neuromuscular blocking agent used should be appropriate for the patient's cardiovascular status. Adequate facilities should be available for postoperative monitoring and ventilation of patients administered alfentanil. It is essential that these facilities be fully equipped to handle all degrees of respiratory depression.
- Patients receiving monitored anesthesia care (mac) should be continuously monitored by persons not involved in the conduct of the surgical or diagnostic procedure; oxygen supplementation should be immediately available and provided where clinically indicated; oxygen saturation should be continuously monitored; the patient should be observed for early signs of hypotension, apnea, upper airway obstruction and/or oxygen desaturation.
- Severe and unpredictable potentiation of monoamine oxidase (MAO) inhibitors has been reported for other opioid analgesics, and rarely with alfentanil. Therefore when alfentanil is administered to patients who have received MAO inhibitors within 14 days, appropriate monitoring and ready availability of vasodilators and betablockers for the treatment of hypertension is recommended.
# Adverse Reactions
## Clinical Trials Experience
- The most common adverse reactions of opioids are respiratory depression and skeletal muscle rigidity, particularly of the truncal muscles. Alfentanil may produce muscular rigidity that involves the skeletal muscles of the neck and extremities. See Clinical pharmacology, warnings, and precautions on the management of respiratory depression and skeletal muscle rigidity.
- The adverse experience profile from 696 patients receiving alfentanil for Monitored Anesthesia Care (MAC) is similar to the profile established with alfentanil during general anesthesia. Respiratory events reported during MAC included hypoxia, apnea, and bradypnea. Other adverse events reported by patients receiving alfentanil for MAC, in order of decreasing frequency, were nausea, hypotension, vomiting, pruritus, confusion, somnolence and agitation.
- The following adverse reaction information is derived from controlled and open clinical trials in 785 patients who received intravenous alfentanil during induction and maintenance of general anesthesia. The controlled trials included treatment comparisons with fentanyl, thiopental sodium, enflurane, saline placebo and halothane. The incidence of certain side effects is influenced by the type of use, e.g., chest wall rigidity has a higher reported incidence in clinical trials of alfentanil induction, and by the type of surgery, e.g., nausea and vomiting have a higher reported incidence in patients undergoing gynecologic surgery. The overall reports of nausea and vomiting with alfentanil were comparable to fentanyl.
Incidence Greater than 1% - Probably Causally Related (Derived from clinical trials)
## Postmarketing Experience
# Drug Interactions
There is limited information regarding Alfentanil Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Alfentanil has been shown to have an embryocidal effect in rats and rabbits when given in doses 2.5 times the upper human dose for a period of 10 days to over 30 days. These effects could have been due to maternal toxicity (decreased food consumption with increased mortality) following prolonged administration of the drug.
- No evidence of teratogenic effects has been observed after administration of alfentanil in rats or rabbits.
- There are no adequate and well-controlled studies in pregnant women. Alfentanil should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Alfentanil in women who are pregnant.
### Labor and Delivery
There are insufficient data to support the use of alfentanil in labor and delivery. Placental transfer of the drug has been reported; therefore, use in labor and delivery is not recommended.
### Nursing Mothers
In one study of nine women undergoing postpartum tubal ligation, significant levels of alfentanil were detected in colostrum four hours after administration of 60 mcg/kg of alfentanil, with no detectable levels present after 28 hours. Caution should be exercised when alfentanil is administered to a nursing woman.
### Pediatric Use
Adequate data to support the use of alfentanil in children under 12 years of age are not presently available.
### Geriatic Use
There is no FDA guidance on the use of Alfentanil in geriatric settings.
### Gender
There is no FDA guidance on the use of Alfentanil with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Alfentanil with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Alfentanil in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Alfentanil in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Alfentanil in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Alfentanil in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Alfentanil Administration in the drug label.
### Monitoring
There is limited information regarding Alfentanil Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Alfentanil and IV administrations.
# Overdosage
- Overdosage would be manifested by extension of the pharmacological actions of alfentanil (see Clinical pharmacology) as with other potent opioid analgesics. No experience of overdosage with alfentanil was reported during clinical trials. The intravenous LD50 of alfentanil is 43 to 51 mg/kg in rats, 72 to 74 mg/kg in mice, 72 to 82 mg/kg in guinea pigs and 60 to 88 mg/kg in dogs. Intravenous administration of an opioid antagonist such as naloxone should be employed as a specific antidote to manage respiratory depression.
- The duration of respiratory depression following overdosage with alfentanil may be longer than the duration of action of the opioid antagonist. Administration of an opioid antagonist should not preclude immediate establishment of a patent airway, administration of oxygen, and assisted or controlled ventilation as indicated for hypoventilation or apnea. If respiratory depression is associated with muscular rigidity, a neuromuscular blocking agent may be required to facilitate assisted or controlled ventilation. Intravenous fluids and vasoactive agents may be required to manage hemodynamic instability.
# Pharmacology
## Mechanism of Action
There is limited information about the mechanism of action of Alfentanil.
## Structure
- Alfentanil HCl Injection, USP is an opioid analgesic chemically designated as N-[1-[2-(4-ethyl-4,5-dihydro 5-oxo-1H-tetrazol-1-yl)ethyl]-4-(methoxymethyl)-4- piperidinyl]-N-phenylpropanamide monohydrochloride (1:1) with a molecular weight of 452.98 and an n-octanol:water partition coefficient of 128:1 at pH 7.4. The structural formula of Alfentanil hydrochloride is:
- Alfentanil HCl Injection, USP is a sterile, non-pyrogenic, preservative free aqueous solution containing alfentanil hydrochloride equivalent to 500 μg per mL of alfentanil base for intravenous injection. The solution, which contains sodium chloride for isotonicity, has a pH range of 4 to 6. Each mL contains: Active: Alfentanil base 500 mcg. Inactives: Sodium Chloride 9 mg and Water for Injection q.s.
## Pharmacodynamics
There is limited information regarding Alfentanil Pharmacodynamics in the drug label.
## Pharmacokinetics
- Alfentanil is an opioid analgesic with a rapid onset of action.
- At doses of 8 to 40 mcg/kg for surgical procedures lasting up to 30 minutes, alfentanil provides analgesic protection against hemodynamic responses to surgical stress with recovery times generally comparable to those seen with equipotent fentanyl dosages.
- For longer procedures, doses of up to 75 mcg/kg attenuate hemodynamic responses to laryngoscopy, intubation and incision, with recovery time comparable to fentanyl. At doses of 50 to 75 mcg/kg followed by a continuous infusion of 0.5 to 3 mcg/kg/min, alfentanil attenuates the catecholamine response with more rapid recovery and reduced need for postoperative analgesics as compared to patients administered enflurane. At doses of 5 mcg/kg, alfentanil provides analgesia for the conscious but sedated patient. Based on patient response, doses higher than 5 mcg/kg may be needed. Elderly or debilitated patients may require lower doses. High intrasubject and intersubject variability in the pharmacokinetic disposition of alfentanil has been reported.
- The pharmacokinetics of alfentanil can be described as a three-compartment model with sequential distribution half-lives of 1 and 14 minutes; and a terminal elimination half-life of 90 to 111 minutes (as compared to a terminal elimination half-life of approximately 475 minutes for fentanyl and approximately 265 minutes for sufentanil at doses of 250 mcg). The liver is the major site of biotransformation.
- Alfentanil has an apparent volume of distribution of 0.4 to 1 L/kg, which is approximately one-fourth to one-tenth that of fentanyl, with an average plasma clearance of 5 mL/kg/min as compared to approximately 8 mL/kg/min for fentanyl.
- Only 1% of the dose is excreted as unchanged drug; urinary excretion is the major route of elimination of metabolites. Plasma protein binding of alfentanil is approximately 92%.
- In one study involving 15 patients administered alfentanil with nitrous oxide/oxygen, a narrow range of plasma alfentanil concentrations, approximately 310 to 340 ng/mL, was shown to provide adequate anesthesia for intra-abdominal surgery, while lower concentrations, approximately 190 ng/mL, blocked responses to skin closure. Plasma concentrations between 100 to 200 ng/mL provided adequate anesthesia for superficial surgery.
- Alfentanil has an immediate onset of action. At dosages of approximately 105 mcg/kg, alfentanil produces hypnosis as determined by EEG patterns; an anesthetic ED90 of 182 mcg/kg for alfentanil in unpremedicated patients has been determined, based upon the ability to block response to placement of a nasopharyngeal airway. Based on clinical trials, induction dosage requirements range from 130 to 245 mcg/kg. For procedures lasting 30 to 60 minutes, loading dosages of up to 50 mcg/kg produce the hemodynamic response to endotracheal intubation and skin incision as comparable to those from fentanyl. A pre-intubation loading dose of 50 to 75 mcg/kg prior to a continuous infusion attenuates the response to laryngoscopy, intubation and incision. Subsequent administration of alfentanil infusion administered at a rate of 0.5 to 3 mcg/kg/min with nitrous oxide/oxygen attenuates sympathetic responses to surgical stress with more rapid recovery than enflurane.
- Requirements for volatile inhalation anesthetics were reduced by thirty to fifty percent during the first 60 minutes of maintenance in patients administered anesthetic doses (above 130 mcg/kg) of alfentanil as compared to patients given doses of 4 to 5 mg/kg thiopental for anesthetic induction. At anesthetic induction dosages, alfentanil provides a deep level of anesthesia during the first hour of anesthetic maintenance and provides attenuation of the hemodynamic response during intubation and incision.
- Following an anesthetic induction dose of alfentanil, requirements for alfentanil infusion are reduced by 30 to 50% for the first hour of maintenance.
- Patients with compromised liver function and those over 65 years of age have been found to have reduced plasma clearance and extended terminal elimination for alfentanil, which may prolong postoperative recovery. Repeated or continuous administration of alfentanil produces increasing plasma concentrations and an accumulation of the drug, particularly in patients with reduced plasma clearance.
- Bradycardia may be seen in patients administered alfentanil. The incidence and degree of bradycardia may be more pronounced when alfentanil is administered in conjunction with non-vagolytic neuromuscular blocking agents or in the absence of anticholinergic agents such as atropine.
- Administration of intravenous diazepam immediately prior to or following high doses of alfentanil has been shown to produce decreases in blood pressure that may be secondary to vasodilation; recovery may also be prolonged.
- Patients administered doses up to 200 mcg/kg of alfentanil have shown no significant increase in histamine levels and no clinical evidence of histamine release.
- Skeletal muscle rigidity is related to the dose and speed of administration of alfentanil. Muscular rigidity will occur with an immediate onset following anesthetic induction dosages. Preventative measures (see Warnings) may reduce the rate and severity.
- The duration and degree of respiratory depression and increased airway resistance usually increase with dose, but have also been observed at lower doses. Although higher doses may produce apnea and a longer duration of respiratory depression, apnea may also occur at low doses.
- During monitored anesthesia care (MAC), attention must be given to the respiratory effects of alfentanil. Decreased oxygen saturation, apnea, decreased respiratory rate, and upper airway obstruction can occur. (See Warnings)
## Nonclinical Toxicology
There is limited information regarding Alfentanil Nonclinical Toxicology in the drug label.
# Clinical Studies
There is limited information regarding Alfentanil Clinical Studies in the drug label.
# How Supplied
- Alfentanil HCl Injection, USP for intravenous use. Each mL contains: Active: Alfentanil base 500 mcg. Inactives: Sodium Chloride 9 mg and WFI q.s. Alfentanil HCl Injection, USP is available as:
- NDC 17478-841-02, 2 mL Ampule in packages of 10
- NDC 17478-841-05, 5 mL Ampule in packages of 10
- NDC 17478-841-10, 10 mL Ampule in packages of 5
- NDC 17478-841-20, 20 mL Ampule in packages of 5
U.S. Patent No. 4,167,574
May 1995, November 1995
Premier Pro™ Rx
Manufactured by: Akorn, Inc.
Lake Forest, IL 60045
PREMIERPro™Rx is a trademark of Premier Inc., used under license.
PAFA0N Rev. 04/13
Principal Display Panel Text for Container Label:
NDC 17478-841-02 2 mL Ampule
Alfentanil HCl
Injection, USP CII
500 mcg/mL
Alfentanil base
Rx only
May be habit forming.
Premier Logo
## Storage
Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Protect from light.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Alfentanil Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Alfentanil 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 Alfentanil Brand Names in the drug label.
# Look-Alike Drug Names
There is limited information regarding Alfentanil Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Alfenta | |
071e4a659072cc3f70f59d1cf1a267f05b801a50 | wikidoc | Ali M. Mir | Ali M. Mir
Ali M. Mir is the Vice President of the Population Association of Pakistan. He was previously the Secretary General of the Association. He serves as Director Programs at the Population Council’s Pakistan Office. He is a medical graduate from the Rawalpindi Medical College, and obtained Masters of Public Health from the University of Leeds UK. He was awarded the prestigious Britannia/Chevening scholarship to pursue studies in the UK. He has attended specialized postgraduate trainings at Harvard University and the Johns Hopkins University in the US.
At the Council he oversees the implementation of a Packard Foundation funded project aiming at developing capacity within the health and population sectors in Pakistan.
He has taught community medicine at the Rawalpindi Medical College and has worked for the government of Pakistan. He has authored a book entitled “A synopsis of Epidemiology and Basic Statistics and edited “An Introduction to Medical Demography and Population Studies”. He has also authored several research articles and has made presentations in Pakistan as well as in the US, China, Iran, Egypt, Ethiopia, India and the Sudan.
He has run courses and taught at the Pakistan Institute of Medical Sciences, Health Services Academy Islamabad, Institutes of Public Health Lahore and Quetta, University of Arid Agriculture Rawalpindi, Civil Services Academy Lahore, National Institute of Population Studies Islamabad and the University of Khartoum, Sudan
He is a member of the International Union for Scientific Study of Population and secretary of the Reproductive Health Research Working Group of Pakistan. | Ali M. Mir
Ali M. Mir is the Vice President of the Population Association of Pakistan.[citation needed] He was previously the Secretary General of the Association.[1] He serves as Director Programs at the Population Council’s Pakistan Office. He is a medical graduate from the Rawalpindi Medical College, and obtained Masters of Public Health from the University of Leeds UK. He was awarded the prestigious Britannia/Chevening scholarship to pursue studies in the UK. He has attended specialized postgraduate trainings at Harvard University and the Johns Hopkins University in the US.
At the Council he oversees the implementation of a Packard Foundation funded project aiming at developing capacity within the health and population sectors in Pakistan.
He has taught community medicine at the Rawalpindi Medical College and has worked for the government of Pakistan. He has authored a book entitled “A synopsis of Epidemiology and Basic Statistics and edited “An Introduction to Medical Demography and Population Studies”. He has also authored several research articles and has made presentations in Pakistan as well as in the US, China, Iran, Egypt, Ethiopia, India and the Sudan.
He has run courses and taught at the Pakistan Institute of Medical Sciences, Health Services Academy Islamabad, Institutes of Public Health Lahore and Quetta, University of Arid Agriculture Rawalpindi, Civil Services Academy Lahore, National Institute of Population Studies Islamabad and the University of Khartoum, Sudan
He is a member of the International Union for Scientific Study of Population and secretary of the Reproductive Health Research Working Group of Pakistan.
# External links
- Population Association of Pakistan | https://www.wikidoc.org/index.php/Ali_M._Mir | |
f116c771130fa42efa778ad2b2a650a595e09f93 | wikidoc | Alirocumab | Alirocumab
For a review of all PCSK9 inhibitors please click here
# Disclaimer
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# Overview
Alirocumab (REGN727 and SAR236553) is an investigational human monoclonal antibody that inhibits PCSK9 for the treatment of hypercholesterolemia. Alirocumab is indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or clinical atherosclerostic cardiovascular disease, who require additional lowering of LDL-C. The effect of alirocumab on cardiovascular morbidity and mortality has not been determined.
# Indication and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Heterozygous Familial Hypercholesterolemia
For patients with heterozygous familial hypercholesterolemia
- Initial dose: 75mg/ml SQ q2w
For patients with heterozygous familial hypercholesterolemia and inadequate LDL-C response
- Dose: 150mg/ml SQ q2w
## Off-Label Use and Dosage (Adult)
Guideline-Supported Use
- There is limited information about the guideline-supported use.
Non–Guideline-Supported Use
# Drug Administration Instructions
- If a dose is missed, instruct the patient to administer the injection within 7 days from the missed dose and then resume the patient's original schedule. If the missed dose is not administered within 7 days, instruct the patient to wait until the next dose on the original schedule.
- Provide proper training to patients and/or caregivers on the preparation and administration of alirocumab prior to use according to the Instructions for Use. Instruct patients and/or caregivers to read and follow the Instructions for Use each time they use alirocumab.
- Allow alirocumab to warm to room temperature for 30 to 40 minutes prior to use. Use alirocumab as soon as possible after it has warmed up. Do NOT use alirocumab if it has been at room temperature for 24 hours or longer.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. If the solution is discolored or contains visible particulate matter, the solution should not be used.
- Follow aseptic injection technique every time alirocumab is administered.
- Administer alirocumab by subcutaneous injection into the thigh, abdomen, or upper arm using a single-dose pre-filled pen or single-dose pre-filled syringe.
- Rotate the injection site with each injection.
- Do NOT inject alirocumab into areas of active skin disease or injury such as sunburns, skin rashes, inflammation, or skin infections.
- Do NOT co-administer alirocumab with other injectable drugs at the same injection site.
# Dosage Forms and Strengths
Alirocumab is a clear, colorless to pale yellow solution available as follows:
Injection: Single-dose pre-filled pen
- 75 mg/mL
- 150 mg/mL
Injection: Single-dose pre-filled syringe
- 75 mg/mL
- 150 mg/mL
# Contraindications
Alirocumab is contraindicated in patients with a history of a serious hypersensitivity reaction to alirocumab. Reactions have included hypersensitivity vasculitis and hypersensitivity reactions requiring hospitalization.
# Warnings and Precautions
## Allergic Reactions
Hypersensitivity reactions (e.g., pruritus, rash, urticaria), including some serious events (e.g., hypersensitivity vasculitis and hypersensitivity reactions requiring hospitalization), have been reported with alirocumab treatment. If signs or symptoms of serious allergic reactions occur, discontinue treatment with alirocumab, treat according to the standard of care, and monitor until signs and symptoms resolve.
# 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.
- The safety of alirocumab was evaluated in 9 placebo-controlled trials that included 2476 patients treated with alirocumab, including 2135 exposed for 6 months and 1999 exposed for more than 1 year (median treatment duration of 65 weeks). The mean age of the population was 59 years, 40% of the population were women, 90% were Caucasians, 4% were Black or African American, and 3% were Asians. At baseline, 37% of patients had a diagnosis of heterozygous familial hypercholesterolemia and 66% had clinical atherosclerotic cardiovascular disease.
- Adverse reactions reported in at least 2% of alirocumab-treated patients, and more frequently than in placebo-treated patients, are shown in the table below:
Adverse reactions led to discontinuation of treatment in 5.3% of patients treated with alirocumab and 5.1% of patients treated with placebo. The most common adverse reactions leading to treatment discontinuation in patients treated with alirocumab were allergic reactions (0.6% versus 0.2% for alirocumab and placebo, respectively) and elevated liver enzymes (0.3% versus <0.1%).
- Local Injection Site Reactions
Local injection site reactions including erythema/redness, itching, swelling, and pain/tenderness were reported more frequently in patients treated with alirocumab (7.2% versus 5.1% for alirocumab and placebo, respectively). Few patients discontinued treatment because of these reactions (0.2% versus 0.4% for alirocumab and placebo, respectively), but patients receiving alirocumab had a greater number of injection site reactions, had more reports of associated symptoms, and had reactions of longer average duration than patients receiving placebo.
- Allergic Reactions
Allergic reactions were reported more frequently in patients treated with alirocumab than in those treated with placebo (8.6% versus 7.8%). The proportion of patients who discontinued treatment due to allergic reactions was higher among those treated with alirocumab (0.6% versus 0.2% ). Serious allergic reactions, such as hypersensitivity, nummular eczema, and hypersensitivity vasculitis were reported in patients using alirocumab in controlled clinical trials .
- Neurocognitive Events
Neurocognitive events were reported in 0.8% of patients treated with alirocumab and 0.7% of patients treated with placebo. Confusion or memory impairment were reported more frequently by those treated with alirocumab (0.2% for each) than in those treated with placebo (<0.1% for each).
- Liver Enzyme Abnormalities
Liver-related disorders (primarily related to abnormalities in liver enzymes) were reported in 2.5% of patients treated with alirocumab and 1.8% of patients treated with placebo, leading to treatment discontinuation in 0.4% and 0.2% of patients, respectively. Increases in serum transaminases to greater than 3 times the upper limit of normal occurred in 1.7% of patients treated with alirocumab and 1.4% of patients treated with placebo.
- Low LDL-C Values
In a pool of both placebo- and active-controlled clinical trials, 796 alirocumab-treated patients had two consecutive calculated LDL-C values <25 mg/dL, and 288 had two consecutive calculated LDL-C values <15 mg/dL. Changes to background lipid-altering therapy (e.g., maximally tolerated statins) were not made in response to low LDL-C values, and alirocumab dosing was not modified or interrupted on this basis. Although adverse consequences of very low LDL-C were not identified in these trials, the long-term effects of very low levels of LDL-C induced by alirocumab are unknown.
## Immunogenicity
- As with all therapeutic proteins, there is a potential for immunogenicity with alirocumab. In a pool of ten placebo- and active-controlled trials, 4.8% of patients treated with alirocumab had anti-drug antibodies (ADA) newly detected after initiating treatment as compared with 0.6% of patients treated with control.
- Patients who developed ADA had a higher incidence of injection site reactions compared with patients who did not develop ADA (10.2% vs 5.9%).
- A total of 1.2% of patients treated with alirocumab developed neutralizing antibodies (NAb) on at least one occasion as compared with no patients treated with control, and 0.3% of patients both tested positive for NAb and exhibited transient or prolonged loss of efficacy. The long-term consequences of continuing alirocumab treatment in the presence of persistent NAb are unknown.
- Immunogenicity data are highly dependent on the sensitivity and specificity of the assay as well as other factors. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to alirocumab with the incidence of antibodies to other products may be misleading.
# Use in Specific Populations
## Pregnancy
Risk Summary
There are no available data on use of alirocumab in pregnant women to inform a drug-associated risk. In animal reproduction studies, there were no effects on embryo-fetal development when rats were subcutaneously administered alirocumab during organogenesis at dose exposures up to 12-fold the exposure at the maximum recommended human dose of 150 mg every two weeks. In monkeys, suppression of the humoral immune response was observed in infant monkeys when alirocumab was dosed during organogenesis to parturition at dose exposures 13-fold the exposure at the maximum recommended human dose of 150 mg every two weeks. No additional effects on pregnancy or neonatal/infant development were observed at dose exposures up to 81-fold the maximum recommended human dose of 150 mg every two weeks. Measurable alirocumab serum concentrations were observed in the infant monkeys at birth at comparable levels to maternal serum, indicating that alirocumab, like other IgG antibodies, crosses the placental barrier. FDA's experience with monoclonal antibodies in humans indicates that they are unlikely to cross the placenta in the first trimester; however, they are likely to cross the placenta in increasing amounts in the second and third trimester. Consider the benefits and risks of alirocumab and possible risks to the fetus before prescribing alirocumab to pregnant women.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.
Data
Animal Data
In Sprague Dawley rats, no effects on embryo-fetal development were observed when alirocumab was dosed at up to 75 mg/kg/dose by the subcutaneous route on gestation days 6 and 12 at exposures 12-fold the maximum recommended human dose of 150 mg every two weeks, based on serum AUC.
In cynomolgus monkeys, suppression of the humoral immune response to keyhole limpet hemocyanin (KLH) antigen was observed in infant monkeys at 4 to 6 months of age when alirocumab was dosed during organogenesis to parturition at 15 mg/kg/week and 75 mg/kg/week by the subcutaneous route, corresponding to 13- and 81-fold the human exposure at the maximum recommended human dose of 150 mg every two weeks, based on serum AUC. The lowest dose tested in the monkey resulted in humoral immune suppression; therefore it is unknown if this effect would be observed at clinical exposure. No study designed to challenge the immune system of infant monkeys was conducted. No additional embryo-fetal, prenatal or postnatal effects were observed in infant monkeys, and no maternal effects were observed, when alirocumab was dosed at up to 75 mg/kg/week by the subcutaneous route, corresponding to maternal exposure of 81-fold the exposure at the maximum recommended human dose of 150 mg every two weeks, based on serum AUC.
## Lactation
Risk Summary
There is no information regarding the presence of alirocumab in human milk, the effects on the breastfed infant, or the effects on milk production. The development and health benefits of breastfeeding should be considered along with the mother's clinical need for alirocumab and any potential adverse effects on the breastfed infant from alirocumab or from the underlying maternal condition. Human IgG is present in human milk, but published data suggest that breastmilk IgG antibodies do not enter the neonatal and infant circulation in substantial amounts.
## Pediatric Use
Safety and efficacy in pediatric patients have not been established.
## Geriatric Use
In controlled studies, 1158 patients treated with alirocumab were ≥65 years of age and 241 patients treated with alirocumab were ≥75 years of age. 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.
## Renal Impairment
No dose adjustment is needed for patients with mild or moderately impaired renal function. No data are available in patients with severe renal impairment.
## Hepatic Impairment
No dose adjustment is needed for patients with mild or moderate hepatic impairment. No data are available in patients with severe hepatic impairment.
# Description
Alirocumab is a human monoclonal antibody (IgG1 isotype) that targets proprotein convertase subtilisin kexin type 9 (PCSK9). Alirocumab is a PCSK9 inhibitor produced by recombinant DNA technology in Chinese Hamster Ovary cell suspension culture. Alirocumab consists of two disulfide-linked human heavy chains, each covalently linked through a disulfide bond to a human kappa light chain. A single N-linked glycosylation site is located in each heavy chain within the CH2 domain of the Fc constant region of the molecule. The variable domains of the heavy and light chains combine to form the PCSK9 binding site within the antibody. Alirocumab has an approximate molecular weight of 146 kDa.
Alirocumab is a sterile, preservative-free, clear, colorless to pale yellow solution for subcutaneous injection. Alirocumab 75 mg/mL or 150 mg/mL solution for subcutaneous injection in a single-dose pre-filled pen or single-dose pre-filled syringe is supplied in a siliconized 1 mL Type-1 clear glass syringe. The needle shield is not made with natural rubber latex.
Each 75 mg/mL pre-filled pen or pre-filled syringe contains 75 mg alirocumab, histidine (8 mM), polysorbate 20 (0.1 mg), sucrose (100 mg), and Water for Injection USP, to pH 6.0.
Each 150 mg/mL pre-filled pen or pre-filled syringe contains 150 mg alirocumab, histidine (6 mM), polysorbate 20 (0.1 mg), sucrose (100 mg), and Water for Injection USP, to pH 6.0.
# Clinical Pharmacology
## Mechanism of Action
Alirocumab is a human monoclonal antibody that binds to proprotein convertase subtilisin kexin type 9 (PCSK9). PCSK9 binds to the low-density lipoprotein receptors (LDLR) on the surface of hepatocytes to promote LDLR degradation within the liver. LDLR is the primary receptor that clears circulating LDL, therefore the decrease in LDLR levels by PCSK9 results in higher blood levels of LDL-C. By inhibiting the binding of PCSK9 to LDLR, alirocumab increases the number of LDLRs available to clear LDL, thereby lowering LDL-C levels.
## Pharmacodynamics
Alirocumab reduced free PCSK9 in a concentration-dependent manner. Following a single subcutaneous administration of alirocumab 75 or 150 mg, maximal suppression of free PCSK9 occurred within 4 to 8 hours. Free PCSK9 concentrations returned to baseline when alirocumab concentrations decreased below the limit of quantitation.
## Pharmacokinetics
Absorption
After subcutaneous (SC) administration of 75 mg to 150 mg alirocumab, median times to maximum serum concentrations (tmax) were 3–7 days. The pharmacokinetics of alirocumab after single SC administration of 75 mg into the abdomen, upper arm, or thigh were similar. The absolute bioavailability of alirocumab after SC administration was about 85% as determined by population pharmacokinetics analysis. A slightly greater than dose proportional increase was observed, with a 2.1- to 2.7-fold increase in total alirocumab concentrations for a 2-fold increase in dose. Steady state was reached after 2 to 3 doses with an accumulation ratio of about 2-fold.
Distribution
Following IV administration, the volume of distribution was about 0.04 to 0.05 L/kg indicating that alirocumab is distributed primarily in the circulatory system.
Metabolism and Elimination
- Specific metabolism studies were not conducted, because alirocumab is a protein. Alirocumab is expected to degrade to small peptides and individual amino acids. In clinical studies where alirocumab was administered in combination with atorvastatin or rosuvastatin, no relevant changes in statin concentrations were observed in the presence of repeated administration of alirocumab, indicating that cytochrome P450 enzymes (mainly CYP3A4 and CYP2C9) and transporter proteins such as P-gp and OATP were not affected by alirocumab.
- Two elimination phases were observed for alirocumab. At low concentrations, the elimination is predominately through saturable binding to target (PCSK9), while at higher concentrations the elimination of alirocumab is largely through a non-saturable proteolytic pathway.
- Based on a population pharmacokinetic analysis, the median apparent half-life of alirocumab at steady state was 17 to 20 days in patients receiving alirocumab at subcutaneous doses of 75 mg Q2W or 150 mg Q2W.
Specific Populations
A population pharmacokinetic analysis was conducted on data from 2799 subjects. Age, body weight, gender, race, and creatinine clearance were found not to significantly influence alirocumab pharmacokinetics. No dose adjustments are recommended for these demographics.
Pediatric
Alirocumab has not been studied in pediatric patients.
Renal Impairment
Since monoclonal antibodies are not known to be eliminated via renal pathways, renal function is not expected to impact the pharmacokinetics of alirocumab.
No data are available in patients with severe renal impairment.
Hepatic Impairment
Following administration of a single 75 mg SC dose, alirocumab pharmacokinetic profiles in subjects with mild and moderate hepatic impairment were similar to those in subjects with normal hepatic function.
No data are available in patients with severe hepatic impairment.
Drug-Drug Interactions
The median apparent half-life of alirocumab is reduced to 12 days when administered with a statin; however, this difference is not clinically meaningful and does not impact dosing recommendations.
# Non Clinical Toxicology
## Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies have not been conducted with alirocumab. The mutagenic potential of alirocumab has not been evaluated; however, monoclonal antibodies are not expected to alter DNA or chromosomes.
There were no adverse effects on surrogate markers of fertility (e.g., estrous cyclicity, testicular volume, ejaculate volume, sperm motility, or total sperm count per ejaculate) in a 6-month chronic toxicology study in sexually-mature monkeys subcutaneously administered at 5, 15, and 75 mg/kg/week at systemic exposures up to 103-fold the 150 mg every two weeks subcutaneous clinical dose based on serum AUC. In addition, there were no adverse alirocumab-related anatomic pathology or histopathology findings in reproductive tissues in rat or monkey toxicology studies at systemic exposures up to 11-fold and 103-fold respectively, in the 6-month studies, compared to clinical systemic exposure following a 150 mg every two weeks dose, based on serum AUC.
## Animal Toxicology and/or Pharmacology
During a 13-week toxicology study of 75 mg/kg once weekly alirocumab in combination with 40 mg/kg once daily atorvastatin in adult monkeys, there were no effects of Alirocumab on the humoral immune response to keyhole limpet hemocyanin (KLH) after one to two months at exposures 100-fold greater than the exposure at the maximum recommended human dose of 150 mg every two weeks, based on AUC.
# Clinical Studies
The efficacy of Alirocumab was investigated in five double-blind placebo-controlled trials that enrolled 3499 patients; 36% were patients with heterozygous familial hypercholesterolemia (HeFH) and 54% were non-FH patients who had clinical atherosclerotic cardiovascular disease. Three of the five trials were conducted exclusively in patients with HeFH. All patients were receiving a maximally tolerated dose of a statin, with or without other lipid-modifying therapies. In the trials that enrolled patients with HeFH, the diagnosis of HeFH was made either by genotyping or clinical criteria ("definite FH" using either the Simon Broome or WHO/Dutch Lipid Network criteria). All trials were at least 52 weeks in duration with the primary efficacy endpoint measured at week 24 (mean percent change in LDL-C from baseline).
Three studies used an initial dose of 75 mg every 2 weeks (Q2W) followed by criteria-based up-titration to 150 mg Q2W at week 12 for patients who did not achieve their pre-defined target LDL-C at week 8. The majority of patients (57% to 83%) who were treated for at least 12 weeks did not require up-titration. Two studies used only a 150 mg Q2W dose.
Study 1 was a multicenter, double-blind, placebo-controlled trial that randomly assigned 1553 patients to Alirocumab 150 mg Q2W and 788 patients to placebo. All patients were taking maximally tolerated doses of statins with or without other lipid-modifying therapy, and required additional LDL-C reduction. The mean age was 61 years (range 18–89), 38% were women, 93% were Caucasian, 3% were Black, and 5% were Hispanic/Latino. Overall, 69% were non-FH patients with clinical atherosclerotic cardiovascular disease and 18% had HeFH. The average LDL-C at baseline was 122 mg/dL.
The proportion of patients who prematurely discontinued study drug prior to the 24-week endpoint was 8% among those treated with Alirocumab and 8% among those treated with placebo.
At week 24, the treatment difference between Alirocumab and placebo in mean LDL-C percent change was -58% (95% CI: -61%, -56%; p-value: <0.0001).
Study 2 was a multicenter, double-blind, placebo-controlled trial that randomly assigned 209 patients to Alirocumab and 107 patients to placebo. Patients were taking maximally tolerated doses of statins with or without other lipid-modifying therapy, and required additional LDL-C reduction.
The mean age was 63 years (range 39–87), 34% were women, 82% were Caucasian, 16% were Black, and 11% were Hispanic/Latino. Overall 84% had clinical atherosclerotic cardiovascular disease. Mean baseline LDL-C was 102 mg/dL.
The proportion of patients who prematurely discontinued study drug prior to the 24-week endpoint was 11% among those treated with Alirocumab and 12% among those treated with placebo.
At week 12, the mean percent change from baseline in LDL-C was -45% with Alirocumab compared to 1% with placebo, and the treatment difference between Alirocumab 75mg Q2W and placebo in mean LDL-C percent change was -46% (95% CI: -53%, -39%).
At week 12, if additional LDL-C lowering was required based on pre-specified LDL-C criteria, Alirocumab was up-titrated to 150 mg Q2W for the remainder of the trial. At week 24, the mean percent change from baseline in LDL-C was -44% with Alirocumab and -2% with placebo, and the treatment difference between Alirocumab and placebo in mean LDL-C percent change was -43% (95% CI: -50%, -35%; p-value: <0.0001). The dose was up-titrated to 150 mg Q2W in 32 (17%) of 191 patients treated with Alirocumab for at least 12 weeks.
Studies 3 and 4 were multicenter, double-blind, placebo-controlled trials that, combined, randomly assigned 490 patients to Alirocumab and 245 patients to placebo. The trials were similar with regard to both design and eligibility criteria. All patients had HeFH, were taking a maximally tolerated dose of statin with or without other lipid-modifying therapy, and required additional LDL-C reduction. The mean age was 52 years (range 20–87), 45% were women, 94% were Caucasian, 1% were Black, and 3% were Hispanic/Latino. Overall, 45% of these patients with HeFH also had clinical atherosclerotic cardiovascular disease. The average LDL-C at baseline was 141 mg/dL.
Considering both trials together, the proportion of patients who prematurely discontinued study drug prior to the 24-week endpoint was 6% among those treated with Alirocumab and 4% among those treated with placebo.
At week 12, the treatment difference between Alirocumab 75 mg Q2W and placebo in mean LDL-C percent change was -48% (95% CI: -52%, -44%).
At week 12, if additional LDL-C lowering was required based on pre-specified LDL-C criteria, Alirocumab was up-titrated to 150 mg Q2W for the remainder of the trials. At week 24, the mean treatment difference between Alirocumab and placebo in mean LDL-C percent change from baseline was -54% (95% CI: -59%, -50%; p-value: <0.0001). The dose was up-titrated to 150 mg Q2W in 196 (42%) of 469 patients treated with Alirocumab for at least 12 weeks. The LDL-C-lowering effect was sustained to week 52.
Study 5 was a multicenter, double-blind, placebo-controlled trial that randomly assigned 72 patients to Alirocumab 150 mg Q2W and 35 patients to placebo. Patients had HeFH with a baseline LDL-C ≥160 mg/dL while taking a maximally tolerated dose of statin with or without other lipid-modifying therapy. The mean age was 51 years (range 18–80), 47% were women, 88% were Caucasian, 2% were Black, and 6% were Hispanic/Latino. Overall, 50% had clinical atherosclerotic cardiovascular disease. The average LDL-C at baseline was 198 mg/dL.
The proportion of patients who discontinued study drug prior to the 24-week endpoint was 10% among those treated with Alirocumab and 0% among those treated with placebo.
At week 24, the mean percent change from baseline in LDL-C was -43% with Alirocumab and -7% with placebo, and the treatment difference between Alirocumab and placebo in mean LDL-C percent change was -36% (95% CI: -49%, -24%; p-value: <0.0001).
# How Supplied/Storage and Handling
Alirocumab is a clear, colorless to pale yellow solution, supplied in single-dose pre-filled pens and single-dose pre-filled glass syringes. Each pre-filled pen or pre-filled syringe of Alirocumab is designed to deliver 1 mL of 75 mg/mL or 150 mg/mL solution.
Alirocumab is available in cartons containing 1 or 2, pre-filled pens and 1 or 2, pre-filled syringes.
Store in a refrigerator at 36°F to 46°F (2°C to 8°C) in the outer carton in order to protect from light.
Do NOT freeze. Do NOT expose to extreme heat. Do NOT shake.
# Patient Counseling Information
For patient counseling information about alirocumab click here.
# Drug Packaging and Label
## Pen
## Injection
# Major Trials
## Synopsis
## Phase II Trials
This randomized, double-blind, placebo-controlled phase 2 trial of 92 patients with LDL-C≥100 mg/dL after treatment with 10 mg of atorvastatin for at least 7 weeks randomized patients to 8 weeks of therapy with either 80 mg of atorvastatin daily plus 150 mg SC alirocumab once every 2 weeks, 10 mg of atorvastatin daily plus 150 mg alirocumab once every 2 weeks, or 80 mg of atorvastatin daily plus SC placebo once every 2 weeks. The trial demonstrated a significant 73.2% reduction from baseline serum LDL-C cholesterol with 80 mg of atorvastatin plus alirocumab compared with 17.3% with the 80 mg atorvastatin plus placebo. Ninety percent of the patients who received alirocumab reached LDL-C concentrations lower than 70 mg/dL compared with 17% of those receiving atorvastatin alone. There were no significant safety signals and the drug was well tolerated.
This randomized, double-blind, placebo-controlled phase 2 trial of 77 adults with heterozygous familial hypercholesterolaemia and LDL-C concentrations of ≥100 mg/dL or higher on stable diet and statin dose, with or without ezetimibe therapy were randomized (1:1:1:1:1) to 5 different treatment arms for 12 weeks: 150 mg SC alirocumab every 4 weeks, 200 mg SC alirocumab every 4 weeks, 300 mg SC alirocumab every 4 weeks, 150 mg SC alirocumab every 2 weeks, or SC placebo. Randomization was stratified by baseline use of ezetimibe. Alirocumab demonstrated a significant reduction in LDL-C at week 12 (28.9%, 31.5%, and 42.5% for the 150, 200, and 300 mg every 4 weeks respectively, and 67.9% for the 150 mg every 2 weeks dose, compared with 10.7% in the placebo arm) with no significant safety signal. There were no increases >3 x ULN in hepatic transaminases or creatine kinase (CK).
This randomized, double-blind, placebo-controlled phase 2 trial of 183 patients with LDL-C ≥100 mg/dL on stable-dose atorvastatin for 6 or more weeks randomized patients to a 12 week treatment course in either one of 6 arms (1:1:1:1:1:1): subcutaneous (SC) placebo every 2 weeks, 50 mg SC alirocumab every 2 weeks, 100 mg SC alirocumab every 2 weeks, 150 mg SC alirocumab every 2 weeks, 200 mg SC alirocumab every 4 weeks alternating with placebo, or 300 mg SC alirocumab every 4 weeks alternating with placebo. Alirocumab demonstrated a significant dose-related reduction in serum LDL-C (40%, 64%, and 72% with 50, 100, and 150 mg respectively, and 43% and 48% with 200 and 300 mg respectively compared with 5% in placebo) with no major safety signals.
## Phase III Trials
### ODYSSEY - COMBO I
COMBO I was a randomized, double blind, trial that randomized 316 adult patients with moderate to very high CV risk and elevated LDL-C despite maximal statin use to either SC alirocumab 75mg every 2 weeks for 52 weeks or a matched placebo. Alirocumab dose was increased at week 12 to 150mg every two weeks if LDL targets failed to be met by week 8. Alirocumab was generally well tolerated, with no reported safety signals in the 75mg or 150mg dose. Alirocumab treatment was associated with a significantly higher reduction in LDL-C from baseline to 24 weeks ( -48.2% for alirocumab vs. -2.3% for placebo; Δ:45.9%; 95% CI: 39.3-52.5; p<0.0001). Patients on alirocumab were more likely to reach LDL targets (75% for alirocumab vs. 9% for placebo). Patients on alirocumab demonstrated a substantial drop in LDL-C within the first 4 weeks, which was sustained to week 52.
COMBO II was a randomized, double-blind, double-dummy, trial that randomized 720 patients with elevated CV risk and LDL-C despite maximal statins use to either SC alirocumab 75 mg every 2 weeks (and PO placebo) or PO ezetimibe 10 mg daily (and SC placebo). Alirocumab was generally well tolerated, with no reported safety signals. Alirocumab treatment was associated with a significantly higher reduction in mean LDL-C values from baselines at week 24 (50.6 ± 1.4% for alirocumab vs. 20.7 ± 1.9% for ezetimibe; P < 0.0001). Patients on alirocumab were more likely to achieve LDL-C <1.8 mmol/L (77.0% vs. 45.6%; P < 0.0001). At week 24, mean LDL-C levels were 1.3 ± 0.04 mmol/L among patients receiving alirocumab, and 2.1 ± 0.05 mmol/L among patients receiving ezetimibe.
### ODYSSEY -ALTERNATIVE
ALTERNATIVE was a randomized, double blind, double dummy trial that randomized 314 adult patients with moderate to very high CV risk and who underwent 2 weeks washout from lipid lowering therapies in a 2:1:1 ratio to 75mg alirocumab every two weeks, or 10mg oral ezetimibe daily, or 20mg oral atorvastatin daily for 24 weeks. Alirocumab was associated with the lowest rates of skeletal muscle associated AEs, followed by ezetimibe and atorvastatin, respectively. Alirocumab was generally well tolerated, with no significant safety signals. Alirocumab treatment was associated with a significantly higher reduction in mean LDL-C from baseline to week 24 compared to ezetimibe (-45.0% for alirocumab vs. -14.6% for ezetimibe; Δ:30.4%; 95% CI: 24.2-36.6; p<0.0001). Patients on alirocumab were more likely to achieve LDL targets (41.9% vs. 4.4%). Alirocumab patients demonstrated a substantial drop in LDL-C in the first 4 weeks, which was sustained for 24 weeks.
### ODYSSEY - MONO
ODYSSEY- MONO was a randomized, double blind, double dummy trial that enrolled 103 adult patients with a 10 year fatal CV risk of 1.00% to 4.99% and LDL-C>100mg/dl. Patients had no established history of coronary heart disease or any CHD risk equivalents. Additionally, patients were not receiving lipid lowering therapy for 4 weeks prior to randomization. Patients were randomized to receive 75mg of SC alirocumab twice weekly or oral ezetimibe 10mg once daily. Alirocumab dose was increased at week 12 to 150mg every two weeks if LDL targets failed to be met by week 8. Alirocumab treatment was associated with a significantly higher reduction in mean LDL-C from baseline to week 24 compared to ezetimibe (-47.2% for alirocumab vs. -15.6% for ezetimibe; Δ:31.6%; 95% CI: 23.0-40.2; p<0.0001). Alirocumab patients demonstrated a substantial drop in LDL-C in the first 4 weeks, which was sustained for 24 weeks. Alirocumab was well tolerated with no safety signals.
ODYSSEY FHI and FH II were multicenter, double-blind, placebo-controlled trials that enrolled a total of 735 heterozygous familial hypercholesterolemia patients and randomized them to either SC alirocumab 75-150 mg every 2 weeks or matching placebo for a total of 78 weeks, on top of a background of lipid lowering therapy.The primary endpoint was the prrcent change in LDL-C from baseline to week 24. Alirocumab administration was associated with a 57.9% reduction compared to placebo in the FH I population (P<0.0001), and a 51.4% reduction compared to placebo in the FH II population (P<0.0001). Alirocumab was well tolerated and there were no safety concerns.
Long term was a randomized, double-blind, placebo-controlled trial that enrolled 2341 patients at high risk for CV events with baseline LDL-C ≥70 mg/dL. Patients were randomized in 2:1 ratio to receive either 150mg SC alirocumab or equivalent placebo once every 2 weeks for 78 weeks. The primary efficacy end point was the percentage change in calculated LDL cholesterol level from baseline to week 24. Alirocumab treatment was associated with a 62% reduction in LDL-C compared to placebo (P<0.001). In an exploratory analysis, alirocumab was associated with a significant reduction in the rate of major adverse cardiovascular events (1.7% vs. 3.3%; hazard ratio, 0.52; 95% confidence interval, 0.31 to 0.90; nominal P=0.02). Alirocumab treatment was associated with a significantly higher incidence of myalgia (5.4% vs. 2.9%; P=0.006).
### ODYSSEY - OPTIONS I
OPTIONS I was a randomized, double blind, trial that enrolled 355 patients with high or very high CVD risk and elevated LDL-C. All patients were receiving 20 or 40 mg of atorvastatin for at least 4 weeks prior to study enrollment. Patients were stratified by their baseline dose of 20mg atorvastatin vs. 40mg atorvastatin prior to randomization. Patients receiving 20mg of atorvastatin were randomized in a 1:1:1 ratio to receive add-on therapy of 75mg SC alirocumab twice weekly, or add-on therapy of 10mg oral ezetimibe once daily, or doubling the atorvastatin dose to 40mg once daily. Patients receiving a baseline 40mg of atorvastatin were randomized in a 1:1:1:1 ratio to receive add-on therapy of 75mg SC aloricumab twice weekly, or add-on therapy of 10mg oral ezetimibe once daily, or doubling atorvastatin dose to 80mg once daily, or switching to 40mg oral rosuvastatin once daily. Patients were followed for 24 weeks.
Among patients receiving a 20mg baseline dose of atorvastatin , add-on therapy of alirocumab was associated with a 44.1% reduction in mean LDL-C compared to 20.5% for ezetimibe, and 5.0% for 40mg atorvastatin. Patients on alirocumab add-on treatment were most likely to achieve LDL-C targets (79.2% for alirocumab vs. 50.3% for ezetimibe vs. 16.0% for 40mg atorvastatin).
Among patients receiving 40mg baseline dose of atorvastatin, add-on therapy of alirocumab was associated with a 54.0% reduction in mean LDL-C compared to 22.6% for ezetimibe, 4.8% for atorvastatin, and 21.5% for rosuvastatin. Patients on alirocumab add-on treatment were most likely to achieve LDL-C targets (77.2% for alirocumab vs. 54.2% for ezetimibe vs. 10.2% for 80mg atorvastatin, and 42.2% for rosuvastatin).
Alirocumab was well tolerated and showed no safety signals. Regardless of baseline dose of atorvastatin, patients experienced a substantial drop in mean LDL-C within the first 4 weeks which was sustained for 24 weeks.
### ODYSSEY - OPTIONS II
OPTIONS II was a randomized, double blind, trial that enrolled 305 patients with high or very high CVD risk and elevated LDL-C. All patients were receiving 10 or 20 mg of rosuvastatin for at least 4 weeks prior to study enrollment. Patients were stratified by their baseline dose of 10mg rosuvastatin vs. 20mg rosuvastatin prior to randomization. Patients receiving 10mg of rosuvastatin were randomized in a 1:1:1 ratio to receive add-on therapy of 75mg SC alirocumab twice weekly, or add-on therapy of 10mg oral ezetimibe once daily, or doubling the rosuvastatin dose to 20mg once daily. Patients receiving a baseline 20mg of rosuvastatin were randomized in a 1:1:1 ratio to receive add-on therapy of 75mg SC aloricumab twice weekly, or add-on therapy of 10mg oral ezetimibe once daily, or doubling rosuvastatin dose to 40mg once daily, Patients were followed for 24 weeks.
Among patients receiving a 10mg baseline dose of rosuvastatin , add-on therapy of alirocumab was associated with a 50.6% reduction in mean LDL-C compared to 14.4% for ezetimibe, and 16.3% for 20mg rosuvastatin. Patients on alirocumab add-on treatment were most likely to achieve LDL-C targets (77.8% for alirocumab vs. 43.1% for ezetimibe vs. 31.3% for 20mg rosuvastatin).
Among patients receiving 20mg baseline dose of rosuvastatin, add-on therapy of alirocumab was associated with a 36.3% reduction in mean LDL-C compared to 11.0% for ezetimibe, and 15.9% for rosuvastatin. Patients on alirocumab add-on treatment were most likely to achieve LDL-C targets (60.1% for alirocumab vs. 43.6% for ezetimibe vs. 29.9% for 40mg rosuvastatin). Results of the 20mg group missed the mark for statistical significance.
Alirocumab was well tolerated and showed no safety signals.
### ODYSSEY - CHOICE I
CHOICE I was a randomized, double blind, placebo controlled clinical trial that enrolled 803 adult patients with uncontrolled hypercholesterolemia and moderate to very high CVD risk receiving maximum dose of statins, have skeletal muscle symptoms associated with statin use or discontinued statin use. Patients were randomized in a 4:2:1 ratio to receive 300mg SC alirocumab every 4 weeks, or 75mg SC alirocumab every 2 weeks, or placebo for 48 weeks. Alirocumab treatment was well tolerated and showed no significant safety signals.
Among patients not receiving statins at baseline; those receiving alirocumab demonstrated a 52.7% reduction in mean LDL-C compared to 0.3% in placebo. Among patients receiving statins at baseline; those receiving alirocumab demonstrated a 48.8% reduction in mean LDL-C compared to 0.1% in placebo.
### ODYSSEY - CHOICE II
CHOICE II was a randomized, double blind, placebo controlled clinical trial that enrolled 233 adult patients with uncontrolled hypercholesterolemia and discontinued statins. This trial enrolled a large subgroup of patients who previously experienced statin associated myopathy. Patients were randomized in a 2:1:1 ratio to receive 150mg SC alirocumab every four weeks, or placebo, or 75mg SC alirocumab every two weeks. Primary effficacy endpoint was the percent change in mean LDL-C from baseline to week 24 in the ITT population compared to placebo. Alirocumab was well tolerated and demonstrated no safety signals. There was a low incidence of musculoskeletal symptoms across all groups. More injection site reactions were associated with the 150mg dose compared to placebo or the 75mg dose.
Patients receiving alirocumab had a 51.7% mean reduction in LDL-C compared to 4.7% in patients receiving placebo. The 75mg twice weekly dose demonstrated a higher efficacy against placebo compared to the 150mg every 4 weeks dose. More patients achieved target LDL-C levels in the 75mg dose group compared to 150mg and placebo groups (70.3% vs. 63.9% vs. 1.8%, respectively).
### ODYSSEY - HIGH FH
HIGH FH was a randomized, double blind, placebo controlled clinical trial that enrolled 107 adult patients with heterozygous familial hypercholesterolemia with poorly controlled cholesterol levels (LDL>150mg/dl) despite maximum stable dose of statins. Patients were randomized in a 2:1 fashion to receive 150mg SC alirocumab every two weeks or placebo for 78 weeks. Alirocumab was well tolerated and demonstrated no safety signals.
Patients on alirocumab had a 45.7% reduction in LDL-C from baseline to week 24 compared to 6.6% reduction in the placebo group. 41.0% of patients in the alirocumab group achieved LDL targets compared to 5.7% in the placebo group.
### ODYSSEY - JAPAN
ODYSSEY JAPAN was a randomized, double blind, placebo controlled clinical trial that enrolled 216 adult patients at 31 sites in Japan. Patients had heterozygous familial hypercholesterolemia and those with high cardiovascular risk with a history of coronary artery disease. Patients had uncontrolled hypercholesterolemia with an elevated LDL-C despite lipid lowering therapy. Eligible patients were randomized in a 2:1 fashion to receive 75mg SC alirocumab every two weeks or placebo, for a duration of 52 weeks. Surprisingly, patients receiving placebo experienced more SAEs compared to patients in the alirocumab group (12.5% for placebo and 7.0% for alirocumab). Alirocumab was well tolerated, and no safety concerns were observed.
Patients receiving alirocumab demonstrated a 62.5% reduction in mean LDL-C from baseline to week 24 compared to placebo; 1.6%. This was demonstrated with a substantial drop in the first 4 weeks and sustained for 52 weeks. 96.7% of patients receiving alirocumab achieved LDL-C targets compared to 10.2% of patients in the placebo group.
### ODYSSEY - ESCAPE
ESCAPE was a randomized, double blind, placebo-controlled trial of 62 adult patients with heterozygous familial hypercholesterolemia with high cardiovascular risk on previous statin treatment and currently undergoing apheresis therapy every week or two weeks for at least 4 weeks prior to randomization. Patients are randomized in a 2:1 ratio to receive 150mg SQ alirocumab once every two weeks or placebo. Alirocumab was well tolerated and generated no significant safety signal.
Patients receiving alirocumab demonstrated a 75% reduction in the rate of apheresis from weeks 7 to 18 compared to placebo. Patients experienced a substantial drop in LDL-C for the first two weeks and the effect was sustained for 52 weeks. Additionally, patients on alirocumab demonstrated a 50% reduction in rate of apheresis in weeks 15-18, compared to placebo.
# Cost-Effectiveness
Doses are administered every two weeks with a cost of $40 a day or $14,600 a year, substantially higher than some generic statins, which can cost as little as $0.10 a day. alirocumab is more expensive to manufacture than statins because it is made in live genetically engineered cells. Manufacturers argue that the drug is cost-effective because it will reduce medical costs of hospitalizations from stroke or myocardial infarction and that the price of the drug reflects its value. alirocumab used in combination with statins can lower cholesterol 40-70% compared to statins that lower LDL an average of 40% . Still, further research into the actual ability of the drug to reduce risk and complications is ongoing. Reduced prices and plans through insurers should help make the drug accessible to patients with lower ability to pay.
# Future Investigations
The following trials are currently underway and study designs, rationale, and results are not yet published.
## ODYSSEY - OUTCOMES
OUTCOMES will be a randomized, double blind, placebo controlled, clinical trial enrolling 18,000 patients over 40 years of age who are hospitalized for acute coronary syndrome with elevated cardiac biomarkers, or ECG changes consistent with ischemia or infarction, and evidence of obstructive coronary artery disease. Patients must demonstrate inadequate control of artherogenic lipoproteins despite maximal statin regimen. Patients will be randomized in a 1:1 ratio to receive 75mg SQ alirocumab every two weeks or a matched placebo for a period of 2 to 5 years. Alirocumab dose may be increased to 150mg SQ q2w if LDL-C is sustained above 50mg/dL after 4 weeks. Doses of alirocumab may be downtitrated from 150mg q2w to 75mg q2w if LDL-C is below 25mg/dL.
The primary endpoint is time to first of a composite of coronary heart disease death, non-fatal MI, Ischemic stroke, or unstable angina requiring hospitalization. Pre-specified secondary outcomes include time to each component of the primary endpoint. Additional genomic analysis will be performed on a subset of patients who consent to it.
The ODYSSEY Outcomes trial seeks to determine whether clinical outcomes are improved by lowering levels of LDL-C and other atherogenic lipoproteins below those achieved on optimal statin therapy alone. The trial is not designed to explore the safety of sustained, very low LDL-C levels. The trial will determine whether further reduction in cardiovascular risk can be achieved by addition of the monoclonal PCSK9 antibody, alirocumab, resulting in further reduction of LDL-C and other atherogenic lipoproteins.
## DM DYSLIPIDEMIA
Efficacy and safety of alirocumab in high cardiovascular risk patients with diabetes.
## DM INSULIN
Efficacy and safety of alirocumab in insulin-treated patients with Type 1 or Type 2 diabetes and high cardiovascular risk.
## KT
A randomized, double-blind, placebo-controlled, parallel group study to evaluate the efficacy and safety of alirocumab in high cardiovascular risk patients with hypercholesterolemia not adequately controlled with their lipid modifying therapy in South Korea and Taiwan. | Alirocumab
For a review of all PCSK9 inhibitors please click here
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Tarek Nafee, M.D. [2],Aysha Aslam, M.B.B.S[3]
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# Overview
Alirocumab (REGN727 and SAR236553) is an investigational human monoclonal antibody that inhibits PCSK9 for the treatment of hypercholesterolemia. Alirocumab is indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or clinical atherosclerostic cardiovascular disease, who require additional lowering of LDL-C. The effect of alirocumab on cardiovascular morbidity and mortality has not been determined.
# Indication and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Heterozygous Familial Hypercholesterolemia
For patients with heterozygous familial hypercholesterolemia
- Initial dose: 75mg/ml SQ q2w
For patients with heterozygous familial hypercholesterolemia and inadequate LDL-C response
- Dose: 150mg/ml SQ q2w
## Off-Label Use and Dosage (Adult)
Guideline-Supported Use
- There is limited information about the guideline-supported use.
Non–Guideline-Supported Use
# Drug Administration Instructions
- If a dose is missed, instruct the patient to administer the injection within 7 days from the missed dose and then resume the patient's original schedule. If the missed dose is not administered within 7 days, instruct the patient to wait until the next dose on the original schedule.
- Provide proper training to patients and/or caregivers on the preparation and administration of alirocumab prior to use according to the Instructions for Use. Instruct patients and/or caregivers to read and follow the Instructions for Use each time they use alirocumab.
- Allow alirocumab to warm to room temperature for 30 to 40 minutes prior to use. Use alirocumab as soon as possible after it has warmed up. Do NOT use alirocumab if it has been at room temperature [77°F (25°C)] for 24 hours or longer.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. If the solution is discolored or contains visible particulate matter, the solution should not be used.
- Follow aseptic injection technique every time alirocumab is administered.
- Administer alirocumab by subcutaneous injection into the thigh, abdomen, or upper arm using a single-dose pre-filled pen or single-dose pre-filled syringe.
- Rotate the injection site with each injection.
- Do NOT inject alirocumab into areas of active skin disease or injury such as sunburns, skin rashes, inflammation, or skin infections.
- Do NOT co-administer alirocumab with other injectable drugs at the same injection site.
# Dosage Forms and Strengths
Alirocumab is a clear, colorless to pale yellow solution available as follows:
Injection: Single-dose pre-filled pen
- 75 mg/mL
- 150 mg/mL
Injection: Single-dose pre-filled syringe
- 75 mg/mL
- 150 mg/mL
# Contraindications
Alirocumab is contraindicated in patients with a history of a serious hypersensitivity reaction to alirocumab. Reactions have included hypersensitivity vasculitis and hypersensitivity reactions requiring hospitalization.
# Warnings and Precautions
## Allergic Reactions
Hypersensitivity reactions (e.g., pruritus, rash, urticaria), including some serious events (e.g., hypersensitivity vasculitis and hypersensitivity reactions requiring hospitalization), have been reported with alirocumab treatment. If signs or symptoms of serious allergic reactions occur, discontinue treatment with alirocumab, treat according to the standard of care, and monitor until signs and symptoms resolve.
# 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.
- The safety of alirocumab was evaluated in 9 placebo-controlled trials that included 2476 patients treated with alirocumab, including 2135 exposed for 6 months and 1999 exposed for more than 1 year (median treatment duration of 65 weeks). The mean age of the population was 59 years, 40% of the population were women, 90% were Caucasians, 4% were Black or African American, and 3% were Asians. At baseline, 37% of patients had a diagnosis of heterozygous familial hypercholesterolemia and 66% had clinical atherosclerotic cardiovascular disease.
- Adverse reactions reported in at least 2% of alirocumab-treated patients, and more frequently than in placebo-treated patients, are shown in the table below:
Adverse reactions led to discontinuation of treatment in 5.3% of patients treated with alirocumab and 5.1% of patients treated with placebo. The most common adverse reactions leading to treatment discontinuation in patients treated with alirocumab were allergic reactions (0.6% versus 0.2% for alirocumab and placebo, respectively) and elevated liver enzymes (0.3% versus <0.1%).
- Local Injection Site Reactions
Local injection site reactions including erythema/redness, itching, swelling, and pain/tenderness were reported more frequently in patients treated with alirocumab (7.2% versus 5.1% for alirocumab and placebo, respectively). Few patients discontinued treatment because of these reactions (0.2% versus 0.4% for alirocumab and placebo, respectively), but patients receiving alirocumab had a greater number of injection site reactions, had more reports of associated symptoms, and had reactions of longer average duration than patients receiving placebo.
- Allergic Reactions
Allergic reactions were reported more frequently in patients treated with alirocumab than in those treated with placebo (8.6% versus 7.8%). The proportion of patients who discontinued treatment due to allergic reactions was higher among those treated with alirocumab (0.6% versus 0.2% ). Serious allergic reactions, such as hypersensitivity, nummular eczema, and hypersensitivity vasculitis were reported in patients using alirocumab in controlled clinical trials [see Warnings and Precautions (5.1)].
- Neurocognitive Events
Neurocognitive events were reported in 0.8% of patients treated with alirocumab and 0.7% of patients treated with placebo. Confusion or memory impairment were reported more frequently by those treated with alirocumab (0.2% for each) than in those treated with placebo (<0.1% for each).
- Liver Enzyme Abnormalities
Liver-related disorders (primarily related to abnormalities in liver enzymes) were reported in 2.5% of patients treated with alirocumab and 1.8% of patients treated with placebo, leading to treatment discontinuation in 0.4% and 0.2% of patients, respectively. Increases in serum transaminases to greater than 3 times the upper limit of normal occurred in 1.7% of patients treated with alirocumab and 1.4% of patients treated with placebo.
- Low LDL-C Values
In a pool of both placebo- and active-controlled clinical trials, 796 alirocumab-treated patients had two consecutive calculated LDL-C values <25 mg/dL, and 288 had two consecutive calculated LDL-C values <15 mg/dL. Changes to background lipid-altering therapy (e.g., maximally tolerated statins) were not made in response to low LDL-C values, and alirocumab dosing was not modified or interrupted on this basis. Although adverse consequences of very low LDL-C were not identified in these trials, the long-term effects of very low levels of LDL-C induced by alirocumab are unknown.
## Immunogenicity
- As with all therapeutic proteins, there is a potential for immunogenicity with alirocumab. In a pool of ten placebo- and active-controlled trials, 4.8% of patients treated with alirocumab had anti-drug antibodies (ADA) newly detected after initiating treatment as compared with 0.6% of patients treated with control.
- Patients who developed ADA had a higher incidence of injection site reactions compared with patients who did not develop ADA (10.2% vs 5.9%).
- A total of 1.2% of patients treated with alirocumab developed neutralizing antibodies (NAb) on at least one occasion as compared with no patients treated with control, and 0.3% of patients both tested positive for NAb and exhibited transient or prolonged loss of efficacy. The long-term consequences of continuing alirocumab treatment in the presence of persistent NAb are unknown.
- Immunogenicity data are highly dependent on the sensitivity and specificity of the assay as well as other factors. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to alirocumab with the incidence of antibodies to other products may be misleading.
# Use in Specific Populations
## Pregnancy
Risk Summary
There are no available data on use of alirocumab in pregnant women to inform a drug-associated risk. In animal reproduction studies, there were no effects on embryo-fetal development when rats were subcutaneously administered alirocumab during organogenesis at dose exposures up to 12-fold the exposure at the maximum recommended human dose of 150 mg every two weeks. In monkeys, suppression of the humoral immune response was observed in infant monkeys when alirocumab was dosed during organogenesis to parturition at dose exposures 13-fold the exposure at the maximum recommended human dose of 150 mg every two weeks. No additional effects on pregnancy or neonatal/infant development were observed at dose exposures up to 81-fold the maximum recommended human dose of 150 mg every two weeks. Measurable alirocumab serum concentrations were observed in the infant monkeys at birth at comparable levels to maternal serum, indicating that alirocumab, like other IgG antibodies, crosses the placental barrier. FDA's experience with monoclonal antibodies in humans indicates that they are unlikely to cross the placenta in the first trimester; however, they are likely to cross the placenta in increasing amounts in the second and third trimester. Consider the benefits and risks of alirocumab and possible risks to the fetus before prescribing alirocumab to pregnant women.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.
Data
Animal Data
In Sprague Dawley rats, no effects on embryo-fetal development were observed when alirocumab was dosed at up to 75 mg/kg/dose by the subcutaneous route on gestation days 6 and 12 at exposures 12-fold the maximum recommended human dose of 150 mg every two weeks, based on serum AUC.
In cynomolgus monkeys, suppression of the humoral immune response to keyhole limpet hemocyanin (KLH) antigen was observed in infant monkeys at 4 to 6 months of age when alirocumab was dosed during organogenesis to parturition at 15 mg/kg/week and 75 mg/kg/week by the subcutaneous route, corresponding to 13- and 81-fold the human exposure at the maximum recommended human dose of 150 mg every two weeks, based on serum AUC. The lowest dose tested in the monkey resulted in humoral immune suppression; therefore it is unknown if this effect would be observed at clinical exposure. No study designed to challenge the immune system of infant monkeys was conducted. No additional embryo-fetal, prenatal or postnatal effects were observed in infant monkeys, and no maternal effects were observed, when alirocumab was dosed at up to 75 mg/kg/week by the subcutaneous route, corresponding to maternal exposure of 81-fold the exposure at the maximum recommended human dose of 150 mg every two weeks, based on serum AUC.
## Lactation
Risk Summary
There is no information regarding the presence of alirocumab in human milk, the effects on the breastfed infant, or the effects on milk production. The development and health benefits of breastfeeding should be considered along with the mother's clinical need for alirocumab and any potential adverse effects on the breastfed infant from alirocumab or from the underlying maternal condition. Human IgG is present in human milk, but published data suggest that breastmilk IgG antibodies do not enter the neonatal and infant circulation in substantial amounts.
## Pediatric Use
Safety and efficacy in pediatric patients have not been established.
## Geriatric Use
In controlled studies, 1158 patients treated with alirocumab were ≥65 years of age and 241 patients treated with alirocumab were ≥75 years of age. 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.
## Renal Impairment
No dose adjustment is needed for patients with mild or moderately impaired renal function. No data are available in patients with severe renal impairment.
## Hepatic Impairment
No dose adjustment is needed for patients with mild or moderate hepatic impairment. No data are available in patients with severe hepatic impairment.
# Description
Alirocumab is a human monoclonal antibody (IgG1 isotype) that targets proprotein convertase subtilisin kexin type 9 (PCSK9). Alirocumab is a PCSK9 inhibitor produced by recombinant DNA technology in Chinese Hamster Ovary cell suspension culture. Alirocumab consists of two disulfide-linked human heavy chains, each covalently linked through a disulfide bond to a human kappa light chain. A single N-linked glycosylation site is located in each heavy chain within the CH2 domain of the Fc constant region of the molecule. The variable domains of the heavy and light chains combine to form the PCSK9 binding site within the antibody. Alirocumab has an approximate molecular weight of 146 kDa.
Alirocumab is a sterile, preservative-free, clear, colorless to pale yellow solution for subcutaneous injection. Alirocumab 75 mg/mL or 150 mg/mL solution for subcutaneous injection in a single-dose pre-filled pen or single-dose pre-filled syringe is supplied in a siliconized 1 mL Type-1 clear glass syringe. The needle shield is not made with natural rubber latex.
Each 75 mg/mL pre-filled pen or pre-filled syringe contains 75 mg alirocumab, histidine (8 mM), polysorbate 20 (0.1 mg), sucrose (100 mg), and Water for Injection USP, to pH 6.0.
Each 150 mg/mL pre-filled pen or pre-filled syringe contains 150 mg alirocumab, histidine (6 mM), polysorbate 20 (0.1 mg), sucrose (100 mg), and Water for Injection USP, to pH 6.0.
# Clinical Pharmacology
## Mechanism of Action
Alirocumab is a human monoclonal antibody that binds to proprotein convertase subtilisin kexin type 9 (PCSK9). PCSK9 binds to the low-density lipoprotein receptors (LDLR) on the surface of hepatocytes to promote LDLR degradation within the liver. LDLR is the primary receptor that clears circulating LDL, therefore the decrease in LDLR levels by PCSK9 results in higher blood levels of LDL-C. By inhibiting the binding of PCSK9 to LDLR, alirocumab increases the number of LDLRs available to clear LDL, thereby lowering LDL-C levels.
## Pharmacodynamics
Alirocumab reduced free PCSK9 in a concentration-dependent manner. Following a single subcutaneous administration of alirocumab 75 or 150 mg, maximal suppression of free PCSK9 occurred within 4 to 8 hours. Free PCSK9 concentrations returned to baseline when alirocumab concentrations decreased below the limit of quantitation.
## Pharmacokinetics
Absorption
After subcutaneous (SC) administration of 75 mg to 150 mg alirocumab, median times to maximum serum concentrations (tmax) were 3–7 days. The pharmacokinetics of alirocumab after single SC administration of 75 mg into the abdomen, upper arm, or thigh were similar. The absolute bioavailability of alirocumab after SC administration was about 85% as determined by population pharmacokinetics analysis. A slightly greater than dose proportional increase was observed, with a 2.1- to 2.7-fold increase in total alirocumab concentrations for a 2-fold increase in dose. Steady state was reached after 2 to 3 doses with an accumulation ratio of about 2-fold.
Distribution
Following IV administration, the volume of distribution was about 0.04 to 0.05 L/kg indicating that alirocumab is distributed primarily in the circulatory system.
Metabolism and Elimination
- Specific metabolism studies were not conducted, because alirocumab is a protein. Alirocumab is expected to degrade to small peptides and individual amino acids. In clinical studies where alirocumab was administered in combination with atorvastatin or rosuvastatin, no relevant changes in statin concentrations were observed in the presence of repeated administration of alirocumab, indicating that cytochrome P450 enzymes (mainly CYP3A4 and CYP2C9) and transporter proteins such as P-gp and OATP were not affected by alirocumab.
- Two elimination phases were observed for alirocumab. At low concentrations, the elimination is predominately through saturable binding to target (PCSK9), while at higher concentrations the elimination of alirocumab is largely through a non-saturable proteolytic pathway.
- Based on a population pharmacokinetic analysis, the median apparent half-life of alirocumab at steady state was 17 to 20 days in patients receiving alirocumab at subcutaneous doses of 75 mg Q2W or 150 mg Q2W.
Specific Populations
A population pharmacokinetic analysis was conducted on data from 2799 subjects. Age, body weight, gender, race, and creatinine clearance were found not to significantly influence alirocumab pharmacokinetics. No dose adjustments are recommended for these demographics.
Pediatric
Alirocumab has not been studied in pediatric patients.
Renal Impairment
Since monoclonal antibodies are not known to be eliminated via renal pathways, renal function is not expected to impact the pharmacokinetics of alirocumab.
No data are available in patients with severe renal impairment.
Hepatic Impairment
Following administration of a single 75 mg SC dose, alirocumab pharmacokinetic profiles in subjects with mild and moderate hepatic impairment were similar to those in subjects with normal hepatic function.
No data are available in patients with severe hepatic impairment.
Drug-Drug Interactions
The median apparent half-life of alirocumab is reduced to 12 days when administered with a statin; however, this difference is not clinically meaningful and does not impact dosing recommendations.
# Non Clinical Toxicology
## Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies have not been conducted with alirocumab. The mutagenic potential of alirocumab has not been evaluated; however, monoclonal antibodies are not expected to alter DNA or chromosomes.
There were no adverse effects on surrogate markers of fertility (e.g., estrous cyclicity, testicular volume, ejaculate volume, sperm motility, or total sperm count per ejaculate) in a 6-month chronic toxicology study in sexually-mature monkeys subcutaneously administered at 5, 15, and 75 mg/kg/week at systemic exposures up to 103-fold the 150 mg every two weeks subcutaneous clinical dose based on serum AUC. In addition, there were no adverse alirocumab-related anatomic pathology or histopathology findings in reproductive tissues in rat or monkey toxicology studies at systemic exposures up to 11-fold and 103-fold respectively, in the 6-month studies, compared to clinical systemic exposure following a 150 mg every two weeks dose, based on serum AUC.
## Animal Toxicology and/or Pharmacology
During a 13-week toxicology study of 75 mg/kg once weekly alirocumab in combination with 40 mg/kg once daily atorvastatin in adult monkeys, there were no effects of Alirocumab on the humoral immune response to keyhole limpet hemocyanin (KLH) after one to two months at exposures 100-fold greater than the exposure at the maximum recommended human dose of 150 mg every two weeks, based on AUC.
# Clinical Studies
The efficacy of Alirocumab was investigated in five double-blind placebo-controlled trials that enrolled 3499 patients; 36% were patients with heterozygous familial hypercholesterolemia (HeFH) and 54% were non-FH patients who had clinical atherosclerotic cardiovascular disease. Three of the five trials were conducted exclusively in patients with HeFH. All patients were receiving a maximally tolerated dose of a statin, with or without other lipid-modifying therapies. In the trials that enrolled patients with HeFH, the diagnosis of HeFH was made either by genotyping or clinical criteria ("definite FH" using either the Simon Broome or WHO/Dutch Lipid Network criteria). All trials were at least 52 weeks in duration with the primary efficacy endpoint measured at week 24 (mean percent change in LDL-C from baseline).
Three studies used an initial dose of 75 mg every 2 weeks (Q2W) followed by criteria-based up-titration to 150 mg Q2W at week 12 for patients who did not achieve their pre-defined target LDL-C at week 8. The majority of patients (57% to 83%) who were treated for at least 12 weeks did not require up-titration. Two studies used only a 150 mg Q2W dose.
Study 1 was a multicenter, double-blind, placebo-controlled trial that randomly assigned 1553 patients to Alirocumab 150 mg Q2W and 788 patients to placebo. All patients were taking maximally tolerated doses of statins with or without other lipid-modifying therapy, and required additional LDL-C reduction. The mean age was 61 years (range 18–89), 38% were women, 93% were Caucasian, 3% were Black, and 5% were Hispanic/Latino. Overall, 69% were non-FH patients with clinical atherosclerotic cardiovascular disease and 18% had HeFH. The average LDL-C at baseline was 122 mg/dL.
The proportion of patients who prematurely discontinued study drug prior to the 24-week endpoint was 8% among those treated with Alirocumab and 8% among those treated with placebo.
At week 24, the treatment difference between Alirocumab and placebo in mean LDL-C percent change was -58% (95% CI: -61%, -56%; p-value: <0.0001).
Study 2 was a multicenter, double-blind, placebo-controlled trial that randomly assigned 209 patients to Alirocumab and 107 patients to placebo. Patients were taking maximally tolerated doses of statins with or without other lipid-modifying therapy, and required additional LDL-C reduction.
The mean age was 63 years (range 39–87), 34% were women, 82% were Caucasian, 16% were Black, and 11% were Hispanic/Latino. Overall 84% had clinical atherosclerotic cardiovascular disease. Mean baseline LDL-C was 102 mg/dL.
The proportion of patients who prematurely discontinued study drug prior to the 24-week endpoint was 11% among those treated with Alirocumab and 12% among those treated with placebo.
At week 12, the mean percent change from baseline in LDL-C was -45% with Alirocumab compared to 1% with placebo, and the treatment difference between Alirocumab 75mg Q2W and placebo in mean LDL-C percent change was -46% (95% CI: -53%, -39%).
At week 12, if additional LDL-C lowering was required based on pre-specified LDL-C criteria, Alirocumab was up-titrated to 150 mg Q2W for the remainder of the trial. At week 24, the mean percent change from baseline in LDL-C was -44% with Alirocumab and -2% with placebo, and the treatment difference between Alirocumab and placebo in mean LDL-C percent change was -43% (95% CI: -50%, -35%; p-value: <0.0001). The dose was up-titrated to 150 mg Q2W in 32 (17%) of 191 patients treated with Alirocumab for at least 12 weeks.
Studies 3 and 4 were multicenter, double-blind, placebo-controlled trials that, combined, randomly assigned 490 patients to Alirocumab and 245 patients to placebo. The trials were similar with regard to both design and eligibility criteria. All patients had HeFH, were taking a maximally tolerated dose of statin with or without other lipid-modifying therapy, and required additional LDL-C reduction. The mean age was 52 years (range 20–87), 45% were women, 94% were Caucasian, 1% were Black, and 3% were Hispanic/Latino. Overall, 45% of these patients with HeFH also had clinical atherosclerotic cardiovascular disease. The average LDL-C at baseline was 141 mg/dL.
Considering both trials together, the proportion of patients who prematurely discontinued study drug prior to the 24-week endpoint was 6% among those treated with Alirocumab and 4% among those treated with placebo.
At week 12, the treatment difference between Alirocumab 75 mg Q2W and placebo in mean LDL-C percent change was -48% (95% CI: -52%, -44%).
At week 12, if additional LDL-C lowering was required based on pre-specified LDL-C criteria, Alirocumab was up-titrated to 150 mg Q2W for the remainder of the trials. At week 24, the mean treatment difference between Alirocumab and placebo in mean LDL-C percent change from baseline was -54% (95% CI: -59%, -50%; p-value: <0.0001). The dose was up-titrated to 150 mg Q2W in 196 (42%) of 469 patients treated with Alirocumab for at least 12 weeks. The LDL-C-lowering effect was sustained to week 52.
Study 5 was a multicenter, double-blind, placebo-controlled trial that randomly assigned 72 patients to Alirocumab 150 mg Q2W and 35 patients to placebo. Patients had HeFH with a baseline LDL-C ≥160 mg/dL while taking a maximally tolerated dose of statin with or without other lipid-modifying therapy. The mean age was 51 years (range 18–80), 47% were women, 88% were Caucasian, 2% were Black, and 6% were Hispanic/Latino. Overall, 50% had clinical atherosclerotic cardiovascular disease. The average LDL-C at baseline was 198 mg/dL.
The proportion of patients who discontinued study drug prior to the 24-week endpoint was 10% among those treated with Alirocumab and 0% among those treated with placebo.
At week 24, the mean percent change from baseline in LDL-C was -43% with Alirocumab and -7% with placebo, and the treatment difference between Alirocumab and placebo in mean LDL-C percent change was -36% (95% CI: -49%, -24%; p-value: <0.0001).
# How Supplied/Storage and Handling
Alirocumab is a clear, colorless to pale yellow solution, supplied in single-dose pre-filled pens and single-dose pre-filled glass syringes. Each pre-filled pen or pre-filled syringe of Alirocumab is designed to deliver 1 mL of 75 mg/mL or 150 mg/mL solution.
Alirocumab is available in cartons containing 1 or 2, pre-filled pens and 1 or 2, pre-filled syringes.
Store in a refrigerator at 36°F to 46°F (2°C to 8°C) in the outer carton in order to protect from light.
Do NOT freeze. Do NOT expose to extreme heat. Do NOT shake.
# Patient Counseling Information
For patient counseling information about alirocumab click here.
# Drug Packaging and Label
## Pen
## Injection
# Major Trials
## Synopsis
## Phase II Trials
This randomized, double-blind, placebo-controlled phase 2 trial of 92 patients with LDL-C≥100 mg/dL after treatment with 10 mg of atorvastatin for at least 7 weeks randomized patients to 8 weeks of therapy with either 80 mg of atorvastatin daily plus 150 mg SC alirocumab once every 2 weeks, 10 mg of atorvastatin daily plus 150 mg alirocumab once every 2 weeks, or 80 mg of atorvastatin daily plus SC placebo once every 2 weeks. The trial demonstrated a significant 73.2% reduction from baseline serum LDL-C cholesterol with 80 mg of atorvastatin plus alirocumab compared with 17.3% with the 80 mg atorvastatin plus placebo. Ninety percent of the patients who received alirocumab reached LDL-C concentrations lower than 70 mg/dL compared with 17% of those receiving atorvastatin alone. There were no significant safety signals and the drug was well tolerated.[2]
This randomized, double-blind, placebo-controlled phase 2 trial of 77 adults with heterozygous familial hypercholesterolaemia and LDL-C concentrations of ≥100 mg/dL or higher on stable diet and statin dose, with or without ezetimibe therapy were randomized (1:1:1:1:1) to 5 different treatment arms for 12 weeks: 150 mg SC alirocumab every 4 weeks, 200 mg SC alirocumab every 4 weeks, 300 mg SC alirocumab every 4 weeks, 150 mg SC alirocumab every 2 weeks, or SC placebo. Randomization was stratified by baseline use of ezetimibe. Alirocumab demonstrated a significant reduction in LDL-C at week 12 (28.9%, 31.5%, and 42.5% for the 150, 200, and 300 mg every 4 weeks respectively, and 67.9% for the 150 mg every 2 weeks dose, compared with 10.7% in the placebo arm) with no significant safety signal. There were no increases >3 x ULN in hepatic transaminases or creatine kinase (CK).[3]
This randomized, double-blind, placebo-controlled phase 2 trial of 183 patients with LDL-C ≥100 mg/dL on stable-dose atorvastatin for 6 or more weeks randomized patients to a 12 week treatment course in either one of 6 arms (1:1:1:1:1:1): subcutaneous (SC) placebo every 2 weeks, 50 mg SC alirocumab every 2 weeks, 100 mg SC alirocumab every 2 weeks, 150 mg SC alirocumab every 2 weeks, 200 mg SC alirocumab every 4 weeks alternating with placebo, or 300 mg SC alirocumab every 4 weeks alternating with placebo. Alirocumab demonstrated a significant dose-related reduction in serum LDL-C (40%, 64%, and 72% with 50, 100, and 150 mg respectively, and 43% and 48% with 200 and 300 mg respectively compared with 5% in placebo) with no major safety signals. [4]
## Phase III Trials
### ODYSSEY - COMBO I
COMBO I was a randomized, double blind, trial that randomized 316 adult patients with moderate to very high CV risk and elevated LDL-C despite maximal statin use to either SC alirocumab 75mg every 2 weeks for 52 weeks or a matched placebo. Alirocumab dose was increased at week 12 to 150mg every two weeks if LDL targets failed to be met by week 8. Alirocumab was generally well tolerated, with no reported safety signals in the 75mg or 150mg dose. Alirocumab treatment was associated with a significantly higher reduction in LDL-C from baseline to 24 weeks ( -48.2% for alirocumab vs. -2.3% for placebo; Δ:45.9%; 95% CI: 39.3-52.5; p<0.0001). Patients on alirocumab were more likely to reach LDL targets (75% for alirocumab vs. 9% for placebo). Patients on alirocumab demonstrated a substantial drop in LDL-C within the first 4 weeks, which was sustained to week 52.
COMBO II was a randomized, double-blind, double-dummy, trial that randomized 720 patients with elevated CV risk and LDL-C despite maximal statins use to either SC alirocumab 75 mg every 2 weeks (and PO placebo) or PO ezetimibe 10 mg daily (and SC placebo). Alirocumab was generally well tolerated, with no reported safety signals. Alirocumab treatment was associated with a significantly higher reduction in mean LDL-C values from baselines at week 24 (50.6 ± 1.4% for alirocumab vs. 20.7 ± 1.9% for ezetimibe; P < 0.0001). Patients on alirocumab were more likely to achieve LDL-C <1.8 mmol/L (77.0% vs. 45.6%; P < 0.0001). At week 24, mean LDL-C levels were 1.3 ± 0.04 mmol/L among patients receiving alirocumab, and 2.1 ± 0.05 mmol/L among patients receiving ezetimibe.[5]
### ODYSSEY -ALTERNATIVE
ALTERNATIVE was a randomized, double blind, double dummy trial that randomized 314 adult patients with moderate to very high CV risk and who underwent 2 weeks washout from lipid lowering therapies in a 2:1:1 ratio to 75mg alirocumab every two weeks, or 10mg oral ezetimibe daily, or 20mg oral atorvastatin daily for 24 weeks. Alirocumab was associated with the lowest rates of skeletal muscle associated AEs, followed by ezetimibe and atorvastatin, respectively. Alirocumab was generally well tolerated, with no significant safety signals. Alirocumab treatment was associated with a significantly higher reduction in mean LDL-C from baseline to week 24 compared to ezetimibe (-45.0% for alirocumab vs. -14.6% for ezetimibe; Δ:30.4%; 95% CI: 24.2-36.6; p<0.0001). Patients on alirocumab were more likely to achieve LDL targets (41.9% vs. 4.4%). Alirocumab patients demonstrated a substantial drop in LDL-C in the first 4 weeks, which was sustained for 24 weeks.
### ODYSSEY - MONO
ODYSSEY- MONO was a randomized, double blind, double dummy trial that enrolled 103 adult patients with a 10 year fatal CV risk of 1.00% to 4.99% and LDL-C>100mg/dl. Patients had no established history of coronary heart disease or any CHD risk equivalents. Additionally, patients were not receiving lipid lowering therapy for 4 weeks prior to randomization. Patients were randomized to receive 75mg of SC alirocumab twice weekly or oral ezetimibe 10mg once daily. Alirocumab dose was increased at week 12 to 150mg every two weeks if LDL targets failed to be met by week 8. Alirocumab treatment was associated with a significantly higher reduction in mean LDL-C from baseline to week 24 compared to ezetimibe (-47.2% for alirocumab vs. -15.6% for ezetimibe; Δ:31.6%; 95% CI: 23.0-40.2; p<0.0001). Alirocumab patients demonstrated a substantial drop in LDL-C in the first 4 weeks, which was sustained for 24 weeks. Alirocumab was well tolerated with no safety signals.
ODYSSEY FHI and FH II were multicenter, double-blind, placebo-controlled trials that enrolled a total of 735 heterozygous familial hypercholesterolemia patients and randomized them to either SC alirocumab 75-150 mg every 2 weeks or matching placebo for a total of 78 weeks, on top of a background of lipid lowering therapy.The primary endpoint was the prrcent change in LDL-C from baseline to week 24. Alirocumab administration was associated with a 57.9% reduction compared to placebo in the FH I population (P<0.0001), and a 51.4% reduction compared to placebo in the FH II population (P<0.0001). Alirocumab was well tolerated and there were no safety concerns.
Long term was a randomized, double-blind, placebo-controlled trial that enrolled 2341 patients at high risk for CV events with baseline LDL-C ≥70 mg/dL. Patients were randomized in 2:1 ratio to receive either 150mg SC alirocumab or equivalent placebo once every 2 weeks for 78 weeks. The primary efficacy end point was the percentage change in calculated LDL cholesterol level from baseline to week 24. Alirocumab treatment was associated with a 62% reduction in LDL-C compared to placebo (P<0.001). In an exploratory analysis, alirocumab was associated with a significant reduction in the rate of major adverse cardiovascular events (1.7% vs. 3.3%; hazard ratio, 0.52; 95% confidence interval, 0.31 to 0.90; nominal P=0.02). Alirocumab treatment was associated with a significantly higher incidence of myalgia (5.4% vs. 2.9%; P=0.006). [6]
### ODYSSEY - OPTIONS I
OPTIONS I was a randomized, double blind, trial that enrolled 355 patients with high or very high CVD risk and elevated LDL-C. All patients were receiving 20 or 40 mg of atorvastatin for at least 4 weeks prior to study enrollment. Patients were stratified by their baseline dose of 20mg atorvastatin vs. 40mg atorvastatin prior to randomization. Patients receiving 20mg of atorvastatin were randomized in a 1:1:1 ratio to receive add-on therapy of 75mg SC alirocumab twice weekly, or add-on therapy of 10mg oral ezetimibe once daily, or doubling the atorvastatin dose to 40mg once daily. Patients receiving a baseline 40mg of atorvastatin were randomized in a 1:1:1:1 ratio to receive add-on therapy of 75mg SC aloricumab twice weekly, or add-on therapy of 10mg oral ezetimibe once daily, or doubling atorvastatin dose to 80mg once daily, or switching to 40mg oral rosuvastatin once daily. Patients were followed for 24 weeks.
Among patients receiving a 20mg baseline dose of atorvastatin , add-on therapy of alirocumab was associated with a 44.1% reduction in mean LDL-C compared to 20.5% for ezetimibe, and 5.0% for 40mg atorvastatin. Patients on alirocumab add-on treatment were most likely to achieve LDL-C targets (79.2% for alirocumab vs. 50.3% for ezetimibe vs. 16.0% for 40mg atorvastatin).
Among patients receiving 40mg baseline dose of atorvastatin, add-on therapy of alirocumab was associated with a 54.0% reduction in mean LDL-C compared to 22.6% for ezetimibe, 4.8% for atorvastatin, and 21.5% for rosuvastatin. Patients on alirocumab add-on treatment were most likely to achieve LDL-C targets (77.2% for alirocumab vs. 54.2% for ezetimibe vs. 10.2% for 80mg atorvastatin, and 42.2% for rosuvastatin).
Alirocumab was well tolerated and showed no safety signals. Regardless of baseline dose of atorvastatin, patients experienced a substantial drop in mean LDL-C within the first 4 weeks which was sustained for 24 weeks.
### ODYSSEY - OPTIONS II
OPTIONS II was a randomized, double blind, trial that enrolled 305 patients with high or very high CVD risk and elevated LDL-C. All patients were receiving 10 or 20 mg of rosuvastatin for at least 4 weeks prior to study enrollment. Patients were stratified by their baseline dose of 10mg rosuvastatin vs. 20mg rosuvastatin prior to randomization. Patients receiving 10mg of rosuvastatin were randomized in a 1:1:1 ratio to receive add-on therapy of 75mg SC alirocumab twice weekly, or add-on therapy of 10mg oral ezetimibe once daily, or doubling the rosuvastatin dose to 20mg once daily. Patients receiving a baseline 20mg of rosuvastatin were randomized in a 1:1:1 ratio to receive add-on therapy of 75mg SC aloricumab twice weekly, or add-on therapy of 10mg oral ezetimibe once daily, or doubling rosuvastatin dose to 40mg once daily, Patients were followed for 24 weeks.
Among patients receiving a 10mg baseline dose of rosuvastatin , add-on therapy of alirocumab was associated with a 50.6% reduction in mean LDL-C compared to 14.4% for ezetimibe, and 16.3% for 20mg rosuvastatin. Patients on alirocumab add-on treatment were most likely to achieve LDL-C targets (77.8% for alirocumab vs. 43.1% for ezetimibe vs. 31.3% for 20mg rosuvastatin).
Among patients receiving 20mg baseline dose of rosuvastatin, add-on therapy of alirocumab was associated with a 36.3% reduction in mean LDL-C compared to 11.0% for ezetimibe, and 15.9% for rosuvastatin. Patients on alirocumab add-on treatment were most likely to achieve LDL-C targets (60.1% for alirocumab vs. 43.6% for ezetimibe vs. 29.9% for 40mg rosuvastatin). Results of the 20mg group missed the mark for statistical significance.
Alirocumab was well tolerated and showed no safety signals.
### ODYSSEY - CHOICE I
CHOICE I was a randomized, double blind, placebo controlled clinical trial that enrolled 803 adult patients with uncontrolled hypercholesterolemia and moderate to very high CVD risk receiving maximum dose of statins, have skeletal muscle symptoms associated with statin use or discontinued statin use. Patients were randomized in a 4:2:1 ratio to receive 300mg SC alirocumab every 4 weeks, or 75mg SC alirocumab every 2 weeks, or placebo for 48 weeks. Alirocumab treatment was well tolerated and showed no significant safety signals.
Among patients not receiving statins at baseline; those receiving alirocumab demonstrated a 52.7% reduction in mean LDL-C compared to 0.3% in placebo. Among patients receiving statins at baseline; those receiving alirocumab demonstrated a 48.8% reduction in mean LDL-C compared to 0.1% in placebo.
### ODYSSEY - CHOICE II
CHOICE II was a randomized, double blind, placebo controlled clinical trial that enrolled 233 adult patients with uncontrolled hypercholesterolemia and discontinued statins. This trial enrolled a large subgroup of patients who previously experienced statin associated myopathy. Patients were randomized in a 2:1:1 ratio to receive 150mg SC alirocumab every four weeks, or placebo, or 75mg SC alirocumab every two weeks. Primary effficacy endpoint was the percent change in mean LDL-C from baseline to week 24 in the ITT population compared to placebo. Alirocumab was well tolerated and demonstrated no safety signals. There was a low incidence of musculoskeletal symptoms across all groups. More injection site reactions were associated with the 150mg dose compared to placebo or the 75mg dose.
Patients receiving alirocumab had a 51.7% mean reduction in LDL-C compared to 4.7% in patients receiving placebo. The 75mg twice weekly dose demonstrated a higher efficacy against placebo compared to the 150mg every 4 weeks dose. More patients achieved target LDL-C levels in the 75mg dose group compared to 150mg and placebo groups (70.3% vs. 63.9% vs. 1.8%, respectively).
### ODYSSEY - HIGH FH
HIGH FH was a randomized, double blind, placebo controlled clinical trial that enrolled 107 adult patients with heterozygous familial hypercholesterolemia with poorly controlled cholesterol levels (LDL>150mg/dl) despite maximum stable dose of statins. Patients were randomized in a 2:1 fashion to receive 150mg SC alirocumab every two weeks or placebo for 78 weeks. Alirocumab was well tolerated and demonstrated no safety signals.
Patients on alirocumab had a 45.7% reduction in LDL-C from baseline to week 24 compared to 6.6% reduction in the placebo group. 41.0% of patients in the alirocumab group achieved LDL targets compared to 5.7% in the placebo group.
### ODYSSEY - JAPAN
ODYSSEY JAPAN was a randomized, double blind, placebo controlled clinical trial that enrolled 216 adult patients at 31 sites in Japan. Patients had heterozygous familial hypercholesterolemia and those with high cardiovascular risk with a history of coronary artery disease. Patients had uncontrolled hypercholesterolemia with an elevated LDL-C despite lipid lowering therapy. Eligible patients were randomized in a 2:1 fashion to receive 75mg SC alirocumab every two weeks or placebo, for a duration of 52 weeks. Surprisingly, patients receiving placebo experienced more SAEs compared to patients in the alirocumab group (12.5% for placebo and 7.0% for alirocumab). Alirocumab was well tolerated, and no safety concerns were observed.
Patients receiving alirocumab demonstrated a 62.5% reduction in mean LDL-C from baseline to week 24 compared to placebo; 1.6%. This was demonstrated with a substantial drop in the first 4 weeks and sustained for 52 weeks. 96.7% of patients receiving alirocumab achieved LDL-C targets compared to 10.2% of patients in the placebo group.
### ODYSSEY - ESCAPE
ESCAPE was a randomized, double blind, placebo-controlled trial of 62 adult patients with heterozygous familial hypercholesterolemia with high cardiovascular risk on previous statin treatment and currently undergoing apheresis therapy every week or two weeks for at least 4 weeks prior to randomization. Patients are randomized in a 2:1 ratio to receive 150mg SQ alirocumab once every two weeks or placebo. Alirocumab was well tolerated and generated no significant safety signal.
Patients receiving alirocumab demonstrated a 75% reduction in the rate of apheresis from weeks 7 to 18 compared to placebo. Patients experienced a substantial drop in LDL-C for the first two weeks and the effect was sustained for 52 weeks. Additionally, patients on alirocumab demonstrated a 50% reduction in rate of apheresis in weeks 15-18, compared to placebo.
# Cost-Effectiveness
Doses are administered every two weeks with a cost of $40 a day or $14,600 a year, substantially higher than some generic statins, which can cost as little as $0.10 a day. alirocumab is more expensive to manufacture than statins because it is made in live genetically engineered cells. Manufacturers argue that the drug is cost-effective because it will reduce medical costs of hospitalizations from stroke or myocardial infarction and that the price of the drug reflects its value. alirocumab used in combination with statins can lower cholesterol 40-70% [6] compared to statins that lower LDL an average of 40% [7]. Still, further research into the actual ability of the drug to reduce risk and complications is ongoing. Reduced prices and plans through insurers should help make the drug accessible to patients with lower ability to pay.
# Future Investigations
The following trials are currently underway and study designs, rationale, and results are not yet published.
## ODYSSEY - OUTCOMES
OUTCOMES will be a randomized, double blind, placebo controlled, clinical trial enrolling 18,000 patients over 40 years of age who are hospitalized for acute coronary syndrome with elevated cardiac biomarkers, or ECG changes consistent with ischemia or infarction, and evidence of obstructive coronary artery disease. Patients must demonstrate inadequate control of artherogenic lipoproteins despite maximal statin regimen. Patients will be randomized in a 1:1 ratio to receive 75mg SQ alirocumab every two weeks or a matched placebo for a period of 2 to 5 years. Alirocumab dose may be increased to 150mg SQ q2w if LDL-C is sustained above 50mg/dL after 4 weeks. Doses of alirocumab may be downtitrated from 150mg q2w to 75mg q2w if LDL-C is below 25mg/dL.
The primary endpoint is time to first of a composite of coronary heart disease death, non-fatal MI, Ischemic stroke, or unstable angina requiring hospitalization. Pre-specified secondary outcomes include time to each component of the primary endpoint. Additional genomic analysis will be performed on a subset of patients who consent to it.
The ODYSSEY Outcomes trial seeks to determine whether clinical outcomes are improved by lowering levels of LDL-C and other atherogenic lipoproteins below those achieved on optimal statin therapy alone. The trial is not designed to explore the safety of sustained, very low LDL-C levels. The trial will determine whether further reduction in cardiovascular risk can be achieved by addition of the monoclonal PCSK9 antibody, alirocumab, resulting in further reduction of LDL-C and other atherogenic lipoproteins.
## DM DYSLIPIDEMIA
Efficacy and safety of alirocumab in high cardiovascular risk patients with diabetes.
## DM INSULIN
Efficacy and safety of alirocumab in insulin-treated patients with Type 1 or Type 2 diabetes and high cardiovascular risk.
## KT
A randomized, double-blind, placebo-controlled, parallel group study to evaluate the efficacy and safety of alirocumab in high cardiovascular risk patients with hypercholesterolemia not adequately controlled with their lipid modifying therapy in South Korea and Taiwan. | https://www.wikidoc.org/index.php/Alirocumab | |
aa285cd08648986c99d6aa931b2b748c4a3958af | wikidoc | Hydrolysis | Hydrolysis
# Overview
Hydrolysis is a chemical reaction or process in which a chemical compound is broken down by reaction with water. It is the type of reaction that is used to break down certain polymers, especially those made by step-growth polymerization. Such polymer degradation is usually catalysed by either acid or alkali, attack often increasing with strength or pH.
# Types
In organic chemistry, hydrolysis can be considered as the reverse or opposite of condensation, a reaction in which two molecular fragments are joined for each water molecule produced. As hydrolysis may be a reversible reaction, condensation and hydrolysis can take place at the same time, with the position of equilibrium determining the amount of each product.
In inorganic chemistry, the word is often applied to solutions of salts and the reactions by which they are converted to new ionic species or to precipitates (oxides, hydroxides, or salts). The addition of a molecule of water to a chemical compound, without forming any other products is usually known as hydration, rather than hydrolysis.
In biochemistry, hydrolysis is considered the reverse or opposite of dehydration synthesis. In hydrolysis, a water molecule (H2O), is added, whereas in dehydration synthesis, a molecule of water is removed.
In electrochemistry, hydrolysis can also refer to the electrolysis of water. In hydrolysis, a voltage is applied across an aqueous medium, which produces a current and breaks the water into its constituents, hydrogen and oxygen.
In polymer chemistry, hydrolysis of polymers can occur during high-temperature processing such as injection moulding leading to chain degradation and loss of product integrity. Polymers most at risk include PET, polycarbonate, nylon and other polymers made by step-growth polymerization. Such materials must be dried prior to moulding.
# Hydrolysis of amide links
In other hydrolysis reactions, such as hydrolysis of an amide link into a carboxylic acid and an amine product or ammonia, only the carboxylic acid product has a hydroxyl group derived from the water. The amine product (or ammonia) gains the remaining hydrogen ion. A more specific case of the hydrolysis of an amide link is hydrolyzing the peptide links of amino acids.
Many polyamide polymers such as nylon 6,6 are attacked and hydrolysed by strong acids. Such attack leads to depolymerization and nylon products fail by fracturing when exposed to even small amounts of acid. The reaction is essentially the reverse of the synthesis from monomers:
Other polymers made by step-growth polymerization are susceptible to similar polymer degradation reactions. The problem is known as stress corrosion cracking.
# Hydrolysis of metal salts
(As noted above, hydrolysis of metal salts is more commonly known as hydration.) Many metal ions are strong Lewis acids, and in water they may undergo hydrolysis to form basic salts. Such salts contain a hydroxyl group that is directly bound to the metal ion in place of a water ligand. The positive charge on metal ions creates an attraction to water, a Lewis base with a non-binding electron pair on the oxygen atom, and alters water's electron density. This in turn increases the polarity of the O-H bond, which now acts as a proton donor under Brønsted-Lowry acid-base theory to release the hydrogen as a H+ ion, increasing the acidity of the solution. For example, aluminium chloride undergoes extensive hydrolysis in water such that the solution becomes very acidic.
This implies that hydrogen chloride is lost in the evaporation of AlCl3 solutions and the residue is a basic salt (in this case an an oxychloride) in place of AlCl3. Such behaviour is also seen with other metal chlorides such as ZnCl2, SnCl2, FeCl3 and lanthanide halides such as DyCl3. With some compounds such as TiCl4, the hydrolysis may go to completion and form the pure hydroxide or oxide, in this case TiO2.
# Hydrolysis of cellulose (Cellulolysis)
Cellulolytic is relating to or causing the hydrolysis of cellulose (i.e. cellulolytic bacteria, fungi or enzymes).
The hydrolysis into glucose (i.e. of cellulose or starch) is called saccharification.
# Irreversibility of hydrolysis under physiological conditions
Under physiological conditions (i.e. in dilute aqueous solution), a hydrolytic cleavage reaction, where the concentration of a metabolic precursor is low (on the order of 10-3 to 10-6 molar), is essentially thermodynamically irreversible. To give an example:
Assuming that x is the final concentration of products, and that C is the initial concentration of A, and W = = 55.5 molar, then x can be calculated with the equation:
let Kd×W = k:
then x = \frac {-k + \sqrt {k^2 + 4kC} } {2}.
For a value of C = 0.001 molar, and k = 1 molar, x/C > 0.999. Less than 0.1% of the original reactant would be present once the reaction is complete.
This theme of physiological irreversibility of hydrolysis is used consistently in metabolic pathways, since many biological processes are driven by the cleavage of anhydrous pyrophosphate bonds. | Hydrolysis
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Hydrolysis is a chemical reaction or process in which a chemical compound is broken down by reaction with water.[1][2] It is the type of reaction that is used to break down certain polymers, especially those made by step-growth polymerization. Such polymer degradation is usually catalysed by either acid or alkali, attack often increasing with strength or pH.
# Types
In organic chemistry, hydrolysis can be considered as the reverse or opposite of condensation, a reaction in which two molecular fragments are joined for each water molecule produced. As hydrolysis may be a reversible reaction, condensation and hydrolysis can take place at the same time, with the position of equilibrium determining the amount of each product.
In inorganic chemistry, the word is often applied to solutions of salts and the reactions by which they are converted to new ionic species or to precipitates (oxides, hydroxides, or salts). The addition of a molecule of water to a chemical compound, without forming any other products is usually known as hydration, rather than hydrolysis.
In biochemistry, hydrolysis is considered the reverse or opposite of dehydration synthesis. In hydrolysis, a water molecule (H2O), is added, whereas in dehydration synthesis, a molecule of water is removed.
In electrochemistry, hydrolysis can also refer to the electrolysis of water. In hydrolysis, a voltage is applied across an aqueous medium, which produces a current and breaks the water into its constituents, hydrogen and oxygen.
In polymer chemistry, hydrolysis of polymers can occur during high-temperature processing such as injection moulding leading to chain degradation and loss of product integrity. Polymers most at risk include PET, polycarbonate, nylon and other polymers made by step-growth polymerization. Such materials must be dried prior to moulding.
# Hydrolysis of amide links
In other hydrolysis reactions, such as hydrolysis of an amide link into a carboxylic acid and an amine product or ammonia, only the carboxylic acid product has a hydroxyl group derived from the water. The amine product (or ammonia) gains the remaining hydrogen ion. A more specific case of the hydrolysis of an amide link is hydrolyzing the peptide links of amino acids.
Many polyamide polymers such as nylon 6,6 are attacked and hydrolysed by strong acids. Such attack leads to depolymerization and nylon products fail by fracturing when exposed to even small amounts of acid. The reaction is essentially the reverse of the synthesis from monomers:
Other polymers made by step-growth polymerization are susceptible to similar polymer degradation reactions. The problem is known as stress corrosion cracking.
# Hydrolysis of metal salts
(As noted above, hydrolysis of metal salts is more commonly known as hydration.) Many metal ions are strong Lewis acids, and in water they may undergo hydrolysis to form basic salts. Such salts contain a hydroxyl group that is directly bound to the metal ion in place of a water ligand. The positive charge on metal ions creates an attraction to water, a Lewis base with a non-binding electron pair on the oxygen atom, and alters water's electron density. This in turn increases the polarity of the O-H bond, which now acts as a proton donor under Brønsted-Lowry acid-base theory to release the hydrogen as a H+ ion, increasing the acidity of the solution. For example, aluminium chloride undergoes extensive hydrolysis in water such that the solution becomes very acidic.
This implies that hydrogen chloride is lost in the evaporation of AlCl3 solutions and the residue is a basic salt (in this case an an oxychloride) in place of AlCl3. Such behaviour is also seen with other metal chlorides such as ZnCl2, SnCl2, FeCl3 and lanthanide halides such as DyCl3. With some compounds such as TiCl4, the hydrolysis may go to completion and form the pure hydroxide or oxide, in this case TiO2.
# Hydrolysis of cellulose (Cellulolysis)
Cellulolytic is relating to or causing the hydrolysis of cellulose (i.e. cellulolytic bacteria, fungi or enzymes).
The hydrolysis into glucose (i.e. of cellulose or starch) is called saccharification.
# Irreversibility of hydrolysis under physiological conditions
Under physiological conditions (i.e. in dilute aqueous solution), a hydrolytic cleavage reaction, where the concentration of a metabolic precursor is low (on the order of 10-3 to 10-6 molar), is essentially thermodynamically irreversible. To give an example:
Assuming that x is the final concentration of products, and that C is the initial concentration of A, and W = [H2O] = 55.5 molar, then x can be calculated with the equation:
let Kd×W = k:
then <math> x = \frac {-k + \sqrt {k^2 + 4kC} } {2}. </math>
For a value of C = 0.001 molar, and k = 1 molar, x/C > 0.999. Less than 0.1% of the original reactant would be present once the reaction is complete.
This theme of physiological irreversibility of hydrolysis is used consistently in metabolic pathways, since many biological processes are driven by the cleavage of anhydrous pyrophosphate bonds. | https://www.wikidoc.org/index.php/Alkaline_hydrolysis | |
c0d87ee03e2cfb4f680b31c08c64ca941cc769ac | wikidoc | Alkalinity | Alkalinity
Alkalinity or AT is a measure of the ability of a solution to neutralize acids to the equivalence point of carbonate or bicarbonate. Alkalinity is closely related to the acid neutralizing capacity (ANC) of a solution and ANC is often incorrectly used to refer to alkalinity. However, the acid neutralizing capacity refers to the combination of the solution and solids present (e.g., suspended matter, or aquifer solids), and the contribution of solids can dominate the ANC (see carbonate minerals below).
The alkalinity is equal to the stoichiometric sum of the bases in solution. In the natural environment carbonate alkalinity tends to make up most of the total alkalinity due to the common occurrence and dissolution of carbonate rocks and presence of carbon dioxide in the atmosphere. Other common natural components that can contribute to alkalinity include borate, hydroxide, phosphate, silicate, nitrate, dissolved ammonia, the conjugate bases of some organic acids and sulfide. Solutions produced in a laboratory may contain a virtually limitless number of bases that contribute to alkalinity. Alkalinity is usually given in the unit mEq/L (milliequivalent per liter).
Alkalinity is sometimes incorrectly used interchangeably with basicity. For example, the pH of a solution can be lowered by the addition of CO2. This will reduce the basicity; however, the alkalinity will remain unchanged (see example below).
# Theoretical treatment of alkalinity
In typical groundwater or seawater the measured alkalinity is set equal to:
AT = T + 2T + T + T + 2T + T + T − sws −
(Subscript T indicates the total concentration of the species in the solution as measured. This is opposed to the free concentration, which takes into account the significant amount of ion pair interactions that occur in seawater.)
Alkalinity can be measured by a sample with a strong acid until all the buffering capacity of the aforementioned ions above the pH of bicarbonate or carbonate is consumed. This point is functionally set to pH 4.5. At this point, all the bases of interest have been protonated to the zero level species, hence they no longer cause alkalinity. For example, the following reactions take place during the addition of acid to a typical seawater solution:
It can be seen from the above protonation reactions that most bases consume one proton (H+) to become a neutral species, thus increasing alkalinity by one per equivalent. CO3−2 however, will consume two protons before becoming a zero level species (CO2), thus it increases alkalinity by two per mole of CO3−2. and decrease alkalintiy, as they act as sources of protons. They are often represented collectively as T.
Alkalinity is typically reported as mg/L as CaCO3. This can be converted into milliEquivalents per Liter (mEq/L) by dividing by 50 (the approximate MW of CaCO3/2).
# Example problems
### Sum of contributing species
The following equations demonstrate the relative contributions of each component to the alkalinity of a typical seawater sample. Contributions are in μmol/kg-H2O and are obtained from A Handbook of Methods for the analysis of carbon dioxide parameters in seawater ","(Salinity = 35, pH = 8.1, Temp = 25°C).
AT = T + 2T + T + T + 3T + T + T − − −
Phosphates and Silicate, being nutrients are typically negligible. At pH = 8.1 and are also negligible. So,
AT = T + 2T + T + T −
AT = 1830 + 2*270 + 100 + 10 − 0.01
AT = 2480 μmol/kg−H2O
### Addition of CO2
The addition (or removal) of CO2 to a solution does not change the alkalinity. This is because the net reaction produces the same number of equivalents of positively contributing species (H+) as negative contributing species (HCO3- and/or CO3--).
At neutral pH's:
CO2 + H2O → HCO3− + H+
At high pH's:
CO2 + H2O → CO3−2 + 2H+
### Dissolution of carbonate rock
Addition of CO2 to a solution in contact with a solid can affect the alkalinity, especially for carbonate minerals in contact with groundwater or seawater . The dissolution (or precipitation) of carbonate rock has a strong influence on the alkalinity. This is because carbonate rock is composed of CaCO3 and its dissociation will add Ca+2 and CO3−2 into solution. Ca+2 will not influence alkalinity, but CO3−2 will increase alkalinity by 2 units. | Alkalinity
Alkalinity or AT is a measure of the ability of a solution to neutralize acids to the equivalence point of carbonate or bicarbonate. Alkalinity is closely related to the acid neutralizing capacity (ANC) of a solution and ANC is often incorrectly used to refer to alkalinity. However, the acid neutralizing capacity refers to the combination of the solution and solids present (e.g., suspended matter, or aquifer solids), and the contribution of solids can dominate the ANC (see carbonate minerals below).
The alkalinity is equal to the stoichiometric sum of the bases in solution. In the natural environment carbonate alkalinity tends to make up most of the total alkalinity due to the common occurrence and dissolution of carbonate rocks and presence of carbon dioxide in the atmosphere. Other common natural components that can contribute to alkalinity include borate, hydroxide, phosphate, silicate, nitrate, dissolved ammonia, the conjugate bases of some organic acids and sulfide. Solutions produced in a laboratory may contain a virtually limitless number of bases that contribute to alkalinity. Alkalinity is usually given in the unit mEq/L (milliequivalent per liter).
Alkalinity is sometimes incorrectly used interchangeably with basicity. For example, the pH of a solution can be lowered by the addition of CO2. This will reduce the basicity; however, the alkalinity will remain unchanged (see example below).
# Theoretical treatment of alkalinity
In typical groundwater or seawater the measured alkalinity is set equal to:
AT = [HCO3−]T + 2[CO3−2]T + [B(OH)4−]T + [OH−]T + 2[PO4−3]T + [HPO4−2]T + [SiO(OH)3−]T − [H+]sws − [HSO4−]
(Subscript T indicates the total concentration of the species in the solution as measured. This is opposed to the free concentration, which takes into account the significant amount of ion pair interactions that occur in seawater.)
Alkalinity can be measured by a sample with a strong acid until all the buffering capacity of the aforementioned ions above the pH of bicarbonate or carbonate is consumed. This point is functionally set to pH 4.5. At this point, all the bases of interest have been protonated to the zero level species, hence they no longer cause alkalinity. For example, the following reactions take place during the addition of acid to a typical seawater solution:
It can be seen from the above protonation reactions that most bases consume one proton (H+) to become a neutral species, thus increasing alkalinity by one per equivalent. CO3−2 however, will consume two protons before becoming a zero level species (CO2), thus it increases alkalinity by two per mole of CO3−2. [H+] and [HSO4−] decrease alkalintiy, as they act as sources of protons. They are often represented collectively as [H+]T.
Alkalinity is typically reported as mg/L as CaCO3. This can be converted into milliEquivalents per Liter (mEq/L) by dividing by 50 (the approximate MW of CaCO3/2).
# Example problems
### Sum of contributing species
The following equations demonstrate the relative contributions of each component to the alkalinity of a typical seawater sample. Contributions are in μmol/kg-H2O and are obtained from A Handbook of Methods for the analysis of carbon dioxide parameters in seawater "[1],"(Salinity = 35, pH = 8.1, Temp = 25°C).
AT = [HCO3−]T + 2[CO3−2]T + [B(OH)4−]T + [OH−]T + 3[PO4−3]T + [HPO4−2]T + [SiO(OH)3−]T − [H+] − [HSO4−] − [HF]
Phosphates and Silicate, being nutrients are typically negligible. At pH = 8.1 [HSO4−] and [HF] are also negligible. So,
AT = [HCO3-]T + 2[CO3−2]T + [B(OH)4−]T + [OH−]T − [H+]
AT = 1830 + 2*270 + 100 + 10 − 0.01
AT = 2480 μmol/kg−H2O
### Addition of CO2
The addition (or removal) of CO2 to a solution does not change the alkalinity. This is because the net reaction produces the same number of equivalents of positively contributing species (H+) as negative contributing species (HCO3- and/or CO3--).
At neutral pH's:
CO2 + H2O → HCO3− + H+
At high pH's:
CO2 + H2O → CO3−2 + 2H+
### Dissolution of carbonate rock
Addition of CO2 to a solution in contact with a solid can affect the alkalinity, especially for carbonate minerals in contact with groundwater or seawater . The dissolution (or precipitation) of carbonate rock has a strong influence on the alkalinity. This is because carbonate rock is composed of CaCO3 and its dissociation will add Ca+2 and CO3−2 into solution. Ca+2 will not influence alkalinity, but CO3−2 will increase alkalinity by 2 units. | https://www.wikidoc.org/index.php/Alkalinity | |
63d000afcbf54e5fd83d2da8ddb65a851a90ebc1 | wikidoc | Haloalkane | Haloalkane
# Overview
The haloalkanes (also known as halogenoalkanes or alkyl halides) are a group of chemical compounds, consisting of alkanes, such as methane or ethane, with one or more halogens linked, such as chlorine or fluorine, making them a type of organic halide. They are known under many chemical and commercial names. As fire extinguishants, propellants and solvents they have or had wide use. Some haloalkanes (those containing chlorine or bromine) are believed to have negative effects on the environment such as ozone depletion. The most widely known family within this group are the chlorofluorocarbons (CFCs).
# General
A haloalkane also known as alkyl halogenide, halogenalkane or halogenoalkane, and alkyl halide is a chemical compound derived from an alkane by substituting one or more hydrogen atoms with halogen atoms. Substitution with fluorine, chlorine, bromine and iodine results in fluoroalkanes, chloroalkanes, bromoalkanes and iodoalkanes, respectively. Mixed compounds are also possible, the best-known examples being the chlorofluorocarbons (CFCs) which are mainly responsible for ozone depletion. Haloalkanes are used in semiconductor device fabrication, as refrigerants, foam blowing agents, solvents, aerosol spray propellants, fire extinguishing agents, and chemical reagents.
Freon is a trade name for a group of chlorofluorocarbons used primarily as a refrigerant. The word Freon is a registered trademark belonging to DuPont.
There are 3 types of haloalkane. In primary (1°) haloalkanes the carbon which carries the halogen atom is only attached to one other alkyl group. However CH3Br is also a primary haloalkane, even though there is no alkyl group. In secondary (2°) haloalkanes the carbon that carries the halogen atom is attached to 2 alkyl groups. In tertiary (3°) haloalkanes the carbon that carries the halogen atom is attached to 3 alkyl groups.
## Chloro fluoro compounds (CFC, HCFC)
Chlorofluorocarbons (CFC) are compounds containing chlorine, fluorine and carbon only, that is they contain no hydrogen. They were formerly used widely in industry, for example as refrigerants, propellants, and cleaning solvents. Their use has been regularly prohibited by the Montreal Protocol, because of effects on the ozone layer (see ozone depletion). They are also a powerful greenhouse gas, in terms of carbon dioxide equivalence (over a time period of one hundred years) between 5000 and 8100 per kg.
Hydrochlorofluorocarbons (HCFCs) are of a class of haloalkanes where not all hydrogen has been replaced by chlorine or fluorine. They are used primarily as chlorofluorocarbon (CFC) substitutes, as the ozone depleting effects are only about 10% of the CFCs.
## Hydro fluoro compounds (HFC)
Hydrofluorocarbons (HFCs) contain no chlorine. They are composed entirely of carbon, hydrogen, and fluorine. They have an even lower global warming potential than HCFCs, and no known effects at all on the ozone layer. Only compounds containing chlorine and bromine are thought to harm the ozone layer. Fluorine itself is not ozone-toxic. However, HFCs and perfluorocarbons do have activity in the entirely different realm of greenhouse gases, which do not destroy ozone, but do cause global warming. Two groups of haloalkanes, hydrofluorocarbons (HFCs) and perfluorocarbons (PFCs), are targets of the Kyoto Protocol.
## Polymer haloalkanes
Chlorinated or fluorinated alkenes can be used for polymerization, resulting in polymer haloalkanes with notable chemical resistance properties. Important examples include polychloroethene (polyvinyl chloride, PVC), and polytetrafluoroethylene (PTFE, Teflon), but many more halogenated polymers exist.
# History
## Original development
Carbon tetrachloride was used in fire extinguishers and glass "anti-fire grenades" from the late nineteenth century until around the end of World War II. Experimentation with chloroalkanes for fire suppression on military aircraft began at least as early as the 1920s.
American engineer Thomas Midgley developed chlorofluorocarbons (CFC) in 1928 as a replacement for ammonia (NH3), chloromethane (CH3Cl), and sulfur dioxide (SO2), which are toxic but were in common use at the time as refrigerants. The new compound developed had to have a low boiling point and be non-toxic and generally non-reactive. In a demonstration for the American Chemical Society, Midgley flamboyantly demonstrated all these properties by inhaling a breath of the gas and using it to blow out a candle.
Midgley specifically developed CCl2F2. However, one of the attractive features is that there exists a whole family of the compounds, each having a unique boiling point which can suit different applications. In addition to their original application as refrigerants, chlorofluoroalkanes have been used as propellants in aerosol cans, cleaning solvents for circuit boards, and blowing agents for making expanded plastics (such as the expanded polystyrene used in packaging materials and disposable coffee cups).
## Development of alternatives
During World War II, various early chloroalkanes were in standard use in military aircraft by some combatants, but these early halons suffered from excessive toxicity. Nevertheless, after the war they slowly became more common in civil aviation as well.
In the 1960s, fluoroalkanes and bromofluoroalkanes became available and were quickly recognized as being among the most effective fire-fighting materials discovered. Much early research with Halon 1301 was conducted under the auspices of the US Armed Forces, while Halon 1211 was, initially, mainly developed in the UK. By the late 1960s they were standard in many applications where water and dry-powder extinguishers posed a threat of damage to the protected property, including computer rooms, telecommunications switches, laboratories, museums and art collections. Beginning with warships, in the 1970s, bromofluoroalkanes also progressively came to be associated with rapid knockdown of severe fires in confined spaces with minimal risk to personnel.
Work on alternatives for chlorofluorocarbons in refrigerants began in the late 1970s after the first warnings of damage to stratospheric ozone were published in the journal Nature in 1974 by Molina and Rowland (who shared the 1995 Nobel Prize for Chemistry for their work). Adding hydrogen and thus creating hydrochlorofluorocarbons (HCFC), chemists made the compounds less stable in the lower atmosphere, enabling them to break down before reaching the ozone layer. Later alternatives dispense with the chlorine, creating hydrofluorocarbons (HFC) with even shorter lifetimes in the lower atmosphere.
By the early 1980s, bromofluoroalkanes were in common use on aircraft, ships and large vehicles as well as in computer facilities and galleries. However, concern was beginning to be felt about the impact of chloroalkanes and bromoalkanes on the ozone layer. The Vienna Convention on Ozone Layer Protection did not cover bromofluoroalkanes as it was thought, at the time, that emergency discharge of extinguishing systems was too small in volume to produce a significant impact, and too important to human safety for restriction.
However, by the time of the Montreal Protocol it was realised that deliberate and accidental discharges during system tests and maintenance accounted for substantially larger volumes than emergency discharges, and consequently halons were brought into the treaty, albeit with many exceptions.
## Phase out
Use of certain chloroalkanes as solvents for large scale application, such as dry cleaning, have been phased out, for example, by the IPPC directive on greenhouse gases in 1994 and by the Volatile Organic Compounds (VOC) directive of the EU in 1997. Permitted chlorofluoroalkane uses are medicinal only.
Finally, bromofluoroalkanes have been largely phased out and the possession of such equipment is prohibited in some countries like the Netherlands and Belgium, from 1 January 2004, based on the Montreal Protocol and guidelines of the European Union.
Production of new stocks ceased in most (probably all) countries as of 1994. However many countries still require aircraft to be fitted with halon fire suppression systems because no safe and completely satisfactory alternative has been discovered for this application. There are also a few other, highly specialised, uses. These programs recycle halon through "halon banks" coordinated by the Halon Recycling Corporation to ensure that discharge to the atmosphere occurs only in a genuine emergency and to conserve remaining stocks.
On September 21, 2007, approximately 200 countries agreed to accelerate the elimination of hydrochlorofluorocarbons entirely by 2020 in a United Nations-sponsored Montreal summit. Developing nations were given until 2030. Many nations, such as the United States and China, who had previously resisted such efforts, signed the treaty.
# Nomenclature
## IUPAC nomenclature
The formal naming of haloalkanes should follow IUPAC nomenclature, which put the halogen as a prefix to the alkane. For example, ethane with bromine becomes bromoethane, methane with four chlorine groups becomes tetrachloromethane. However, many of these compounds have already an established trivial name, which is endorsed by the IUPAC nomenclature, for example chloroform (trichloromethane) and methylene chloride (dichloromethane). For unambiguity, this article follows the systematic naming scheme throughout.
## Alternative nomenclature for refrigerants
The refrigerant naming system is mainly used for fluorinated and chlorinated short alkanes for refrigerant use. In the US the standard is specified in ANSI/ASHRAE Standard 34-1992, with additional annual supplements. The specified ANSI/ASHRAE prefixes were FC (fluorocarbon) or R (refrigerant), but today most are prefixed by a more specific classification:
- CFC—list of chlorofluorocarbons
- HCFC—list of hydrochlorofluorocarbons
- HFC—list of hydrofluorocarbons
- FC—list of fluorocarbons
- PFC—list of perfluorocarbons (completely fluorinated)
The decoding system for CFC-01234a is:
- 0 = Number of double bonds (omitted if zero)
- 1 = Carbon atoms -1 (omitted if zero)
- 2 = Hydrogen atoms +1
- 3 = Fluorine atoms
- 4 = Replaced by Bromine ("B" prefix added)
- a = Letter added to identify isomers, the "normal" isomer in any number has the smallest mass difference on each carbon, and a, b, or c are added as the masses diverge from normal.
Other coding systems are in use as well.
## Overview of named compounds
# Synthesis
Alkyl halides can be synthesized from alkanes, alkenes, or alcohols.
## From alkanes
Alkanes react with halogens by free radical halogenation. In this reaction a hydrogen atom is removed from the alkane, then replaced by a halogen atom by reaction with a diatomic halogen molecule. Thus:
Steps 2 and 3 keep repeating, each providing the reactive intermediate needed for the other step. This is called a radical chain reaction. This reaction continues until the radicals are used up by one of three termination steps.
Note that Step 4 results in the same product as Step 3, the desired haloalkane, but through the destruction of two radicals. Step 5 is just the reverse of Step 1 and Step 6 accounts for the small contamination of this reaction by larger alkanes and their subsequent haloalkanes.
## From alkenes
Preparation of haloalkane:
- An alkene reacts with a dry hydrogen halide (HX) like hydrogen chloride (HCl) or hydrogen bromide (HBr) to form a haloalkane. The double bond of the alkene is replaced by two new bonds, one with the halogen and one with the hydrogen atom of the hydrohalic acid. Markovnikov's rule states that in this reaction, the halogen is more likely to become attached to the more substituted carbon. This is a electrophilic addition reaction. It gives a Markovnikov addition product. For example:
Water must be absent otherwise there will be a side product(water). The reaction is necessarily to be carried out in a dry inert solvent such as CCl4 or directly in the gaseous phase.
- Alkenes also react with halogens (X2) to form haloalkanes with two neighboring halogen atoms(Dihaloalkane). This is sometimes known as "decolorizing" the halogen, since the reagent X2 is colored and the product is usually colorless. For example:
## From alcohols
Tertiary alkanol reacts with hydrochloric acid directly to produce tertiary chloroalkane, but if primary or secondary alkanol is used, an activator such as zinc chloride is needed. Alternatively the conversion may be performed directly using thionyl chloride which is called the Darzen's process.The Darzen's process is one of the most convenient methods known because the bi-products are gaseous and thus escape, leaving behind pure alkyl chloride. Alkanol may likewise be converted to bromoalkane using hydrobromic acid or phosphorus tribromide or iodoalkane using red phosphorus and iodine (equivalent to phosphorus triiodide). Two examples:
## By substitution of alcohol in the absence of water
Halogenating agents are:
- Phosphorus pentachloride
- Thionyl chloride
- hydrogen chloride
- Phosphorus with Bromine
- Phosphorus with Iodine
- Hydrogen chloride with zinc chloride
# Reactions of haloalkanes
Haloalkanes are reactive towards nucleophiles. They are polar molecules: the carbon to which the halogen is attached is slightly electropositive where the halogen is slightly electronegative. This results in an electron deficient (electrophilic) carbon which, inevitably, attracts nucleophiles.
## Substitution reactions
Substitution reactions involve the replacement of the halogen with another molecule - thus leaving saturated hydrocarbons, as well as the halogen product.
Hydrolysis - a reaction in which water breaks a bond--is a good example of the nucleophilic nature of halogenoalkanes. The polar bond attracts a hydroxide ion, OH-. (NaOH(aq) being a common source of this ion). This OH- is a nucleophile with a clearly negative charge, as it has excess electrons it donates them to the carbon, which results in a covalent bond between the two. Thus C-X is broken by heterolytic fission resulting in a halide ion, X-. As can be seen, the OH is now attached to the alkyl group, creating an alcohol. (Hydrolysis of bromoethane, for example, yields ethanol).
One should note that within the halogen series, the C-X bond weakens as one goes to heavier halogens, and this affects the rate of reaction. Thus, the C-I of an iodoalkane generally reacts faster than the C-F of a fluoroalkane.
Apart from hydrolysis, there are a few other isolated examples of nucleophilic substitution:
- Ammonia (NH3) and bromoethane yields a mixture of ethylamine, diethylamine, and triethylamine (as their bromide salts), and tetraethylammonium bromide.
- Cyanide (CN-) added to bromoethane will form propionitrile (CH3CH2CN), a nitrile, and Br-. Nitriles can be further hydrolyzed into carboxylic acids.
## Elimination reactions
Rather than creating a molecule with the halogen substituted with something else, one can completely eliminate both the halogen and a nearby hydrogen, thus forming an alkene. For example, with bromoethane and NaOH in ethanol, the hydroxide ion OH- attracts a hydrogen atom - thus removing a hydrogen and bromine from bromoethane. This results in C2H4 (ethylene), H2O and Br-.
# Applications
## Propellant
One major use of CFCs has been as propellants in aerosol inhalers for drugs used to treat asthma. The conversion of these devices and treatments from CFC to halocarbons that do not have the same effect on the ozone layer is well under way. The hydrofluoroalkane propellant's ability to solubilize medications and excipients is markedly different from CFCs and as a result requires a considerable amount of effort to reformulate (a significant amount of development effort has also been required to develop non-CFC alternatives to CFC-based refrigerants, particularly for applications where the refrigeration mechanism cannot be modified or replaced). They have now been outlawed in all 50 U.S. states universally.
## Fire extinguishing
At high temperatures, halons decompose to release halogen atoms that combine readily with active hydrogen atoms, quenching the flame propagation reaction even when adequate fuel, oxygen and heat remains. The chemical reaction in a flame proceeds as a free radical chain reaction; by sequestering the radicals which propagate the reaction, halons are able to "poison" the fire at much lower concentrations than are required by fire suppressants using the more traditional methods of cooling, oxygen deprivation, or fuel dilution.
For example, Halon 1301 total flooding systems are typically used at concentrations no higher than 7% v/v in air, and can suppress many fires at 2.9% v/v. By contrast, carbon dioxide fire suppression flood systems are operated from 34% concentration by volume (surface-only combustion of liquid fuels) up to 75% (dust traps). Carbon dioxide can cause severe distress at concentrations of 3 to 6%, and has caused death by respiratory paralysis in a few minutes at 10% concentration. Halon 1301 causes only slight giddiness at its effective concentration of 5%, and even at 15% persons remain conscious but impaired and suffer no long term effects. (Experimental animals have also been exposed to 2% concentrations of Halon 1301 for 30 hours per week for 4 months, with no discernible health effects at all.) Halon 1211 also has low toxicity, although it is more toxic than Halon 1301, and thus considered unsuitable for flooding systems.
However, Halon 1301 fire suppression is not completely non-toxic; very high temperature flame, or contact with red-hot metal, can cause decomposition of Halon 1301 to toxic byproducts. The presence of such byproducts is readily detected because they include hydrobromic acid and hydrofluoric acid, which are intensely irritating. Halons are very effective on Class A (organic solids), B (flammable liquids and gases) and C (electrical) fires, but they are totally unsuitable for Class D (metal) fires, as they will not only produce toxic gas and fail to halt the fire, but in some cases pose a risk of explosion. Halons can be used on Class K (kitchen oils and greases) fires, but offer no advantages over specialised foams.
Halon 1211 is typically used in hand-held extinguishers, in which a stream of liquid halon is directed at a smaller fire by a user. The stream evaporates under reduced pressure, producing strong local cooling, as well as a high concentration of halon in the immediate vicinity of the fire. In this mode, extinguishment is achieved by cooling and oxygen deprivation at the core of the fire, as well as radical quenching over a larger area. After fire suppression, the halon moves away with the surrounding air, leaving no residue.
Halon 1301 is more usually employed in total flooding systems. In these systems, banks of halon cylinders are kept pressurised to about 4 MPa (600 PSI) with compressed nitrogen, and a fixed piping network leads to the protected enclosure. On triggering, the entire measured contents of one or more cylinders are discharged into the enclosure in a few seconds, through nozzles designed to ensure uniform mixing throughout the room. The quantity dumped is pre-calculated to achieve the desired concentration, typically 3-7% v/v. This level is maintained for some time, typically with a minimum of ten minutes and sometimes up to a twenty minute 'soak' time, to ensure all items have cooled so reignition is unlikely to occur, then the air in the enclosure is purged, generally via a fixed purge system that is activated by the proper authorities. During this time the enclosure may be entered by persons wearing SCBA. (There exists a common myth that this is because halon is highly toxic; in
fact it is because it can cause giddiness and mildly impaired perception, and also due to the risk of combustion byproducts.)
Flooding systems may be manually operated or automatically triggered by a VESDA or other automatic detection system. In the latter case, a warning siren and strobe lamp will first be activated for a few seconds to warn personnel to evacuate the area. The rapid discharge of halon and consequent rapid cooling fills the air with fog, and is accompanied by a loud, disorienting noise.
Due to environmental concerns, alternatives are being deployed.
Halon 1301 is also used in the F-16 fighters to prevent the fuel vapors in the fuel tanks from becoming explosive; when the aircraft enters area with the possibility of unfriendly fire, Halon 1301 is injected into the fuel tanks for one-time use. Due to environmental concerns, trifluoroiodomethane (CF3I) is being considered as an alternative.
# Environmental issues
Since the late 1970s the use of CFCs has been heavily regulated because of their destructive effects on the ozone layer. After the development of his electron capture detector, James Lovelock was the first to detect the widespread presence of CFCs in the air, finding a concentration of 60 parts per trillion of CFC-11 over Ireland. In a self-funded research expedition ending in 1973, Lovelock went on to measure the concentration of CFC-11 in both the Arctic and Antarctic, finding the presence of the gas in each of 50 air samples collected, but incorrectly concluding that CFC's are not hazardous to the environment. The experiment did however provide the first useful data on the presence of CFC's in the atmosphere. The damage caused by CFC's discovered by Sherry Rowland and Mario Molina who, after hearing a lecture on the subject of Lovelocks work, embarked on research resulting in the first published paper suggesting the connection in 1974. It turns out that one of CFCs' most attractive features—their unreactivity—has been instrumental in making them one of the most significant pollutants. CFCs' lack of reactivity gives them a lifespan which can exceed 100 years in some cases. This gives them time to diffuse into the upper stratosphere. Here, the sun's ultraviolet radiation is strong enough to break off the chlorine atom, which on its own is a highly reactive free radical. This catalyzes the break up of ozone into oxygen by means of a variety of mechanisms, of which the simplest is:
Since the chlorine is regenerated at the end of these reactions, a single Cl atom can destroy many thousands of ozone molecules. Reaction schemes similar to this one (but more complicated) are believed to be the cause of the ozone hole observed over the poles and upper latitudes of the Earth. Decreases in stratospheric ozone may lead to increases in skin cancer.
In 1975, the US state of Oregon enacted the world's first ban of CFCs (legislation introduced by Walter F. Brown). The United States and several European countries banned the use of CFCs in aerosol spray cans in 1978, but continued to use them in refrigeration, foam blowing, and as solvents for cleaning electronic equipment. By 1985, scientists observed a dramatic seasonal depletion of the ozone layer over Antarctica. International attention to CFCs resulted in a meeting of world diplomats in Montreal in 1987. They forged a treaty, the Montreal Protocol, which called for drastic reductions in the production of CFCs. On March 2, 1989, 12 European Community nations agreed to ban the production of all CFCs by the end of the century. In 1990, diplomats met in London and voted to significantly strengthen the Montreal Protocol by calling for a complete elimination of CFCs by the year 2000. By the year 2010 CFCs should be completely eliminated from developing countries as well.
Because the only available CFC gases in countries adhering to the treaty is from recycling, their prices have gone up considerably. A worldwide end to production should also terminate the smuggling of this material, such as from Mexico to the United States.
A number of substitutes for CFCs have been introduced. Hydrochlorofluorocarbons (HCFCs) are much more reactive than CFCs, so a large fraction of the HCFCs emitted break down in the troposphere, and hence are removed before they have a chance to affect the ozone layer. Nevertheless, a significant fraction of the HCFCs do break down in the stratosphere and they have contributed to more chlorine buildup there than originally predicted. Development of non-chlorine based chemical compounds as a substitute for CFCs and HCFCs continues. One such class are the hydrofluorocarbons (HFCs), which contain only hydrogen and fluorine. One of these compounds, HFC-134a, is now used in place of CFC-12 in automobile air conditioners; which itself may contribute to global warming (see HFC-134a).
There is concern that halons are being broken down in the atmosphere to bromine, which reacts with ozone, leading to depletion of the ozone layer (this is similar to the case of chlorofluorocarbons such as freon). These issues are complicated: the kinds of fires that require halon extinguishers to be put out will typically cause more damage to the ozone layer than the halon itself, not to mention human and property damage. However, fire extinguisher systems must be tested regularly, and these tests may lead to damage. As a result, some regulatory measures have been taken, and halons are being phased out in most of the world.
In the United States, purchase and use of freon gases is regulated by the Environmental Protection Agency, and substantial fines have been levied for their careless venting. Also, licenses, good for life, are required to buy or use these chemicals. The EPA website discusses these rules in great detail, and also lists numerous private companies that are approved to give examinations for these certificates.
There are two kinds of licenses. Obtaining a "Section 609" license to use CFCs to recharge old (pre-1993 model year) car air conditioners is fairly easy and requires only an online multiple choice test offered by several companies. Companies that use unlicensed technicians for CFC recharge operations are subject to a US$15,000 fine per technician by the EPA.
The "Section 608" license, needed to recharge CFC-using stationary and non-automobile mobile units, is also multiple choice but more difficult. A general knowledge test is required, plus separate exams for small size (such as home refrigerator) units, and for high and low pressure systems. These are respectively called Parts I, II, and III. A person who takes and passes all tests receives a "Universal" license; otherwise, one that is endorsed only for the respectively passed Parts. While the general knowledge and Part I exams can be taken online, taking them before a proctor (which has to be done for Parts II and III) lets the applicant pass these tests with lower scores.
# Safety
Haloalkanes in copper tubing open to the environment can turn into phosgene gas after coming in contact with extreme heat, such as while brazing or in a fire situation. Other ways that phosgene can be created is by passing the haloalkane through an internal combustion engine, or by inhaling it through a lit cigarette, cigar or pipe. Phosgene is a substance that was used as a chemical weapon in World War I. Low exposure can cause irritation, but high levels cause fluid to collect in the lungs, possibly resulting in death. | Haloalkane
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
The haloalkanes (also known as halogenoalkanes or alkyl halides) are a group of chemical compounds, consisting of alkanes, such as methane or ethane, with one or more halogens linked, such as chlorine or fluorine, making them a type of organic halide. They are known under many chemical and commercial names. As fire extinguishants, propellants and solvents they have or had wide use. Some haloalkanes (those containing chlorine or bromine) are believed to have negative effects on the environment such as ozone depletion. The most widely known family within this group are the chlorofluorocarbons (CFCs).
# General
A haloalkane also known as alkyl halogenide, halogenalkane or halogenoalkane, and alkyl halide is a chemical compound derived from an alkane by substituting one or more hydrogen atoms with halogen atoms. Substitution with fluorine, chlorine, bromine and iodine results in fluoroalkanes, chloroalkanes, bromoalkanes and iodoalkanes, respectively. Mixed compounds are also possible, the best-known examples being the chlorofluorocarbons (CFCs) which are mainly responsible for ozone depletion. Haloalkanes are used in semiconductor device fabrication, as refrigerants, foam blowing agents, solvents, aerosol spray propellants, fire extinguishing agents, and chemical reagents.
Freon is a trade name for a group of chlorofluorocarbons used primarily as a refrigerant. The word Freon is a registered trademark belonging to DuPont.
There are 3 types of haloalkane. In primary (1°) haloalkanes the carbon which carries the halogen atom is only attached to one other alkyl group. However CH3Br is also a primary haloalkane, even though there is no alkyl group. In secondary (2°) haloalkanes the carbon that carries the halogen atom is attached to 2 alkyl groups. In tertiary (3°) haloalkanes the carbon that carries the halogen atom is attached to 3 alkyl groups.
## Chloro fluoro compounds (CFC, HCFC)
Chlorofluorocarbons (CFC) are compounds containing chlorine, fluorine and carbon only, that is they contain no hydrogen. They were formerly used widely in industry, for example as refrigerants, propellants, and cleaning solvents. Their use has been regularly prohibited by the Montreal Protocol, because of effects on the ozone layer (see ozone depletion). They are also a powerful greenhouse gas, in terms of carbon dioxide equivalence (over a time period of one hundred years) between 5000 and 8100 per kg. [1]
Hydrochlorofluorocarbons (HCFCs) are of a class of haloalkanes where not all hydrogen has been replaced by chlorine or fluorine. They are used primarily as chlorofluorocarbon (CFC) substitutes, as the ozone depleting effects are only about 10% of the CFCs.
## Hydro fluoro compounds (HFC)
Hydrofluorocarbons (HFCs) contain no chlorine. They are composed entirely of carbon, hydrogen, and fluorine. They have an even lower global warming potential than HCFCs, and no known effects at all on the ozone layer. Only compounds containing chlorine and bromine are thought to harm the ozone layer. Fluorine itself is not ozone-toxic. [2] However, HFCs and perfluorocarbons do have activity in the entirely different realm of greenhouse gases, which do not destroy ozone, but do cause global warming. Two groups of haloalkanes, hydrofluorocarbons (HFCs) and perfluorocarbons (PFCs), are targets of the Kyoto Protocol. [2]
## Polymer haloalkanes
Chlorinated or fluorinated alkenes can be used for polymerization, resulting in polymer haloalkanes with notable chemical resistance properties. Important examples include polychloroethene (polyvinyl chloride, PVC), and polytetrafluoroethylene (PTFE, Teflon), but many more halogenated polymers exist.
# History
## Original development
Carbon tetrachloride was used in fire extinguishers and glass "anti-fire grenades" from the late nineteenth century until around the end of World War II. Experimentation with chloroalkanes for fire suppression on military aircraft began at least as early as the 1920s.
American engineer Thomas Midgley developed chlorofluorocarbons (CFC) in 1928 as a replacement for ammonia (NH3), chloromethane (CH3Cl), and sulfur dioxide (SO2), which are toxic but were in common use at the time as refrigerants. The new compound developed had to have a low boiling point and be non-toxic and generally non-reactive. In a demonstration for the American Chemical Society, Midgley flamboyantly demonstrated all these properties by inhaling a breath of the gas and using it to blow out a candle.[citation needed]
Midgley specifically developed CCl2F2. However, one of the attractive features is that there exists a whole family of the compounds, each having a unique boiling point which can suit different applications. In addition to their original application as refrigerants, chlorofluoroalkanes have been used as propellants in aerosol cans, cleaning solvents for circuit boards, and blowing agents for making expanded plastics (such as the expanded polystyrene used in packaging materials and disposable coffee cups).
## Development of alternatives
During World War II, various early chloroalkanes were in standard use in military aircraft by some combatants, but these early halons suffered from excessive toxicity. Nevertheless, after the war they slowly became more common in civil aviation as well.
In the 1960s, fluoroalkanes and bromofluoroalkanes became available and were quickly recognized as being among the most effective fire-fighting materials discovered. Much early research with Halon 1301 was conducted under the auspices of the US Armed Forces, while Halon 1211 was, initially, mainly developed in the UK. By the late 1960s they were standard in many applications where water and dry-powder extinguishers posed a threat of damage to the protected property, including computer rooms, telecommunications switches, laboratories, museums and art collections. Beginning with warships, in the 1970s, bromofluoroalkanes also progressively came to be associated with rapid knockdown of severe fires in confined spaces with minimal risk to personnel.
Work on alternatives for chlorofluorocarbons in refrigerants began in the late 1970s after the first warnings of damage to stratospheric ozone were published in the journal Nature in 1974 by Molina and Rowland (who shared the 1995 Nobel Prize for Chemistry for their work). Adding hydrogen and thus creating hydrochlorofluorocarbons (HCFC), chemists made the compounds less stable in the lower atmosphere, enabling them to break down before reaching the ozone layer. Later alternatives dispense with the chlorine, creating hydrofluorocarbons (HFC) with even shorter lifetimes in the lower atmosphere.
By the early 1980s, bromofluoroalkanes were in common use on aircraft, ships and large vehicles as well as in computer facilities and galleries. However, concern was beginning to be felt about the impact of chloroalkanes and bromoalkanes on the ozone layer. The Vienna Convention on Ozone Layer Protection did not cover bromofluoroalkanes as it was thought, at the time, that emergency discharge of extinguishing systems was too small in volume to produce a significant impact, and too important to human safety for restriction.
However, by the time of the Montreal Protocol it was realised that deliberate and accidental discharges during system tests and maintenance accounted for substantially larger volumes than emergency discharges, and consequently halons were brought into the treaty, albeit with many exceptions.
## Phase out
Use of certain chloroalkanes as solvents for large scale application, such as dry cleaning, have been phased out, for example, by the IPPC directive on greenhouse gases in 1994 and by the Volatile Organic Compounds (VOC) directive of the EU in 1997. Permitted chlorofluoroalkane uses are medicinal only.
Finally, bromofluoroalkanes have been largely phased out and the possession of such equipment is prohibited in some countries like the Netherlands and Belgium, from 1 January 2004, based on the Montreal Protocol and guidelines of the European Union.
Production of new stocks ceased in most (probably all) countries as of 1994. However many countries still require aircraft to be fitted with halon fire suppression systems because no safe and completely satisfactory alternative has been discovered for this application. There are also a few other, highly specialised, uses. These programs recycle halon through "halon banks" coordinated by the Halon Recycling Corporation[3] to ensure that discharge to the atmosphere occurs only in a genuine emergency and to conserve remaining stocks.
On September 21, 2007, approximately 200 countries agreed to accelerate the elimination of hydrochlorofluorocarbons entirely by 2020 in a United Nations-sponsored Montreal summit. Developing nations were given until 2030. Many nations, such as the United States and China, who had previously resisted such efforts, signed the treaty. [4]
# Nomenclature
## IUPAC nomenclature
The formal naming of haloalkanes should follow IUPAC nomenclature, which put the halogen as a prefix to the alkane. For example, ethane with bromine becomes bromoethane, methane with four chlorine groups becomes tetrachloromethane. However, many of these compounds have already an established trivial name, which is endorsed by the IUPAC nomenclature, for example chloroform (trichloromethane) and methylene chloride (dichloromethane). For unambiguity, this article follows the systematic naming scheme throughout.
## Alternative nomenclature for refrigerants
The refrigerant naming system is mainly used for fluorinated and chlorinated short alkanes for refrigerant use. In the US the standard is specified in ANSI/ASHRAE Standard 34-1992, with additional annual supplements.[5] The specified ANSI/ASHRAE prefixes were FC (fluorocarbon) or R (refrigerant), but today most are prefixed by a more specific classification:
- CFC—list of chlorofluorocarbons
- HCFC—list of hydrochlorofluorocarbons
- HFC—list of hydrofluorocarbons
- FC—list of fluorocarbons
- PFC—list of perfluorocarbons (completely fluorinated)
The decoding system for CFC-01234a is:
- 0 = Number of double bonds (omitted if zero)
- 1 = Carbon atoms -1 (omitted if zero)
- 2 = Hydrogen atoms +1
- 3 = Fluorine atoms
- 4 = Replaced by Bromine ("B" prefix added)
- a = Letter added to identify isomers, the "normal" isomer in any number has the smallest mass difference on each carbon, and a, b, or c are added as the masses diverge from normal.
Other coding systems are in use as well.
## Overview of named compounds
# Synthesis
Alkyl halides can be synthesized from alkanes, alkenes, or alcohols.
## From alkanes
Alkanes react with halogens by free radical halogenation. In this reaction a hydrogen atom is removed from the alkane, then replaced by a halogen atom by reaction with a diatomic halogen molecule. Thus:
Steps 2 and 3 keep repeating, each providing the reactive intermediate needed for the other step. This is called a radical chain reaction. This reaction continues until the radicals are used up by one of three termination steps.
Note that Step 4 results in the same product as Step 3, the desired haloalkane, but through the destruction of two radicals. Step 5 is just the reverse of Step 1 and Step 6 accounts for the small contamination of this reaction by larger alkanes and their subsequent haloalkanes.
## From alkenes
Preparation of haloalkane:
- An alkene reacts with a dry hydrogen halide (HX) like hydrogen chloride (HCl) or hydrogen bromide (HBr) to form a haloalkane. The double bond of the alkene is replaced by two new bonds, one with the halogen and one with the hydrogen atom of the hydrohalic acid. Markovnikov's rule states that in this reaction, the halogen is more likely to become attached to the more substituted carbon. This is a electrophilic addition reaction. It gives a Markovnikov addition product. For example:
Water must be absent otherwise there will be a side product(water). The reaction is necessarily to be carried out in a dry inert solvent such as CCl4 or directly in the gaseous phase.
- Alkenes also react with halogens (X2) to form haloalkanes with two neighboring halogen atoms(Dihaloalkane). This is sometimes known as "decolorizing" the halogen, since the reagent X2 is colored and the product is usually colorless. For example:
## From alcohols
Tertiary alkanol reacts with hydrochloric acid directly to produce tertiary chloroalkane, but if primary or secondary alkanol is used, an activator such as zinc chloride is needed. Alternatively the conversion may be performed directly using thionyl chloride which is called the Darzen's process.The Darzen's process is one of the most convenient methods known because the bi-products are gaseous and thus escape, leaving behind pure alkyl chloride. Alkanol may likewise be converted to bromoalkane using hydrobromic acid or phosphorus tribromide or iodoalkane using red phosphorus and iodine (equivalent to phosphorus triiodide). Two examples:
## By substitution of alcohol in the absence of water
Halogenating agents are:
- Phosphorus pentachloride
- Thionyl chloride
- hydrogen chloride
- Phosphorus with Bromine
- Phosphorus with Iodine
- Hydrogen chloride with zinc chloride
# Reactions of haloalkanes
Haloalkanes are reactive towards nucleophiles. They are polar molecules: the carbon to which the halogen is attached is slightly electropositive where the halogen is slightly electronegative. This results in an electron deficient (electrophilic) carbon which, inevitably, attracts nucleophiles.
## Substitution reactions
Substitution reactions involve the replacement of the halogen with another molecule - thus leaving saturated hydrocarbons, as well as the halogen product.
Hydrolysis - a reaction in which water breaks a bond--is a good example of the nucleophilic nature of halogenoalkanes. The polar bond attracts a hydroxide ion, OH-. (NaOH(aq) being a common source of this ion). This OH- is a nucleophile with a clearly negative charge, as it has excess electrons it donates them to the carbon, which results in a covalent bond between the two. Thus C-X is broken by heterolytic fission resulting in a halide ion, X-. As can be seen, the OH is now attached to the alkyl group, creating an alcohol. (Hydrolysis of bromoethane, for example, yields ethanol).
One should note that within the halogen series, the C-X bond weakens as one goes to heavier halogens, and this affects the rate of reaction. Thus, the C-I of an iodoalkane generally reacts faster than the C-F of a fluoroalkane.
Apart from hydrolysis, there are a few other isolated examples of nucleophilic substitution:
- Ammonia (NH3) and bromoethane yields a mixture of ethylamine, diethylamine, and triethylamine (as their bromide salts), and tetraethylammonium bromide.
- Cyanide (CN-) added to bromoethane will form propionitrile (CH3CH2CN), a nitrile, and Br-. Nitriles can be further hydrolyzed into carboxylic acids.
## Elimination reactions
Rather than creating a molecule with the halogen substituted with something else, one can completely eliminate both the halogen and a nearby hydrogen, thus forming an alkene. For example, with bromoethane and NaOH in ethanol, the hydroxide ion OH- attracts a hydrogen atom - thus removing a hydrogen and bromine from bromoethane. This results in C2H4 (ethylene), H2O and Br-.
# Applications
## Propellant
One major use of CFCs has been as propellants in aerosol inhalers for drugs used to treat asthma. The conversion of these devices and treatments from CFC to halocarbons that do not have the same effect on the ozone layer is well under way. The hydrofluoroalkane propellant's ability to solubilize medications and excipients is markedly different from CFCs and as a result requires a considerable amount of effort to reformulate (a significant amount of development effort has also been required to develop non-CFC alternatives to CFC-based refrigerants, particularly for applications where the refrigeration mechanism cannot be modified or replaced). They have now been outlawed in all 50 U.S. states universally.
## Fire extinguishing
At high temperatures, halons decompose to release halogen atoms that combine readily with active hydrogen atoms, quenching the flame propagation reaction even when adequate fuel, oxygen and heat remains. The chemical reaction in a flame proceeds as a free radical chain reaction; by sequestering the radicals which propagate the reaction, halons are able to "poison" the fire at much lower concentrations than are required by fire suppressants using the more traditional methods of cooling, oxygen deprivation, or fuel dilution.
For example, Halon 1301 total flooding systems are typically used at concentrations no higher than 7% v/v in air, and can suppress many fires at 2.9% v/v. By contrast, carbon dioxide fire suppression flood systems are operated from 34% concentration by volume (surface-only combustion of liquid fuels) up to 75% (dust traps). Carbon dioxide can cause severe distress at concentrations of 3 to 6%, and has caused death by respiratory paralysis in a few minutes at 10% concentration. Halon 1301 causes only slight giddiness at its effective concentration of 5%, and even at 15% persons remain conscious but impaired and suffer no long term effects. (Experimental animals have also been exposed to 2% concentrations of Halon 1301 for 30 hours per week for 4 months, with no discernible health effects at all.) Halon 1211 also has low toxicity, although it is more toxic than Halon 1301, and thus considered unsuitable for flooding systems.
However, Halon 1301 fire suppression is not completely non-toxic; very high temperature flame, or contact with red-hot metal, can cause decomposition of Halon 1301 to toxic byproducts. The presence of such byproducts is readily detected because they include hydrobromic acid and hydrofluoric acid, which are intensely irritating. Halons are very effective on Class A (organic solids), B (flammable liquids and gases) and C (electrical) fires, but they are totally unsuitable for Class D (metal) fires, as they will not only produce toxic gas and fail to halt the fire, but in some cases pose a risk of explosion. Halons can be used on Class K (kitchen oils and greases) fires, but offer no advantages over specialised foams.
Halon 1211 is typically used in hand-held extinguishers, in which a stream of liquid halon is directed at a smaller fire by a user. The stream evaporates under reduced pressure, producing strong local cooling, as well as a high concentration of halon in the immediate vicinity of the fire. In this mode, extinguishment is achieved by cooling and oxygen deprivation at the core of the fire, as well as radical quenching over a larger area. After fire suppression, the halon moves away with the surrounding air, leaving no residue.
Halon 1301 is more usually employed in total flooding systems. In these systems, banks of halon cylinders are kept pressurised to about 4 MPa (600 PSI) with compressed nitrogen, and a fixed piping network leads to the protected enclosure. On triggering, the entire measured contents of one or more cylinders are discharged into the enclosure in a few seconds, through nozzles designed to ensure uniform mixing throughout the room. The quantity dumped is pre-calculated to achieve the desired concentration, typically 3-7% v/v. This level is maintained for some time, typically with a minimum of ten minutes and sometimes up to a twenty minute 'soak' time, to ensure all items have cooled so reignition is unlikely to occur, then the air in the enclosure is purged, generally via a fixed purge system that is activated by the proper authorities. During this time the enclosure may be entered by persons wearing SCBA. (There exists a common myth that this is because halon is highly toxic; in
fact it is because it can cause giddiness and mildly impaired perception, and also due to the risk of combustion byproducts.)
Flooding systems may be manually operated or automatically triggered by a VESDA or other automatic detection system. In the latter case, a warning siren and strobe lamp will first be activated for a few seconds to warn personnel to evacuate the area. The rapid discharge of halon and consequent rapid cooling fills the air with fog, and is accompanied by a loud, disorienting noise.
Due to environmental concerns, alternatives are being deployed.[6]
Halon 1301 is also used in the F-16 fighters to prevent the fuel vapors in the fuel tanks from becoming explosive; when the aircraft enters area with the possibility of unfriendly fire, Halon 1301 is injected into the fuel tanks for one-time use. Due to environmental concerns, trifluoroiodomethane (CF3I) is being considered as an alternative.[7]
# Environmental issues
Template:Pollution
Since the late 1970s the use of CFCs has been heavily regulated because of their destructive effects on the ozone layer. After the development of his electron capture detector, James Lovelock was the first to detect the widespread presence of CFCs in the air, finding a concentration of 60 parts per trillion of CFC-11 over Ireland. In a self-funded research expedition ending in 1973, Lovelock went on to measure the concentration of CFC-11 in both the Arctic and Antarctic, finding the presence of the gas in each of 50 air samples collected, but incorrectly concluding that CFC's are not hazardous to the environment. The experiment did however provide the first useful data on the presence of CFC's in the atmosphere. The damage caused by CFC's discovered by Sherry Rowland and Mario Molina who, after hearing a lecture on the subject of Lovelocks work, embarked on research resulting in the first published paper suggesting the connection in 1974. It turns out that one of CFCs' most attractive features—their unreactivity—has been instrumental in making them one of the most significant pollutants. CFCs' lack of reactivity gives them a lifespan which can exceed 100 years in some cases. This gives them time to diffuse into the upper stratosphere. Here, the sun's ultraviolet radiation is strong enough to break off the chlorine atom, which on its own is a highly reactive free radical. This catalyzes the break up of ozone into oxygen by means of a variety of mechanisms, of which the simplest is:
Since the chlorine is regenerated at the end of these reactions, a single Cl atom can destroy many thousands of ozone molecules. Reaction schemes similar to this one (but more complicated) are believed to be the cause of the ozone hole observed over the poles and upper latitudes of the Earth. Decreases in stratospheric ozone may lead to increases in skin cancer.
In 1975, the US state of Oregon enacted the world's first ban of CFCs (legislation introduced by Walter F. Brown). The United States and several European countries banned the use of CFCs in aerosol spray cans in 1978, but continued to use them in refrigeration, foam blowing, and as solvents for cleaning electronic equipment. By 1985, scientists observed a dramatic seasonal depletion of the ozone layer over Antarctica. International attention to CFCs resulted in a meeting of world diplomats in Montreal in 1987. They forged a treaty, the Montreal Protocol, which called for drastic reductions in the production of CFCs. On March 2, 1989, 12 European Community nations agreed to ban the production of all CFCs by the end of the century. In 1990, diplomats met in London and voted to significantly strengthen the Montreal Protocol by calling for a complete elimination of CFCs by the year 2000. By the year 2010 CFCs should be completely eliminated from developing countries as well.
Because the only available CFC gases in countries adhering to the treaty is from recycling, their prices have gone up considerably. A worldwide end to production should also terminate the smuggling of this material, such as from Mexico to the United States.
A number of substitutes for CFCs have been introduced. Hydrochlorofluorocarbons (HCFCs) are much more reactive than CFCs, so a large fraction of the HCFCs emitted break down in the troposphere, and hence are removed before they have a chance to affect the ozone layer. Nevertheless, a significant fraction of the HCFCs do break down in the stratosphere and they have contributed to more chlorine buildup there than originally predicted. Development of non-chlorine based chemical compounds as a substitute for CFCs and HCFCs continues. One such class are the hydrofluorocarbons (HFCs), which contain only hydrogen and fluorine. One of these compounds, HFC-134a, is now used in place of CFC-12 in automobile air conditioners; which itself may contribute to global warming (see HFC-134a).
There is concern that halons are being broken down in the atmosphere to bromine, which reacts with ozone, leading to depletion of the ozone layer (this is similar to the case of chlorofluorocarbons such as freon). These issues are complicated: the kinds of fires that require halon extinguishers to be put out will typically cause more damage to the ozone layer than the halon itself, not to mention human and property damage. However, fire extinguisher systems must be tested regularly, and these tests may lead to damage. As a result, some regulatory measures have been taken, and halons are being phased out in most of the world.
In the United States, purchase and use of freon gases is regulated by the Environmental Protection Agency, and substantial fines have been levied for their careless venting. Also, licenses, good for life, are required to buy or use these chemicals. The EPA website discusses these rules in great detail, and also lists numerous private companies that are approved to give examinations for these certificates.
There are two kinds of licenses. Obtaining a "Section 609" license to use CFCs to recharge old (pre-1993 model year) car air conditioners is fairly easy and requires only an online multiple choice test offered by several companies. Companies that use unlicensed technicians for CFC recharge operations are subject to a US$15,000 fine per technician by the EPA.
The "Section 608" license, needed to recharge CFC-using stationary and non-automobile mobile units, is also multiple choice but more difficult. A general knowledge test is required, plus separate exams for small size (such as home refrigerator) units, and for high and low pressure systems. These are respectively called Parts I, II, and III. A person who takes and passes all tests receives a "Universal" license; otherwise, one that is endorsed only for the respectively passed Parts. While the general knowledge and Part I exams can be taken online, taking them before a proctor (which has to be done for Parts II and III) lets the applicant pass these tests with lower scores.
# Safety
Haloalkanes in copper tubing open to the environment can turn into phosgene gas after coming in contact with extreme heat, such as while brazing or in a fire situation. Other ways that phosgene can be created is by passing the haloalkane through an internal combustion engine, or by inhaling it through a lit cigarette, cigar or pipe. Phosgene is a substance that was used as a chemical weapon in World War I. Low exposure can cause irritation, but high levels cause fluid to collect in the lungs, possibly resulting in death. | https://www.wikidoc.org/index.php/Alkyl_halide | |
7525667c177877d847163254f3cb5afdafc4d117 | wikidoc | Alkylation | Alkylation
# Overview
Alkylation is the transfer of an alkyl group from one molecule to another. The alkyl group may be transferred as an alkyl carbocation, a free radical, a carbanion or a carbene (or their equivalents).
Alkylating agents are widely used in chemistry because the alkyl group is probably the most common group encountered in organic molecules. Many biological target molecules or their synthetic precursors comprise of an alkyl chain, with specific functional groups in a specific order. Selective alkylation, or adding parts to the chain with the desired functional groups, is used, especially if there is no commonly available biological precursor.
In oil refining contexts, alkylation refers to a particular alkylation of isobutane with olefins. It is a major aspect of the upgrading of petroleum.
Alkylating agents are often very toxic, due to their ability to alkylate DNA. They should be handled with proper PPE. This mechanism of toxicity is also responsible for the ability of some alkylating agents to perform as anti-cancer drugs in the form of alkylating antineoplastic agents, and also as chemical weapons such as mustard gas.
# Alkylating agents
Alkylating agents are classified according to their nucleophilic or electrophilic character.
## Nucleophilic alkylating agents
Examples include the use of organometallic compounds such as Grignard (organomagnesium), organolithium, organocopper, and organosodium reagents. These compounds typically can add to an electron-deficient carbon atom such as at a carbonyl group. Nucleophilic alkylating agents can also displace halide substituents on a carbon atom. In the presence of catalysts, they also alkylate alkyl and aryl halides, as exemplified by Suzuki couplings.
## Electrophilic alkylating agents
Electrophilic alkylating agents deliver the equivalent of an alkyl cation. Examples include the use of alkyl halides with a Lewis acid catalyst to alkylate aromatic substrates in Friedel-Crafts reactions. Alkyl halides can also react directly with amines to form C-N bonds; the same holds true for other nucleophiles such as alcohols, carboxylic acids, thiols, etc.
The electrophilic alkylating agents are commonly of concern as alkylating antineoplastic agent that attaches an alkyl group to DNA. The modify the information-encoding nucleic acids.
## Radical alkylating agents
## Carbene alkylating agents
Carbenes are extremely reactive and are known to attack even unactivated C-H bonds. Carbenes can be generated by elimination of a diazo group. A metal can form a carbene equivalent called a transition metal carbene complex.
# In biology
Methylation is the most common type of alkylation, being associated with the transfer of a methyl group. Methylation in nature is typically effected by vitamin B12-derived enzymes, where the methyl group is carried by cobalt. In methanogenesis, coenzyme M is methylated by tetrahydromethanopterin.
Electrophilic compounds may alkylate different nucleophiles in the body. The toxicity, carcinogenity, and paradoxically, cancer cell-killing abilities of different DNA alkylating agents are an example.
# Oil refining
In a standard oil refinery process, isobutane is alkylated with low-molecular-weight alkenes (primarily a mixture of propylene and butylene) in the presence of a strong acid catalyst, either sulfuric acid or hydrofluoric acid. In an oil refinery it is referred to as a sulfuric acid alkylation unit (SAAU) or a hydrofluoric alkylation unit, (HFAU). However, oil refinery employees may simply refer to the unit as the Alkyl unit. The catalyst is able to protonate the alkenes (propylene, butylene) to produce reactive carbocations, which alkylate isobutane. The reaction is carried out at mild temperatures (0 and 30 °C) in a two-phase reaction. The phases separate spontaneously, so the acid phase is vigoriously mixed with the hydrocarbon phase to create sufficient contact surface.
The product is called alkylate and is composed of a mixture of high-octane, branched-chain paraffinic hydrocarbons (mostly isopentane and isooctane). Alkylate is a premium gasoline blending stock because it has exceptional antiknock properties and is clean burning. The octane number of the alkylate depends mainly upon the kind of olefins used and upon operating conditions. For example, isooctane results from combining butylene with isobutane and has an octane rating of 100 by definition. There are other products in the alkylate, so the octane rating will vary accordingly.
Most crude oils contain only 10 to 40 percent of their hydrocarbon constituents in the gasoline range, so refineries use cracking processes, which convert high molecular weight hydrocarbons into smaller and more volatile compounds. Polymerization converts small gaseous olefins into liquid gasoline-size hydrocarbons. Alkylation processes transform small olefin and iso-paraffin molecules into larger iso-paraffins with a high octane number.
Combining cracking, polymerization, and alkylation can result in a gasoline yield representing 70 percent of the starting crude oil. More advanced processes, such as cyclicization of paraffins and dehydrogenation of naphthenes to form aromatic hydrocarbons in a catalytic reformer, have also been developed to increase the octane rating of gasoline. Modern refinery operation can be shifted to produce almost any fuel type with specified performance criteria from a single crude feedstock.
In the entire range of refinery processes, alkylation is a very important process that enhances the yield of high-octane gasoline. | Alkylation
# Overview
Alkylation is the transfer of an alkyl group from one molecule to another. The alkyl group may be transferred as an alkyl carbocation, a free radical, a carbanion or a carbene (or their equivalents).
Alkylating agents are widely used in chemistry because the alkyl group is probably the most common group encountered in organic molecules. Many biological target molecules or their synthetic precursors comprise of an alkyl chain, with specific functional groups in a specific order. Selective alkylation, or adding parts to the chain with the desired functional groups, is used, especially if there is no commonly available biological precursor.
In oil refining contexts, alkylation refers to a particular alkylation of isobutane with olefins. It is a major aspect of the upgrading of petroleum.
Alkylating agents are often very toxic, due to their ability to alkylate DNA. They should be handled with proper PPE. This mechanism of toxicity is also responsible for the ability of some alkylating agents to perform as anti-cancer drugs in the form of alkylating antineoplastic agents, and also as chemical weapons such as mustard gas.
# Alkylating agents
Alkylating agents are classified according to their nucleophilic or electrophilic character.
## Nucleophilic alkylating agents
Examples include the use of organometallic compounds such as Grignard (organomagnesium), organolithium, organocopper, and organosodium reagents. These compounds typically can add to an electron-deficient carbon atom such as at a carbonyl group. Nucleophilic alkylating agents can also displace halide substituents on a carbon atom. In the presence of catalysts, they also alkylate alkyl and aryl halides, as exemplified by Suzuki couplings.
## Electrophilic alkylating agents
Electrophilic alkylating agents deliver the equivalent of an alkyl cation. Examples include the use of alkyl halides with a Lewis acid catalyst to alkylate aromatic substrates in Friedel-Crafts reactions. Alkyl halides can also react directly with amines to form C-N bonds; the same holds true for other nucleophiles such as alcohols, carboxylic acids, thiols, etc.
The electrophilic alkylating agents are commonly of concern as alkylating antineoplastic agent that attaches an alkyl group to DNA. The modify the information-encoding nucleic acids.
## Radical alkylating agents
## Carbene alkylating agents
Carbenes are extremely reactive and are known to attack even unactivated C-H bonds. Carbenes can be generated by elimination of a diazo group. A metal can form a carbene equivalent called a transition metal carbene complex.
# In biology
Methylation is the most common type of alkylation, being associated with the transfer of a methyl group. Methylation in nature is typically effected by vitamin B12-derived enzymes, where the methyl group is carried by cobalt. In methanogenesis, coenzyme M is methylated by tetrahydromethanopterin.
Electrophilic compounds may alkylate different nucleophiles in the body. The toxicity, carcinogenity, and paradoxically, cancer cell-killing abilities of different DNA alkylating agents are an example.
# Oil refining
In a standard oil refinery process, isobutane is alkylated with low-molecular-weight alkenes (primarily a mixture of propylene and butylene) in the presence of a strong acid catalyst, either sulfuric acid or hydrofluoric acid. In an oil refinery it is referred to as a sulfuric acid alkylation unit (SAAU) or a hydrofluoric alkylation unit, (HFAU). However, oil refinery employees may simply refer to the unit as the Alkyl unit. The catalyst is able to protonate the alkenes (propylene, butylene) to produce reactive carbocations, which alkylate isobutane. The reaction is carried out at mild temperatures (0 and 30 °C) in a two-phase reaction. The phases separate spontaneously, so the acid phase is vigoriously mixed with the hydrocarbon phase to create sufficient contact surface.
The product is called alkylate and is composed of a mixture of high-octane, branched-chain paraffinic hydrocarbons (mostly isopentane and isooctane). Alkylate is a premium gasoline blending stock because it has exceptional antiknock properties and is clean burning. The octane number of the alkylate depends mainly upon the kind of olefins used and upon operating conditions. For example, isooctane results from combining butylene with isobutane and has an octane rating of 100 by definition. There are other products in the alkylate, so the octane rating will vary accordingly.
Most crude oils contain only 10 to 40 percent of their hydrocarbon constituents in the gasoline range, so refineries use cracking processes, which convert high molecular weight hydrocarbons into smaller and more volatile compounds. Polymerization converts small gaseous olefins into liquid gasoline-size hydrocarbons. Alkylation processes transform small olefin and iso-paraffin molecules into larger iso-paraffins with a high octane number.
Combining cracking, polymerization, and alkylation can result in a gasoline yield representing 70 percent of the starting crude oil. More advanced processes, such as cyclicization of paraffins and dehydrogenation of naphthenes to form aromatic hydrocarbons in a catalytic reformer, have also been developed to increase the octane rating of gasoline. Modern refinery operation can be shifted to produce almost any fuel type with specified performance criteria from a single crude feedstock.
In the entire range of refinery processes, alkylation is a very important process that enhances the yield of high-octane gasoline.
# External links
- Macrogalleria page on polycarbonate production
- Alkylating+agents at the US National Library of Medicine Medical Subject Headings (MeSH)
Template:WS
Template:Jb1 | https://www.wikidoc.org/index.php/Alkylating_agent | |
914c3269d6f1b6d157b609bf36951f3bbc0e0999 | wikidoc | Cetirizine | Cetirizine
Synonyms / Brand Names:
# Dosing and Administration
Adults and Children 12 Years of Age and Older: The recommended dose of ZYRTEC-D 12 HOUR™ Extended Release Tablets is one tablet twice daily for adults and children 12 years of age and older.
Dose Adjustment for Renal and Hepatic Impairment: In patients with decreased renal function(creatinine clearance 11-31 mL/min), patients on hemodialysis (creatinine clearance less than 7 mL/min), and in hepatically impaired patients, a dose of one tablet once daily is recommended.
ZYRTEC-D 12 HOUR™ Extended Release Tablets may be given with or without food and should be swallowed whole, avoiding breaking or chewing the tablet.
Adapted from the FDA Package Insert. | Cetirizine
Synonyms / Brand Names:
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Dosing and Administration
Adults and Children 12 Years of Age and Older: The recommended dose of ZYRTEC-D 12 HOUR™ Extended Release Tablets is one tablet twice daily for adults and children 12 years of age and older.
Dose Adjustment for Renal and Hepatic Impairment: In patients with decreased renal function(creatinine clearance 11-31 mL/min), patients on hemodialysis (creatinine clearance less than 7 mL/min), and in hepatically impaired patients, a dose of one tablet once daily is recommended.
ZYRTEC-D 12 HOUR™ Extended Release Tablets may be given with or without food and should be swallowed whole, avoiding breaking or chewing the tablet.
Adapted from the FDA Package Insert. | https://www.wikidoc.org/index.php/All_Day_Allergy | |
d3235ad6661185f446c48a3fb8e9301fb082975a | wikidoc | Polyploidy | Polyploidy
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
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# Overview
Polyploidy occurs in cells and organisms when there are more than two homologous sets of chromosomes. Polyploid types are labelled according to the number of chromosome sets in the nucleus:
- triploid (three sets; 3x), for example the genus Tardigrada
- tetraploid (four sets; 4x), for example Salmonidae fish
- pentaploid (five sets; 5x)
- hexaploid (six sets; 6x), for example wheat
- oktoploid (eight sets; 8x), for example Acipenser (genus of sturgeon fish)
- dekaploid (ten sets; 10x), for example certain strawberries
- dodecaploid (twelve sets; 12x), for example the plant Celosia argentea
Most organisms are normally diploid; polyploidy may occur due to abnormal cell division. It is most commonly found in plants. Haploidy may also occur as a normal stage in an organism's life. A haploid has only one set of chromosomes.
Polyploidy occurs in some animals, such as goldfish, salmon, and salamanders, but is especially common among ferns and flowering plants, including both wild and cultivated species. Wheat, for example, after millennia of hybridization and modification by humans, has strains that are diploid (two sets of chromosomes), tetraploid (four sets of chromosomes) with the common name of durum or macaroni wheat, and hexaploid (six sets of chromosomes) with the common name of bread wheat. Many agriculturally important plants of the genus Brassica are also tetraploids; their relationship is described by the Triangle of U.
The occurrence of polyploidy is a mechanism of speciation and is known to have resulted in new species of the plant Salsify (also known as "goatsbeard").
Examples in animals are more common in the ‘lower’ forms such as flatworms, leeches, and brine shrimp. Polyploid animals are often sterile, so they often reproduce by parthenogenesis. Polyploid salamanders and lizards are also quite common and parthenogenetic. While mammalian liver cells are polyploid, rare instances of polyploid mammals are known, but most often result in prenatal death.
The only known exception to this rule is an octodontid rodent of Argentina's harsh desert regions, known as the Red Viscacha-Rat (Tympanoctomys barrerae). This rodent is not a rat, but kin to number is 102 and so its cells are roughly twice normal size. Its closest living relation is Octomys mimax, the Andean Viscacha-Rat of the same family, whose 2n=56. It is surmised that an Octomys-like ancestor produced tetraploid (i.e., 4n=112) offspring that were, by virtue of their doubled chromosomes, reproductively isolated from their parents; but that these likely survived the ordinarily catastrophic effects of polyploidy in mammals by shedding (via translocation or some similar mechanism) the "extra" set of sex chromosomes gained at this doubling.
Polyploidy can be induced in cell culture by some chemicals: the best known is colchicine, which can result in chromosome doubling, though its use may have other less obvious consequences as well.
There are large number of polyploid crop varieties - See Polyploid Crops below.
There are few naturally occurring polyploid conifers. One example is the giant tree Sequoia sempervirens or Coast Redwood which is a hexaploid (6x) with 66 chromosomes (2n=6x=66), although the origin is unclear .
# Polyploidy in humans (Aneuploidy)
True polyploidy rarely occurs in humans, although it occurs in some tissues (especially in the liver). Polyploidy refers to a numerical change in a whole set of chromosomes. Organisms in which a particular chromosome, or chromosome segment, is under- or overrepresented are said to be aneuploid (from the Greek words meaning "not," "good," and "fold"). Therefore the distinction between aneuploidy and polyploidy is that aneuploidy refers to a numerical change in part of the chromosome, whereas polyploidy refers to a numerical change in the whole set of chromosomes. : Cytogenetic Variation (p109)]
Aneuploidy occurs in humans in the form of triploidy (69,XXX) and tetraploidy (92,XXXX), not to be confused with 47,XXX or 48, XXXX aneuploidy. Triploidy, usually due to polyspermy, occurs in about 2-3% of all human pregnancies and ~15% of miscarriages. The vast majority of triploid conceptions end as miscarriage and those that do survive to term typically die shortly after birth. In some cases survival past birth may occur longer if there is mixoploidy with both a diploid and a triploid cell population present.
Triploidy may be the result of either digyny (the extra haploid set is from the mother) or diandry (the extra haploid set is from the father). Diandry is almost always caused by the fertilization of an egg by two sperm (dispermy). Digyny is most commonly caused by either failure of one meiotic division during oogenesis leading to a diploid oocyte or failure to extrude one polar body from the oocyte. Diandry appears to predominate among early miscarriages while digyny predominates among triploidy that survives into the fetal period. However, among early miscarriages, digyny is also more common in those cases <8.5 weeks gestational age or those in which an embryo is present. There are also two distinct phenotypes in triploid placentas and fetuses that are dependent on the origin of the extra haploid set. In digyny there is typically an asymmetric poorly grown fetus, with marked adrenal hypoplasia and a very small placenta. In diandry, the fetus (when present) is typically normally grown or symmetrically growth restricted, with normal adrenal glands and an abnormally large cystic placenta that is called a partial hydatidiform mole. These parent-of-origin effects reflect the effects of genomic imprinting.
Complete tetraploidy is more rarely diagnosed than triploidy, but is observed in 1-2% of early miscarriages. However, some tetraploid cells are not uncommonly found in chromosome analysis at prenatal diagnosis and these are generally considered ‘harmless’. It is not clear whether these tetraploid cells simply tend to arise during in vitro cell culture or whether they are also present in placental cells in vivo. There are, at any rate, very few clinical reports of fetuses/infants diagnosed with tetraploidy mosaicism.
Mixoploidy is quite commonly observed in human preimplantation embryos and includes haploid/diploid as well as diploid/tetraploid mixed cell populations. It is unknown whether these embryos fail to implant and are therefore rarely detected in ongoing pregnancies or if there is simply a selective process favoring the diploid cells.
# Polyploidy in plants
Polyploidy is pervasive in plants and some estimates suggest that 30-80% of living plant species are polyploid, and many lineages show evidence of ancient polyploidy (paleopolyploidy) in their genomes. Huge explosions in angiosperm species diversity appear to have coincided with the timing of ancient genome duplications shared by many species. Polyploid plants can arise spontaneously in nature by several mechanisms, including meiotic or mitotic failures, and fusion of unreduced (2n) gametes. Both autopolyploids (eg. potato) and allopolyploids (eg. canola, wheat, cotton) can be found among both wild and domesticated plant species. Most polyploids display heterosis relative to their parental species, and may display novel variation or morphologies that may contribute to the processes of speciation and eco-niche exploitation. The mechanisms leading to novel variation in newly formed allopolyploids may include gene dosage effects (resulting from more numerous copies of genome content), the reunion of divergent gene regulatory hierarchies, chromosomal rearrangements, and epigenetic remodeling, all of which affect gene content and/or expression levels. Many of these rapid changes may contribute to reproductive isolation and speciation.
## Polyploid crops
Polyploid plants tend to be larger and better at flourishing in early succession habitats such as farm fields. In the breeding of crops, the tallest and best thriving plants are selected for. Thus, many crops (and agricultural weeds) may have unintentionally been bred to a higher level of ploidy.
The induction of polyploids is a common technique to overcome the sterility of a hybrid species during plant breeding. For example, Triticale is the hybrid of wheat (Triticum turgidum) and rye (Secale cereale). It combines sought-after characteristics of the parents, but the initial hybrids are sterile. After polyploidization, the hybrid becomes fertile and can thus be further propagated to become triticale.
In some situations polyploid crops are preferred because they are sterile. For example many seedless fruit varieties are seedless as a result of polyploidy. Such crops are propagated using asexual techniques such as grafting.
Polyploidy in crop plants is most commonly induced by treating seeds with the chemical colchicine.
## Examples of Polyploid Crops
- Triploid crops: banana, apple, ginger, watermelon, citrus
- Tetraploid crops: durum or macaroni wheat, maize, cotton, potato, cabbage, leek, tobacco, peanut, kinnow, Pelargonium
- Hexaploid crops: chrysanthemum, bread wheat, triticale, oat
- Octaploid crops: strawberry, dahlia, pansies, sugar cane
Some crops are found in a variety of ploidy. Apples, tulips and lilies are commonly found as both diploid and as triploid. Daylilies (Hemerocallis) cultivars are available as either diploid or tetraploid. Kinnows can be tetraploid, diploid, or triploid.
# Terminology
## Autopolyploidy
Autopolyploids are polyploids with multiple chromosome sets derived from a single species. Autopolyploids can arise from a spontaneous, naturally occurring genome doubling (for example, the potato). Others might form following fusion of 2n gametes unreduced gametes). Bananas and apples can be found as triploid autopolyploids. Autopolyploid plants typically display polysomic inheritance, and are therefore often infertile and propagated clonally
## Allopolyploidy
Allopolyploids are polyploids with chromosomes derived from different species. Triticale is an example of an allopolyploid, having six chromosome sets, four from wheat (Triticum turgidum) and two from rye (Secale cereale). Amphidiploid is another word for an allopolyploid. Some of the best examples of allopolyploids come from the Brassicas, and the Triangle of U describes the relationships among the three common diploid Brassicas (B. oleracea, B. rapa, and B. nigra) and three allotetraploids (B. napus, B. juncea, and B. carinata) derived from hybridization among the diploids.
## Homoeologous
The term is used to describe the relationship of similar chromosomes or parts of chromosomes brought together following inter-species hybridization and allopolyploidization, and whose relationship was completely homologous in an ancestral species. In allopolyploids, the homologous chromosomes within each parental sub-genome should pair faithfully during meiosis, leading to disomic inheritance; however in some allopolyploids, the homoeologous chromosomes of the parental genomes may be nearly as similar to one another as the homolgous chromosomes, leading to tetrasomic inheritance (four chromosomes pairing at meiosis), intergenomic recombination, and reduced fertility.
## Homologous
The term is used to describe the relationship of similar chromosomes that pair at mitosis and meiosis. In a diploid, one homolog is derived from the male parent (pollen or sperm) and one is derived from the female parent (egg). During meiosis and gametogenesis, homologous chromosomes pair and exchange genetic material by recombination, leading to the production of sperm/pollen or eggs with chromosome haplotypes containing novel genetic variation.
## Karyotype
A karyotype is the characteristic chromosome complement of a eukaryote species. The preparation and study of karyotypes is part of cytology and, more specifically, cytogenetics.
Although the replication and transcription of DNA is highly standardized in eukaryotes, the same cannot be said for their karotypes, which are highly variable between species in chromosome number and in detailed organization despite being constructed out of the same macromolecules. In some cases there is even significant variation within species. This variation provides the basis for a range of studies in what might be called evolutionary cytology.
## Paralogous
The term is used to describe the relationship among duplicated genes or portions of chromosomes that derived from a common ancestral DNA. Paralogous segments of DNA may arise spontaneously by errors during DNA replication, copy and paste transposons, or whole genome duplications.
## Paleopolyploidy
Ancient genome duplications probably occurred in the evolutionary history of all life. Duplication events that occurred long ago in the history of various evolutionary lineages can be difficult to detect because of subsequent diploidization (such that a polyploid starts to behave cytogenetically as a diploid over time) as mutations and gene translations gradually make one copy of each chromosome unlike its other copy.
In many cases, these events can be inferred only through comparing sequenced genomes. Examples of unexpected but recently confirmed ancient genome duplications include the baker's yeast (Saccharomyces cerevisiae), mustard weed/thale cress (Arabidopsis thaliana), rice (Oryza sativa), and an early evolutionary ancestor of the vertebrates (which includes the human lineage) and another near the origin of the teleost fishes. Angiosperms (flowering plants) have paleopolyploidy in their ancestry. All eukaryotes probably have experienced a polyploidy event at some point in their evolutionary history. | Polyploidy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [2] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
# Overview
Polyploidy occurs in cells and organisms when there are more than two homologous sets of chromosomes. Polyploid types are labelled according to the number of chromosome sets in the nucleus:
- triploid (three sets; 3x), for example the genus Tardigrada
- tetraploid (four sets; 4x), for example Salmonidae fish
- pentaploid (five sets; 5x)
- hexaploid (six sets; 6x), for example wheat
- oktoploid (eight sets; 8x), for example Acipenser (genus of sturgeon fish)
- dekaploid (ten sets; 10x), for example certain strawberries
- dodecaploid (twelve sets; 12x), for example the plant Celosia argentea
Most organisms are normally diploid; polyploidy may occur due to abnormal cell division. It is most commonly found in plants. Haploidy may also occur as a normal stage in an organism's life. A haploid has only one set of chromosomes.
Polyploidy occurs in some animals, such as goldfish, salmon, and salamanders, but is especially common among ferns and flowering plants, including both wild and cultivated species. Wheat, for example, after millennia of hybridization and modification by humans, has strains that are diploid (two sets of chromosomes), tetraploid (four sets of chromosomes) with the common name of durum or macaroni wheat, and hexaploid (six sets of chromosomes) with the common name of bread wheat. Many agriculturally important plants of the genus Brassica are also tetraploids; their relationship is described by the Triangle of U.
The occurrence of polyploidy is a mechanism of speciation and is known to have resulted in new species of the plant Salsify (also known as "goatsbeard").
Examples in animals are more common in the ‘lower’ forms such as flatworms, leeches, and brine shrimp. Polyploid animals are often sterile, so they often reproduce by parthenogenesis. Polyploid salamanders and lizards are also quite common and parthenogenetic. While mammalian liver cells are polyploid, rare instances of polyploid mammals are known, but most often result in prenatal death.
The only known exception to this rule is an octodontid rodent of Argentina's harsh desert regions, known as the Red Viscacha-Rat (Tympanoctomys barrerae). This rodent is not a rat, but kin to [uinea pigs and chinchillas. Its "new" diploid [2n] number is 102 and so its cells are roughly twice normal size. Its closest living relation is Octomys mimax, the Andean Viscacha-Rat of the same family, whose 2n=56. It is surmised that an Octomys-like ancestor produced tetraploid (i.e., 4n=112) offspring that were, by virtue of their doubled chromosomes, reproductively isolated from their parents; but that these likely survived the ordinarily catastrophic effects of polyploidy in mammals by shedding (via translocation or some similar mechanism) the "extra" set of sex chromosomes gained at this doubling.
Polyploidy can be induced in cell culture by some chemicals: the best known is colchicine, which can result in chromosome doubling, though its use may have other less obvious consequences as well.
There are large number of polyploid crop varieties - See Polyploid Crops below.
There are few naturally occurring polyploid conifers. One example is the giant tree Sequoia sempervirens or Coast Redwood which is a hexaploid (6x) with 66 chromosomes (2n=6x=66), although the origin is unclear [1].
# Polyploidy in humans (Aneuploidy)
True polyploidy rarely occurs in humans, although it occurs in some tissues (especially in the liver). Polyploidy refers to a numerical change in a whole set of chromosomes. Organisms in which a particular chromosome, or chromosome segment, is under- or overrepresented are said to be aneuploid (from the Greek words meaning "not," "good," and "fold"). Therefore the distinction between aneuploidy and polyploidy is that aneuploidy refers to a numerical change in part of the chromosome, whereas polyploidy refers to a numerical change in the whole set of chromosomes. [2]: Cytogenetic Variation (p109)]
Aneuploidy occurs in humans in the form of triploidy (69,XXX) and tetraploidy (92,XXXX), not to be confused with 47,XXX or 48, XXXX aneuploidy. Triploidy, usually due to polyspermy, occurs in about 2-3% of all human pregnancies and ~15% of miscarriages. The vast majority of triploid conceptions end as miscarriage and those that do survive to term typically die shortly after birth. In some cases survival past birth may occur longer if there is mixoploidy with both a diploid and a triploid cell population present.
Triploidy may be the result of either digyny (the extra haploid set is from the mother) or diandry (the extra haploid set is from the father). Diandry is almost always caused by the fertilization of an egg by two sperm (dispermy). Digyny is most commonly caused by either failure of one meiotic division during oogenesis leading to a diploid oocyte or failure to extrude one polar body from the oocyte. Diandry appears to predominate among early miscarriages while digyny predominates among triploidy that survives into the fetal period. However, among early miscarriages, digyny is also more common in those cases <8.5 weeks gestational age or those in which an embryo is present. There are also two distinct phenotypes in triploid placentas and fetuses that are dependent on the origin of the extra haploid set. In digyny there is typically an asymmetric poorly grown fetus, with marked adrenal hypoplasia and a very small placenta. In diandry, the fetus (when present) is typically normally grown or symmetrically growth restricted, with normal adrenal glands and an abnormally large cystic placenta that is called a partial hydatidiform mole. These parent-of-origin effects reflect the effects of genomic imprinting.
Complete tetraploidy is more rarely diagnosed than triploidy, but is observed in 1-2% of early miscarriages. However, some tetraploid cells are not uncommonly found in chromosome analysis at prenatal diagnosis and these are generally considered ‘harmless’. It is not clear whether these tetraploid cells simply tend to arise during in vitro cell culture or whether they are also present in placental cells in vivo. There are, at any rate, very few clinical reports of fetuses/infants diagnosed with tetraploidy mosaicism.
Mixoploidy is quite commonly observed in human preimplantation embryos and includes haploid/diploid as well as diploid/tetraploid mixed cell populations. It is unknown whether these embryos fail to implant and are therefore rarely detected in ongoing pregnancies or if there is simply a selective process favoring the diploid cells.
# Polyploidy in plants
Polyploidy is pervasive in plants and some estimates suggest that 30-80% of living plant species are polyploid, and many lineages show evidence of ancient polyploidy (paleopolyploidy) in their genomes.[3] Huge explosions in angiosperm species diversity appear to have coincided with the timing of ancient genome duplications shared by many species.[4] Polyploid plants can arise spontaneously in nature by several mechanisms, including meiotic or mitotic failures, and fusion of unreduced (2n) gametes.[5] Both autopolyploids (eg. potato) and allopolyploids (eg. canola, wheat, cotton) can be found among both wild and domesticated plant species. Most polyploids display heterosis relative to their parental species, and may display novel variation or morphologies that may contribute to the processes of speciation and eco-niche exploitation.[6] The mechanisms leading to novel variation in newly formed allopolyploids may include gene dosage effects (resulting from more numerous copies of genome content), the reunion of divergent gene regulatory hierarchies, chromosomal rearrangements, and epigenetic remodeling, all of which affect gene content and/or expression levels.[7] Many of these rapid changes may contribute to reproductive isolation and speciation.
## Polyploid crops
Polyploid plants tend to be larger and better at flourishing in early succession habitats such as farm fields. In the breeding of crops, the tallest and best thriving plants are selected for. Thus, many crops (and agricultural weeds) may have unintentionally been bred to a higher level of ploidy.
The induction of polyploids is a common technique to overcome the sterility of a hybrid species during plant breeding. For example, Triticale is the hybrid of wheat (Triticum turgidum) and rye (Secale cereale). It combines sought-after characteristics of the parents, but the initial hybrids are sterile. After polyploidization, the hybrid becomes fertile and can thus be further propagated to become triticale.
In some situations polyploid crops are preferred because they are sterile. For example many seedless fruit varieties are seedless as a result of polyploidy. Such crops are propagated using asexual techniques such as grafting.
Polyploidy in crop plants is most commonly induced by treating seeds with the chemical colchicine.
## Examples of Polyploid Crops
- Triploid crops: banana, apple, ginger, watermelon, citrus[8]
- Tetraploid crops: durum or macaroni wheat, maize, cotton, potato, cabbage, leek, tobacco, peanut, kinnow, Pelargonium
- Hexaploid crops: chrysanthemum, bread wheat, triticale, oat
- Octaploid crops: strawberry, dahlia, pansies, sugar cane
Some crops are found in a variety of ploidy. Apples, tulips and lilies are commonly found as both diploid and as triploid. Daylilies (Hemerocallis) cultivars are available as either diploid or tetraploid. Kinnows can be tetraploid, diploid, or triploid.
# Terminology
## Autopolyploidy
Autopolyploids are polyploids with multiple chromosome sets derived from a single species. Autopolyploids can arise from a spontaneous, naturally occurring genome doubling (for example, the potato). Others might form following fusion of 2n gametes unreduced gametes). Bananas and apples can be found as triploid autopolyploids. Autopolyploid plants typically display polysomic inheritance, and are therefore often infertile and propagated clonally
## Allopolyploidy
Allopolyploids are polyploids with chromosomes derived from different species. Triticale is an example of an allopolyploid, having six chromosome sets, four from wheat (Triticum turgidum) and two from rye (Secale cereale). Amphidiploid is another word for an allopolyploid. Some of the best examples of allopolyploids come from the Brassicas, and the Triangle of U describes the relationships among the three common diploid Brassicas (B. oleracea, B. rapa, and B. nigra) and three allotetraploids (B. napus, B. juncea, and B. carinata) derived from hybridization among the diploids.
## Homoeologous
The term is used to describe the relationship of similar chromosomes or parts of chromosomes brought together following inter-species hybridization and allopolyploidization, and whose relationship was completely homologous in an ancestral species. In allopolyploids, the homologous chromosomes within each parental sub-genome should pair faithfully during meiosis, leading to disomic inheritance; however in some allopolyploids, the homoeologous chromosomes of the parental genomes may be nearly as similar to one another as the homolgous chromosomes, leading to tetrasomic inheritance (four chromosomes pairing at meiosis), intergenomic recombination, and reduced fertility.
## Homologous
The term is used to describe the relationship of similar chromosomes that pair at mitosis and meiosis. In a diploid, one homolog is derived from the male parent (pollen or sperm) and one is derived from the female parent (egg). During meiosis and gametogenesis, homologous chromosomes pair and exchange genetic material by recombination, leading to the production of sperm/pollen or eggs with chromosome haplotypes containing novel genetic variation.
## Karyotype
A karyotype is the characteristic chromosome complement of a eukaryote species.[9][10] The preparation and study of karyotypes is part of cytology and, more specifically, cytogenetics.
Although the replication and transcription of DNA is highly standardized in eukaryotes, the same cannot be said for their karotypes, which are highly variable between species in chromosome number and in detailed organization despite being constructed out of the same macromolecules. In some cases there is even significant variation within species. This variation provides the basis for a range of studies in what might be called evolutionary cytology.
## Paralogous
The term is used to describe the relationship among duplicated genes or portions of chromosomes that derived from a common ancestral DNA. Paralogous segments of DNA may arise spontaneously by errors during DNA replication, copy and paste transposons, or whole genome duplications.
## Paleopolyploidy
Ancient genome duplications probably occurred in the evolutionary history of all life. Duplication events that occurred long ago in the history of various evolutionary lineages can be difficult to detect because of subsequent diploidization (such that a polyploid starts to behave cytogenetically as a diploid over time) as mutations and gene translations gradually make one copy of each chromosome unlike its other copy.
In many cases, these events can be inferred only through comparing sequenced genomes. Examples of unexpected but recently confirmed ancient genome duplications include the baker's yeast (Saccharomyces cerevisiae), mustard weed/thale cress (Arabidopsis thaliana), rice (Oryza sativa), and an early evolutionary ancestor of the vertebrates (which includes the human lineage) and another near the origin of the teleost fishes. Angiosperms (flowering plants) have paleopolyploidy in their ancestry. All eukaryotes probably have experienced a polyploidy event at some point in their evolutionary history. | https://www.wikidoc.org/index.php/Allopolyploid | |
3eab253e94ca4afc1673dedfcd3530d5f1e81eb9 | wikidoc | Allostasis | Allostasis
Allostasis is the process of achieving stability, or homeostasis, through physiological or behavioral change. This can be carried out by means of alteration in HPA axis hormones, the autonomic nervous system, cytokines, or a number of other systems, and is generally adaptive in the short term
# Definition
The concept of Allostasis was proposed by Sterling and Eyer in 1988 to describe an additional process of reestablishing homeostasis, but one that responds to a challenge instead of to subtle ebb and flow. This theory suggests that both homeostasis and allostasis are endogenous systems responses aiming at maintaining the internal stability of an organism. Homeostasis, from the Greek homeo, means “same,” while stasis means “stable;” thus, “remaining stable by staying the same.” Allostasis was coined similarly, from the Greek allo, which means “variable;” thus, “remaining stable by being variable”
# Types of Allostasis
Wingfield states:
The concept of allostasis, maintaining stability through change, is a fundamental process through which organisms actively adjust to both predictable and unpredictable events... Allostatic load refers to the cumulative cost to the body of allostasis, with allostatic overload... being a state in which serious pathophysiology can occur... Using the balance between energy input and expenditure as the basis for applying the concept of allostasis, two types of allostatic overload have been proposed.
Accordingly, McEwen and Wingfield propose two types of allostatic load which result in different responses:
Type 1 allostatic overload occurs when energy demand exceeds supply, resulting in activation of the emergency life history stage. This serves to direct the animal away from normal life history stages into a survival mode that decreases allostatic load and regains positive energy balance. The normal life cycle can be resumed when the perturbation passes.
Type 2 allostatic overload begins when there is sufficient or even excess energy consumption accompanied by social conflict and other types of social dysfunction. The latter is the case in human society and certain situations affecting animals in captivity. In all cases, secretion of glucocorticosteroids and activity of other mediators of allostasis such as the autonomic nervous system, CNS neurotransmitters, and inflammatory cytokines wax and wane with allostatic load. If allostatic load is chronically high, then pathologies develop. Type 2 allostatic overload does not trigger an escape response, and can only be counteracted through learning and changes in the social structure.,
With respect to most neuroendocrine responses, including corticosteroids and catecholamines, type 1 and type 2 allostatic reactions are indistinguishable. The response of thyroid homeostasis is different, however: T3 concentrations are down-regulated in type 1 allostasis, but up-regulated in type 2 allostasis
# Role of Adaptogens
The use of adaptogens can help reduce allostatic load. Adaptogens are substances, herbal or pharmaceutical, which are nontoxic in normal doses, produce a nonspecific defensive response to stress, and have a normalizing influence on the body. They normalize the hypothalamic-pituitary-adrenal axis (HPA axis). As defined, adaptogens constitute a new class of natural, homeostatic and allostatic metabolic regulators. Adaptogens have a normalizing effect on the body and are capable of either toning down the activity of hyperfunctioning systems or strengthening the activity of hypofunctioning systems.
# Difference between Homeostasis and Allostasis
The key difference between allostasis and homeostasis is popularized by Robert Sapolsky's book Why Zebras Don't Get Ulcers:
Homeostasis is the regulation of the body to a balance, by single point tuning such as blood oxygen level, blood glucose or blood pH. For example, if a person walking in the desert is hot, the body will sweat. However he would quickly become dehydrated. Allostasis is adaptation to a more dynamic balance. In our dehydration example, sweat is only a small part of the process. Many other systems will have to adapt their functioning as well, both to reduce water use and to support the other systems that are changing. Kidneys may reduce urine output. Mucous membrane in the mouth, nose and eyes may dry out; urine and sweat output will decrease; the release of arginine vasopressin (AVP) will increase; and veins and arteries will constrict to maintain blood pressure with a smaller blood volume.
This change may be adaptive. If a dehydrated person is lost in the desert and his body acted as it did under normal conditions, he or she would lose too much water too quickly, dehydrate and die. However, maintenance of allostatic changes over a long period may result in allostatic load. If our desert wanderer is rescued, but continues to be stressed and hence does not reinstate normal body function, his systems will quickly wear out. The human body is amazingly adaptable, but it cannot maintain allostatic overload for very long without consequence. | Allostasis
Allostasis is the process of achieving stability, or homeostasis, through physiological or behavioral change. This can be carried out by means of alteration in HPA axis hormones, the autonomic nervous system, cytokines, or a number of other systems, and is generally adaptive in the short term [1]
# Definition
The concept of Allostasis was proposed by Sterling and Eyer in 1988 to describe an additional process of reestablishing homeostasis, but one that responds to a challenge instead of to subtle ebb and flow. This theory suggests that both homeostasis and allostasis are endogenous systems responses aiming at maintaining the internal stability of an organism. Homeostasis, from the Greek homeo, means “same,” while stasis means “stable;” thus, “remaining stable by staying the same.” Allostasis was coined similarly, from the Greek allo, which means “variable;” thus, “remaining stable by being variable”[2][3]
# Types of Allostasis
Wingfield states:
The concept of allostasis, maintaining stability through change, is a fundamental process through which organisms actively adjust to both predictable and unpredictable events... Allostatic load refers to the cumulative cost to the body of allostasis, with allostatic overload... being a state in which serious pathophysiology can occur... Using the balance between energy input and expenditure as the basis for applying the concept of allostasis, two types of allostatic overload have been proposed. [4]
Accordingly, McEwen and Wingfield propose two types of allostatic load which result in different responses:
Type 1 allostatic overload occurs when energy demand exceeds supply, resulting in activation of the emergency life history stage. This serves to direct the animal away from normal life history stages into a survival mode that decreases allostatic load and regains positive energy balance. The normal life cycle can be resumed when the perturbation passes.
Type 2 allostatic overload begins when there is sufficient or even excess energy consumption accompanied by social conflict and other types of social dysfunction. The latter is the case in human society and certain situations affecting animals in captivity. In all cases, secretion of glucocorticosteroids and activity of other mediators of allostasis such as the autonomic nervous system, CNS neurotransmitters, and inflammatory cytokines wax and wane with allostatic load. If allostatic load is chronically high, then pathologies develop. Type 2 allostatic overload does not trigger an escape response, and can only be counteracted through learning and changes in the social structure.[5], [6]
With respect to most neuroendocrine responses, including corticosteroids and catecholamines, type 1 and type 2 allostatic reactions are indistinguishable. The response of thyroid homeostasis is different, however: T3 concentrations are down-regulated in type 1 allostasis, but up-regulated in type 2 allostasis[7]
# Role of Adaptogens
The use of adaptogens can help reduce allostatic load. Adaptogens are substances, herbal or pharmaceutical, which are nontoxic in normal doses, produce a nonspecific defensive response to stress, and have a normalizing influence on the body. They normalize the hypothalamic-pituitary-adrenal axis (HPA axis). As defined, adaptogens constitute a new class of natural, homeostatic and allostatic metabolic regulators. [8][9] Adaptogens have a normalizing effect on the body and are capable of either toning down the activity of hyperfunctioning systems or strengthening the activity of hypofunctioning systems.
# Difference between Homeostasis and Allostasis
The key difference between allostasis and homeostasis is popularized by Robert Sapolsky's book Why Zebras Don't Get Ulcers:
Homeostasis is the regulation of the body to a balance, by single point tuning such as blood oxygen level, blood glucose or blood pH. For example, if a person walking in the desert is hot, the body will sweat. However he would quickly become dehydrated. Allostasis is adaptation to a more dynamic balance. In our dehydration example, sweat is only a small part of the process. Many other systems will have to adapt their functioning as well, both to reduce water use and to support the other systems that are changing. Kidneys may reduce urine output. Mucous membrane in the mouth, nose and eyes may dry out; urine and sweat output will decrease; the release of arginine vasopressin (AVP) will increase; and veins and arteries will constrict to maintain blood pressure with a smaller blood volume.
This change may be adaptive. If a dehydrated person is lost in the desert and his body acted as it did under normal conditions, he or she would lose too much water too quickly, dehydrate and die. However, maintenance of allostatic changes over a long period may result in allostatic load. If our desert wanderer is rescued, but continues to be stressed and hence does not reinstate normal body function, his systems will quickly wear out. The human body is amazingly adaptable, but it cannot maintain allostatic overload for very long without consequence. | https://www.wikidoc.org/index.php/Allostasis | |
31f264335a0b479dadb48bbf52572a03944b825f | wikidoc | Alogliptin | Alogliptin
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# Overview
Alogliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor that is FDA approved for the treatment of type 2 diabetes mellitus. Common adverse reactions include nasopharyngitis, headache and upper respiratory tract infection.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Monotherapy and Combination Therapy
- NESINA is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus in multiple clinical settings.
- The recommended dose of NESINA is 25 mg once daily.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Alogliptin in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Alogliptin in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Alogliptin in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Alogliptin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Alogliptin in pediatric patients.
# Contraindications
- History of a serious hypersensitivity reaction to alogliptin-containing products, such as anaphylaxis, angioedema or severe cutaneous adverse reactions.
# Warnings
### Precautions
- Pancreatitis
- There have been postmarketing reports of acute pancreatitis in patients taking NESINA. After initiation of NESINA, patients should be observed carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, NESINA should promptly be discontinued and appropriate management should be initiated. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using NESINA.
- Hypersensitivity Reactions
- There have been postmarketing reports of serious hypersensitivity reactions in patients treated with NESINA. These reactions include anaphylaxis, angioedema and severe cutaneous adverse reactions, including Stevens-Johnson syndrome. If a serious hypersensitivity reaction is suspected, discontinue NESINA, assess for other potential causes for the event and institute alternative treatment for diabetes. Use caution in a patient with a history of angioedema with another DPP-4 inhibitor because it is unknown whether such patients will be predisposed to angioedema with NESINA.
- Hepatic Effects
- There have been postmarketing reports of fatal and nonfatal hepatic failure in patients taking NESINA, although some of the reports contain insufficient information necessary to establish the probable cause. In randomized controlled studies, serum alanine aminotransferase (ALT) elevations greater than three times the upper limit of normal (ULN) were observed: 1.3% in alogliptin-treated patients and 1.5% in all comparator-treated patients.
- Patients with type 2 diabetes may have fatty liver disease, which may cause liver test abnormalities, and they may also have other forms of liver disease, many of which can be treated or managed. Therefore, obtaining a liver test panel and assessing the patient before initiating NESINA therapy is recommended. In patients with abnormal liver tests, NESINA should be initiated with caution.
- Measure liver tests promptly in patients who report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice. In this clinical context, if the patient is found to have clinically significant liver enzyme elevations and if abnormal liver tests persist or worsen, NESINA should be interrupted and investigation done to establish the probable cause. NESINA should not be restarted in these patients without another explanation for the liver test abnormalities.
- Use with Medications Known to Cause Hypoglycemia
- Insulin and insulin secretagogues, such as sulfonylureas, are known to cause hypoglycemia. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with NESINA.
- Macrovascular Outcomes
- There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with NESINA or any other antidiabetic drug.
# 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.
- Approximately 8500 patients with type 2 diabetes have been treated with NESINA in 14 randomized, double-blind, controlled clinical trials with approximately 2900 subjects randomized to placebo and approximately 2200 to an active comparator. The mean exposure to NESINA was 40 weeks with more than 2400 subjects treated for more than one year. Among these patients, 63% had a history of hypertension, 51% had a history of dyslipidemia, 25% had a history of myocardial infarction, 8% had a history of unstable angina and 7% had a history of congestive heart failure. The mean duration of diabetes was seven years, the mean body mass index (BMI) was 31 kg/m2 (51% of patients had a BMI ≥30 kg/m2), and the mean age was 57 years (24% of patients ≥65 years of age).
- Two placebo-controlled monotherapy trials of 12 and 26 weeks of duration were conducted in patients treated with NESINA 12.5 mg daily, NESINA 25 mg daily and placebo. Four placebo-controlled add-on combination therapy trials of 26 weeks duration were also conducted: with metformin, with a sulfonylurea, with a thiazolidinedione and with insulin.
- Four placebo-controlled and one active-controlled trials of 16 weeks up through two years in duration were conducted in combination with metformin, in combination with pioglitazone and with pioglitazone added to a background of metformin therapy.
- Three active-controlled trials of 52 weeks in duration were conducted in patients treated with pioglitazone and metformin, in combination with metformin and as monotherapy compared to glipizide.
- In a pooled analysis of these 14 controlled clinical trials, the overall incidence of adverse events was 66% in patients treated with NESINA 25 mg compared to 62% with placebo and 70% with active comparator. Overall discontinuation of therapy due to adverse events was 4.7% with NESINA 25 mg compared to 4.5% with placebo or 6.2% with active comparator.
- Adverse reactions reported in ≥4% of patients treated with NESINA 25 mg and more frequently than in patients who received placebo are summarized in Table 1.
- Pancreatitis
- In the clinical trial program, pancreatitis was reported in 11 of 5902 (0.2%) patients receiving NESINA 25 mg daily compared to five of 5183 (<0.1%) patients receiving all comparators.
- Hypersensitivity Reactions
- In a pooled analysis, the overall incidence of hypersensitivity reactions was 0.6% with NESINA 25 mg compared to 0.8% with all comparators. A single event of serum sickness was reported in a patient treated with NESINA 25 mg.
- Hypoglycemia
- Hypoglycemic events were documented based upon a blood glucose value and/or clinical signs and symptoms of hypoglycemia.
- In the monotherapy study, the incidence of hypoglycemia was 1.5% in patients treated with NESINA compared to 1.6% with placebo. The use of NESINA as add-on therapy to glyburide or insulin did not increase the incidence of hypoglycemia compared to placebo. In a monotherapy study comparing NESINA to a sulfonylurea in elderly patients, the incidence of hypoglycemia was 5.4% with NESINA compared to 26% with glipizide (Table 2).
- Vital Signs
- No clinically meaningful changes in vital signs or in electrocardiograms were observed in patients treated with NESINA.
- Laboratory Tests
- No clinically meaningful changes in hematology, serum chemistry or urinalysis were observed in patients treated with NESINA.
## Postmarketing Experience
- The following adverse reactions have been identified during the postmarketing use of NESINA outside the United States. 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.
- Hypersensitivity reactions including anaphylaxis, angioedema, rash, urticaria and severe cutaneous adverse reactions, including Stevens-Johnson syndrome, hepatic enzyme elevations, fulminant hepatic failure and acute pancreatitis.
# Drug Interactions
- NESINA is primarily renally excreted. Cytochrome (CYP) P450-related metabolism is negligible. No significant drug-drug interactions were observed with the CYP-substrates or inhibitors tested or with renally excreted drugs.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category B
- No adequate or well-controlled studies in pregnant women have been conducted with NESINA. Based on animal data, NESINA is not predicted to increase the risk of developmental abnormalities. Because animal reproduction studies are not always predictive of human risk and exposure, NESINA, like other antidiabetic medications, should be used during pregnancy only if clearly needed.
- Alogliptin administered to pregnant rabbits and rats during the period of organogenesis was not teratogenic at doses of up to 200 mg/kg and 500 mg/kg, or 149 times and 180 times, respectively, the clinical dose based on plasma drug exposure (AUC).
- Doses of alogliptin up to 250 mg/kg (approximately 95 times clinical exposure based on AUC) given to pregnant rats from gestation Day 6 to lactation Day 20 did not harm the developing embryo or adversely affect growth and development of offspring.
- Placental transfer of alogliptin into the fetus was observed following oral dosing to pregnant rats.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Alogliptin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Alogliptin during labor and delivery.
### Nursing Mothers
- Alogliptin is secreted in the milk of lactating rats in a 2:1 ratio to plasma. It is not known whether alogliptin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when NESINA is administered to a nursing woman.
### Pediatric Use
- Safety and effectiveness of NESINA in pediatric patients have not been established.
### Geriatic Use
- Of the total number of patients (N=8507) in clinical safety and efficacy studies treated with NESINA, 2064 (24.3%) patients were 65 years and older and 341 (4%) patients were 75 years and older. No overall differences in safety or effectiveness were observed between patients 65 years and over and younger patients. While this clinical experience has not identified differences in responses between the elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out.
### Gender
There is no FDA guidance on the use of Alogliptin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Alogliptin with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Alogliptin in patients with renal impairment.
### Hepatic Impairment
- No dose adjustments are required in patients with mild to moderate hepatic impairment (Child-Pugh Grade A and B) based on insignificant change in systemic exposures (e.g., AUC) compared to subjects with normal hepatic function in a pharmacokinetic study. NESINA has not been studied in patients with severe hepatic impairment (Child-Pugh Grade C). Use caution when administering NESINA to patients with liver disease.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Alogliptin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Alogliptin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Alogliptin in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Alogliptin in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- The highest doses of NESINA administered in clinical trials were single doses of 800 mg to healthy subjects and doses of 400 mg once daily for 14 days to patients with type 2 diabetes (equivalent to 32 times and 16 times the maximum recommended clinical dose of 25 mg, respectively). No serious adverse events were observed at these doses.
### Management
- In the event of an overdose, it is reasonable to institute the necessary clinical monitoring and supportive therapy as dictated by the patient's clinical status. Per clinical judgment, it may be reasonable to initiate removal of unabsorbed material from the gastrointestinal tract.
- Alogliptin is minimally dialyzable; over a three-hour hemodialysis session, approximately 7% of the drug was removed. Therefore, hemodialysis is unlikely to be beneficial in an overdose situation. It is not known if NESINA is dialyzable by peritoneal dialysis.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Alogliptin in the drug label.
# Pharmacology
## Mechanism of Action
- Increased concentrations of the incretin hormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are released into the bloodstream from the small intestine in response to meals. These hormones cause insulin release from the pancreatic beta cells in a glucose-dependent manner but are inactivated by the DPP-4 enzyme within minutes. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, reducing hepatic glucose production. In patients with type 2 diabetes, concentrations of GLP-1 are reduced but the insulin response to GLP-1 is preserved. Alogliptin is a DPP-4 inhibitor that slows the inactivation of the incretin hormones, thereby increasing their bloodstream concentrations and reducing fasting and postprandial glucose concentrations in a glucose-dependent manner in patients with type 2 diabetes mellitus. Alogliptin selectively binds to and inhibits DPP-4 but not DPP-8 or DPP-9 activity in vitro at concentrations approximating therapeutic exposures.
## Structure
- NESINA tablets contain the active ingredient alogliptin, which is a selective, orally bioavailable inhibitor of the enzymatic activity of dipeptidyl peptidase-4 (DPP-4).
- Chemically, alogliptin is prepared as a benzoate salt, which is identified as 2-({6--3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl}methyl)benzonitrile monobenzoate. It has a molecular formula of C18H21N5O2C7H6O2 and a molecular weight of 461.51 daltons. The structural formula is:
- Alogliptin benzoate is a white to off-white crystalline powder containing one asymmetric carbon in the aminopiperidine moiety. It is soluble in dimethylsulfoxide, sparingly soluble in water and methanol, slightly soluble in ethanol and very slightly soluble in octanol and isopropyl acetate.
- Each NESINA tablet contains 34 mg, 17 mg or 8.5 mg alogliptin benzoate, which is equivalent to 25 mg, 12.5 mg or 6.25 mg, respectively, of alogliptin and the following inactive ingredients: mannitol, microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium and magnesium stearate. In addition, the film coating contains the following inactive ingredients: hypromellose, titanium dioxide, ferric oxide (red or yellow) and polyethylene glycol, and is marked with printing ink (Gray F1).
## Pharmacodynamics
- Single-dose administration of NESINA to healthy subjects resulted in a peak inhibition of DPP-4 within two to three hours after dosing. The peak inhibition of DPP-4 exceeded 93% across doses of 12.5 mg to 800 mg. Inhibition of DPP-4 remained above 80% at 24 hours for doses greater than or equal to 25 mg. Peak and total exposure over 24 hours to active GLP-1 were three- to four-fold greater with NESINA (at doses of 25 to 200 mg) than placebo. In a 16-week, double-blind, placebo-controlled study, NESINA 25 mg demonstrated decreases in postprandial glucagon while increasing postprandial active GLP-1 levels compared to placebo over an eight-hour period following a standardized meal. It is unclear how these findings relate to changes in overall glycemic control in patients with type 2 diabetes mellitus. In this study, NESINA 25 mg demonstrated decreases in two-hour postprandial glucose compared to placebo (-30 mg/dL versus 17 mg/dL, respectively).
- Multiple-dose administration of alogliptin to patients with type 2 diabetes also resulted in a peak inhibition of DPP-4 within one to two hours and exceeded 93% across all doses (25 mg, 100 mg and 400 mg) after a single dose and after 14 days of once-daily dosing. At these doses of NESINA, inhibition of DPP-4 remained above 81% at 24 hours after 14 days of dosing.
- Cardiac Electrophysiology
- In a randomized, placebo-controlled, four-arm, parallel-group study, 257 subjects were administered either alogliptin 50 mg, alogliptin 400 mg, moxifloxacin 400 mg or placebo once daily for a total of seven days. No increase in QTc was observed with either dose of alogliptin. At the 400 mg dose, peak alogliptin plasma concentrations were 19-fold higher than the peak concentrations following the maximum recommended clinical dose of 25 mg.
## Pharmacokinetics
- The pharmacokinetics of NESINA has been studied in healthy subjects and in patients with type 2 diabetes. After administration of single, oral doses up to 800 mg in healthy subjects, the peak plasma alogliptin concentration (median Tmax) occurred one to two hours after dosing. At the maximum recommended clinical dose of 25 mg, NESINA was eliminated with a mean terminal half-life (T1/2) of approximately 21 hours.
- After multiple-dose administration up to 400 mg for 14 days in patients with type 2 diabetes, accumulation of alogliptin was minimal with an increase in total (i.e., AUC) and peak (i.e., Cmax) alogliptin exposures of 34% and 9%, respectively. Total and peak exposure to alogliptin increased proportionally across single doses and multiple doses of alogliptin ranging from 25 mg to 400 mg. The intersubject coefficient of variation for alogliptin AUC was 17%. The pharmacokinetics of NESINA was also shown to be similar in healthy subjects and in patients with type 2 diabetes.
- Absorption
- The absolute bioavailability of NESINA is approximately 100%. Administration of NESINA with a high-fat meal results in no significant change in total and peak exposure to alogliptin. NESINA may therefore be administered with or without food.
- Distribution
- Following a single, 12.5 mg intravenous infusion of alogliptin to healthy subjects, the volume of distribution during the terminal phase was 417 L, indicating that the drug is well distributed into tissues.
- Alogliptin is 20% bound to plasma proteins.
- Metabolism
- Alogliptin does not undergo extensive metabolism and 60% to 71% of the dose is excreted as unchanged drug in the urine.
- Two minor metabolites were detected following administration of an oral dose of alogliptin, N-demethylated, M-I (<1% of the parent compound), and N-acetylated alogliptin, M-II (<6% of the parent compound). M-I is an active metabolite and is an inhibitor of DPP-4 similar to the parent molecule; M-II does not display any inhibitory activity toward DPP-4 or other DPP-related enzymes. In vitro data indicate that CYP2D6 and CYP3A4 contribute to the limited metabolism of alogliptin.
- Alogliptin exists predominantly as the (R)-enantiomer (>99%) and undergoes little or no chiral conversion in vivo to the (S)-enantiomer. The (S)-enantiomer is not detectable at the 25 mg dose.
- Excretion
- The primary route of elimination of alogliptin-derived radioactivity occurs via renal excretion (76%) with 13% recovered in the feces, achieving a total recovery of 89% of the administered radioactive dose. The renal clearance of alogliptin (9.6 L/hr) indicates some active renal tubular secretion and systemic clearance was 14.0 L/hr.
- Specific Populations
- Renal Impairment
- A single-dose, open-label study was conducted to evaluate the pharmacokinetics of alogliptin 50 mg in patients with chronic renal impairment compared with healthy subjects.
- In patients with mild renal impairment (creatinine clearance ≥60 to <90 mL/min), an approximate 1.2-fold increase in plasma AUC of alogliptin was observed. Because increases of this magnitude are not considered clinically relevant, dose adjustment for patients with mild renal impairment is not recommended.
- In patients with moderate renal impairment (CrCl ≥30 to <60 mL/min), an approximate two-fold increase in plasma AUC of alogliptin was observed. To maintain similar systemic exposures of NESINA to those with normal renal function, the recommended dose is 12.5 mg once daily in patients with moderate renal impairment.
- In patients with severe renal impairment (CrCl ≥15 to <30 mL/min) and ESRD (CrCl <15 mL/min or requiring dialysis), an approximate three- and four-fold increase in plasma AUC of alogliptin were observed, respectively. Dialysis removed approximately 7% of the drug during a three-hour dialysis session. NESINA may be administered without regard to the timing of the dialysis. To maintain similar systemic exposures of NESINA to those with normal renal function, the recommended dose is 6.25 mg once daily in patients with severe renal impairment, as well as in patients with ESRD requiring dialysis.
- Hepatic Impairment
- Total exposure to alogliptin was approximately 10% lower and peak exposure was approximately 8% lower in patients with moderate hepatic impairment (Child-Pugh Grade B) compared to healthy subjects. The magnitude of these reductions is not considered to be clinically meaningful. Patients with severe hepatic impairment (Child-Pugh Grade C) have not been studied. Use caution when administering NESINA to patients with liver disease.
- Gender
- No dose adjustment of NESINA is necessary based on gender. Gender did not have any clinically meaningful effect on the pharmacokinetics of alogliptin.
- Geriatric
- No dose adjustment of NESINA is necessary based on age. Age did not have any clinically meaningful effect on the pharmacokinetics of alogliptin.
- Pediatric
- Studies characterizing the pharmacokinetics of alogliptin in pediatric patients have not been performed.
- Race
- No dose adjustment of NESINA is necessary based on race. Race (White, Black, and Asian) did not have any clinically meaningful effect on the pharmacokinetics of alogliptin.
- Drug Interactions
- In Vitro Assessment of Drug Interactions
- In vitro studies indicate that alogliptin is neither an inducer of CYP1A2, CYP2B6, CYP2C9, CYP2C19 and CYP3A4, nor an inhibitor of CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP3A4 and CYP2D6 at clinically relevant concentrations.
- In Vivo Assessment of Drug Interactions
- Effects of Alogliptin on the Pharmacokinetics of Other Drugs
- In clinical studies, alogliptin did not meaningfully increase the systemic exposure to the following drugs that are metabolized by CYP isozymes or excreted unchanged in urine (Figure 1). No dose adjustment of NESINA is recommended based on results of the described pharmacokinetic studies.
## Nonclinical Toxicology
- Rats were administered oral doses of 75, 400 and 800 mg/kg alogliptin for two years. No drug-related tumors were observed up to 75 mg/kg or approximately 32 times the maximum recommended clinical dose of 25 mg, based on AUC exposure. At higher doses (approximately 308 times the maximum recommended clinical dose of 25 mg), a combination of thyroid C-cell adenomas and carcinomas increased in male but not female rats. No drug-related tumors were observed in mice after administration of 50, 150 or 300 mg/kg alogliptin for two years, or up to approximately 51 times the maximum recommended clinical dose of 25 mg, based on AUC exposure.
- Alogliptin was not mutagenic or clastogenic, with and without metabolic activation, in the Ames test with S. typhimurium and E. coli or the cytogenetic assay in mouse lymphoma cells. Alogliptin was negative in the in vivo mouse micronucleus study.
- In a fertility study in rats, alogliptin had no adverse effects on early embryonic development, mating or fertility at doses up to 500 mg/kg, or approximately 172 times the clinical dose based on plasma drug exposure (AUC).
# Clinical Studies
- NESINA has been studied as monotherapy and in combination with metformin, a sulfonylurea, a thiazolidinedione (either alone or in combination with metformin or a sulfonylurea) and insulin (either alone or in combination with metformin).
- A total of 8673 patients with type 2 diabetes were randomized in 10 double-blind, placebo- or active-controlled clinical safety and efficacy studies conducted to evaluate the effects of NESINA on glycemic control. The racial distribution of patients exposed to study medication was 68% Caucasian, 15% Asian, 7% Black and 9% other racial groups. The ethnic distribution was 30% Hispanic. Patients had an overall mean age of 55 years (range 21 to 80 years).
- In patients with type 2 diabetes, treatment with NESINA produced clinically meaningful and statistically significant improvements in A1C compared to placebo. As is typical for trials of agents to treat type 2 diabetes, the mean reduction in A1C with NESINA appears to be related to the degree of A1C elevation at baseline.
- NESINA had similar changes from baseline in serum lipids compared to placebo.
- A total of 1768 patients with type 2 diabetes participated in three double-blind studies to evaluate the efficacy and safety of NESINA in patients with inadequate glycemic control on diet and exercise. All three studies had a four-week, single-blind, placebo run-in period followed by a 26-week randomized treatment period. Patients who failed to meet prespecified hyperglycemic goals during the 26-week treatment periods received glycemic rescue therapy.
- In a 26-week, double-blind, placebo-controlled study, a total of 329 patients (mean baseline A1C = 8%) were randomized to receive NESINA 12.5 mg, NESINA 25 mg or placebo once daily. Treatment with NESINA 25 mg resulted in statistically significant improvements from baseline in A1C and fasting plasma glucose (FPG) compared to placebo at Week 26 (Table 3). A total of 8% of patients receiving NESINA 25 mg and 30% of those receiving placebo required glycemic rescue therapy.
- Improvements in A1C were not affected by gender, age or baseline BMI.
- The mean change in body weight with NESINA was similar to placebo.
- In a 26-week, double-blind, active-controlled study, a total of 655 patients (mean baseline A1C = 8.8%) were randomized to receive NESINA 25 mg alone, pioglitazone 30 mg alone, NESINA 12.5 mg with pioglitazone 30 mg or NESINA 25 mg with pioglitazone 30 mg once daily. Coadministration of NESINA 25 mg with pioglitazone 30 mg resulted in statistically significant improvements from baseline in A1C and FPG compared to NESINA 25 mg alone and to pioglitazone 30 mg alone (Table 4). A total of 3% of patients receiving NESINA 25 mg coadministered with pioglitazone 30 mg, 11% of those receiving NESINA 25 mg alone and 6% of those receiving pioglitazone 30 mg alone required glycemic rescue.
- Improvements in A1C were not affected by gender, age or baseline BMI.
- The mean increase in body weight was similar between pioglitazone alone and NESINA when coadministered with pioglitazone.
- In a 26-week, double-blind, placebo-controlled study, a total of 784 patients inadequately controlled on diet and exercise alone (mean baseline A1C = 8.4%) were randomized to one of seven treatment groups: placebo; metformin HCl 500 mg or metformin HCl 1000 mg twice daily; NESINA 12.5 mg twice daily; NESINA 25 mg daily; or NESINA 12.5 mg in combination with metformin HCl 500 mg or metformin HCl 1000 mg twice daily. Both coadministration treatment arms (NESINA 12.5 mg + metformin HCl 500 mg and NESINA 12.5 mg + metformin HCl 1000 mg) resulted in statistically significant improvements in A1C and FPG when compared with their respective individual alogliptin and metformin component regimens (Table 5). Coadministration treatment arms demonstrated improvements in two-hour postprandial glucose (PPG) compared to NESINA alone or metformin alone (Table 5). A total of 12.3% of patients receiving NESINA 12.5 mg + metformin HCl 500 mg, 2.6% of patients receiving NESINA 12.5 mg + metformin HCl 1000 mg, 17.3% of patients receiving NESINA 12.5 mg, 22.9% of patients receiving metformin HCl 500 mg, 10.8% of patients receiving metformin HCl 1000 mg and 38.7% of patients receiving placebo required glycemic rescue.
- Improvements in A1C were not affected by gender, age, race or baseline BMI. The mean decrease in body weight was similar between metformin alone and NESINA when coadministered with metformin.
- A total of 2081 patients with type 2 diabetes participated in two 26-week, double-blind, placebo-controlled studies to evaluate the efficacy and safety of NESINA as add-on therapy to metformin. In both studies, patients were inadequately controlled on metformin at a dose of at least 1500 mg per day or at the maximum tolerated dose. All patients entered a four-week, single-blind placebo run-in period prior to randomization. Patients who failed to meet prespecified hyperglycemic goals during the 26-week treatment periods received glycemic rescue therapy.
- In the first 26-week, placebo-controlled study, a total of 527 patients already on metformin (mean baseline A1C = 8%) were randomized to receive NESINA 12.5 mg, NESINA 25 mg or placebo. Patients were maintained on a stable dose of metformin (median dose = 1700 mg) during the treatment period. NESINA 25 mg in combination with metformin resulted in statistically significant improvements from baseline in A1C and FPG at Week 26, when compared to placebo (Table 6). A total of 8% of patients receiving NESINA 25 mg and 24% of patients receiving placebo required glycemic rescue.
- Improvements in A1C were not affected by gender, age, baseline BMI or baseline metformin dose.
- The mean decrease in body weight was similar between NESINA and placebo when given in combination with metformin.
- In the second 26-week, double-blind, placebo-controlled study, a total of 1554 patients already on metformin (mean baseline A1C = 8.5%) were randomized to one of 12 double-blind treatment groups: placebo; 12.5 mg or 25 mg of NESINA alone; 15 mg, 30 mg or 45 mg of pioglitazone alone; or 12.5 mg or 25 mg of NESINA in combination with 15 mg, 30 mg or 45 mg of pioglitazone. Patients were maintained on a stable dose of metformin (median dose = 1700 mg) during the treatment period. Coadministration of NESINA and pioglitazone provided statistically significant improvements in A1C and FPG compared to placebo, to NESINA alone or to pioglitazone alone when added to background metformin therapy (Table 7, Figure 3). In addition, improvements from baseline A1C were comparable between NESINA alone and pioglitazone alone (15 mg, 30 mg and 45 mg) at Week 26. A total of 4%, 5% or 2% of patients receiving NESINA 25 mg with 15 mg, 30 mg or 45 mg pioglitazone, 33% of patients receiving placebo, 13% of patients receiving NESINA 25 mg and 10%, 15% or 9% of patients receiving pioglitazone 15 mg, 30 mg or 45 mg alone required glycemic rescue.
- Improvements in A1C were not affected by gender, age or baseline BMI.
- The mean increase in body weight was similar between pioglitazone alone and NESINA when coadministered with pioglitazone.
- In a 26-week, placebo-controlled study, a total of 493 patients inadequately controlled on a thiazolidinedione alone or in combination with metformin or a sulfonylurea (10 mg) (mean baseline A1C = 8%) were randomized to receive NESINA 12.5 mg, NESINA 25 mg or placebo. Patients were maintained on a stable dose of pioglitazone (median dose = 30 mg) during the treatment period; those who were also previously treated on metformin (median dose = 2000 mg) or sulfonylurea (median dose = 10 mg) prior to randomization were maintained on the combination therapy during the treatment period. All patients entered into a four-week, single-blind placebo run-in period prior to randomization. Patients who failed to meet prespecified hyperglycemic goals during the 26-week treatment period received glycemic rescue therapy.
- The addition of NESINA 25 mg once daily to pioglitazone therapy resulted in statistically significant improvements from baseline in A1C and FPG at Week 26, compared to placebo (Table 8). A total of 9% of patients who were receiving NESINA 25 mg and 12% of patients receiving placebo required glycemic rescue.
- Improvements in A1C were not affected by gender, age, baseline BMI or baseline pioglitazone dose.
- Clinically meaningful reductions in A1C were observed with NESINA compared to placebo regardless of whether subjects were receiving concomitant metformin or sulfonylurea (-0.2% placebo versus -0.9% NESINA) therapy or pioglitazone alone (0% placebo versus -0.52% NESINA).
- The mean increase in body weight was similar between NESINA and placebo when given in combination with pioglitazone.
- In a 52-week, active-comparator study, a total of 803 patients inadequately controlled (mean baseline A1C = 8.2%) on a current regimen of pioglitazone 30 mg and metformin at least 1500 mg per day or at the maximum tolerated dose were randomized to either receive the addition of NESINA 25 mg or the titration of pioglitazone 30 mg to 45 mg following a four-week, single-blind placebo run-in period. Patients were maintained on a stable dose of metformin (median dose = 1700 mg). Patients who failed to meet prespecified hyperglycemic goals during the 52-week treatment period received glycemic rescue therapy.
- In combination with pioglitazone and metformin, NESINA 25 mg was shown to be statistically superior in lowering A1C and FPG compared with the titration of pioglitazone from 30 mg to 45 mg at Week 26 and at Week 52 (Table 9; results shown only for Week 52). A total of 11% of patients in the NESINA 25 mg treatment group and 22% of patients in the pioglitazone up-titration group required glycemic rescue.
- Improvements in A1C were not affected by gender, age, race or baseline BMI.
- The mean increase in body weight was similar in both treatment arms.
- In a 26-week, placebo-controlled study, a total of 500 patients inadequately controlled on a sulfonylurea (mean baseline A1C = 8.1%) were randomized to receive NESINA 12.5 mg, NESINA 25 mg or placebo. Patients were maintained on a stable dose of glyburide (median dose = 10 mg) during the treatment period. All patients entered into a four-week, single-blind, placebo run-in period prior to randomization. Patients who failed to meet prespecified hyperglycemic goals during the 26-week treatment period received glycemic rescue therapy.
- The addition of NESINA 25 mg to glyburide therapy resulted in statistically significant improvements from baseline in A1C at Week 26 when compared to placebo (Table 10). Improvements in FPG observed with NESINA 25 mg were not statistically significant compared with placebo. A total of 16% of patients receiving NESINA 25 mg and 28% of those receiving placebo required glycemic rescue.
- Improvements in A1C were not affected by gender, age, baseline BMI or baseline glyburide dose.
- The mean change in body weight was similar between NESINA and placebo when given in combination with glyburide.
- In a 26-week, placebo-controlled study, a total of 390 patients inadequately controlled on insulin alone (42%) or in combination with metformin (58%) (mean baseline A1C = 9.3%) were randomized to receive NESINA 12.5 mg, NESINA 25 mg or placebo. Patients were maintained on their insulin regimen (median dose = 55 IU) upon randomization and those previously treated with insulin in combination with metformin (median dose = 1700 mg) prior to randomization continued on the combination regimen during the treatment period. Patients entered the trial on short-, intermediate- or long-acting (basal) insulin or premixed insulin. Patients who failed to meet prespecified hyperglycemic goals during the 26-week treatment period received glycemic rescue therapy.
- The addition of NESINA 25 mg once daily to insulin therapy resulted in statistically significant improvements from baseline in A1C and FPG at Week 26, when compared to placebo (Table 11). A total of 20% of patients receiving NESINA 25 mg and 40% of those receiving placebo required glycemic rescue.
- Improvements in A1C were not affected by gender, age, baseline BMI or baseline insulin dose. Clinically meaningful reductions in A1C were observed with NESINA compared to placebo regardless of whether subjects were receiving concomitant metformin and insulin (-0.2% placebo versus -0.8% NESINA) therapy or insulin alone (0.1% placebo versus -0.7% NESINA).
- The mean increase in body weight was similar between NESINA and placebo when given in combination with insulin.
# How Supplied
- NESINA tablets are available as film-coated tablets containing 25 mg, 12.5 mg or 6.25 mg of alogliptin as follows:
- 25 mg tablet: light red, oval, biconvex, film-coated, with "TAK ALG-25" printed on one side, available in:
- NDC 64764-250-30 Bottles of 30 tablets
- NDC 64764-250-90 Bottles of 90 tablets
- NDC 64764-250-50 Bottles of 500 tablets
- 12.5 mg tablet: yellow, oval, biconvex, film-coated, with "TAK ALG-12.5" printed on one side, available in:
- NDC 64764-125-30 Bottles of 30 tablets
- NDC 64764-125-90 Bottles of 90 tablets
- NDC 64764-125-50 Bottles of 500 tablets
- 6.25 mg tablet: light pink, oval, biconvex, film-coated, with "TAK ALG-6.25" printed on one side, available in:
- NDC 64764-625-30 Bottles of 30 tablets
- NDC 64764-625-90 Bottles of 90 tablets
- Storage
- Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F).
## Storage
There is limited information regarding Alogliptin Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Inform patients of the potential risks and benefits of NESINA.
- Patients should be informed that acute pancreatitis has been reported during use of NESINA. Patients should be informed that persistent, severe abdominal pain, sometimes radiating to the back, which may or may not be accompanied by vomiting, is the hallmark symptom of acute pancreatitis. Patients should be instructed to promptly discontinue NESINA and contact their physician if persistent severe abdominal pain occurs.
- Patients should be informed that allergic reactions have been reported during use of NESINA. If symptoms of allergic reactions (including skin rash, hives and swelling of the face, lips, tongue and throat that may cause difficulty in breathing or swallowing) occur, patients should be instructed to discontinue NESINA and seek medical advice promptly.
- Patients should be informe d that postmarketing reports of liver injury, sometimes fatal, have been reported during use of NESINA. If signs or symptoms of liver injury occur, patients should be instructed to discontinue NESINA and seek medical advice promptly.
- Inform patients that hypoglycemia can occur, particularly when an insulin secretagogue or insulin is used in combination with NESINA. Explain the risks, symptoms and appropriate management of hypoglycemia.
- Instruct patients to take NESINA only as prescribed. If a dose is missed, advise patients not to double their next dose.
- Instruct patients to read the Medication Guide before starting NESINA therapy and to reread each time the prescription is refilled. Instruct patients to inform their healthcare provider if an unusual symptom develops or if a symptom persists or worsens.
# Precautions with Alcohol
- Alcohol-Alogliptin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- NESINA®
# Look-Alike Drug Names
There is limited information regarding Alogliptin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Alogliptin
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
Alogliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor that is FDA approved for the treatment of type 2 diabetes mellitus. Common adverse reactions include nasopharyngitis, headache and upper respiratory tract infection.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Monotherapy and Combination Therapy
- NESINA is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus in multiple clinical settings.
- The recommended dose of NESINA is 25 mg once daily.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Alogliptin in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Alogliptin in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Alogliptin in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Alogliptin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Alogliptin in pediatric patients.
# Contraindications
- History of a serious hypersensitivity reaction to alogliptin-containing products, such as anaphylaxis, angioedema or severe cutaneous adverse reactions.
# Warnings
### Precautions
- Pancreatitis
- There have been postmarketing reports of acute pancreatitis in patients taking NESINA. After initiation of NESINA, patients should be observed carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, NESINA should promptly be discontinued and appropriate management should be initiated. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using NESINA.
- Hypersensitivity Reactions
- There have been postmarketing reports of serious hypersensitivity reactions in patients treated with NESINA. These reactions include anaphylaxis, angioedema and severe cutaneous adverse reactions, including Stevens-Johnson syndrome. If a serious hypersensitivity reaction is suspected, discontinue NESINA, assess for other potential causes for the event and institute alternative treatment for diabetes. Use caution in a patient with a history of angioedema with another DPP-4 inhibitor because it is unknown whether such patients will be predisposed to angioedema with NESINA.
- Hepatic Effects
- There have been postmarketing reports of fatal and nonfatal hepatic failure in patients taking NESINA, although some of the reports contain insufficient information necessary to establish the probable cause. In randomized controlled studies, serum alanine aminotransferase (ALT) elevations greater than three times the upper limit of normal (ULN) were observed: 1.3% in alogliptin-treated patients and 1.5% in all comparator-treated patients.
- Patients with type 2 diabetes may have fatty liver disease, which may cause liver test abnormalities, and they may also have other forms of liver disease, many of which can be treated or managed. Therefore, obtaining a liver test panel and assessing the patient before initiating NESINA therapy is recommended. In patients with abnormal liver tests, NESINA should be initiated with caution.
- Measure liver tests promptly in patients who report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice. In this clinical context, if the patient is found to have clinically significant liver enzyme elevations and if abnormal liver tests persist or worsen, NESINA should be interrupted and investigation done to establish the probable cause. NESINA should not be restarted in these patients without another explanation for the liver test abnormalities.
- Use with Medications Known to Cause Hypoglycemia
- Insulin and insulin secretagogues, such as sulfonylureas, are known to cause hypoglycemia. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with NESINA.
- Macrovascular Outcomes
- There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with NESINA or any other antidiabetic drug.
# 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.
- Approximately 8500 patients with type 2 diabetes have been treated with NESINA in 14 randomized, double-blind, controlled clinical trials with approximately 2900 subjects randomized to placebo and approximately 2200 to an active comparator. The mean exposure to NESINA was 40 weeks with more than 2400 subjects treated for more than one year. Among these patients, 63% had a history of hypertension, 51% had a history of dyslipidemia, 25% had a history of myocardial infarction, 8% had a history of unstable angina and 7% had a history of congestive heart failure. The mean duration of diabetes was seven years, the mean body mass index (BMI) was 31 kg/m2 (51% of patients had a BMI ≥30 kg/m2), and the mean age was 57 years (24% of patients ≥65 years of age).
- Two placebo-controlled monotherapy trials of 12 and 26 weeks of duration were conducted in patients treated with NESINA 12.5 mg daily, NESINA 25 mg daily and placebo. Four placebo-controlled add-on combination therapy trials of 26 weeks duration were also conducted: with metformin, with a sulfonylurea, with a thiazolidinedione and with insulin.
- Four placebo-controlled and one active-controlled trials of 16 weeks up through two years in duration were conducted in combination with metformin, in combination with pioglitazone and with pioglitazone added to a background of metformin therapy.
- Three active-controlled trials of 52 weeks in duration were conducted in patients treated with pioglitazone and metformin, in combination with metformin and as monotherapy compared to glipizide.
- In a pooled analysis of these 14 controlled clinical trials, the overall incidence of adverse events was 66% in patients treated with NESINA 25 mg compared to 62% with placebo and 70% with active comparator. Overall discontinuation of therapy due to adverse events was 4.7% with NESINA 25 mg compared to 4.5% with placebo or 6.2% with active comparator.
- Adverse reactions reported in ≥4% of patients treated with NESINA 25 mg and more frequently than in patients who received placebo are summarized in Table 1.
- Pancreatitis
- In the clinical trial program, pancreatitis was reported in 11 of 5902 (0.2%) patients receiving NESINA 25 mg daily compared to five of 5183 (<0.1%) patients receiving all comparators.
- Hypersensitivity Reactions
- In a pooled analysis, the overall incidence of hypersensitivity reactions was 0.6% with NESINA 25 mg compared to 0.8% with all comparators. A single event of serum sickness was reported in a patient treated with NESINA 25 mg.
- Hypoglycemia
- Hypoglycemic events were documented based upon a blood glucose value and/or clinical signs and symptoms of hypoglycemia.
- In the monotherapy study, the incidence of hypoglycemia was 1.5% in patients treated with NESINA compared to 1.6% with placebo. The use of NESINA as add-on therapy to glyburide or insulin did not increase the incidence of hypoglycemia compared to placebo. In a monotherapy study comparing NESINA to a sulfonylurea in elderly patients, the incidence of hypoglycemia was 5.4% with NESINA compared to 26% with glipizide (Table 2).
- Vital Signs
- No clinically meaningful changes in vital signs or in electrocardiograms were observed in patients treated with NESINA.
- Laboratory Tests
- No clinically meaningful changes in hematology, serum chemistry or urinalysis were observed in patients treated with NESINA.
## Postmarketing Experience
- The following adverse reactions have been identified during the postmarketing use of NESINA outside the United States. 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.
- Hypersensitivity reactions including anaphylaxis, angioedema, rash, urticaria and severe cutaneous adverse reactions, including Stevens-Johnson syndrome, hepatic enzyme elevations, fulminant hepatic failure and acute pancreatitis.
# Drug Interactions
- NESINA is primarily renally excreted. Cytochrome (CYP) P450-related metabolism is negligible. No significant drug-drug interactions were observed with the CYP-substrates or inhibitors tested or with renally excreted drugs.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category B
- No adequate or well-controlled studies in pregnant women have been conducted with NESINA. Based on animal data, NESINA is not predicted to increase the risk of developmental abnormalities. Because animal reproduction studies are not always predictive of human risk and exposure, NESINA, like other antidiabetic medications, should be used during pregnancy only if clearly needed.
- Alogliptin administered to pregnant rabbits and rats during the period of organogenesis was not teratogenic at doses of up to 200 mg/kg and 500 mg/kg, or 149 times and 180 times, respectively, the clinical dose based on plasma drug exposure (AUC).
- Doses of alogliptin up to 250 mg/kg (approximately 95 times clinical exposure based on AUC) given to pregnant rats from gestation Day 6 to lactation Day 20 did not harm the developing embryo or adversely affect growth and development of offspring.
- Placental transfer of alogliptin into the fetus was observed following oral dosing to pregnant rats.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Alogliptin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Alogliptin during labor and delivery.
### Nursing Mothers
- Alogliptin is secreted in the milk of lactating rats in a 2:1 ratio to plasma. It is not known whether alogliptin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when NESINA is administered to a nursing woman.
### Pediatric Use
- Safety and effectiveness of NESINA in pediatric patients have not been established.
### Geriatic Use
- Of the total number of patients (N=8507) in clinical safety and efficacy studies treated with NESINA, 2064 (24.3%) patients were 65 years and older and 341 (4%) patients were 75 years and older. No overall differences in safety or effectiveness were observed between patients 65 years and over and younger patients. While this clinical experience has not identified differences in responses between the elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out.
### Gender
There is no FDA guidance on the use of Alogliptin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Alogliptin with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Alogliptin in patients with renal impairment.
### Hepatic Impairment
- No dose adjustments are required in patients with mild to moderate hepatic impairment (Child-Pugh Grade A and B) based on insignificant change in systemic exposures (e.g., AUC) compared to subjects with normal hepatic function in a pharmacokinetic study. NESINA has not been studied in patients with severe hepatic impairment (Child-Pugh Grade C). Use caution when administering NESINA to patients with liver disease.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Alogliptin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Alogliptin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Alogliptin in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Alogliptin in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- The highest doses of NESINA administered in clinical trials were single doses of 800 mg to healthy subjects and doses of 400 mg once daily for 14 days to patients with type 2 diabetes (equivalent to 32 times and 16 times the maximum recommended clinical dose of 25 mg, respectively). No serious adverse events were observed at these doses.
### Management
- In the event of an overdose, it is reasonable to institute the necessary clinical monitoring and supportive therapy as dictated by the patient's clinical status. Per clinical judgment, it may be reasonable to initiate removal of unabsorbed material from the gastrointestinal tract.
- Alogliptin is minimally dialyzable; over a three-hour hemodialysis session, approximately 7% of the drug was removed. Therefore, hemodialysis is unlikely to be beneficial in an overdose situation. It is not known if NESINA is dialyzable by peritoneal dialysis.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Alogliptin in the drug label.
# Pharmacology
## Mechanism of Action
- Increased concentrations of the incretin hormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are released into the bloodstream from the small intestine in response to meals. These hormones cause insulin release from the pancreatic beta cells in a glucose-dependent manner but are inactivated by the DPP-4 enzyme within minutes. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, reducing hepatic glucose production. In patients with type 2 diabetes, concentrations of GLP-1 are reduced but the insulin response to GLP-1 is preserved. Alogliptin is a DPP-4 inhibitor that slows the inactivation of the incretin hormones, thereby increasing their bloodstream concentrations and reducing fasting and postprandial glucose concentrations in a glucose-dependent manner in patients with type 2 diabetes mellitus. Alogliptin selectively binds to and inhibits DPP-4 but not DPP-8 or DPP-9 activity in vitro at concentrations approximating therapeutic exposures.
## Structure
- NESINA tablets contain the active ingredient alogliptin, which is a selective, orally bioavailable inhibitor of the enzymatic activity of dipeptidyl peptidase-4 (DPP-4).
- Chemically, alogliptin is prepared as a benzoate salt, which is identified as 2-({6-[(3R)-3-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl}methyl)benzonitrile monobenzoate. It has a molecular formula of C18H21N5O2•C7H6O2 and a molecular weight of 461.51 daltons. The structural formula is:
- Alogliptin benzoate is a white to off-white crystalline powder containing one asymmetric carbon in the aminopiperidine moiety. It is soluble in dimethylsulfoxide, sparingly soluble in water and methanol, slightly soluble in ethanol and very slightly soluble in octanol and isopropyl acetate.
- Each NESINA tablet contains 34 mg, 17 mg or 8.5 mg alogliptin benzoate, which is equivalent to 25 mg, 12.5 mg or 6.25 mg, respectively, of alogliptin and the following inactive ingredients: mannitol, microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium and magnesium stearate. In addition, the film coating contains the following inactive ingredients: hypromellose, titanium dioxide, ferric oxide (red or yellow) and polyethylene glycol, and is marked with printing ink (Gray F1).
## Pharmacodynamics
- Single-dose administration of NESINA to healthy subjects resulted in a peak inhibition of DPP-4 within two to three hours after dosing. The peak inhibition of DPP-4 exceeded 93% across doses of 12.5 mg to 800 mg. Inhibition of DPP-4 remained above 80% at 24 hours for doses greater than or equal to 25 mg. Peak and total exposure over 24 hours to active GLP-1 were three- to four-fold greater with NESINA (at doses of 25 to 200 mg) than placebo. In a 16-week, double-blind, placebo-controlled study, NESINA 25 mg demonstrated decreases in postprandial glucagon while increasing postprandial active GLP-1 levels compared to placebo over an eight-hour period following a standardized meal. It is unclear how these findings relate to changes in overall glycemic control in patients with type 2 diabetes mellitus. In this study, NESINA 25 mg demonstrated decreases in two-hour postprandial glucose compared to placebo (-30 mg/dL versus 17 mg/dL, respectively).
- Multiple-dose administration of alogliptin to patients with type 2 diabetes also resulted in a peak inhibition of DPP-4 within one to two hours and exceeded 93% across all doses (25 mg, 100 mg and 400 mg) after a single dose and after 14 days of once-daily dosing. At these doses of NESINA, inhibition of DPP-4 remained above 81% at 24 hours after 14 days of dosing.
- Cardiac Electrophysiology
- In a randomized, placebo-controlled, four-arm, parallel-group study, 257 subjects were administered either alogliptin 50 mg, alogliptin 400 mg, moxifloxacin 400 mg or placebo once daily for a total of seven days. No increase in QTc was observed with either dose of alogliptin. At the 400 mg dose, peak alogliptin plasma concentrations were 19-fold higher than the peak concentrations following the maximum recommended clinical dose of 25 mg.
## Pharmacokinetics
- The pharmacokinetics of NESINA has been studied in healthy subjects and in patients with type 2 diabetes. After administration of single, oral doses up to 800 mg in healthy subjects, the peak plasma alogliptin concentration (median Tmax) occurred one to two hours after dosing. At the maximum recommended clinical dose of 25 mg, NESINA was eliminated with a mean terminal half-life (T1/2) of approximately 21 hours.
- After multiple-dose administration up to 400 mg for 14 days in patients with type 2 diabetes, accumulation of alogliptin was minimal with an increase in total (i.e., AUC) and peak (i.e., Cmax) alogliptin exposures of 34% and 9%, respectively. Total and peak exposure to alogliptin increased proportionally across single doses and multiple doses of alogliptin ranging from 25 mg to 400 mg. The intersubject coefficient of variation for alogliptin AUC was 17%. The pharmacokinetics of NESINA was also shown to be similar in healthy subjects and in patients with type 2 diabetes.
- Absorption
- The absolute bioavailability of NESINA is approximately 100%. Administration of NESINA with a high-fat meal results in no significant change in total and peak exposure to alogliptin. NESINA may therefore be administered with or without food.
- Distribution
- Following a single, 12.5 mg intravenous infusion of alogliptin to healthy subjects, the volume of distribution during the terminal phase was 417 L, indicating that the drug is well distributed into tissues.
- Alogliptin is 20% bound to plasma proteins.
- Metabolism
- Alogliptin does not undergo extensive metabolism and 60% to 71% of the dose is excreted as unchanged drug in the urine.
- Two minor metabolites were detected following administration of an oral dose of [14C] alogliptin, N-demethylated, M-I (<1% of the parent compound), and N-acetylated alogliptin, M-II (<6% of the parent compound). M-I is an active metabolite and is an inhibitor of DPP-4 similar to the parent molecule; M-II does not display any inhibitory activity toward DPP-4 or other DPP-related enzymes. In vitro data indicate that CYP2D6 and CYP3A4 contribute to the limited metabolism of alogliptin.
- Alogliptin exists predominantly as the (R)-enantiomer (>99%) and undergoes little or no chiral conversion in vivo to the (S)-enantiomer. The (S)-enantiomer is not detectable at the 25 mg dose.
- Excretion
- The primary route of elimination of [14C] alogliptin-derived radioactivity occurs via renal excretion (76%) with 13% recovered in the feces, achieving a total recovery of 89% of the administered radioactive dose. The renal clearance of alogliptin (9.6 L/hr) indicates some active renal tubular secretion and systemic clearance was 14.0 L/hr.
- Specific Populations
- Renal Impairment
- A single-dose, open-label study was conducted to evaluate the pharmacokinetics of alogliptin 50 mg in patients with chronic renal impairment compared with healthy subjects.
- In patients with mild renal impairment (creatinine clearance [CrCl] ≥60 to <90 mL/min), an approximate 1.2-fold increase in plasma AUC of alogliptin was observed. Because increases of this magnitude are not considered clinically relevant, dose adjustment for patients with mild renal impairment is not recommended.
- In patients with moderate renal impairment (CrCl ≥30 to <60 mL/min), an approximate two-fold increase in plasma AUC of alogliptin was observed. To maintain similar systemic exposures of NESINA to those with normal renal function, the recommended dose is 12.5 mg once daily in patients with moderate renal impairment.
- In patients with severe renal impairment (CrCl ≥15 to <30 mL/min) and ESRD (CrCl <15 mL/min or requiring dialysis), an approximate three- and four-fold increase in plasma AUC of alogliptin were observed, respectively. Dialysis removed approximately 7% of the drug during a three-hour dialysis session. NESINA may be administered without regard to the timing of the dialysis. To maintain similar systemic exposures of NESINA to those with normal renal function, the recommended dose is 6.25 mg once daily in patients with severe renal impairment, as well as in patients with ESRD requiring dialysis.
- Hepatic Impairment
- Total exposure to alogliptin was approximately 10% lower and peak exposure was approximately 8% lower in patients with moderate hepatic impairment (Child-Pugh Grade B) compared to healthy subjects. The magnitude of these reductions is not considered to be clinically meaningful. Patients with severe hepatic impairment (Child-Pugh Grade C) have not been studied. Use caution when administering NESINA to patients with liver disease.
- Gender
- No dose adjustment of NESINA is necessary based on gender. Gender did not have any clinically meaningful effect on the pharmacokinetics of alogliptin.
- Geriatric
- No dose adjustment of NESINA is necessary based on age. Age did not have any clinically meaningful effect on the pharmacokinetics of alogliptin.
- Pediatric
- Studies characterizing the pharmacokinetics of alogliptin in pediatric patients have not been performed.
- Race
- No dose adjustment of NESINA is necessary based on race. Race (White, Black, and Asian) did not have any clinically meaningful effect on the pharmacokinetics of alogliptin.
- Drug Interactions
- In Vitro Assessment of Drug Interactions
- In vitro studies indicate that alogliptin is neither an inducer of CYP1A2, CYP2B6, CYP2C9, CYP2C19 and CYP3A4, nor an inhibitor of CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP3A4 and CYP2D6 at clinically relevant concentrations.
- In Vivo Assessment of Drug Interactions
- Effects of Alogliptin on the Pharmacokinetics of Other Drugs
- In clinical studies, alogliptin did not meaningfully increase the systemic exposure to the following drugs that are metabolized by CYP isozymes or excreted unchanged in urine (Figure 1). No dose adjustment of NESINA is recommended based on results of the described pharmacokinetic studies.
## Nonclinical Toxicology
- Rats were administered oral doses of 75, 400 and 800 mg/kg alogliptin for two years. No drug-related tumors were observed up to 75 mg/kg or approximately 32 times the maximum recommended clinical dose of 25 mg, based on AUC exposure. At higher doses (approximately 308 times the maximum recommended clinical dose of 25 mg), a combination of thyroid C-cell adenomas and carcinomas increased in male but not female rats. No drug-related tumors were observed in mice after administration of 50, 150 or 300 mg/kg alogliptin for two years, or up to approximately 51 times the maximum recommended clinical dose of 25 mg, based on AUC exposure.
- Alogliptin was not mutagenic or clastogenic, with and without metabolic activation, in the Ames test with S. typhimurium and E. coli or the cytogenetic assay in mouse lymphoma cells. Alogliptin was negative in the in vivo mouse micronucleus study.
- In a fertility study in rats, alogliptin had no adverse effects on early embryonic development, mating or fertility at doses up to 500 mg/kg, or approximately 172 times the clinical dose based on plasma drug exposure (AUC).
# Clinical Studies
- NESINA has been studied as monotherapy and in combination with metformin, a sulfonylurea, a thiazolidinedione (either alone or in combination with metformin or a sulfonylurea) and insulin (either alone or in combination with metformin).
- A total of 8673 patients with type 2 diabetes were randomized in 10 double-blind, placebo- or active-controlled clinical safety and efficacy studies conducted to evaluate the effects of NESINA on glycemic control. The racial distribution of patients exposed to study medication was 68% Caucasian, 15% Asian, 7% Black and 9% other racial groups. The ethnic distribution was 30% Hispanic. Patients had an overall mean age of 55 years (range 21 to 80 years).
- In patients with type 2 diabetes, treatment with NESINA produced clinically meaningful and statistically significant improvements in A1C compared to placebo. As is typical for trials of agents to treat type 2 diabetes, the mean reduction in A1C with NESINA appears to be related to the degree of A1C elevation at baseline.
- NESINA had similar changes from baseline in serum lipids compared to placebo.
- A total of 1768 patients with type 2 diabetes participated in three double-blind studies to evaluate the efficacy and safety of NESINA in patients with inadequate glycemic control on diet and exercise. All three studies had a four-week, single-blind, placebo run-in period followed by a 26-week randomized treatment period. Patients who failed to meet prespecified hyperglycemic goals during the 26-week treatment periods received glycemic rescue therapy.
- In a 26-week, double-blind, placebo-controlled study, a total of 329 patients (mean baseline A1C = 8%) were randomized to receive NESINA 12.5 mg, NESINA 25 mg or placebo once daily. Treatment with NESINA 25 mg resulted in statistically significant improvements from baseline in A1C and fasting plasma glucose (FPG) compared to placebo at Week 26 (Table 3). A total of 8% of patients receiving NESINA 25 mg and 30% of those receiving placebo required glycemic rescue therapy.
- Improvements in A1C were not affected by gender, age or baseline BMI.
- The mean change in body weight with NESINA was similar to placebo.
- In a 26-week, double-blind, active-controlled study, a total of 655 patients (mean baseline A1C = 8.8%) were randomized to receive NESINA 25 mg alone, pioglitazone 30 mg alone, NESINA 12.5 mg with pioglitazone 30 mg or NESINA 25 mg with pioglitazone 30 mg once daily. Coadministration of NESINA 25 mg with pioglitazone 30 mg resulted in statistically significant improvements from baseline in A1C and FPG compared to NESINA 25 mg alone and to pioglitazone 30 mg alone (Table 4). A total of 3% of patients receiving NESINA 25 mg coadministered with pioglitazone 30 mg, 11% of those receiving NESINA 25 mg alone and 6% of those receiving pioglitazone 30 mg alone required glycemic rescue.
- Improvements in A1C were not affected by gender, age or baseline BMI.
- The mean increase in body weight was similar between pioglitazone alone and NESINA when coadministered with pioglitazone.
- In a 26-week, double-blind, placebo-controlled study, a total of 784 patients inadequately controlled on diet and exercise alone (mean baseline A1C = 8.4%) were randomized to one of seven treatment groups: placebo; metformin HCl 500 mg or metformin HCl 1000 mg twice daily; NESINA 12.5 mg twice daily; NESINA 25 mg daily; or NESINA 12.5 mg in combination with metformin HCl 500 mg or metformin HCl 1000 mg twice daily. Both coadministration treatment arms (NESINA 12.5 mg + metformin HCl 500 mg and NESINA 12.5 mg + metformin HCl 1000 mg) resulted in statistically significant improvements in A1C and FPG when compared with their respective individual alogliptin and metformin component regimens (Table 5). Coadministration treatment arms demonstrated improvements in two-hour postprandial glucose (PPG) compared to NESINA alone or metformin alone (Table 5). A total of 12.3% of patients receiving NESINA 12.5 mg + metformin HCl 500 mg, 2.6% of patients receiving NESINA 12.5 mg + metformin HCl 1000 mg, 17.3% of patients receiving NESINA 12.5 mg, 22.9% of patients receiving metformin HCl 500 mg, 10.8% of patients receiving metformin HCl 1000 mg and 38.7% of patients receiving placebo required glycemic rescue.
- Improvements in A1C were not affected by gender, age, race or baseline BMI. The mean decrease in body weight was similar between metformin alone and NESINA when coadministered with metformin.
- A total of 2081 patients with type 2 diabetes participated in two 26-week, double-blind, placebo-controlled studies to evaluate the efficacy and safety of NESINA as add-on therapy to metformin. In both studies, patients were inadequately controlled on metformin at a dose of at least 1500 mg per day or at the maximum tolerated dose. All patients entered a four-week, single-blind placebo run-in period prior to randomization. Patients who failed to meet prespecified hyperglycemic goals during the 26-week treatment periods received glycemic rescue therapy.
- In the first 26-week, placebo-controlled study, a total of 527 patients already on metformin (mean baseline A1C = 8%) were randomized to receive NESINA 12.5 mg, NESINA 25 mg or placebo. Patients were maintained on a stable dose of metformin (median dose = 1700 mg) during the treatment period. NESINA 25 mg in combination with metformin resulted in statistically significant improvements from baseline in A1C and FPG at Week 26, when compared to placebo (Table 6). A total of 8% of patients receiving NESINA 25 mg and 24% of patients receiving placebo required glycemic rescue.
- Improvements in A1C were not affected by gender, age, baseline BMI or baseline metformin dose.
- The mean decrease in body weight was similar between NESINA and placebo when given in combination with metformin.
- In the second 26-week, double-blind, placebo-controlled study, a total of 1554 patients already on metformin (mean baseline A1C = 8.5%) were randomized to one of 12 double-blind treatment groups: placebo; 12.5 mg or 25 mg of NESINA alone; 15 mg, 30 mg or 45 mg of pioglitazone alone; or 12.5 mg or 25 mg of NESINA in combination with 15 mg, 30 mg or 45 mg of pioglitazone. Patients were maintained on a stable dose of metformin (median dose = 1700 mg) during the treatment period. Coadministration of NESINA and pioglitazone provided statistically significant improvements in A1C and FPG compared to placebo, to NESINA alone or to pioglitazone alone when added to background metformin therapy (Table 7, Figure 3). In addition, improvements from baseline A1C were comparable between NESINA alone and pioglitazone alone (15 mg, 30 mg and 45 mg) at Week 26. A total of 4%, 5% or 2% of patients receiving NESINA 25 mg with 15 mg, 30 mg or 45 mg pioglitazone, 33% of patients receiving placebo, 13% of patients receiving NESINA 25 mg and 10%, 15% or 9% of patients receiving pioglitazone 15 mg, 30 mg or 45 mg alone required glycemic rescue.
- Improvements in A1C were not affected by gender, age or baseline BMI.
- The mean increase in body weight was similar between pioglitazone alone and NESINA when coadministered with pioglitazone.
- In a 26-week, placebo-controlled study, a total of 493 patients inadequately controlled on a thiazolidinedione alone or in combination with metformin or a sulfonylurea (10 mg) (mean baseline A1C = 8%) were randomized to receive NESINA 12.5 mg, NESINA 25 mg or placebo. Patients were maintained on a stable dose of pioglitazone (median dose = 30 mg) during the treatment period; those who were also previously treated on metformin (median dose = 2000 mg) or sulfonylurea (median dose = 10 mg) prior to randomization were maintained on the combination therapy during the treatment period. All patients entered into a four-week, single-blind placebo run-in period prior to randomization. Patients who failed to meet prespecified hyperglycemic goals during the 26-week treatment period received glycemic rescue therapy.
- The addition of NESINA 25 mg once daily to pioglitazone therapy resulted in statistically significant improvements from baseline in A1C and FPG at Week 26, compared to placebo (Table 8). A total of 9% of patients who were receiving NESINA 25 mg and 12% of patients receiving placebo required glycemic rescue.
- Improvements in A1C were not affected by gender, age, baseline BMI or baseline pioglitazone dose.
- Clinically meaningful reductions in A1C were observed with NESINA compared to placebo regardless of whether subjects were receiving concomitant metformin or sulfonylurea (-0.2% placebo versus -0.9% NESINA) therapy or pioglitazone alone (0% placebo versus -0.52% NESINA).
- The mean increase in body weight was similar between NESINA and placebo when given in combination with pioglitazone.
- In a 52-week, active-comparator study, a total of 803 patients inadequately controlled (mean baseline A1C = 8.2%) on a current regimen of pioglitazone 30 mg and metformin at least 1500 mg per day or at the maximum tolerated dose were randomized to either receive the addition of NESINA 25 mg or the titration of pioglitazone 30 mg to 45 mg following a four-week, single-blind placebo run-in period. Patients were maintained on a stable dose of metformin (median dose = 1700 mg). Patients who failed to meet prespecified hyperglycemic goals during the 52-week treatment period received glycemic rescue therapy.
- In combination with pioglitazone and metformin, NESINA 25 mg was shown to be statistically superior in lowering A1C and FPG compared with the titration of pioglitazone from 30 mg to 45 mg at Week 26 and at Week 52 (Table 9; results shown only for Week 52). A total of 11% of patients in the NESINA 25 mg treatment group and 22% of patients in the pioglitazone up-titration group required glycemic rescue.
- Improvements in A1C were not affected by gender, age, race or baseline BMI.
- The mean increase in body weight was similar in both treatment arms.
- In a 26-week, placebo-controlled study, a total of 500 patients inadequately controlled on a sulfonylurea (mean baseline A1C = 8.1%) were randomized to receive NESINA 12.5 mg, NESINA 25 mg or placebo. Patients were maintained on a stable dose of glyburide (median dose = 10 mg) during the treatment period. All patients entered into a four-week, single-blind, placebo run-in period prior to randomization. Patients who failed to meet prespecified hyperglycemic goals during the 26-week treatment period received glycemic rescue therapy.
- The addition of NESINA 25 mg to glyburide therapy resulted in statistically significant improvements from baseline in A1C at Week 26 when compared to placebo (Table 10). Improvements in FPG observed with NESINA 25 mg were not statistically significant compared with placebo. A total of 16% of patients receiving NESINA 25 mg and 28% of those receiving placebo required glycemic rescue.
- Improvements in A1C were not affected by gender, age, baseline BMI or baseline glyburide dose.
- The mean change in body weight was similar between NESINA and placebo when given in combination with glyburide.
- In a 26-week, placebo-controlled study, a total of 390 patients inadequately controlled on insulin alone (42%) or in combination with metformin (58%) (mean baseline A1C = 9.3%) were randomized to receive NESINA 12.5 mg, NESINA 25 mg or placebo. Patients were maintained on their insulin regimen (median dose = 55 IU) upon randomization and those previously treated with insulin in combination with metformin (median dose = 1700 mg) prior to randomization continued on the combination regimen during the treatment period. Patients entered the trial on short-, intermediate- or long-acting (basal) insulin or premixed insulin. Patients who failed to meet prespecified hyperglycemic goals during the 26-week treatment period received glycemic rescue therapy.
- The addition of NESINA 25 mg once daily to insulin therapy resulted in statistically significant improvements from baseline in A1C and FPG at Week 26, when compared to placebo (Table 11). A total of 20% of patients receiving NESINA 25 mg and 40% of those receiving placebo required glycemic rescue.
- Improvements in A1C were not affected by gender, age, baseline BMI or baseline insulin dose. Clinically meaningful reductions in A1C were observed with NESINA compared to placebo regardless of whether subjects were receiving concomitant metformin and insulin (-0.2% placebo versus -0.8% NESINA) therapy or insulin alone (0.1% placebo versus -0.7% NESINA).
- The mean increase in body weight was similar between NESINA and placebo when given in combination with insulin.
# How Supplied
- NESINA tablets are available as film-coated tablets containing 25 mg, 12.5 mg or 6.25 mg of alogliptin as follows:
- 25 mg tablet: light red, oval, biconvex, film-coated, with "TAK ALG-25" printed on one side, available in:
- NDC 64764-250-30 Bottles of 30 tablets
- NDC 64764-250-90 Bottles of 90 tablets
- NDC 64764-250-50 Bottles of 500 tablets
- 12.5 mg tablet: yellow, oval, biconvex, film-coated, with "TAK ALG-12.5" printed on one side, available in:
- NDC 64764-125-30 Bottles of 30 tablets
- NDC 64764-125-90 Bottles of 90 tablets
- NDC 64764-125-50 Bottles of 500 tablets
- 6.25 mg tablet: light pink, oval, biconvex, film-coated, with "TAK ALG-6.25" printed on one side, available in:
- NDC 64764-625-30 Bottles of 30 tablets
- NDC 64764-625-90 Bottles of 90 tablets
- Storage
- Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F).
## Storage
There is limited information regarding Alogliptin Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Inform patients of the potential risks and benefits of NESINA.
- Patients should be informed that acute pancreatitis has been reported during use of NESINA. Patients should be informed that persistent, severe abdominal pain, sometimes radiating to the back, which may or may not be accompanied by vomiting, is the hallmark symptom of acute pancreatitis. Patients should be instructed to promptly discontinue NESINA and contact their physician if persistent severe abdominal pain occurs.
- Patients should be informed that allergic reactions have been reported during use of NESINA. If symptoms of allergic reactions (including skin rash, hives and swelling of the face, lips, tongue and throat that may cause difficulty in breathing or swallowing) occur, patients should be instructed to discontinue NESINA and seek medical advice promptly.
- Patients should be informe d that postmarketing reports of liver injury, sometimes fatal, have been reported during use of NESINA. If signs or symptoms of liver injury occur, patients should be instructed to discontinue NESINA and seek medical advice promptly.
- Inform patients that hypoglycemia can occur, particularly when an insulin secretagogue or insulin is used in combination with NESINA. Explain the risks, symptoms and appropriate management of hypoglycemia.
- Instruct patients to take NESINA only as prescribed. If a dose is missed, advise patients not to double their next dose.
- Instruct patients to read the Medication Guide before starting NESINA therapy and to reread each time the prescription is refilled. Instruct patients to inform their healthcare provider if an unusual symptom develops or if a symptom persists or worsens.
# Precautions with Alcohol
- Alcohol-Alogliptin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- NESINA®[1]
# Look-Alike Drug Names
There is limited information regarding Alogliptin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Alogliptin | |
46054be0fadbcfdd824b0918362309075a12d39c | wikidoc | Alprazolam | Alprazolam
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# Overview
Alprazolam is a benzodiazepine that is FDA approved for the treatment of anxiety disorders and panic disorder. Common adverse reactions include constipation, xerostomia, dysarthria, fatigue, irritability, reduced libido, somnolence and confusion.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
## Anxiety Disorders and Transient Symptoms of Anxiety
Dosing information
- 0.25 to 0.5 mg PO tid. The dose may be increased to achieve a maximum therapeutic effect, at intervals of 3 to 4 days, to a maximum daily dose of 4 mg, given in divided doses. The lowest possible effective dose should be employed and the need for continued treatment reassessed frequently. The risk of dependence may increase with dose and duration of treatment.
- In all patients, dosage should be reduced gradually when discontinuing therapy or when decreasing the daily dosage. Although there are no systematically collected data to support a specific discontinuation schedule, it is suggested that the daily dosage be decreased by no more than 0.5 mg every 3 days. Some patients may require an even slower dosage reduction.
## Panic Disorder
Dosing information
- The successful treatment of many panic disorder patients has required the use of alprazolam at doses greater than 4 mg daily. In controlled trials conducted to establish the efficacy of alprazolam in panic disorder, doses in the range of 1 to 10 mg daily were used. The mean dosage employed was approximately 5 to 6 mg daily. Among the approximately 1700 patients participating in the panic disorder development program, about 300 received Alprazolam in dosages of greater than 7 mg/day, including approximately 100 patients who received maximum dosages of greater than 9 mg/day. Occasional patients required as much as 10 mg a day to achieve a successful response.
## Dose Titration
- Initial treatment: 0.5 mg PO tid. Depending on the response, the dose may be increased at intervals of 3 to 4 days in increments of no more than 1 mg per day. Slower titration to the dose levels greater than 4 mg/day may be advisable to allow full expression of the pharmacodynamic effect of Alprazolam. To lessen the possibility of inter dose symptoms, the times of administration should be distributed as evenly as possible throughout the waking hours, that is, on a three or four times per day schedule.
- Generally, therapy should be initiated at a low dose to minimize the risk of adverse responses in patients especially sensitive to the drug. Dose should be advanced until an acceptable therapeutic response (ie, a substantial reduction in or total elimination of panic attacks) is achieved, intolerance occurs, or the maximum recommended dose is attained.
## Dose Maintenance
- For patients receiving doses greater than 4 mg/day, periodic reassessment and consideration of dosage reduction is advised. In a controlled post marketing dose-response study, patients treated with doses of Alprazolam greater than 4 mg/day for 3 months were able to taper to 50% of their total maintenance dose without apparent loss of clinical benefit. Because of the danger of withdrawal, abrupt discontinuation of treatment should be avoided.
- The necessary duration of treatment for panic disorder patients responding to Alprazolam is unknown. After a period of extended freedom from attacks, a carefully supervised tapered discontinuation may be attempted, but there is evidence that this may often be difficult to accomplish without recurrence of symptoms and/or the manifestation of withdrawal phenomena.
## Dose Reduction
- Because of the danger of withdrawal, abrupt discontinuation of treatment should be avoided.
- In all patients, dosage should be reduced gradually when discontinuing therapy or when decreasing the daily dosage. Although there are no systematically collected data to support a specific discontinuation schedule, it is suggested that the daily dosage be decreased by no more than 0.5 mg every three days. Some patients may require an even slower dosage reduction.
- In any case, reduction of dose must be undertaken under close supervision and must be gradual. If significant withdrawal symptoms develop, the previous dosing schedule should be re-instituted and, only after stabilization, should a less rapid schedule of discontinuation be attempted. In a controlled post marketing discontinuation study of panic disorder patients which compared this recommended taper schedule with a slower taper schedule, no difference was observed between the groups in the proportion of patients who tapered to zero dose; however, the slower schedule was associated with a reduction in symptoms associated with a withdrawal syndrome. It is suggested that the dose be reduced by no more than 0.5 mg every 3 days, with the understanding that some patients may benefit from an even more gradual discontinuation. Some patients may prove resistant to all discontinuation regimens.
## Dosing in Special Populations
- In elderly patients, in patients with advanced liver disease or in patients with debilitating disease, the usual starting dose: 0.25 mg PO bid or tid. This may be gradually increased if needed and tolerated. The elderly may be especially sensitive to the effects of benzodiazepines. If side effects occur at the recommended starting dose, the dose may be lowered.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of alprazolam in adult patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of alprazolam in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- The pharmacokinetics of alprazolam in pediatric patients have not been studied.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of alprazolam in pediatric patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of alprazolam in pediatric patients.
# Contraindications
- Alprazolam tablets are contraindicated in patients with known sensitivity to this drug or other benzodiazepines. Alprazolam may be used in patients with open angle glaucoma who are receiving appropriate therapy, but is contraindicated in patients with acute narrow angle glaucoma.
- Alprazolam is contraindicated with ketoconazole and itraconazole, since these medications significantly impair the oxidative metabolism mediated by cytochrome P450 3A (CYP3A) .
# Warnings
### Dependence and Withdrawal Reactions, Including Seizures
- Certain adverse clinical events, some life-threatening, are a direct consequence of physical dependence to Alprazolam. These include a spectrum of withdrawal symptoms; the most important is seizure . Even after relatively short term use at the doses recommended for the treatment of transient anxiety and anxiety disorder (ie, 0.75 to 4.0 mg per day), there is some risk of dependence. Spontaneous reporting system data suggest that the risk of dependence and its severity appear to be greater in patients treated with doses greater than 4 mg/day and for long periods (more than 12 weeks). However, in a controlled post marketing discontinuation study of panic disorder patients, the duration of treatment (3 months compared to 6 months) had no effect on the ability of patients to taper to zero dose. In contrast, patients treated with doses of alprazolam greater than 4 mg/day had more difficulty tapering to zero dose than those treated with less than 4 mg/day.
### The Importance of Dose and the Risks of Alprazolam as a Treatment for Panic Disorder
- Because the management of panic disorder often requires the use of average daily doses of alprazolam above 4 mg, the risk of dependence among panic disorder patients may be higher than that among those treated for less severe anxiety. Experience in randomized placebo-controlled discontinuation studies of patients with panic disorder showed a high rate of rebound and withdrawal symptoms in patients treated with alprazolam compared to placebo-treated patients.
- Relapse or return of illness was defined as a return of symptoms characteristic of panic disorder (primarily panic attacks) to levels approximately equal to those seen at baseline before active treatment was initiated. Rebound refers to a return of symptoms of panic disorder to a level substantially greater in frequency, or more severe in intensity than seen at baseline. withdrawal symptoms were identified as those which were generally not characteristic of panic disorder and which occurred for the first time more frequently during discontinuation than at baseline.
- In a controlled clinical trial in which 63 patients were randomized to alprazolam and where withdrawal symptoms were specifically sought, the following were identified as symptoms of withdrawal: heightened sensory perception, impaired concentration, dysosmia, clouded sensorium, paresthesias, muscle cramps, muscle twitch, diarrhea, blurred vision, appetite decrease, and weight loss. Other symptoms, such as anxiety and insomnia, were frequently seen during discontinuation, but it could not be determined if they were due to return of illness, rebound, or withdrawal.
- In two controlled trials of 6 to 8 weeks duration where the ability of patients to discontinue medication was measured, 71%–93% of patients treated with alprazolam tapered completely off therapy compared to 89%–96% of placebo-treated patients. In a controlled post marketing discontinuation study of panic disorder patients, the duration of treatment (3 months compared to 6 months) had no effect on the ability of patients to taper to zero dose.
- Seizures attributable to alprazolam were seen after drug discontinuance or dose reduction in 8 of 1980 patients with panic disorder or in patients participating in clinical trials where doses of alprazolam greater than 4 mg/day for over 3 months were permitted. Five of these cases clearly occurred during abrupt dose reduction, or discontinuation from daily doses of 2 to 10 mg. Three cases occurred in situations where there was not a clear relationship to abrupt dose reduction or discontinuation. In one instance, seizure occurred after discontinuation from a single dose of 1 mg after tapering at a rate of 1 mg every 3 days from 6 mg daily. In two other instances, the relationship to taper is indeterminate; in both of these cases the patients had been receiving doses of 3 mg daily prior to seizure. The duration of use in the above 8 cases ranged from 4 to 22 weeks. There have been occasional voluntary reports of patients developing seizures while apparently tapering gradually from alprazolam. The risk of seizure seems to be greatest 24–72 hours after discontinuation.
### Status Epilepticus and its Treatment
- The medical event voluntary reporting system shows that withdrawal seizures have been reported in association with the discontinuation of alprazolam. In most cases, only a single seizure was reported; however, multiple seizures and status epilepticus were reported as well.
### Interdose Symptoms
- Early morning anxiety and emergence of anxiety symptoms between doses of alprazolam have been reported in patients with panic disorder taking prescribed maintenance doses of alprazolam. These symptoms may reflect the development of tolerance or a time interval between doses which is longer than the duration of clinical action of the administered dose. In either case, it is presumed that the prescribed dose is not sufficient to maintain plasma levels above those needed to prevent relapse, rebound or withdrawal symptoms over the entire course of the interdosing interval. In these situations, it is recommended that the same total daily dose be given divided as more frequent administrations .
### Risk of Dose Reduction
- Withdrawal reactions may occur when dosage reduction occurs for any reason. This includes purposeful tapering, but also inadvertent reduction of dose (eg, the patient forgets, the patient is admitted to a hospital). Therefore, the dosage of alprazolam should be reduced or discontinued gradually .
### CNS Depression and Impaired Performance
- Because of its CNS depressant effects, patients receiving alprazolam should be cautioned against engaging in hazardous occupations or activities requiring complete mental alertness such as operating machinery or driving a motor vehicle. For the same reason, patients should be cautioned about the simultaneous ingestion of alcohol and other CNS depressant drugs during treatment with alprazolam.
### Risk of Fetal Harm
- Benzodiazepines can potentially cause fetal harm when administered to pregnant women. If alprazolam 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. Because of experience with other members of the benzodiazepine class, alprazolam is assumed to be capable of causing an increased risk of congenital abnormalities when administered to a pregnant woman during the first trimester. Because use of these drugs is rarely a matter of urgency, their use during the first trimester should almost always be avoided. The possibility that a woman of childbearing potential may be pregnant at the time of institution of therapy should be considered. Patients should be advised that if they become pregnant during therapy or intend to become pregnant they should communicate with their physicians about the desirability of discontinuing the drug.
### Alprazolam Interaction with Drugs that Inhibit Metabolism via Cytochrome P4503A
- The initial step in alprazolam metabolism is hydroxylation catalyzed by cytochrome P450 3A (CYP3A). Drugs that inhibit this metabolic pathway may have a profound effect on the clearance of alprazolam. Consequently, alprazolam should be avoided in patients receiving very potent inhibitors of CYP3A. With drugs inhibiting CYP3A to a lesser but still significant degree, alprazolam should be used only with caution and consideration of appropriate dosage reduction. For some drugs, an interaction with alprazolam has been quantified with clinical data; for other drugs, interactions are predicted from in vitro data and/or experience with similar drugs in the same pharmacologic class.
- The following are examples of drugs known to inhibit the metabolism of alprazolam and/or related benzodiazepines, presumably through inhibition of CYP3A.
### Potent CYP3A Inhibitors
### Azole Antifungal Agents
- Ketoconazole and itraconazole are potent CYP3A inhibitors and have been shown in vivo to increase plasma alprazolam concentrations 3.98 fold and 2.70 fold, respectively. The coadministration of alprazolam with these agents is not recommended. Other azole-type antifungal agents should also be considered potent CYP3A inhibitors and the coadministration of alprazolam with them is not recommended .
### Drugs Demonstrated to be CYP 3A Inhibitors on the Basis of Clinical Studies Involving Alprazolam (Caution and Consideration of Appropriate Alprazolam Dose Reduction are Recommended during Coadministration with the Following Drugs)
### Nefazodone
- Coadministration of nefazodone increased alprazolam concentration two-fold.
### Fluvoxamine
- Coadministration of fluvoxamine approximately doubled the maximum plasma concentration of alprazolam, decreased clearance by 49%, increased half-life by 71%, and decreased measured psychomotor performance.
### Cimetidine
- Coadministration of cimetidine increased the maximum plasma concentration of alprazolam by 86%, decreased clearance by 42%, and increased half-life by 16%.
### HIV protease inhibitors
- Interactions involving HIV protease inhibitors (eg, ritonavir) and alprazolam are complex and time dependent. Low doses of ritonavir resulted in a large impairment of alprazolam clearance, prolonged its elimination half-life and enhanced clinical effects. However, upon extended exposure to ritonavir, CYP3A induction offset this inhibition. This interaction will require a dose-adjustment or discontinuation of alprazolam.
### Other Drugs Possibly Affecting Alprazolam Metabolism
- Other drugs possibly affecting alprazolam metabolism by inhibition of CYP3A are discussed in the PRECAUTIONS section
# Precaution
## General
### Suicide
- As with other psychotropic medications, the usual precautions with respect to administration of the drug and size of the prescription are indicated for severely depressed patients or those in whom there is reason to expect concealed suicidal ideation or plans. panic disorder has been associated with primary and secondary major depressive disorders and increased reports of suicide among untreated patients.
### Mania
- Episodes of hypomania and mania have been reported in association with the use of alprazolam in patients with depression.
### Uricosuric Effect
- Alprazolam has a weak uricosuric effect. Although other medications with weak uricosuric effect have been reported to cause acute renal failure, there have been no reported instances of acute renal failure attributable to therapy with alprazolam.
### Use in Patients with Concomitant Illness
- It is recommended that the dosage be limited to the smallest effective dose to preclude the development of ataxia or oversedation which may be a particular problem in elderly or debilitated patients. The usual precautions in treating patients with impaired renal, hepatic or pulmonary function should be observed. There have been rare reports of death in patients with severe pulmonary disease shortly after the initiation of treatment with alprazolam. A decreased systemic alprazolam elimination rate (eg, increased plasma half-life) has been observed in both alcoholic liver disease patients and obese patients receiving alprazolam .
# Adverse Reactions
## Clinical Trials Experience
- Side effects to Alprazolam Tablets, if they occur, are generally observed at the beginning of therapy and usually disappear upon continued medication. In the usual patient, the most frequent side effects are likely to be an extension of the pharmacological activity of alprazolam, eg, drowsiness or light-headedness.
- The data cited in the two tables below are estimates of untoward clinical event incidence among patients who participated under the following clinical conditions: relatively short duration (ie, four weeks) placebo-controlled clinical studies with dosages up to 4 mg/day of alprazolam (for the management of anxiety disorders or for the short-term relief of the symptoms of anxiety) and short-term (up to ten weeks) placebo-controlled clinical studies with dosages up to 10 mg/day of alprazolam in patients with panic disorder, with or without agoraphobia.
- These data cannot be used to predict precisely the incidence of untoward events in the course of usual medical practice where patient characteristics, and other factors often differ from those in clinical trials. These figures cannot be compared with those obtained from other clinical studies involving related drug products and placebo as each group of drug trials are conducted under a different set of conditions.
- Comparison of the cited figures, however, can provide the prescriber with some basis for estimating the relative contributions of drug and non-drug factors to the untoward event incidence in the population studied. Even this use must be approached cautiously, as a drug may relieve a symptom in one patient but induce it in others. (For example, an anxiolytic drug may relieve dry mouth {a symptom of anxiety} in some subjects but induce it in others.)
- Additionally, for anxiety disorders the cited figures can provide the prescriber with an indication as to the frequency with which physician intervention (eg, increased surveillance, decreased dosage or discontinuation of drug therapy) may be necessary because of the untoward clinical event.
- In addition to the relatively common (ie, greater than 1%) untoward events enumerated in the table above, the following adverse events have been reported in association with the use of benzodiazepines: dystonia, irritability, concentration difficulties, anorexia, transient amnesia or memory impairment, loss of coordination, fatigue, seizures, sedation, slurred speech, jaundice, musculoskeletal weakness, pruritus, diplopia, dysarthria, changes in libido, menstrual irregularities, incontinence and urinary retention.
- In addition to the relatively common (ie, greater than 1%) untoward events enumerated in the table above, the following adverse events have been reported in association with the use of alprazolam: seizures, hallucinations, depersonalization, taste alterations, diplopia, elevated bilirubin, elevated hepatic enzymes, and jaundice.
- Panic disorder has been associated with primary and secondary major depressive disorders and increased reports of suicide among untreated patients .
### Adverse Events Reported as Reasons for Discontinuation in Treatment of panic disorder in Placebo-Controlled Trials
- In a larger database comprised of both controlled and uncontrolled studies in which 641 patients received alprazolam, discontinuation-emergent symptoms which occurred at a rate of over 5% in patients treated with alprazolam and at a greater rate than the placebo treated group were as follows:
- From the studies cited, it has not been determined whether these symptoms are clearly related to the dose and duration of therapy with alprazolam in patients with panic disorder. There have also been reports of withdrawal seizures upon rapid decrease or abrupt discontinuation of alprazolam Tablets .
- To discontinue treatment in patients taking alprazolam, the dosage should be reduced slowly in keeping with good medical practice. It is suggested that the daily dosage of alprazolam be decreased by no more than 0.5 mg every three days . Some patients may benefit from an even slower dosage reduction. In a controlled post marketing discontinuation study of panic disorder patients which compared this recommended taper schedule with a slower taper schedule, no difference was observed between the groups in the proportion of patients who tapered to zero dose; however, the slower schedule was associated with a reduction in symptoms associated with a withdrawal syndrome.
- As with all benzodiazepines, paradoxical reactions such as stimulation, increased muscle spasticity, sleep disturbances, hallucinations and other adverse behavioral effects such as agitation, rage, irritability, and aggressive or hostile behavior have been reported rarely. In many of the spontaneous case reports of adverse behavioral effects, patients were receiving other CNS drugs concomitantly and/or were described as having underlying psychiatric conditions. Should any of the above events occur, alprazolam should be discontinued. Isolated published reports involving small numbers of patients have suggested that patients who have borderline personality disorder, a prior history of violent or aggressive behavior, or alcohol or substance abuse may be at risk for such events. Instances of irritability, hostility, and intrusive thoughts have been reported during discontinuation of alprazolam in patients with posttraumatic stress disorder.
### Post Introduction Reports
- Various adverse drug reactions have been reported in association with the use of alprazolam since market introduction. The majority of these reactions were reported through the medical event voluntary reporting system. Because of the spontaneous nature of the reporting of medical events and the lack of controls, a causal relationship to the use of alprazolam cannot be readily determined. Reported events include: gastrointestinal disorder, hypomania, mania, liver enzyme elevations, hepatitis, hepatic failure, Stevens-Johnson syndrome, photosensitivity reaction, angioedema, peripheral edema, hyperprolactinemia, gynecomastia, and galactorrhea.
## Postmarketing Experience
- There is limited information regarding Postmarketing Experience of Alprazolam in the drug label.
# Drug Interactions
### Use with Other CNS Depressants
- If Alprazolam Tablets are to be combined with other psychotropic agents or anticonvulsant drugs, careful consideration should be given to the pharmacology of the agents to be employed, particularly with compounds which might potentiate the action of benzodiazepines. The benzodiazepines, including alprazolam, produce additive CNS depressant effects when co-administered with other psychotropic medications, anticonvulsants, antihistaminics, ethanol and other drugs which themselves produce CNS depression.
### Use with Digoxin
- Increased digoxin concentrations have been reported when alprazolam was given, especially in elderly (>65 years of age). Patients who receive alprazolam and digoxin should therefore be monitored for signs and symptoms related to digoxin toxicity.
### Use with Imipramine and Desipramine
- The steady state plasma concentrations of imipramine and desipramine have been reported to be increased an average of 31% and 20%, respectively, by the concomitant administration of Alprazolam Tablets in doses up to 4 mg/day. The clinical significance of these changes is unknown.
### Drugs that inhibit alprazolam metabolism via cytochrome P450 3A
- The initial step in alprazolam metabolism is hydroxylation catalyzed by cytochrome P450 3A (CYP3A). Drugs which inhibit this metabolic pathway may have a profound effect on the clearance of alprazolam .
### Drugs demonstrated to be CYP3A inhibitors of possible clinical significance on the basis of clinical studies involving alprazolam (caution is recommended during coadministration with alprazolam)
Fluoxetine
- Coadministration of fluoxetine with alprazolam increased the maximum plasma concentration of alprazolam by 46%, decreased clearance by 21%, increased half-life by 17%, and decreased measured psychomotor performance.
Propoxyphene
- Coadministration of propoxyphene decreased the maximum plasma concentration of alprazolam by 6%, decreased clearance by 38%, and increased half-life by 58%.
Oral Contraceptives
- Coadministration of oral contraceptives increased the maximum plasma concentration of alprazolam by 18%, decreased clearance by 22%, and increased half-life by 29%.
Drugs and other substances demonstrated to be CYP 3A inhibitors on the basis of clinical studies involving benzodiazepines metabolized similarly to alprazolam or on the basis of in vitro studies with alprazolam or other benzodiazepines (caution is recommended during coadministration with alprazolam)
- Available data from clinical studies of benzodiazepines other than alprazolam suggest a possible drug interaction with alprazolam for the following: diltiazem, isoniazid, macrolide antibiotics such as erythromycin and clarithromycin, and grapefruit juice. Data from in vitro studies of alprazolam suggest a possible drug interaction with alprazolam for the following: sertraline and paroxetine. However, data from an in vivo drug interaction study involving a single dose of alprazolam 1 mg and steady state dose of sertraline (50 to 150 mg/day) did not reveal any clinically significant changes in the pharmacokinetics of alprazolam. Data from in vitro studies of benzodiazepines other than alprazolam suggest a possible drug interaction for the following: ergotamine, cyclosporine, amiodarone, nicardipine, and nifedipine. Caution is recommended during the coadministration of any of these with alprazolam .
### Drugs demonstrated to be inducers of CYP3A
- Carbamazepine can increase alprazolam metabolism and therefore can decrease plasma levels of alprazolam.
### Drug/Laboratory Test Interactions
- Although interactions between benzodiazepines and commonly employed clinical laboratory tests have occasionally been reported, there is no consistent pattern for a specific drug or specific test.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
- It should be considered that the child born of a mother who is receiving benzodiazepines may be at some risk for withdrawal symptoms from the drug during the postnatal period. Also, neonatal flaccidity and respiratory problems have been reported in children born of mothers who have been receiving benzodiazepines.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Alprazolam in women who are pregnant.
### Labor and Delivery
- Alprazolam has no established use in labor or delivery.
### Nursing Mothers
- Benzodiazepines are known to be excreted in human milk. It should be assumed that alprazolam is as well. Chronic administration of diazepam to nursing mothers has been reported to cause their infants to become lethargic and to lose weight. As a general rule, nursing should not be undertaken by mothers who must use Alprazolam.
### Pediatric Use
- Safety and effectiveness of Alprazolam in individuals below 18 years of age have not been established.
### Geriatic Use
- The elderly may be more sensitive to the effects of benzodiazepines. They exhibit higher plasma alprazolam concentrations due to reduced clearance of the drug as compared with a younger population receiving the same doses. The smallest effective dose of Alprazolam should be used in the elderly to preclude the development of ataxia and oversedation
### Gender
There is no FDA guidance on the use of Alprazolam with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Alprazolam with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Alprazolam in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Alprazolam in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Alprazolam in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Alprazolam in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- FDA Package Insert for alprazolam contains no information regarding Drug Monitoring.
# IV Compatibility
- There is limited information about the IV Compatibility.
# Overdosage
Clinical Experience
- Manifestations of alprazolam overdosage include somnolence, confusion, impaired coordination, diminished reflexes and coma. Death has been reported in association with overdoses of alprazolam by itself, as it has with other benzodiazepines. In addition, fatalities have been reported in patients who have overdosed with a combination of a single benzodiazepine, including alprazolam, and alcohol; alcohol levels seen in some of these patients have been lower than those usually associated with alcohol-induced fatality.
- The acute oral LD50 in rats is 331–2171 mg/kg. Other experiments in animals have indicated that cardiopulmonary collapse can occur following massive intravenous doses of alprazolam (over 195 mg/kg; 975 times the maximum recommended daily human dose of 10 mg/day). Animals could be resuscitated with positive mechanical ventilation and the intravenous infusion of norepinephrine bitartrate.
- Animal experiments have suggested that forced diuresis or hemodialysis are probably of little value in treating overdosage.
General Treatment of Overdose
- Overdosage reports with alprazolam Tablets are limited. As in all cases of drug overdosage, respiration, pulse rate, and blood pressure should be monitored. General supportive measures should be employed, along with immediate gastric lavage. Intravenous fluids should be administered and an adequate airway maintained. If hypotension occurs, it may be combated by the use of vasopressors. Dialysis is of limited value. As with the management of intentional overdosing with any drug, it should be borne in mind that multiple agents may have been ingested.
- Flumazenil, a specific benzodiazepine receptor antagonist, is indicated for the complete or partial reversal of the sedative effects of benzodiazepines and may be used in situations when an overdose with a benzodiazepine is known or suspected. Prior to the administration of flumazenil, necessary measures should be instituted to secure airway, ventilation and intravenous access. Flumazenil is intended as an adjunct to, not as a substitute for, proper management of benzodiazepine overdose. Patients treated with flumazenil should be monitored for re-sedation, respiratory depression, and other residual benzodiazepine effects for an appropriate period after treatment. The prescriber should be aware of a risk of seizure in association with flumazenil treatment, particularly in long-term benzodiazepine users and in cyclic antidepressant overdose.
# Pharmacology
## Mechanism of Action
- CNS agents of the 1,4 benzodiazepine class presumably exert their effects by binding at stereo specific receptors at several sites within the central nervous system. Their exact mechanism of action is unknown. Clinically, all benzodiazepines cause a dose-related central nervous system depressant activity varying from mild impairment of task performance to hypnosis.
## Structure
- Alprazolam Tablets contain alprazolam which is a triazolo analog of the 1,4 benzodiazepine class of central nervous system-active compounds.
- The chemical name of alprazolam is 8-Chloro-1-methyl-6-phenyl-4H-s-triazolo benzodiazepine.
- The structural formula is represented to the right:
- Alprazolam is a white crystalline powder, which is soluble in methanol or ethanol but which has no appreciable solubility in water at physiological pH.
- Each alprazolam tablet, for oral administration, contains 0.25, 0.5, 1 or 2 mg of alprazolam.
## Pharmacodynamics
- CNS agents of the 1,4 benzodiazepine class presumably exert their effects by binding at stereo specific receptors at several sites within the central nervous system. Their exact mechanism of action is unknown. Clinically, all benzodiazepines cause a dose-related central nervous system depressant activity varying from mild impairment of task performance to hypnosis.
## Pharmacokinetics
### Absorption
- Following oral administration, alprazolam is readily absorbed. Peak concentrations in the plasma occur in 1 to 2 hours following administration. Plasma levels are proportionate to the dose given; over the dose range of 0.5 to 3.0 mg, peak levels of 8.0 to 37 ng/mL were observed. Using a specific assay methodology, the mean plasma elimination half-life of alprazolam has been found to be about 11.2 hours (range: 6.3–26.9 hours) in healthy adults.
### Distribution
- In vitro, alprazolam is bound (80 percent) to human serum protein. Serum albumin accounts for the majority of the binding.
### Metabolism/Elimination
- Alprazolam is extensively metabolized in humans, primarily by cytochrome P450 3A4 (CYP3A4), to two major metabolites in the plasma: 4-hydroxyalprazolam and α-hydroxyalprazolam. A benzophenone derived from alprazolam is also found in humans. Their half-lives appear to be similar to that of alprazolam. The plasma concentrations of 4-hydroxyalprazolam and α-hydroxyalprazolam relative to unchanged alprazolam concentration were always less than 4%. The reported relative potencies in benzodiazepine receptor binding experiments and in animal models of induced seizure inhibition are 0.20 and 0.66, respectively, for 4-hydroxyalprazolam and α-hydroxyalprazolam. Such low concentrations and the lesser potencies of 4-hydroxyalprazolam and α-hydroxyalprazolam suggest that they are unlikely to contribute much to the pharmacological effects of alprazolam. The benzophenone metabolite is essentially inactive.
- Alprazolam and its metabolites are excreted primarily in the urine.
### Special Populations
- Changes in the absorption, distribution, metabolism and excretion of benzodiazepines have been reported in a variety of disease states including alcoholism, impaired hepatic function and impaired renal function. Changes have also been demonstrated in geriatric patients. A mean half-life of alprazolam of 16.3 hours has been observed in healthy elderly subjects (range: 9.0–26.9 hours, n=16) compared to 11.0 hours (range: 6.3–15.8 hours, n=16) in healthy adult subjects. In patients with alcoholic liver disease the half-life of alprazolam ranged between 5.8 and 65.3 hours (mean: 19.7 hours, n=17) as compared to between 6.3 and 26.9 hours (mean=11.4 hours, n=17) in healthy subjects. In an obese group of subjects the half-life of alprazolam ranged between 9.9 and 40.4 hours (mean=21.8 hours, n=12) as compared to between 6.3 and 15.8 hours (mean=10.6 hours, n=12) in healthy subjects.
- Because of its similarity to other benzodiazepines, it is assumed that alprazolam undergoes transplacental passage and that it is excreted in human milk.
Race
- Maximal concentrations and half-life of alprazolam are approximately 15% and 25% higher in Asians compared to Caucasians.
Pediatrics
- The pharmacokinetics of alprazolam in pediatric patients have not been studied.
Gender
- Gender has no effect on the pharmacokinetics of alprazolam.
Cigarette Smoking
- Alprazolam concentrations may be reduced by up to 50% in smokers compared to non-smokers.
### Drug-Drug Interactions
- Alprazolam is primarily eliminated by metabolism via cytochrome P450 3A (CYP3A). Most of the interactions that have been documented with alprazolam are with drugs that inhibit or induce CYP3A4.
- Compounds that are potent inhibitors of CYP3A would be expected to increase plasma alprazolam concentrations. Drug products that have been studied in vivo, along with their effect on increasing alprazolam AUC, are as follows: ketoconazole, 3.98 fold; itraconazole, 2.70 fold; nefazodone, 1.98 fold; fluvoxamine, 1.96 fold; and erythromycin, 1.61 fold .
- CYP3A inducers would be expected to decrease alprazolam concentrations and this has been observed in vivo. The oral clearance of alprazolam (given in a 0.8 mg single dose) was increased from 0.90±0.21 mL/min/kg to 2.13±0.54 mL/min/kg and the elimination t1/2 was shortened (from 17.1±4.9 to 7.7 ±1.7 h) following administration of 300 mg/day carbamazepine for 10 days . However, the carbamazepine dose used in this study was fairly low compared to the recommended doses (1000–1200 mg/day); the effect at usual carbamazepine doses is unknown.
- Interactions involving HIV protease inhibitors (eg, ritonavir) and alprazolam are complex and time dependent. Short-term low doses of ritonavir (4 doses of 200 mg) reduced alprazolam clearance to 41% of control values, prolonged its elimination half-life (mean values, 30 versus 13 h) and enhanced clinical effects. However, upon extended exposure to ritonavir (500 mg, twice daily), CYP3A induction offset this inhibition. Alprazolam AUC and Cmax was reduced by 12% and 16%, respectively, in the presence of ritonavir .
- The ability of alprazolam to induce human hepatic enzyme systems has not yet been determined. However, this is not a property of benzodiazepines in general. Further, alprazolam did not affect the prothrombin or plasma warfarin levels in male volunteers administered sodium warfarin orally.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
- No evidence of carcinogenic potential was observed during 2-year bioassay studies of alprazolam in rats at doses up to 30 mg/kg/day (150 times the maximum recommended daily human dose of 10 mg/day) and in mice at doses up to 10 mg/kg/day (50 times the maximum recommended daily human dose).
- Alprazolam was not mutagenic in the rat micronucleus test at doses up to 100 mg/kg, which is 500 times the maximum recommended daily human dose of 10 mg/day. Alprazolam also was not mutagenic in vitro in the DNA Damage/Alkaline Elution Assay or the Ames Assay.
- Alprazolam produced no impairment of fertility in rats at doses up to 5 mg/kg/day, which is 25 times the maximum recommended daily human dose of 10 mg/day.
# Clinical Studies
### Anxiety disorders
- Alprazolam Tablets were compared to placebo in double blind clinical studies (doses up to 4 mg/day) in patients with a diagnosis of anxiety or anxiety with associated depressive symptomatology. Alprazolam was significantly better than placebo at each of the evaluation periods of these 4-week studies as judged by the following psychometric instruments: Physician's Global Impressions, Hamilton anxiety Rating Scale, Target Symptoms, Patient's Global Impressions and Self-Rating Symptom Scale.
### Panic disorder
- Support for the effectiveness of Alprazolam in the treatment of panic disorder came from three short-term, placebo-controlled studies (up to 10 weeks) in patients with diagnoses closely corresponding to DSM-III-R criteria for panic disorder.
- The average dose of alprazolam was 5–6 mg/day in two of the studies, and the doses of alprazolam were fixed at 2 and 6 mg/day in the third study. In all three studies, Alprazolam was superior to placebo on a variable defined as "the number of patients with zero panic attacks" (range, 37–83% met this criterion), as well as on a global improvement score. In two of the three studies, alprazolam was superior to placebo on a variable defined as "change from baseline on the number of panic attacks per week" (range, 3.3–5.2), and also on a phobia rating scale. A subgroup of patients who were improved on alprazolam during short-term treatment in one of these trials was continued on an open basis up to 8 months, without apparent loss of benefit.
# How Supplied
- Alprazolam Tablets are available as follows:
- 0.25 mg (white, oval, scored, imprinted "Alprazolam 0.25")
- 0.5 mg (peach, oval, scored, imprinted "Alprazolam 0.5")
- 1 mg (blue, oval, scored, imprinted "Alprazolam 1.0")
- 2 mg (white, oblong, multi-scored, imprinted "Alprazolam " on one side and "2" on the reverse side)
## 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
- To assure safe and effective use of benzodiazepines, all patients prescribed alprazolam should be provided with the following guidance.
- Inform your physician about any alcohol consumption and medicine you are taking now, including medication you may buy without a prescription. Alcohol should generally not be used during treatment with benzodiazepines.
Not recommended for use in pregnancy. Therefore, inform your physician if you are pregnant, if you are planning to have a child, or if you become pregnant while you are taking this medication.
- Inform your physician if you are nursing.
- Until you experience how this medication affects you, do not drive a car or operate potentially dangerous machinery, etc.
- Do not increase the dose even if you think the medication "does not work anymore" without consulting your physician. benzodiazepines, even when used as recommended, may produce emotional and/or physical dependence.
- Do not stop taking this medication abruptly or decrease the dose without consulting your physician, since withdrawal symptoms can occur.
- Additional advice for panic disorder patients
- The use of alprazolam at doses greater than 4 mg/day, often necessary to treat panic disorder, is accompanied by risks that you need to carefully consider. When used at doses greater than 4 mg/day, which may or may not be required for your treatment, alprazolam has the potential to cause severe emotional and physical dependence in some patients and these patients may find it exceedingly difficult to terminate treatment. In two controlled trials of 6 to 8 weeks duration where the ability of patients to discontinue medication was measured, 7 to 29% of patients treated with alprazolam did not completely taper off therapy. In a controlled postmarketing discontinuation study of panic disorder patients, the patients treated with doses of alprazolam greater than 4 mg/day had more difficulty tapering to zero dose than patients treated with less than 4 mg/day. In all cases, it is important that your physician help you discontinue this medication in a careful and safe manner to avoid overly extended use of Alprazolam.
- In addition, the extended use at doses greater than 4 mg/day appears to increase the incidence and severity of withdrawal reactions when alprazolam is discontinued. These are generally minor but seizure can occur, especially if you reduce the dose too rapidly or discontinue the medication abruptly. seizure can be life-threatening.
# Precautions with Alcohol
- Inform your physician about any alcohol consumption and medicine you are taking now, including medication you may buy without a prescription. Alcohol should generally not be used during treatment with benzodiazepines.
# Brand Names
- ALPRAZOLAM
# Look-Alike Drug Names
There is limited information regarding Alprazolam Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Alprazolam
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
Alprazolam is a benzodiazepine that is FDA approved for the treatment of anxiety disorders and panic disorder. Common adverse reactions include constipation, xerostomia, dysarthria, fatigue, irritability, reduced libido, somnolence and confusion.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
## Anxiety Disorders and Transient Symptoms of Anxiety
Dosing information
- 0.25 to 0.5 mg PO tid. The dose may be increased to achieve a maximum therapeutic effect, at intervals of 3 to 4 days, to a maximum daily dose of 4 mg, given in divided doses. The lowest possible effective dose should be employed and the need for continued treatment reassessed frequently. The risk of dependence may increase with dose and duration of treatment.
- In all patients, dosage should be reduced gradually when discontinuing therapy or when decreasing the daily dosage. Although there are no systematically collected data to support a specific discontinuation schedule, it is suggested that the daily dosage be decreased by no more than 0.5 mg every 3 days. Some patients may require an even slower dosage reduction.
## Panic Disorder
Dosing information
- The successful treatment of many panic disorder patients has required the use of alprazolam at doses greater than 4 mg daily. In controlled trials conducted to establish the efficacy of alprazolam in panic disorder, doses in the range of 1 to 10 mg daily were used. The mean dosage employed was approximately 5 to 6 mg daily. Among the approximately 1700 patients participating in the panic disorder development program, about 300 received Alprazolam in dosages of greater than 7 mg/day, including approximately 100 patients who received maximum dosages of greater than 9 mg/day. Occasional patients required as much as 10 mg a day to achieve a successful response.
## Dose Titration
- Initial treatment: 0.5 mg PO tid. Depending on the response, the dose may be increased at intervals of 3 to 4 days in increments of no more than 1 mg per day. Slower titration to the dose levels greater than 4 mg/day may be advisable to allow full expression of the pharmacodynamic effect of Alprazolam. To lessen the possibility of inter dose symptoms, the times of administration should be distributed as evenly as possible throughout the waking hours, that is, on a three or four times per day schedule.
- Generally, therapy should be initiated at a low dose to minimize the risk of adverse responses in patients especially sensitive to the drug. Dose should be advanced until an acceptable therapeutic response (ie, a substantial reduction in or total elimination of panic attacks) is achieved, intolerance occurs, or the maximum recommended dose is attained.
## Dose Maintenance
- For patients receiving doses greater than 4 mg/day, periodic reassessment and consideration of dosage reduction is advised. In a controlled post marketing dose-response study, patients treated with doses of Alprazolam greater than 4 mg/day for 3 months were able to taper to 50% of their total maintenance dose without apparent loss of clinical benefit. Because of the danger of withdrawal, abrupt discontinuation of treatment should be avoided.
- The necessary duration of treatment for panic disorder patients responding to Alprazolam is unknown. After a period of extended freedom from attacks, a carefully supervised tapered discontinuation may be attempted, but there is evidence that this may often be difficult to accomplish without recurrence of symptoms and/or the manifestation of withdrawal phenomena.
## Dose Reduction
- Because of the danger of withdrawal, abrupt discontinuation of treatment should be avoided.
- In all patients, dosage should be reduced gradually when discontinuing therapy or when decreasing the daily dosage. Although there are no systematically collected data to support a specific discontinuation schedule, it is suggested that the daily dosage be decreased by no more than 0.5 mg every three days. Some patients may require an even slower dosage reduction.
- In any case, reduction of dose must be undertaken under close supervision and must be gradual. If significant withdrawal symptoms develop, the previous dosing schedule should be re-instituted and, only after stabilization, should a less rapid schedule of discontinuation be attempted. In a controlled post marketing discontinuation study of panic disorder patients which compared this recommended taper schedule with a slower taper schedule, no difference was observed between the groups in the proportion of patients who tapered to zero dose; however, the slower schedule was associated with a reduction in symptoms associated with a withdrawal syndrome. It is suggested that the dose be reduced by no more than 0.5 mg every 3 days, with the understanding that some patients may benefit from an even more gradual discontinuation. Some patients may prove resistant to all discontinuation regimens.
## Dosing in Special Populations
- In elderly patients, in patients with advanced liver disease or in patients with debilitating disease, the usual starting dose: 0.25 mg PO bid or tid. This may be gradually increased if needed and tolerated. The elderly may be especially sensitive to the effects of benzodiazepines. If side effects occur at the recommended starting dose, the dose may be lowered.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of alprazolam in adult patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of alprazolam in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- The pharmacokinetics of alprazolam in pediatric patients have not been studied.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of alprazolam in pediatric patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of alprazolam in pediatric patients.
# Contraindications
- Alprazolam tablets are contraindicated in patients with known sensitivity to this drug or other benzodiazepines. Alprazolam may be used in patients with open angle glaucoma who are receiving appropriate therapy, but is contraindicated in patients with acute narrow angle glaucoma.
- Alprazolam is contraindicated with ketoconazole and itraconazole, since these medications significantly impair the oxidative metabolism mediated by cytochrome P450 3A (CYP3A) .
# Warnings
### Dependence and Withdrawal Reactions, Including Seizures
- Certain adverse clinical events, some life-threatening, are a direct consequence of physical dependence to Alprazolam. These include a spectrum of withdrawal symptoms; the most important is seizure . Even after relatively short term use at the doses recommended for the treatment of transient anxiety and anxiety disorder (ie, 0.75 to 4.0 mg per day), there is some risk of dependence. Spontaneous reporting system data suggest that the risk of dependence and its severity appear to be greater in patients treated with doses greater than 4 mg/day and for long periods (more than 12 weeks). However, in a controlled post marketing discontinuation study of panic disorder patients, the duration of treatment (3 months compared to 6 months) had no effect on the ability of patients to taper to zero dose. In contrast, patients treated with doses of alprazolam greater than 4 mg/day had more difficulty tapering to zero dose than those treated with less than 4 mg/day.
### The Importance of Dose and the Risks of Alprazolam as a Treatment for Panic Disorder
- Because the management of panic disorder often requires the use of average daily doses of alprazolam above 4 mg, the risk of dependence among panic disorder patients may be higher than that among those treated for less severe anxiety. Experience in randomized placebo-controlled discontinuation studies of patients with panic disorder showed a high rate of rebound and withdrawal symptoms in patients treated with alprazolam compared to placebo-treated patients.
- Relapse or return of illness was defined as a return of symptoms characteristic of panic disorder (primarily panic attacks) to levels approximately equal to those seen at baseline before active treatment was initiated. Rebound refers to a return of symptoms of panic disorder to a level substantially greater in frequency, or more severe in intensity than seen at baseline. withdrawal symptoms were identified as those which were generally not characteristic of panic disorder and which occurred for the first time more frequently during discontinuation than at baseline.
- In a controlled clinical trial in which 63 patients were randomized to alprazolam and where withdrawal symptoms were specifically sought, the following were identified as symptoms of withdrawal: heightened sensory perception, impaired concentration, dysosmia, clouded sensorium, paresthesias, muscle cramps, muscle twitch, diarrhea, blurred vision, appetite decrease, and weight loss. Other symptoms, such as anxiety and insomnia, were frequently seen during discontinuation, but it could not be determined if they were due to return of illness, rebound, or withdrawal.
- In two controlled trials of 6 to 8 weeks duration where the ability of patients to discontinue medication was measured, 71%–93% of patients treated with alprazolam tapered completely off therapy compared to 89%–96% of placebo-treated patients. In a controlled post marketing discontinuation study of panic disorder patients, the duration of treatment (3 months compared to 6 months) had no effect on the ability of patients to taper to zero dose.
- Seizures attributable to alprazolam were seen after drug discontinuance or dose reduction in 8 of 1980 patients with panic disorder or in patients participating in clinical trials where doses of alprazolam greater than 4 mg/day for over 3 months were permitted. Five of these cases clearly occurred during abrupt dose reduction, or discontinuation from daily doses of 2 to 10 mg. Three cases occurred in situations where there was not a clear relationship to abrupt dose reduction or discontinuation. In one instance, seizure occurred after discontinuation from a single dose of 1 mg after tapering at a rate of 1 mg every 3 days from 6 mg daily. In two other instances, the relationship to taper is indeterminate; in both of these cases the patients had been receiving doses of 3 mg daily prior to seizure. The duration of use in the above 8 cases ranged from 4 to 22 weeks. There have been occasional voluntary reports of patients developing seizures while apparently tapering gradually from alprazolam. The risk of seizure seems to be greatest 24–72 hours after discontinuation.
### Status Epilepticus and its Treatment
- The medical event voluntary reporting system shows that withdrawal seizures have been reported in association with the discontinuation of alprazolam. In most cases, only a single seizure was reported; however, multiple seizures and status epilepticus were reported as well.
### Interdose Symptoms
- Early morning anxiety and emergence of anxiety symptoms between doses of alprazolam have been reported in patients with panic disorder taking prescribed maintenance doses of alprazolam. These symptoms may reflect the development of tolerance or a time interval between doses which is longer than the duration of clinical action of the administered dose. In either case, it is presumed that the prescribed dose is not sufficient to maintain plasma levels above those needed to prevent relapse, rebound or withdrawal symptoms over the entire course of the interdosing interval. In these situations, it is recommended that the same total daily dose be given divided as more frequent administrations .
### Risk of Dose Reduction
- Withdrawal reactions may occur when dosage reduction occurs for any reason. This includes purposeful tapering, but also inadvertent reduction of dose (eg, the patient forgets, the patient is admitted to a hospital). Therefore, the dosage of alprazolam should be reduced or discontinued gradually .
### CNS Depression and Impaired Performance
- Because of its CNS depressant effects, patients receiving alprazolam should be cautioned against engaging in hazardous occupations or activities requiring complete mental alertness such as operating machinery or driving a motor vehicle. For the same reason, patients should be cautioned about the simultaneous ingestion of alcohol and other CNS depressant drugs during treatment with alprazolam.
### Risk of Fetal Harm
- Benzodiazepines can potentially cause fetal harm when administered to pregnant women. If alprazolam 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. Because of experience with other members of the benzodiazepine class, alprazolam is assumed to be capable of causing an increased risk of congenital abnormalities when administered to a pregnant woman during the first trimester. Because use of these drugs is rarely a matter of urgency, their use during the first trimester should almost always be avoided. The possibility that a woman of childbearing potential may be pregnant at the time of institution of therapy should be considered. Patients should be advised that if they become pregnant during therapy or intend to become pregnant they should communicate with their physicians about the desirability of discontinuing the drug.
### Alprazolam Interaction with Drugs that Inhibit Metabolism via Cytochrome P4503A
- The initial step in alprazolam metabolism is hydroxylation catalyzed by cytochrome P450 3A (CYP3A). Drugs that inhibit this metabolic pathway may have a profound effect on the clearance of alprazolam. Consequently, alprazolam should be avoided in patients receiving very potent inhibitors of CYP3A. With drugs inhibiting CYP3A to a lesser but still significant degree, alprazolam should be used only with caution and consideration of appropriate dosage reduction. For some drugs, an interaction with alprazolam has been quantified with clinical data; for other drugs, interactions are predicted from in vitro data and/or experience with similar drugs in the same pharmacologic class.
- The following are examples of drugs known to inhibit the metabolism of alprazolam and/or related benzodiazepines, presumably through inhibition of CYP3A.
### Potent CYP3A Inhibitors
### Azole Antifungal Agents
- Ketoconazole and itraconazole are potent CYP3A inhibitors and have been shown in vivo to increase plasma alprazolam concentrations 3.98 fold and 2.70 fold, respectively. The coadministration of alprazolam with these agents is not recommended. Other azole-type antifungal agents should also be considered potent CYP3A inhibitors and the coadministration of alprazolam with them is not recommended .
### Drugs Demonstrated to be CYP 3A Inhibitors on the Basis of Clinical Studies Involving Alprazolam (Caution and Consideration of Appropriate Alprazolam Dose Reduction are Recommended during Coadministration with the Following Drugs)
### Nefazodone
- Coadministration of nefazodone increased alprazolam concentration two-fold.
### Fluvoxamine
- Coadministration of fluvoxamine approximately doubled the maximum plasma concentration of alprazolam, decreased clearance by 49%, increased half-life by 71%, and decreased measured psychomotor performance.
### Cimetidine
- Coadministration of cimetidine increased the maximum plasma concentration of alprazolam by 86%, decreased clearance by 42%, and increased half-life by 16%.
### HIV protease inhibitors
- Interactions involving HIV protease inhibitors (eg, ritonavir) and alprazolam are complex and time dependent. Low doses of ritonavir resulted in a large impairment of alprazolam clearance, prolonged its elimination half-life and enhanced clinical effects. However, upon extended exposure to ritonavir, CYP3A induction offset this inhibition. This interaction will require a dose-adjustment or discontinuation of alprazolam.
### Other Drugs Possibly Affecting Alprazolam Metabolism
- Other drugs possibly affecting alprazolam metabolism by inhibition of CYP3A are discussed in the PRECAUTIONS section
# Precaution
## General
### Suicide
- As with other psychotropic medications, the usual precautions with respect to administration of the drug and size of the prescription are indicated for severely depressed patients or those in whom there is reason to expect concealed suicidal ideation or plans. panic disorder has been associated with primary and secondary major depressive disorders and increased reports of suicide among untreated patients.
### Mania
- Episodes of hypomania and mania have been reported in association with the use of alprazolam in patients with depression.
### Uricosuric Effect
- Alprazolam has a weak uricosuric effect. Although other medications with weak uricosuric effect have been reported to cause acute renal failure, there have been no reported instances of acute renal failure attributable to therapy with alprazolam.
### Use in Patients with Concomitant Illness
- It is recommended that the dosage be limited to the smallest effective dose to preclude the development of ataxia or oversedation which may be a particular problem in elderly or debilitated patients. The usual precautions in treating patients with impaired renal, hepatic or pulmonary function should be observed. There have been rare reports of death in patients with severe pulmonary disease shortly after the initiation of treatment with alprazolam. A decreased systemic alprazolam elimination rate (eg, increased plasma half-life) has been observed in both alcoholic liver disease patients and obese patients receiving alprazolam .
# Adverse Reactions
## Clinical Trials Experience
- Side effects to Alprazolam Tablets, if they occur, are generally observed at the beginning of therapy and usually disappear upon continued medication. In the usual patient, the most frequent side effects are likely to be an extension of the pharmacological activity of alprazolam, eg, drowsiness or light-headedness.
- The data cited in the two tables below are estimates of untoward clinical event incidence among patients who participated under the following clinical conditions: relatively short duration (ie, four weeks) placebo-controlled clinical studies with dosages up to 4 mg/day of alprazolam (for the management of anxiety disorders or for the short-term relief of the symptoms of anxiety) and short-term (up to ten weeks) placebo-controlled clinical studies with dosages up to 10 mg/day of alprazolam in patients with panic disorder, with or without agoraphobia.
- These data cannot be used to predict precisely the incidence of untoward events in the course of usual medical practice where patient characteristics, and other factors often differ from those in clinical trials. These figures cannot be compared with those obtained from other clinical studies involving related drug products and placebo as each group of drug trials are conducted under a different set of conditions.
- Comparison of the cited figures, however, can provide the prescriber with some basis for estimating the relative contributions of drug and non-drug factors to the untoward event incidence in the population studied. Even this use must be approached cautiously, as a drug may relieve a symptom in one patient but induce it in others. (For example, an anxiolytic drug may relieve dry mouth {a symptom of anxiety} in some subjects but induce it [an untoward event] in others.)
- Additionally, for anxiety disorders the cited figures can provide the prescriber with an indication as to the frequency with which physician intervention (eg, increased surveillance, decreased dosage or discontinuation of drug therapy) may be necessary because of the untoward clinical event.
- In addition to the relatively common (ie, greater than 1%) untoward events enumerated in the table above, the following adverse events have been reported in association with the use of benzodiazepines: dystonia, irritability, concentration difficulties, anorexia, transient amnesia or memory impairment, loss of coordination, fatigue, seizures, sedation, slurred speech, jaundice, musculoskeletal weakness, pruritus, diplopia, dysarthria, changes in libido, menstrual irregularities, incontinence and urinary retention.
- In addition to the relatively common (ie, greater than 1%) untoward events enumerated in the table above, the following adverse events have been reported in association with the use of alprazolam: seizures, hallucinations, depersonalization, taste alterations, diplopia, elevated bilirubin, elevated hepatic enzymes, and jaundice.
- Panic disorder has been associated with primary and secondary major depressive disorders and increased reports of suicide among untreated patients .
### Adverse Events Reported as Reasons for Discontinuation in Treatment of panic disorder in Placebo-Controlled Trials
- In a larger database comprised of both controlled and uncontrolled studies in which 641 patients received alprazolam, discontinuation-emergent symptoms which occurred at a rate of over 5% in patients treated with alprazolam and at a greater rate than the placebo treated group were as follows:
- From the studies cited, it has not been determined whether these symptoms are clearly related to the dose and duration of therapy with alprazolam in patients with panic disorder. There have also been reports of withdrawal seizures upon rapid decrease or abrupt discontinuation of alprazolam Tablets .
- To discontinue treatment in patients taking alprazolam, the dosage should be reduced slowly in keeping with good medical practice. It is suggested that the daily dosage of alprazolam be decreased by no more than 0.5 mg every three days . Some patients may benefit from an even slower dosage reduction. In a controlled post marketing discontinuation study of panic disorder patients which compared this recommended taper schedule with a slower taper schedule, no difference was observed between the groups in the proportion of patients who tapered to zero dose; however, the slower schedule was associated with a reduction in symptoms associated with a withdrawal syndrome.
- As with all benzodiazepines, paradoxical reactions such as stimulation, increased muscle spasticity, sleep disturbances, hallucinations and other adverse behavioral effects such as agitation, rage, irritability, and aggressive or hostile behavior have been reported rarely. In many of the spontaneous case reports of adverse behavioral effects, patients were receiving other CNS drugs concomitantly and/or were described as having underlying psychiatric conditions. Should any of the above events occur, alprazolam should be discontinued. Isolated published reports involving small numbers of patients have suggested that patients who have borderline personality disorder, a prior history of violent or aggressive behavior, or alcohol or substance abuse may be at risk for such events. Instances of irritability, hostility, and intrusive thoughts have been reported during discontinuation of alprazolam in patients with posttraumatic stress disorder.
### Post Introduction Reports
- Various adverse drug reactions have been reported in association with the use of alprazolam since market introduction. The majority of these reactions were reported through the medical event voluntary reporting system. Because of the spontaneous nature of the reporting of medical events and the lack of controls, a causal relationship to the use of alprazolam cannot be readily determined. Reported events include: gastrointestinal disorder, hypomania, mania, liver enzyme elevations, hepatitis, hepatic failure, Stevens-Johnson syndrome, photosensitivity reaction, angioedema, peripheral edema, hyperprolactinemia, gynecomastia, and galactorrhea.
## Postmarketing Experience
- There is limited information regarding Postmarketing Experience of Alprazolam in the drug label.
# Drug Interactions
### Use with Other CNS Depressants
- If Alprazolam Tablets are to be combined with other psychotropic agents or anticonvulsant drugs, careful consideration should be given to the pharmacology of the agents to be employed, particularly with compounds which might potentiate the action of benzodiazepines. The benzodiazepines, including alprazolam, produce additive CNS depressant effects when co-administered with other psychotropic medications, anticonvulsants, antihistaminics, ethanol and other drugs which themselves produce CNS depression.
### Use with Digoxin
- Increased digoxin concentrations have been reported when alprazolam was given, especially in elderly (>65 years of age). Patients who receive alprazolam and digoxin should therefore be monitored for signs and symptoms related to digoxin toxicity.
### Use with Imipramine and Desipramine
- The steady state plasma concentrations of imipramine and desipramine have been reported to be increased an average of 31% and 20%, respectively, by the concomitant administration of Alprazolam Tablets in doses up to 4 mg/day. The clinical significance of these changes is unknown.
### Drugs that inhibit alprazolam metabolism via cytochrome P450 3A
- The initial step in alprazolam metabolism is hydroxylation catalyzed by cytochrome P450 3A (CYP3A). Drugs which inhibit this metabolic pathway may have a profound effect on the clearance of alprazolam .
### Drugs demonstrated to be CYP3A inhibitors of possible clinical significance on the basis of clinical studies involving alprazolam (caution is recommended during coadministration with alprazolam)
Fluoxetine
- Coadministration of fluoxetine with alprazolam increased the maximum plasma concentration of alprazolam by 46%, decreased clearance by 21%, increased half-life by 17%, and decreased measured psychomotor performance.
Propoxyphene
- Coadministration of propoxyphene decreased the maximum plasma concentration of alprazolam by 6%, decreased clearance by 38%, and increased half-life by 58%.
Oral Contraceptives
- Coadministration of oral contraceptives increased the maximum plasma concentration of alprazolam by 18%, decreased clearance by 22%, and increased half-life by 29%.
Drugs and other substances demonstrated to be CYP 3A inhibitors on the basis of clinical studies involving benzodiazepines metabolized similarly to alprazolam or on the basis of in vitro studies with alprazolam or other benzodiazepines (caution is recommended during coadministration with alprazolam)
- Available data from clinical studies of benzodiazepines other than alprazolam suggest a possible drug interaction with alprazolam for the following: diltiazem, isoniazid, macrolide antibiotics such as erythromycin and clarithromycin, and grapefruit juice. Data from in vitro studies of alprazolam suggest a possible drug interaction with alprazolam for the following: sertraline and paroxetine. However, data from an in vivo drug interaction study involving a single dose of alprazolam 1 mg and steady state dose of sertraline (50 to 150 mg/day) did not reveal any clinically significant changes in the pharmacokinetics of alprazolam. Data from in vitro studies of benzodiazepines other than alprazolam suggest a possible drug interaction for the following: ergotamine, cyclosporine, amiodarone, nicardipine, and nifedipine. Caution is recommended during the coadministration of any of these with alprazolam .
### Drugs demonstrated to be inducers of CYP3A
- Carbamazepine can increase alprazolam metabolism and therefore can decrease plasma levels of alprazolam.
### Drug/Laboratory Test Interactions
- Although interactions between benzodiazepines and commonly employed clinical laboratory tests have occasionally been reported, there is no consistent pattern for a specific drug or specific test.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
- It should be considered that the child born of a mother who is receiving benzodiazepines may be at some risk for withdrawal symptoms from the drug during the postnatal period. Also, neonatal flaccidity and respiratory problems have been reported in children born of mothers who have been receiving benzodiazepines.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Alprazolam in women who are pregnant.
### Labor and Delivery
- Alprazolam has no established use in labor or delivery.
### Nursing Mothers
- Benzodiazepines are known to be excreted in human milk. It should be assumed that alprazolam is as well. Chronic administration of diazepam to nursing mothers has been reported to cause their infants to become lethargic and to lose weight. As a general rule, nursing should not be undertaken by mothers who must use Alprazolam.
### Pediatric Use
- Safety and effectiveness of Alprazolam in individuals below 18 years of age have not been established.
### Geriatic Use
- The elderly may be more sensitive to the effects of benzodiazepines. They exhibit higher plasma alprazolam concentrations due to reduced clearance of the drug as compared with a younger population receiving the same doses. The smallest effective dose of Alprazolam should be used in the elderly to preclude the development of ataxia and oversedation
### Gender
There is no FDA guidance on the use of Alprazolam with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Alprazolam with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Alprazolam in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Alprazolam in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Alprazolam in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Alprazolam in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- FDA Package Insert for alprazolam contains no information regarding Drug Monitoring.
# IV Compatibility
- There is limited information about the IV Compatibility.
# Overdosage
Clinical Experience
- Manifestations of alprazolam overdosage include somnolence, confusion, impaired coordination, diminished reflexes and coma. Death has been reported in association with overdoses of alprazolam by itself, as it has with other benzodiazepines. In addition, fatalities have been reported in patients who have overdosed with a combination of a single benzodiazepine, including alprazolam, and alcohol; alcohol levels seen in some of these patients have been lower than those usually associated with alcohol-induced fatality.
- The acute oral LD50 in rats is 331–2171 mg/kg. Other experiments in animals have indicated that cardiopulmonary collapse can occur following massive intravenous doses of alprazolam (over 195 mg/kg; 975 times the maximum recommended daily human dose of 10 mg/day). Animals could be resuscitated with positive mechanical ventilation and the intravenous infusion of norepinephrine bitartrate.
- Animal experiments have suggested that forced diuresis or hemodialysis are probably of little value in treating overdosage.
General Treatment of Overdose
- Overdosage reports with alprazolam Tablets are limited. As in all cases of drug overdosage, respiration, pulse rate, and blood pressure should be monitored. General supportive measures should be employed, along with immediate gastric lavage. Intravenous fluids should be administered and an adequate airway maintained. If hypotension occurs, it may be combated by the use of vasopressors. Dialysis is of limited value. As with the management of intentional overdosing with any drug, it should be borne in mind that multiple agents may have been ingested.
- Flumazenil, a specific benzodiazepine receptor antagonist, is indicated for the complete or partial reversal of the sedative effects of benzodiazepines and may be used in situations when an overdose with a benzodiazepine is known or suspected. Prior to the administration of flumazenil, necessary measures should be instituted to secure airway, ventilation and intravenous access. Flumazenil is intended as an adjunct to, not as a substitute for, proper management of benzodiazepine overdose. Patients treated with flumazenil should be monitored for re-sedation, respiratory depression, and other residual benzodiazepine effects for an appropriate period after treatment. The prescriber should be aware of a risk of seizure in association with flumazenil treatment, particularly in long-term benzodiazepine users and in cyclic antidepressant overdose.
# Pharmacology
## Mechanism of Action
- CNS agents of the 1,4 benzodiazepine class presumably exert their effects by binding at stereo specific receptors at several sites within the central nervous system. Their exact mechanism of action is unknown. Clinically, all benzodiazepines cause a dose-related central nervous system depressant activity varying from mild impairment of task performance to hypnosis.
## Structure
- Alprazolam Tablets contain alprazolam which is a triazolo analog of the 1,4 benzodiazepine class of central nervous system-active compounds.
- The chemical name of alprazolam is 8-Chloro-1-methyl-6-phenyl-4H-s-triazolo [4,3-α] [1,4] benzodiazepine.
- The structural formula is represented to the right:
- Alprazolam is a white crystalline powder, which is soluble in methanol or ethanol but which has no appreciable solubility in water at physiological pH.
- Each alprazolam tablet, for oral administration, contains 0.25, 0.5, 1 or 2 mg of alprazolam.
## Pharmacodynamics
- CNS agents of the 1,4 benzodiazepine class presumably exert their effects by binding at stereo specific receptors at several sites within the central nervous system. Their exact mechanism of action is unknown. Clinically, all benzodiazepines cause a dose-related central nervous system depressant activity varying from mild impairment of task performance to hypnosis.
## Pharmacokinetics
### Absorption
- Following oral administration, alprazolam is readily absorbed. Peak concentrations in the plasma occur in 1 to 2 hours following administration. Plasma levels are proportionate to the dose given; over the dose range of 0.5 to 3.0 mg, peak levels of 8.0 to 37 ng/mL were observed. Using a specific assay methodology, the mean plasma elimination half-life of alprazolam has been found to be about 11.2 hours (range: 6.3–26.9 hours) in healthy adults.
### Distribution
- In vitro, alprazolam is bound (80 percent) to human serum protein. Serum albumin accounts for the majority of the binding.
### Metabolism/Elimination
- Alprazolam is extensively metabolized in humans, primarily by cytochrome P450 3A4 (CYP3A4), to two major metabolites in the plasma: 4-hydroxyalprazolam and α-hydroxyalprazolam. A benzophenone derived from alprazolam is also found in humans. Their half-lives appear to be similar to that of alprazolam. The plasma concentrations of 4-hydroxyalprazolam and α-hydroxyalprazolam relative to unchanged alprazolam concentration were always less than 4%. The reported relative potencies in benzodiazepine receptor binding experiments and in animal models of induced seizure inhibition are 0.20 and 0.66, respectively, for 4-hydroxyalprazolam and α-hydroxyalprazolam. Such low concentrations and the lesser potencies of 4-hydroxyalprazolam and α-hydroxyalprazolam suggest that they are unlikely to contribute much to the pharmacological effects of alprazolam. The benzophenone metabolite is essentially inactive.
- Alprazolam and its metabolites are excreted primarily in the urine.
### Special Populations
- Changes in the absorption, distribution, metabolism and excretion of benzodiazepines have been reported in a variety of disease states including alcoholism, impaired hepatic function and impaired renal function. Changes have also been demonstrated in geriatric patients. A mean half-life of alprazolam of 16.3 hours has been observed in healthy elderly subjects (range: 9.0–26.9 hours, n=16) compared to 11.0 hours (range: 6.3–15.8 hours, n=16) in healthy adult subjects. In patients with alcoholic liver disease the half-life of alprazolam ranged between 5.8 and 65.3 hours (mean: 19.7 hours, n=17) as compared to between 6.3 and 26.9 hours (mean=11.4 hours, n=17) in healthy subjects. In an obese group of subjects the half-life of alprazolam ranged between 9.9 and 40.4 hours (mean=21.8 hours, n=12) as compared to between 6.3 and 15.8 hours (mean=10.6 hours, n=12) in healthy subjects.
- Because of its similarity to other benzodiazepines, it is assumed that alprazolam undergoes transplacental passage and that it is excreted in human milk.
Race
- Maximal concentrations and half-life of alprazolam are approximately 15% and 25% higher in Asians compared to Caucasians.
Pediatrics
- The pharmacokinetics of alprazolam in pediatric patients have not been studied.
Gender
- Gender has no effect on the pharmacokinetics of alprazolam.
Cigarette Smoking
- Alprazolam concentrations may be reduced by up to 50% in smokers compared to non-smokers.
### Drug-Drug Interactions
- Alprazolam is primarily eliminated by metabolism via cytochrome P450 3A (CYP3A). Most of the interactions that have been documented with alprazolam are with drugs that inhibit or induce CYP3A4.
- Compounds that are potent inhibitors of CYP3A would be expected to increase plasma alprazolam concentrations. Drug products that have been studied in vivo, along with their effect on increasing alprazolam AUC, are as follows: ketoconazole, 3.98 fold; itraconazole, 2.70 fold; nefazodone, 1.98 fold; fluvoxamine, 1.96 fold; and erythromycin, 1.61 fold .
- CYP3A inducers would be expected to decrease alprazolam concentrations and this has been observed in vivo. The oral clearance of alprazolam (given in a 0.8 mg single dose) was increased from 0.90±0.21 mL/min/kg to 2.13±0.54 mL/min/kg and the elimination t1/2 was shortened (from 17.1±4.9 to 7.7 ±1.7 h) following administration of 300 mg/day carbamazepine for 10 days . However, the carbamazepine dose used in this study was fairly low compared to the recommended doses (1000–1200 mg/day); the effect at usual carbamazepine doses is unknown.
- Interactions involving HIV protease inhibitors (eg, ritonavir) and alprazolam are complex and time dependent. Short-term low doses of ritonavir (4 doses of 200 mg) reduced alprazolam clearance to 41% of control values, prolonged its elimination half-life (mean values, 30 versus 13 h) and enhanced clinical effects. However, upon extended exposure to ritonavir (500 mg, twice daily), CYP3A induction offset this inhibition. Alprazolam AUC and Cmax was reduced by 12% and 16%, respectively, in the presence of ritonavir .
- The ability of alprazolam to induce human hepatic enzyme systems has not yet been determined. However, this is not a property of benzodiazepines in general. Further, alprazolam did not affect the prothrombin or plasma warfarin levels in male volunteers administered sodium warfarin orally.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
- No evidence of carcinogenic potential was observed during 2-year bioassay studies of alprazolam in rats at doses up to 30 mg/kg/day (150 times the maximum recommended daily human dose of 10 mg/day) and in mice at doses up to 10 mg/kg/day (50 times the maximum recommended daily human dose).
- Alprazolam was not mutagenic in the rat micronucleus test at doses up to 100 mg/kg, which is 500 times the maximum recommended daily human dose of 10 mg/day. Alprazolam also was not mutagenic in vitro in the DNA Damage/Alkaline Elution Assay or the Ames Assay.
- Alprazolam produced no impairment of fertility in rats at doses up to 5 mg/kg/day, which is 25 times the maximum recommended daily human dose of 10 mg/day.
# Clinical Studies
### Anxiety disorders
- Alprazolam Tablets were compared to placebo in double blind clinical studies (doses up to 4 mg/day) in patients with a diagnosis of anxiety or anxiety with associated depressive symptomatology. Alprazolam was significantly better than placebo at each of the evaluation periods of these 4-week studies as judged by the following psychometric instruments: Physician's Global Impressions, Hamilton anxiety Rating Scale, Target Symptoms, Patient's Global Impressions and Self-Rating Symptom Scale.
### Panic disorder
- Support for the effectiveness of Alprazolam in the treatment of panic disorder came from three short-term, placebo-controlled studies (up to 10 weeks) in patients with diagnoses closely corresponding to DSM-III-R criteria for panic disorder.
- The average dose of alprazolam was 5–6 mg/day in two of the studies, and the doses of alprazolam were fixed at 2 and 6 mg/day in the third study. In all three studies, Alprazolam was superior to placebo on a variable defined as "the number of patients with zero panic attacks" (range, 37–83% met this criterion), as well as on a global improvement score. In two of the three studies, alprazolam was superior to placebo on a variable defined as "change from baseline on the number of panic attacks per week" (range, 3.3–5.2), and also on a phobia rating scale. A subgroup of patients who were improved on alprazolam during short-term treatment in one of these trials was continued on an open basis up to 8 months, without apparent loss of benefit.
# How Supplied
- Alprazolam Tablets are available as follows:
- 0.25 mg (white, oval, scored, imprinted "Alprazolam 0.25")
- 0.5 mg (peach, oval, scored, imprinted "Alprazolam 0.5")
- 1 mg (blue, oval, scored, imprinted "Alprazolam 1.0")
- 2 mg (white, oblong, multi-scored, imprinted "Alprazolam " on one side and "2" on the reverse side)
## 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
- To assure safe and effective use of benzodiazepines, all patients prescribed alprazolam should be provided with the following guidance.
- Inform your physician about any alcohol consumption and medicine you are taking now, including medication you may buy without a prescription. Alcohol should generally not be used during treatment with benzodiazepines.
Not recommended for use in pregnancy. Therefore, inform your physician if you are pregnant, if you are planning to have a child, or if you become pregnant while you are taking this medication.
- Inform your physician if you are nursing.
- Until you experience how this medication affects you, do not drive a car or operate potentially dangerous machinery, etc.
- Do not increase the dose even if you think the medication "does not work anymore" without consulting your physician. benzodiazepines, even when used as recommended, may produce emotional and/or physical dependence.
- Do not stop taking this medication abruptly or decrease the dose without consulting your physician, since withdrawal symptoms can occur.
- Additional advice for panic disorder patients
- The use of alprazolam at doses greater than 4 mg/day, often necessary to treat panic disorder, is accompanied by risks that you need to carefully consider. When used at doses greater than 4 mg/day, which may or may not be required for your treatment, alprazolam has the potential to cause severe emotional and physical dependence in some patients and these patients may find it exceedingly difficult to terminate treatment. In two controlled trials of 6 to 8 weeks duration where the ability of patients to discontinue medication was measured, 7 to 29% of patients treated with alprazolam did not completely taper off therapy. In a controlled postmarketing discontinuation study of panic disorder patients, the patients treated with doses of alprazolam greater than 4 mg/day had more difficulty tapering to zero dose than patients treated with less than 4 mg/day. In all cases, it is important that your physician help you discontinue this medication in a careful and safe manner to avoid overly extended use of Alprazolam.
- In addition, the extended use at doses greater than 4 mg/day appears to increase the incidence and severity of withdrawal reactions when alprazolam is discontinued. These are generally minor but seizure can occur, especially if you reduce the dose too rapidly or discontinue the medication abruptly. seizure can be life-threatening.
# Precautions with Alcohol
- Inform your physician about any alcohol consumption and medicine you are taking now, including medication you may buy without a prescription. Alcohol should generally not be used during treatment with benzodiazepines.
# Brand Names
- ALPRAZOLAM
# Look-Alike Drug Names
There is limited information regarding Alprazolam Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Aloram | |
c961e9f075f77c7af9819b07c6e6c828e06a3b2d | wikidoc | Interferon | Interferon
# Overview
Interferons (IFNs) are natural proteins produced by the cells of the immune system of most vertebrates in response to challenges by foreign agents such as viruses, parasites and tumor cells. Interferons belong to the large class of glycoproteins known as cytokines. Interferons are produced by a wide variety of cells in response to the presence of double-stranded RNA, a key indicator of viral infection. Interferons assist the immune response by inhibiting viral replication within host cells, activating natural killer cells, increasing antigen presentation to lymphocytes, and inducing the resistance of host cells to viral infection.
# Types of interferon
There are three major classes of interferons that have been described for humans according to the type of receptor through which they signal:
- Interferon type I: All type I IFNs bind to a specific cell surface receptor complex known as the IFN-α receptor (IFNAR) that consists of IFNAR1 and IFNAR2 chains. The type I interferons present in humans are IFN-α, IFN-β and IFN-ω.
- Interferon type II: Binds to IFNGR. In humans this is IFN-γ.
- Interferon type III: Signal through a receptor complex consisting of IL10R2 (also called CRF2-4) and IFNLR1 (also called CRF2-12)
# Signaling pathway
While there is evidence to suggest other signaling mechanisms exist, the JAK-STAT signaling pathway is the best-characterised and commonly accepted IFN signaling pathway.
# Natural function and synthesis
Interferons in general have several effects in common. They are antiviral and possess antioncogenic properties, macrophage and natural killer lymphocyte activation, and enhancement of major histocompatibility complex glycoprotein classes I and II, and thus presentation of foreign (microbial) peptides to T cells. In a majority of cases, the production of interferons is induced in response to microbes such as viruses and bacteria and their products (viral glycoproteins, viral RNA, bacterial endotoxin, bacterial flagella, CpG sites), as well as mitogens and other cytokines, for example interleukin 1, interleukin 2, interleukin-12, tumor necrosis factor and colony-stimulating factor, that are synthesised in the response to the appearance of various antigens in the body. Their metabolism and excretion take place mainly in the liver and kidneys. They rarely pass the placenta but they can cross the blood-brain barrier.
# Viral induction of interferons
All classes of interferon are very important in fighting RNA virus infections. However, their presence also accounts for some of the host symptoms, such as sore muscles and fever. They are secreted when abnormally large amounts of dsRNA are found in a cell. dsRNA is normally present in very low quantities. The dsRNA acts like a trigger for the production of interferon (via Toll Like Receptor 3 (TLR 3) a pattern recognition receptor of the innate immune system which leads to activation of the transcription factor IRF3 and late phase NF kappa Beta). The gene that codes for this cytokine is switched on in an infected cell, and the interferon synthesized and secreted to surrounding cells.
As the original cell dies from the cytolytic RNA virus, these thousands of viruses will infect nearby cells. However, these cells have received interferon, which essentially warns these other cells that there's a wolf in the pack of sheep. They then start producing large amounts of a protein known as protein kinase R (or PKR). If a virus infects a cell that has been “pre-warned” by interferon, it is like charging into a hail of bullets for the virus. The PKR is indirectly activated by the dsRNA (actually by 2'-5' oligoadenylate produced by the 2'-5' oligoadenylate-synthetase which is produced due to TLR3 activation), and begins transferring phosphate groups (phosphorylating) to a protein known as eIF-2, a eukaryotic translation initiation factor. After phosphorylation, eIF2 has a reduced ability to initiate translation, the production of proteins coded by cellular mRNA. This prevents viral replication and inhibits normal cell ribosome function, killing both the virus and the host cell if the response is active for a sufficient amount of time. All RNA within the cell is also degraded, preventing the mRNA from being translated by eIF2 if some of the eIF2 failed to be phosphorylated.
Furthermore, interferon leads to upregulation of MHC I and therefore to increased presentation of viral peptides to cytotoxic CD8 T cells, as well as to a change in the proteasome (exchange of some beta subunits by b1i, b2i, b5i - then known as the immunoproteasome) which leads to increased production of MHC I compatible peptides.
Interferon can cause increased p53 activity in virus infected cells. It acts as an inducer and causes increased production of the p53 gene product. This promotes apoptosis, limiting the ability of the virus to spread. Increased levels of transcription are observed even in cells which are not infected, but only infected cells show increased apoptosis. This increased transcription may serve to prepare susceptible cells so they can respond quickly in the case of infection. When p53 is induced by viral presence, it behaves differently than it usually does. Some p53 target genes are expressed under viral load, but others, especially those that respond to DNA damage, aren’t. One of the genes that is not activated is p21, which can promote cell survival. Leaving this gene inactive would help promote the apoptotic effect. Interferon enhances the apoptotic effects of p53, but it is not strictly required. Normal cells exhibit a stronger apoptotic response than cells without p53.
Additionally, interferon has been shown to have therapeutic effect against certain cancers. It is probable that one mechanism of this effect is p53 induction. This could be useful clinically: Interferons could supplement or replace chemotherapy drugs that activate p53 but also cause unwanted side effects..Some of these side effects can be serious, severe and permanent.
# Virus resistance to interferons
In a study of the blocking of interferon (IFN) by the Japanese Encephalitis Virus (JEV), a group of researchers infected human recombinant IFN-alpha with JEV, DEN-2, and PL406, which are all viruses, and found that some viruses have manifested methods that give them a way around the IFN-alpha/beta response. The viruses need to master these methods so they can have the ability to carry on viral replication and production of new viruses. The ways that viruses find a way around the IFN response is through the inhibition of interferon signaling, production, and the blocking of the functions of IFN-induced proteins.
It is not unusual to find viruses encoding for a multiple number of mechanisms to allow them to elude the IFN response at many different levels. While doing the study with JEV, Lin and his coworkers found that with IFN-alpha's inability to block JEV means that JEV may be able to block IFN-alpha signaling which in turn would prevent IFN from having STAT1, STAT2, ISGF3, and IRF-9 signaling. DEN-2 also significantly reduces interferon ability to active JAK-STAT.Some other viral gene products that have been found to have an effect on IFN signaling include EBNA-2, Polyomavirus large T antigen, EBV EBNA1, HPV E7, HCMV, and HHV8. "Several poxviruses encode a soluble IFN receptor homologue that acts as a decoy to inhibit the biological activity of IFN," and that activity is for IFN to "bind to their cognate recepors on the cell surface to iniate a signaling cascade, known as the Janus kinase(JAK)-signal transducer and activation of transcription(Stat) pathways. For example, in a study done by a group of researcher, they found that the B18R protein, which acts as a type 1 IFN receptor and is produced by the vaccinia virus, it was found that the B18R protein inhibited IFN's ability to begin the phosphorylation of JAK1 which reduced the antiviral effect of IFN.
Some viruses can encode proteins that bind to dsRNA. In a study where the researchers infected Human U cells with reovirus-sigma3 protein and then, using the Western blot test, they found that reovirus-sigma3 protein does bind to dsRNA. Along with that, another study in which the researchers infected mouse L cells with vaccinia virus E3L found that E3L encodes the p25 protein that binds to dsRNA. Without double stranded RNA (dsRNA), because it is bound to by the proteins, it is not able to create IFN-induced PKR and 2'-5' oligoadenylate-synthetase making IFN ineffective. It was also found that JEV was able to inhibit IFN-alpha's ability to activate or create ISGs such as PKR. PKR was not able to be found in the JEV infected cells and PKR RNA levels were found to be lower in those same infected cells, and this disruption of PKR can occur, for example, in cells infected with flavaviruses.
The H5N1 influenza virus, also known as bird flu, has been shown to have resistance to interferon and other anti-viral cytokines. This is part of the reason for its high mortality rates in humans. It is resistant due to a single amino acid mutation in Non-Structual protein 1 (NS1), the precise mechanism of how this confers immunity is unclear (reference is Lethal H5N1 influenza viruses escape host anti-viral cytokine responses, Sang Heui Seo, Nature Med, 2002).
# Pharmaceutical uses
## Uses
Just as their natural function, interferons have antiviral, antiseptic and antioncogenic properties when administered as drugs.
Interferon therapy is used (in combination with chemotherapy and radiation) as a treatment for many cancers.
More than half of hepatitis C patients treated with interferon respond with better blood tests and better liver biopsies. There is some evidence that giving interferon immediately following infection can prevent hepatitis C; however, people infected by hepatitis C often do not display symptoms of HCV until months or years later.
Interferon is also used in the treatment and control of the neurological disorder multiple sclerosis, an autoimmune disorder.
Administered intranasally in very low doses, interferon is extensively used in Eastern Europe and Russia as a method to prevent and treat viral respiratory diseases such as cold and flu. However, mechanisms of such action of interferon are not well understood; it is thought that doses must be larger by several orders of magnitude to have any effect on the virus. Consequently, most Western scientists are skeptical of any claims of good efficacy.
## Route of administration
When used in the systemic therapy, IFN-α and IFN-γ are mostly administered by an intramuscular injection. The injection of interferons in the muscle, in the vein, or under skin is generally well tolerated.
Interferon alpha can also be induced with small imidazoquinoline molecules by activation of TLR7 receptor. Aldara (Imiquimod) cream works with this mechanism to induce IFN alpha and IL12 and approved by FDA to treat Actinic Keratosis, Superficial Basal Cell Carcinoma, and External Genital Warts.
## Adverse effects
The most frequent adverse effects are flu-like symptoms: increased body temperature, feeling ill, fatigue, headache, muscle pain, convulsion, dizziness, hair thinning, and depression. Erythema, pain and hardness on the spot of injection are also frequently observed. Interferon therapy causes immunosuppression and can result in some infections manifesting in unusual ways.
All known adverse effects are usually reversible and disappear a few days after the therapy has been finished.
## Types
Several different types of interferon are now approved for use in humans.
More recently, the FDA approved pegylated interferon-alpha, in which polyethylene glycol is added to make the interferon last longer in the body. (Pegylated interferon-alpha-2b was approved in January 2001; pegylated interferon-alpha-2a was approved in October 2002.) The pegylated form is injected once weekly, rather than three times per week for conventional interferon-alpha. Used in combination with the antiviral drug ribavirin, pegylated interferon produces sustained cure rates of 75% or better in people with genotype 2 or 3 hepatitis C (which is easier to treat) but still less than 50% in people with genotype 1 (which is most common in the U.S. and Western Europe).
Interferon-beta (Interferon beta-1a and Interferon beta-1b) is used in the treatment and control of multiple sclerosis. By an as-yet-unknown mechanism, interferon-beta inhibits the production of Th1 cytokines and the activation of monocytes.
# History
While aiming to develop an improved vaccine for smallpox, two Japanese virologists, Yasu-ichi Nagano and Yasuhiko Kojima working at the the Institute for Infectious Diseases at the University of Tokyo, noticed that rabbit-skin or testis previously inoculated with UV-inactivated virus exhibited inhibition of viral growth when re-infected at the same site with live virus. They hypothesised that this was due to some inhibitory factor, and began to characterise it by fractionation of the UV-irradiated viral homogenates using an ultracentrifuge. They published these findings in 1954 in the French journal now known as “Journal de la Société de Biologie”. While this paper demonstrated that the activity could be separated from the virus particles, it could not reconcile the antiviral activity demonstrated in the rabbit skin experiments, with the observation that the same supernatant led to the production of antiviral antibodies in mice. A further paper in 1958, involving triple-ultracentrifugation of the homogenate demonstrated that the inhibitory factor was distinct from the virus particles, leading to trace contamination being ascribed to the 1954 observations.
Meanwhile, the British virologist Alick Isaacs and the Swiss researcher Jean Lindenmann, at the National Institute for Medical Research in London, noticed an interference effect caused by heat-inactivated influenza virus on the growth of live influenza virus in chicken egg membranes in a nutritive solution chorioallantoic membrane. They published their results in 1957; in this paper they coined the term ‘interferon’, and today that specific interfering agent is known as a ‘Type I interferon’.
Nagano’s work was never fully appreciated in the scientific community; possibly because it was printed in French, but also because his in vivo system was perhaps too complex to provide clear results in the characterisation and purification of interferon. As time passed, Nagano became aware that his work had not been widely recognised, yet did not actively seek revaluation of his status in field of interferon research. As such, the majority of the credit for discovery of the interferon goes to Isaacs and Lindenmann, with whom there is no record of Nagano ever having made personal contact.
## As a drug
Interferon was scarce and expensive until 1980 when the interferon gene was inserted into bacteria using recombinant DNA technology, allowing mass cultivation and purification from bacterial cultures or derived from yeast (e.g. Reiferon Retard is the first yeast derived interferon-alpha 2a).
# Misc. facts
- Interferon is species-specific: the substance prepared from infected eggs protected only chicken cells from virus infection, while the similar substance prepared from mice protected only mouse cells.
- Produced by many cells in the human body by a receptor dependent feedback mechanism.
- Interferons are part of the "first-wave" immune response of the innate immune system, acting within hours, whereas antibody production takes days.
- Global sales ~ 5 billion US $. The second most successful pharmaceutical ever to come from genetic engineering.
- A book was written about it: Toine Pieters, Interferon: The Science and Selling of a Miracle Drug (London: Routledge, 2005), xiv+264 pp., ISBN: 0-415-34246-5
- There are two types of IFNs: Type I (binding to IFN-aR1 and IFN-aR2c receptors; IFNAR1 chain is not the major ligand-binding chain), and type II (binding to IFN-gammaR1 and IFN-gammaR2 receptors).
- In general, exposure of human cells to viruses or double stranded RNAs induces the production of IFN-a, IFN-b, and IFN-o species.
- For the most part, the IFN-alpha species are not glycosylated, although some contain carbohydrates.
- The IFN-alpha family represents a family of related and homologous proteins, each exhibiting a unique activity profile. Each IFN-a species seems to exhibit a distinct profile of activities
- The IFNs and IFN-like molecules signal through the Jak-Stat pathway. The receptor for the Type I IFNs consists of two chains, IFN-aR1 and IFN-aR2c. The ligand INF-alpha is a monomer that binds to the two-chain complex of IFN-aR1 and INF-aR2c.
- Within each subtype of mammalian Type I IFN, there is additional variability in gene duplication. The IFN-a genes are duplicated to a much greater extent than any other subtype of Type I IFN. This observation in conjunction with the observation that the IFN-a subtypes generally possess the highest specific antiviral activity imply that physiologically, the body likely uses IFN-a as the primary antiviral defense protein and that the major function of IFN-a is defense.
- STRUCTURE: The Type I IFNs consist of five a-helices (labeled A–E) which are linked by one overhand loop (AB loop) and three shorter segments (BC, CD, and DE loops). Helices A, B, C, and E are arranged in an antiparallel fashion to form a left-handed four-helix bundle. The AB loop contains short segments of 3_10 helix and is best described in three segments labeled AB1, AB2, and AB3. In all Type I IFNs, the AB1 loop encircles and is linked to helix E by a disulfide bond. An additional disulfide bond is observed in most IFN-a subtypes but not IFN-b, which connects the N-terminus of the molecule to helix C. The AB loop is critical for high-affinity IFNAR2 binding and suggest that sequence differences in this region may hold the key to differences in biological activity between the different IFN-a subtypes.
- The NMR structure of IFNAR2 has been determined and exhibits the same general structure as IFN-gammaR1. However, the interdomain angle is approximately 90 degrees rather than 120 degrees. Only loops in N-terminal domain (L2–L4) have been shown to be important for IFN-a2 binding.
- The IFNs were the first of the proteins we now recognize as members of the Class II cytokine family.
- IFNa2 contain 165 amino acids; according to circular dichroism measurements ~68% of the residues adopt helical conformation.INFa2 is composed of five a-helices, labeled A–E, linked by one long overhand connection (AB loop) and three short segments (BC, CD and DE loops). The topology of the molecule resembles the classical up-up-down-down four-helixbundle motif; helices A, B, C, and E comprise the helix bundle.
- Type I IFNs are stable at acidic pH (pH 2) and are represented by two major subtypes, the fibroblast or beta interferon (IFN-b) and the leukocyte or alpha family of interferons (IFN-a).The only known interferon of type II is IFN-g, which is produced exclusively by lymphocytes.
# Pharmaceutical forms of interferons in the market
- Rebif, liquid form of Interferon beta 1a
- Avonex, lyophilized form of Interferon beta 1a
- Cinnovex, generic/biosimilar form of Interferon beta 1a (Avonex)
- Betaseron, Interferon beta 1b
- Roferon A. regular Interferon-alpha2a
- Intron-A, regular Interferon-alpha2b
- PEGASYS, Pegylated Interferon alpha 2a
- Berlex, Interferon beta 1b
- PegIntron, Pegylated Interferon alpha 2b
- Reiferon Etard , pegylated Interferon alpha 2a | Interferon
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Interferons (IFNs) are natural proteins produced by the cells of the immune system of most vertebrates in response to challenges by foreign agents such as viruses, parasites and tumor cells. Interferons belong to the large class of glycoproteins known as cytokines. Interferons are produced by a wide variety of cells in response to the presence of double-stranded RNA, a key indicator of viral infection. Interferons assist the immune response by inhibiting viral replication within host cells, activating natural killer cells, increasing antigen presentation to lymphocytes, and inducing the resistance of host cells to viral infection.
# Types of interferon
There are three major classes of interferons that have been described for humans according to the type of receptor through which they signal:
- Interferon type I: All type I IFNs bind to a specific cell surface receptor complex known as the IFN-α receptor (IFNAR) that consists of IFNAR1 and IFNAR2 chains. The type I interferons present in humans are IFN-α, IFN-β and IFN-ω[1].
- Interferon type II: Binds to IFNGR. In humans this is IFN-γ.
- Interferon type III: Signal through a receptor complex consisting of IL10R2 (also called CRF2-4) and IFNLR1 (also called CRF2-12)
# Signaling pathway
While there is evidence to suggest other signaling mechanisms exist, the JAK-STAT signaling pathway is the best-characterised and commonly accepted IFN signaling pathway.
# Natural function and synthesis
Interferons in general have several effects in common. They are antiviral and possess antioncogenic properties, macrophage and natural killer lymphocyte activation, and enhancement of major histocompatibility complex glycoprotein classes I and II, and thus presentation of foreign (microbial) peptides to T cells. In a majority of cases, the production of interferons is induced in response to microbes such as viruses and bacteria and their products (viral glycoproteins, viral RNA, bacterial endotoxin, bacterial flagella, CpG sites), as well as mitogens and other cytokines, for example interleukin 1, interleukin 2, interleukin-12, tumor necrosis factor and colony-stimulating factor, that are synthesised in the response to the appearance of various antigens in the body. Their metabolism and excretion take place mainly in the liver and kidneys. They rarely pass the placenta but they can cross the blood-brain barrier.
# Viral induction of interferons
All classes of interferon are very important in fighting RNA virus infections. However, their presence also accounts for some of the host symptoms, such as sore muscles and fever. They are secreted when abnormally large amounts of dsRNA are found in a cell. dsRNA is normally present in very low quantities. The dsRNA acts like a trigger for the production of interferon (via Toll Like Receptor 3 (TLR 3) a pattern recognition receptor of the innate immune system which leads to activation of the transcription factor IRF3 and late phase NF kappa Beta). The gene that codes for this cytokine is switched on in an infected cell, and the interferon synthesized and secreted to surrounding cells.
As the original cell dies from the cytolytic RNA virus, these thousands of viruses will infect nearby cells. However, these cells have received interferon, which essentially warns these other cells that there's a wolf in the pack of sheep. They then start producing large amounts of a protein known as protein kinase R (or PKR). If a virus infects a cell that has been “pre-warned” by interferon, it is like charging into a hail of bullets for the virus. The PKR is indirectly activated by the dsRNA (actually by 2'-5' oligoadenylate produced by the 2'-5' oligoadenylate-synthetase which is produced due to TLR3 activation), and begins transferring phosphate groups (phosphorylating) to a protein known as eIF-2, a eukaryotic translation initiation factor. After phosphorylation, eIF2 has a reduced ability to initiate translation, the production of proteins coded by cellular mRNA. This prevents viral replication and inhibits normal cell ribosome function, killing both the virus and the host cell if the response is active for a sufficient amount of time. All RNA within the cell is also degraded, preventing the mRNA from being translated by eIF2 if some of the eIF2 failed to be phosphorylated.
Furthermore, interferon leads to upregulation of MHC I and therefore to increased presentation of viral peptides to cytotoxic CD8 T cells, as well as to a change in the proteasome (exchange of some beta subunits by b1i, b2i, b5i - then known as the immunoproteasome) which leads to increased production of MHC I compatible peptides.
Interferon can cause increased p53 activity in virus infected cells. It acts as an inducer and causes increased production of the p53 gene product. This promotes apoptosis, limiting the ability of the virus to spread. Increased levels of transcription are observed even in cells which are not infected, but only infected cells show increased apoptosis. This increased transcription may serve to prepare susceptible cells so they can respond quickly in the case of infection. When p53 is induced by viral presence, it behaves differently than it usually does. Some p53 target genes are expressed under viral load, but others, especially those that respond to DNA damage, aren’t. One of the genes that is not activated is p21, which can promote cell survival. Leaving this gene inactive would help promote the apoptotic effect. Interferon enhances the apoptotic effects of p53, but it is not strictly required. Normal cells exhibit a stronger apoptotic response than cells without p53.[2][3]
Additionally, interferon has been shown to have therapeutic effect against certain cancers. It is probable that one mechanism of this effect is p53 induction. This could be useful clinically: Interferons could supplement or replace chemotherapy drugs that activate p53 but also cause unwanted side effects.[2].Some of these side effects can be serious, severe and permanent.
# Virus resistance to interferons
In a study of the blocking of interferon (IFN) by the Japanese Encephalitis Virus (JEV), a group of researchers infected human recombinant IFN-alpha with JEV, DEN-2, and PL406, which are all viruses, and found that some viruses have manifested methods that give them a way around the IFN-alpha/beta response. The viruses need to master these methods so they can have the ability to carry on viral replication and production of new viruses.[4] The ways that viruses find a way around the IFN response is through the inhibition of interferon signaling, production, and the blocking of the functions of IFN-induced proteins.[4]
It is not unusual to find viruses encoding for a multiple number of mechanisms to allow them to elude the IFN response at many different levels.[4] While doing the study with JEV, Lin and his coworkers found that with IFN-alpha's inability to block JEV means that JEV may be able to block IFN-alpha signaling which in turn would prevent IFN from having STAT1, STAT2, ISGF3, and IRF-9 signaling.[4] DEN-2 also significantly reduces interferon ability to active JAK-STAT.[4]Some other viral gene products that have been found to have an effect on IFN signaling include EBNA-2, Polyomavirus large T antigen, EBV EBNA1, HPV E7, HCMV, and HHV8.[5] "Several poxviruses encode a soluble IFN receptor homologue that acts as a decoy to inhibit the biological activity of IFN," and that activity is for IFN to "bind to their cognate recepors on the cell surface to iniate a signaling cascade, known as the Janus kinase(JAK)-signal transducer and activation of transcription(Stat) pathways.[4] For example, in a study done by a group of researcher, they found that the B18R protein, which acts as a type 1 IFN receptor and is produced by the vaccinia virus, it was found that the B18R protein inhibited IFN's ability to begin the phosphorylation of JAK1 which reduced the antiviral effect of IFN.[6]
Some viruses can encode proteins that bind to dsRNA. In a study where the researchers infected Human U cells with reovirus-sigma3 protein and then, using the Western blot test, they found that reovirus-sigma3 protein does bind to dsRNA.[7] Along with that, another study in which the researchers infected mouse L cells with vaccinia virus E3L found that E3L encodes the p25 protein that binds to dsRNA.[8] Without double stranded RNA (dsRNA), because it is bound to by the proteins, it is not able to create IFN-induced PKR and 2'-5' oligoadenylate-synthetase making IFN ineffective.[9] It was also found that JEV was able to inhibit IFN-alpha's ability to activate or create ISGs such as PKR.[4] PKR was not able to be found in the JEV infected cells and PKR RNA levels were found to be lower in those same infected cells, and this disruption of PKR can occur, for example, in cells infected with flavaviruses.[4]
The H5N1 influenza virus, also known as bird flu, has been shown to have resistance to interferon and other anti-viral cytokines. This is part of the reason for its high mortality rates in humans. It is resistant due to a single amino acid mutation in Non-Structual protein 1 (NS1), the precise mechanism of how this confers immunity is unclear (reference is Lethal H5N1 influenza viruses escape host anti-viral cytokine responses, Sang Heui Seo, Nature Med, 2002).
# Pharmaceutical uses
## Uses
Just as their natural function, interferons have antiviral, antiseptic and antioncogenic properties when administered as drugs.
Interferon therapy is used (in combination with chemotherapy and radiation) as a treatment for many cancers.
More than half of hepatitis C patients treated with interferon respond with better blood tests and better liver biopsies. There is some evidence that giving interferon immediately following infection can prevent hepatitis C; however, people infected by hepatitis C often do not display symptoms of HCV until months or years later.
Interferon is also used in the treatment and control of the neurological disorder multiple sclerosis, an autoimmune disorder.
Administered intranasally in very low doses, interferon is extensively used in Eastern Europe and Russia as a method to prevent and treat viral respiratory diseases such as cold and flu. However, mechanisms of such action of interferon are not well understood; it is thought that doses must be larger by several orders of magnitude to have any effect on the virus. Consequently, most Western scientists are skeptical of any claims of good efficacy.[10]
## Route of administration
When used in the systemic therapy, IFN-α and IFN-γ are mostly administered by an intramuscular injection. The injection of interferons in the muscle, in the vein, or under skin is generally well tolerated.
Interferon alpha can also be induced with small imidazoquinoline molecules by activation of TLR7 receptor. Aldara (Imiquimod) cream works with this mechanism to induce IFN alpha and IL12 and approved by FDA to treat Actinic Keratosis, Superficial Basal Cell Carcinoma, and External Genital Warts.
## Adverse effects
The most frequent adverse effects are flu-like symptoms: increased body temperature, feeling ill, fatigue, headache, muscle pain, convulsion, dizziness, hair thinning, and depression. Erythema, pain and hardness on the spot of injection are also frequently observed. Interferon therapy causes immunosuppression and can result in some infections manifesting in unusual ways.[11]
All known adverse effects are usually reversible and disappear a few days after the therapy has been finished.
## Types
Several different types of interferon are now approved for use in humans.
More recently, the FDA approved pegylated interferon-alpha, in which polyethylene glycol is added to make the interferon last longer in the body. (Pegylated interferon-alpha-2b was approved in January 2001; pegylated interferon-alpha-2a was approved in October 2002.) The pegylated form is injected once weekly, rather than three times per week for conventional interferon-alpha. Used in combination with the antiviral drug ribavirin, pegylated interferon produces sustained cure rates of 75% or better in people with genotype 2 or 3 hepatitis C (which is easier to treat) but still less than 50% in people with genotype 1 (which is most common in the U.S. and Western Europe).
Interferon-beta (Interferon beta-1a and Interferon beta-1b) is used in the treatment and control of multiple sclerosis. By an as-yet-unknown mechanism, interferon-beta inhibits the production of Th1 cytokines and the activation of monocytes.
# History
While aiming to develop an improved vaccine for smallpox, two Japanese virologists, Yasu-ichi Nagano and Yasuhiko Kojima working at the the Institute for Infectious Diseases at the University of Tokyo, noticed that rabbit-skin or testis previously inoculated with UV-inactivated virus exhibited inhibition of viral growth when re-infected at the same site with live virus. They hypothesised that this was due to some inhibitory factor, and began to characterise it by fractionation of the UV-irradiated viral homogenates using an ultracentrifuge. They published these findings in 1954 in the French journal now known as “Journal de la Société de Biologie”.[12] While this paper demonstrated that the activity could be separated from the virus particles, it could not reconcile the antiviral activity demonstrated in the rabbit skin experiments, with the observation that the same supernatant led to the production of antiviral antibodies in mice. A further paper in 1958, involving triple-ultracentrifugation of the homogenate demonstrated that the inhibitory factor was distinct from the virus particles, leading to trace contamination being ascribed to the 1954 observations.[13][14]
Meanwhile, the British virologist Alick Isaacs and the Swiss researcher Jean Lindenmann, at the National Institute for Medical Research in London, noticed an interference effect caused by heat-inactivated influenza virus on the growth of live influenza virus in chicken egg membranes in a nutritive solution chorioallantoic membrane. They published their results in 1957;[15] in this paper they coined the term ‘interferon’, and today that specific interfering agent is known as a ‘Type I interferon’.[16]
Nagano’s work was never fully appreciated in the scientific community; possibly because it was printed in French, but also because his in vivo system was perhaps too complex to provide clear results in the characterisation and purification of interferon. As time passed, Nagano became aware that his work had not been widely recognised, yet did not actively seek revaluation of his status in field of interferon research. As such, the majority of the credit for discovery of the interferon goes to Isaacs and Lindenmann, with whom there is no record of Nagano ever having made personal contact.[17]
## As a drug
Interferon was scarce and expensive until 1980 when the interferon gene was inserted into bacteria using recombinant DNA technology, allowing mass cultivation and purification from bacterial cultures [18] or derived from yeast (e.g. Reiferon Retard is the first yeast derived interferon-alpha 2a).
# Misc. facts
- Interferon is species-specific: the substance prepared from infected eggs protected only chicken cells from virus infection, while the similar substance prepared from mice protected only mouse cells.
- Produced by many cells in the human body by a receptor dependent feedback mechanism.
- Interferons are part of the "first-wave" immune response of the innate immune system, acting within hours, whereas antibody production takes days.
- Global sales ~ 5 billion US $. The second most successful pharmaceutical ever to come from genetic engineering.
- A book was written about it: Toine Pieters, Interferon: The Science and Selling of a Miracle Drug (London: Routledge, 2005), xiv+264 pp., ISBN: 0-415-34246-5
- There are two types of IFNs: Type I (binding to IFN-aR1 and IFN-aR2c receptors; IFNAR1 chain is not the major ligand-binding chain), and type II (binding to IFN-gammaR1 and IFN-gammaR2 receptors).
- In general, exposure of human cells to viruses or double stranded RNAs induces the production of IFN-a, IFN-b, and IFN-o species.
- For the most part, the IFN-alpha species are not glycosylated, although some contain carbohydrates.
- The IFN-alpha family represents a family of related and homologous proteins, each exhibiting a unique activity profile. Each IFN-a species seems to exhibit a distinct profile of activities [antiviral, antiproliferative, and stimulation of cytotoxic activities of natural killer (NK) cells and T cells]
- The IFNs and IFN-like molecules signal through the Jak-Stat pathway. The receptor for the Type I IFNs consists of two chains, IFN-aR1 and IFN-aR2c. The ligand INF-alpha is a monomer that binds to the two-chain complex of IFN-aR1 and INF-aR2c.
- Within each subtype of mammalian Type I IFN, there is additional variability in gene duplication. The IFN-a genes are duplicated to a much greater extent than any other subtype of Type I IFN. This observation in conjunction with the observation that the IFN-a subtypes generally possess the highest specific antiviral activity imply that physiologically, the body likely uses IFN-a as the primary antiviral defense protein and that the major function of IFN-a is defense.
- STRUCTURE: The Type I IFNs consist of five a-helices (labeled A–E) which are linked by one overhand loop (AB loop) and three shorter segments (BC, CD, and DE loops). Helices A, B, C, and E are arranged in an antiparallel fashion to form a left-handed four-helix bundle. The AB loop contains short segments of 3_10 helix and is best described in three segments labeled AB1, AB2, and AB3. In all Type I IFNs, the AB1 loop encircles and is linked to helix E by a disulfide bond. An additional disulfide bond is observed in most IFN-a subtypes but not IFN-b, which connects the N-terminus of the molecule to helix C. The AB loop is critical for high-affinity IFNAR2 binding and suggest that sequence differences in this region may hold the key to differences in biological activity between the different IFN-a subtypes.
- The NMR structure of IFNAR2 has been determined and exhibits the same general structure as IFN-gammaR1. However, the interdomain angle is approximately 90 degrees rather than 120 degrees. Only loops in N-terminal domain (L2–L4) have been shown to be important for IFN-a2 binding.
- The IFNs were the first of the proteins we now recognize as members of the Class II cytokine family.
- IFNa2 contain 165 amino acids; according to circular dichroism measurements ~68% of the residues adopt helical conformation.INFa2 is composed of five a-helices, labeled A–E, linked by one long overhand connection (AB loop) and three short segments (BC, CD and DE loops). The topology of the molecule resembles the classical up-up-down-down four-helixbundle motif; helices A, B, C, and E comprise the helix bundle.
- Type I IFNs are stable at acidic pH (pH 2) and are represented by two major subtypes, the fibroblast or beta interferon (IFN-b) and the leukocyte or alpha family of interferons (IFN-a).The only known interferon of type II is IFN-g, which is produced exclusively by lymphocytes.
# Pharmaceutical forms of interferons in the market
- Rebif, liquid form of Interferon beta 1a
- Avonex, lyophilized form of Interferon beta 1a
- Cinnovex, generic/biosimilar form of Interferon beta 1a (Avonex)
- Betaseron, Interferon beta 1b
- Roferon A. regular Interferon-alpha2a
- Intron-A, regular Interferon-alpha2b
- PEGASYS, Pegylated Interferon alpha 2a
- Berlex, Interferon beta 1b
- PegIntron, Pegylated Interferon alpha 2b
- Reiferon Etard , pegylated Interferon alpha 2a | https://www.wikidoc.org/index.php/Alpha-interferon | |
9c17adf0281550f272a8a2b45177546f538a05b2 | wikidoc | Tocopherol | Tocopherol
# Overview
Tocopherol, a class of chemical compounds of which many have vitamin E activity, describes a series of organic compounds consisting of various methylated phenols. Because the vitamin activity was first identified in 1936 from a dietary fertility factor in rats, it was given the name "tocopherol" from the Greek words “τοκος” , and “φορειν”, meaning in sum "to carry a pregnancy," with the ending "-ol" signifying its status as a chemical alcohol.
Tocotrienols, which are related compounds, may also have vitamin E activity. All of these various derivatives with vitamin activity, may correctly be referred to as "vitamin E". Tocopherols and tocotrienols are fat-soluble antioxidants.
The compound α-tocopherol, a common form of tocopherol added to food products, is denoted by the E number "E307".
# Forms
Natural vitamin E exists in eight different forms, four tocopherols and four tocotrienols. All feature a chromanol ring, with a hydroxyl group that can donate a hydrogen atom to reduce free radicals and a hydrophobic side chain which allows for penetration into biological membranes. Both the tocopherols and tocotrienols occur in alpha, beta, gamma and delta forms, determined by the number of methyl groups on the chromanol ring. Each form has slightly different biological activity.
As a food additive, tocopherol is labeled with these E numbers: "E307" (α-tocopherol), "E308" (γ-tocopherol), and "E309" (δ-tocopherol). Vitamin E capsules are sometimes used as visible markers in magnetic resonance imaging.
## Alpha-Tocopherol
Alpha-tocopherol is traditionally considered the most active biological antioxidant in humans. The measurement of "vitamin E" activity in international units (IU) was based on fertility enhancement by the prevention of spontaneous abortions in pregnant rats relative to alpha tocopherol. It increases naturally to about 150% of normal in the maternal circulation during human pregnancies.
1 IU of tocopherol is defined as ⅔ milligrams of RRR-alpha-tocopherol (formerly named d-alpha-tocopherol or sometimes ddd-alpha-tocopherol). 1 IU is also defined as 1 milligram of the 8-isomer mix all-rac-alpha-tocopheryl acetate (commercially now "called" dl-alpha-tocopheryl acetate, even though it is more precisely dl,dl,dl-alpha-tocopherol acetate). However, 1 IU of this racemic mixture is not now considered equivalent to 1 IU of natural (RRR) α-tocopherol, and the Institute of Medicine and the USDA now convert IU's of the racemic mixture to milligrams of equivalent RRR using 1 IU racemic mixture = 0.45 "milligrams α-tocopherol".
The original dl,l,l semi-synthetic molecular mix, originally called dl-alpha-tocopherol acetate also, but actually more precisely known as 2-ambo-alpha-tocopherol, is no longer manufactured.
### Pill Images
## Other R, R, R Tocopherol
The other R, R, R tocopherol vitamins are slowly being recognized as research begins to elucidate their additional roles in the human body. Many naturopathic and orthomolecular medicine advocates suggest that vitamin E supplements contain at least 20% by weight of the other natural vitamin E isomers.
## Tocotrienols
Tocotrienols, with four d- isomers, also belong to the vitamin E family. The four tocotrienols have structures corresponding to the four tocopherols, except with an unsaturated bond in each of the three isoprene units that form the hydrocarbon tail. Tocopherols have a saturated phytyl tail.
# History
During feeding experiments with rats Herbert McLean Evans concluded in 1922 that besides vitamins B and C, an unknown vitamin existed. Although every other nutrition was present, the rats were not fertile. This condition could be changed by additional feeding with wheat germ. It took several years until 1936 when the substance was isolated from wheat germ and the formula C29H50O2 was determined. Evans also found that the compound reacted like an alcohol and concluded that one of the oxygen atoms was part of an OH (hydroxyl) group. As noted in the introduction, the vitamin was given its name by Evans from Greek words meaning "to bear young" with the addition of the -ol as an alcohol.
The structure was determined shortly thereafter in 1938.
# Recommended Amounts
The U.S. Dietary Reference Intake (DRI) Recommended Daily Amount (RDA) for a 25-year old male for Vitamin E is 15 mg/day. The DRI for vitamin E is based on the alpha-tocopherol form because it is the most active form as originally tested. Results of two national surveys, the National Health and Nutrition Examination Survey (NHANES III 1988-91) and the Continuing Survey of Food Intakes of Individuals (1994 CSFII) indicated that the dietary intakes of most Americans do not provide the recommended amounts of vitamin E. However, a 2000 Institute of Medicine (IOM) report on vitamin E states that intake estimates of vitamin E may be low because energy and fat intake is often underreported in national surveys and because the kind and amount of fat added during cooking is often not known. The IOM states that most North American adults get enough vitamin E from their normal diets to meet current recommendations. However, they do caution individuals who consume low fat diets because vegetable oils are such a good dietary source of vitamin E. "Low-fat diets can substantially decrease vitamin E intakes if food choices are not carefully made to enhance alpha-tocopherol intakes". Vitamin E supplements are absorbed best when taken with meals.
Because vitamin E can act as an anticoagulant and may increase the risk of bleeding problems, many agencies have set an upper tolerable intake level (UL) for vitamin E at 1,000 mg (1,500 IU) per day.
# Sources
In foods, the most abundant sources of vitamin E are vegetable oils such as palm oil, sunflower, corn, soybean, and olive oil. Nuts, sunflower seeds, seabuckthorn berries, kiwi fruit, and wheat germ are also good sources. Other sources of vitamin E are whole grains, fish, peanut butter, goats milk, and green leafy vegetables. Fortified breakfast cereals are also an important source of vitamin E in the United States. Although originally extracted from wheat germ oil, most natural vitamin E supplements are now derived from vegetable oils, usually soybean oil.
The content of Vitamin E for rich sources follows:
- Wheat germ oil (215.4 mg/100 g)
- Sunflower oil (55.8 mg/100 g)
- Hazelnut (26.0 mg/100 g)
- Walnut oil (20.0 mg/100 g)
- Peanut oil (17.2 mg/100 g)
- Olive oil (12.0 mg/100 g)
- Peanut (9.0 mg/100 g)
- Pollard (2.4 mg/100 g)
- Corn (2.0 mg/100 g)
- Asparagus (1.5 mg/100 g)
- Oats (1.5 mg/100 g)
- Chestnut (1.2 mg/100 g)
- Coconut (1.0 mg/100 g)
- Tomatoes (0.9 mg/100 g)
- Carrots (0.6 mg/100 g)
- Goat's milk (0.1 mg/100ml)
# Deficiency
There are three specific situations when a vitamin E deficiency is likely to occur. It is seen in persons who cannot absorb dietary fat, has been found in premature, very low birth weight infants (birth weights less than 1500 grams, or 3.5 pounds), and is seen in individuals with rare disorders of fat metabolism. A vitamin E deficiency is usually characterized by neurological problems due to poor nerve conduction.
Individuals who cannot absorb fat may require a vitamin E supplement because some dietary fat is needed for the absorption of vitamin E from the gastrointestinal tract. Anyone diagnosed with cystic fibrosis, individuals who have had part or all of their stomach removed, and individuals with malabsorptive problems such as Crohn's disease, liver disease or pancreatic insufficiency may not absorb fat and should discuss the need for supplemental vitamin E with their physician (3). People who cannot absorb fat often pass greasy stools or have chronic diarrhea and bloating.
Very low birth weight infants may be deficient in vitamin E. A neonatologist, a pediatrician specializing in the care of newborns, typically evaluates the nutritional needs of premature infants.
Abetalipoproteinemia is a rare inherited disorder of fat metabolism that results in poor absorption of dietary fat and vitamin E. The vitamin E deficiency associated with this disease causes problems such as poor transmission of nerve impulses, muscle weakness, and degeneration of the retina that can cause blindness. Individuals with abetalipoproteinemia may be prescribed special vitamin E supplements by a physician to treat this disorder. In addition, there is a rare genetic condition termed isolated vitamin E deficiency or ataxia with isolated with vitamin E deficiency, caused by mutations in the tocopherol transfer protein gene. These individuals have an extremely poor capacity to absorb vitamin E and develop neurological complications that are reversible by supplementation with high doses of vitamin E.
Also, in adults, erythrocyte membrane fragility results as the erythrocytes are oxidized.
# Supplements
Commercial vitamin E supplements can be classified into several distinct categories:
- Fully synthetic vitamin E, "dl-alpha-tocopherol", the most inexpensive, most commonly sold supplement form usually as the acetate ester;
- Semi-synthetic "natural source" vitamin E esters, the "natural source" forms used in tablets and multiple vitamins. These are highly fractionated d-alpha tocopherol or its esters, often made by synthetic methylation of gamma and beta d,d,d tocopherol vitamers extracted from plant oils.
- Less fractionated "natural mixed tocopherols" and high d-gamma-tocopherol fraction supplements
## Synthetic All-racemic
Synthetic vitamin E derived from petroleum products is manufactured as all-racemic alpha tocopheryl acetate with three chiral centers. This mixture has only one alpha tocopherol molecule (moiety) in 8 molecules as actual R, R,R-alpha tocopherol.
The 8-isomer "all-rac" vitamin E is always marked on labels simply as "dl-tocopherol" or "dl-tocopheryl acetate", even though it is (if fully written out) actually dl,dl,dl-tocopherol. The present largest manufacturers of this type are DSM and BASF.
(An earlier semisynthetic vitamin E actually contained 50% d,d,d-alpha tocopherol moiety and 50% l,d,d-alpha-tocopherol moiety, as synthesized by an earlier process which started with a plant sterol intermediate with the correct chirality in the tail, and thus resulted in a racemic mixture at only one chiral center. This form, known as 2-ambo tocopherol, is no longer made.)
Natural alpha-tocopherol is the RRR-alpha (or ddd-alpha) form. The synthetic dl,dl,dl-alpha ("dl-alpha") form is not as active as the natural ddd-alpha ("d-alpha") tocopherol form. This is mainly due to nearly complete vitamin inactivity of the 4 possible chiral alpha epimers which are represented by the "l" or "S" enantiomer at the first chiral center (an S or l configuration between the chromanol ring and the tail, i.e., the SRR, SRS, SSR, and SSS epimers). Unnatural 2R chiral forms with natural R configuration at this key center, but S at the other centers in the tail (RSR, RRS), appear to retain substantial RRR vitamin activity because they are recognized by the alpha tocopherol transport protein, and thus maintained in the plasma, where the other four epimers are not. Thus, the synthetic all-rac-α-tocopherol probably has only about half the vitamin activity of RRR-α-tocopherol in humans, even though the ratio of activities of the 8 isomer sythetic mixture to the natural vitamin is 1 to 1.36 in the rat pregnancy model.
Although it is clear that synthetic form is not as active as the natural alpha tocopherol form, in the ratios discussed above, specific information on any side effects of the seven synthetic vitamin E epimers is not readily available. Naturopathic and orthomolecular medicine advocates have held that none of the synthetic vitamin E forms have merit for cancer, circulatory and heart diseases, but hold this opinion without being able to point to definitive studies of the matter.
## Natural and Semi-synthetic
Semisynthetic "natural source" vitamin E, manufacturers convert the common natural beta, gamma and delta tocopherol isomers into the alpha form by adding methyl groups to yield d-alpha tocopherol. The largest manufacturers of this form are presently Cognis,Cargill and Archer Daniels Midland. Manufacturers also commonly convert the alcohol form of the vitamins to esters using acetic or succinic acid. These tocopheryl esters are more stable and are easy to use in tablets and multiple vitamin pills.
Because only alpha tocopherols were officially counted as "vitamin E" in supplements, refiners and manufacturers faced enormous economic pressure to esterify and methylate the other natural tocopherol isomers, d-beta-, d-gamma- and d-delta-tocopherol into d-alpha tocopheryl acetate or succinate. However, these alpha tocopheryl esters have been shown to be variably and less efficiently absorbed in humans than in the original normative tests using rats. In the healthy human body, the semisynthetic forms are easily de-esterified over several days, primarily in the liver, but not for common problems in premature babies, aged or ill patients.
Tocopheryl nicotinate and tocopheryl linolate esters are used in cosmetics and some pharmaceuticals.
## Mixed Tocopherols
"Mixed tocopherols" in the US contain at least 20% w/w other natural R, R,R- tocopherols, i.e. R, R,R-alpha-tocopherol content plus at least 25% R, R,R-beta-, R, R,R-gamma-, R, R,R-delta-tocopherols.
Some premium brands may contain 200% w/w or more of the other tocopherols and measurable tocotrienols. Some mixed tocopherols with higher gamma-tocopherol content are marketed as "High Gamma-Tocopherol". The label should report each component in milligrams, except R, R,R-alpha-tocopherol may still be reported in IU. Mixed tocopherols can also be found in various nutritional supplements manufactured by high end supplement companies.
# Other Uses
Conventional medical studies on vitamin E, as of 2006 and as below, use either a synthetic all-racemic ("d, l-") alpha tocopheryl ester (acetate or succinate) or a semi-synthetic d-alpha tocopheryl ester (acetate or succinate). Proponents of megavitamin, orthomolecular and naturally based therapies have advocated, for the last two thirds of a century, and have used the natural tocopherols, often mixed tocopherols with an additional 25% - 200% w/w d-beta-, d-gamma-, and d-delta-tocopherol. Based on various clinical, experimental, patent, and individual data, natural health proponents have long held that the other poorly studied tocopherols, especially the abundant d-gamma-tocopherol, in combination with other antioxidants such as selenium, coQ10, vitamin C, vitamin K2, mixed carotenoids, and lipoic acid, provide unique biochemical benefits. The methodology, interpretation and reporting of conventional vitamin E studies have even become contentious within conventional medicine circles.
## Controversy
"Megadoses" of Vitamin E are not recommended by many government agencies, due to a possible increased risk of bleeding. Two meta-analyses have concluded that synthetic and semisynthetic vitamin E supplements (alpha tocopheryl esters) increase mortality, although these meta-analyses have been repeatedly challenged in the nutrition literature for cofounders and selection bias.
A 2005 meta-analysis by Miller found that high-dosage vitamin E supplements may increase all-cause mortality. "High dose" vitamin E esters (>400 units/day) were also associated with an increased risk in all-cause mortality of 39 per 10,000 persons, and a statistically significant relation existed between dose and mortality, with increased risk at doses exceeding 150 units per day. These trials included synthetic beta-carotene and other cofounders.
The Miller study was rebutted by Houston in the Journal of the American Nutraceutical Association. Furthermore, Rosenberg concluded that "toxicity symptoms have not been reported even at intakes of 800 IU per kilogram of body weight daily for 5 months" according to the Food and Nutrition Board (Rosenberg, et al), an amount that corresponds to 60,000 IU per day for a 75 kg adult.
A review of a number of randomized controlled trials in the scientific literature by the Cochrane Collaboration published in JAMA in 2007 also found an increase in mortality, of 4% (Relative Risk 1.04, 95% confidence interval 1.01-1.07), or 400 per 10,000 persons.
## As a Preservative
Vitamin E is widely used in industry as an inexpensive preservative (namely for cosmetics and foods). Vitamin E containing products are commonly used in the belief that vitamin E is good for the skin; many cosmetics include it, often labeled as tocopherol acetate, tocopheryl linoleate or tocopheryl nicotinate. Individuals can still experience allergic reactions to some tocopheryl esters or develop a rash and hives that may spread over the entire body from the use of topical products with alpha tocopheryl esters.
## Reduce Scarring
Topical use of Vitamin E is often claimed by manufacturers of skin creams and lotions to play a role in encouraging skin healing and reducing scarring after injuries such as burns on the basis of limited research, but the weak evidence of a benefit of silicon gel sheeting with or without added Vitamin E is limited by the poor quality of the research. Indeed one study found that it did not improve or worsened the cosmetic appearance in 90% of patients, with a third developing contact dermatitis.
## During Pregnancy
Recent studies into the use of both vitamin C and the single isomer vitamin E esters as possible help in preventing oxidative stress leading to pre-eclampsia has failed to show significant benefits, but did increase the rate of babies born with a low birthweight in one study. However, earlier work that suggested vitamin K (similar structures to natural E isomers) and C together have 91% benefit in nausea and vomiting remains unaddressed.
## Heart Disease
Preliminary research has led to a widely held belief that vitamin E may help prevent or delay coronary heart disease, but larger controlled studies have not shown any benefit. Many researchers advance the belief that oxidative modification of LDL (also called "bad" cholesterol) promotes blockages in coronary arteries that may lead to atherosclerosis and heart attacks. Vitamin E may help prevent or delay coronary heart disease by limiting the oxidation of LDL. Vitamin E also may help prevent the formation of blood clots, which could lead to a heart attack. Observational studies have associated lower rates of heart disease with higher vitamin E intake. A study of approximately 90,000 nurses suggested that the incidence of heart disease was 30% to 40% lower among nurses with the highest intake of vitamin E from diet and supplements. The range of intakes from both diet and supplements in this group was 21.6 to 1,000 IU (32 to 1,500 mg), with the median intake being 208 IU (139 mg). A 1994 review of 5,133 Finnish men and women aged 30 - 69 years suggested that increased dietary intake of vitamin E was associated with decreased mortality (death) from heart disease.
But even though these observations are promising, randomized clinical trials have consistently shown lack of benefit to the role of vitamin E supplements in heart disease.
### Supportive Trial Data
- The Heart Outcomes Prevention Evaluation (HOPE) study followed almost 10,000 patients for 4.5 years who were at high risk for heart attack or stroke. In this intervention study the subjects who received 265 mg (400) IU of vitamin E daily did not experience significantly fewer cardiovascular events or hospitalizations for heart failure or chest pain when compared to those who received a sugar pill. The researchers suggested that it is unlikely that the vitamin E supplement provided any protection against cardiovascular disease in the HOPE study. The HOPE study was extended to evaluate whether long-term supplementation with vitamin E decreases the risk of cancer, cancer death, and major cardiovascular events (HOPE-The Ongoing Outcomes ). Nearly 4500 patients were followed for a median time period of 7 years. This study did not find any significant differences in cancer incidence, cancer deaths, and major cardiovascular events, but found a higher rate of heart failure (17%) and hospitalizations for heart failure (21%) among the subjects.
- The Women's Angiographic Vitamin and Estrogen trial was a randomized, double-blind, placebo-controlled study which enrolled 423 postmenopausal women with some degree of coronary stenosis, to study the efficacy of estrogen replacement and antioxidant vitamins (vitamin C and vitamin E) in preventing angiographic progression of coronary artery disease. The study reported no cardiovascular benefit in women taking supplements compared to those on placebo. Moreover all-cause mortality was significantly higher in women taking the supplements.
- The Women's Health study was a randomized, placebo-controlled, 2×2 factorial study in which 39,876 apparently healthy US women aged ≥45 years were enrolled to assess whether vitamin E supplementation decreases risks of cardiovascular disease and cancer among healthy women. All the women were randomly assigned to receive vitamin E or placebo and aspirin or placebo. After a mean follow-up period of 10.1 years, the study reported no significant benefit on the incidences of cardiovascular events, cancer and all-cause mortality in the group taking vitamin E. However a significant reduction of 24% was observed in cardiovascular mortality.
- The Physicians' Health Study II was a randomized, double-blind, placebo-controlled factorial trial designed to evaluate whether long-term vitamin E or vitamin C supplementation decreases the risk of major cardiovascular events among men. 14,641 US male physicians ≥50 years of age were enrolled in this study. The subjects were randomly assigned to receive either alternate day vitamin E and daily vitamin C or a placebo. After a mean follow-up of 8 years the study found that neither vitamin E nor vitamin C supplementation reduced the risk of major cardiovascular events.
Furthermore, meta analysis of several trials of antioxidants, including vitamin E, have not shown any benefit to vitamin E supplementation for preventing coronary heart disease. One study suggested that Vitamin E (as alpha-tocopherol only) supplementation may increase the risk for heart failure. Supplementing alpha-tocopherol without gamma-tocopherol is known to lead to reduced serum gamma- and delta-tocopherol concentrations.
Orthomolecular and naturopathic medicine use much different types of vitamin E, the natural mixed tocopherols, and other supportive cofactors such as, selenium, vitamin C, carnitine, lysine, and co-Q10 for various cardiovascular diseases. See also Orthomolecular medicine:Vitamin E controversy.
On September 10, 2007, the American Heart Association (in its journal Circulation) stated that women taking regular doses of vitamin E or Tocopherol were 21% less likely to suffer a blood clot. Dr. Robert Glynn of Harvard Medical School said it was an interesting finding but not yet proven and further research must confirm the link in the prevention of venous thromboembolism, and patients must not stop taking prescribed blood thinners.
## Cancer
Antioxidants such as vitamin E help protect against the damaging effects of free radicals, which may contribute to the development of chronic diseases such as cancer. Vitamin E also may block the formation of nitrosamines, which are carcinogens formed in the stomach from nitrites consumed in the diet. It also may protect against the development of cancers by enhancing immune function. To date, human trials and surveys that have tried to associate vitamin E with incidence of cancer remain generally inconclusive.
Some evidence associates higher intake of vitamin E with a decreased incidence of prostate cancer (see ATBC study) and breast cancer. Some studies correlate additional cofactors, such as specific vitamin E isomers, e.g. gamma-tocopherol, and other nutrients, e.g. selenium, with dramatic risk reductions in prostate cancer. However, an examination of the effect of dietary factors, including vitamin E, on incidence of postmenopausal breast cancer in over 18,000 women from New York State did not associate a greater vitamin E intake with a reduced risk of developing breast cancer. A study of the effect on lung cancer in smokers also showed no benefit.
A study of women in Iowa provided evidence that an increased dietary intake of vitamin E may decrease the risk of colon cancer, especially in women under 65 years of age. On the other hand, vitamin E intake was not statistically associated with risk of colon cancer in almost 2,000 adults with cancer who were compared to controls without cancer. At this time there is limited evidence to recommend vitamin E supplements for the prevention of cancer.
Recent studies have found that increased intake of vitamin E, especially among smokers may be responsible for an increase in the incidence of lung cancer, with one study finding an increase in the incidence of lung cancer by 7% for each 100IU of vitamin E taken daily.
## Cataracts
A cataract is a condition of clouding of the tissue of the lens of the eye. They increase the risk of disability and blindness in aging adults. Antioxidants are being studied to determine whether they can help prevent or delay cataract growth. Observational studies have found that lens clarity, which is used to diagnose cataracts, was better in regular users of vitamin E supplements and in persons with higher blood levels of vitamin E. A study of middle aged male smokers, however, did not demonstrate any effect from vitamin E supplements on the incidence of cataract formation. The effects of smoking, a major risk factor for developing cataracts, may have overridden any potential benefit from the vitamin E, but the conflicting results also indicate a need for further studies before researchers can confidently recommend extra vitamin E for the prevention of cataracts.
It is important to note that the term "cataract" may be used in common parlance for an opacity involving any tissue of the eye, for example a corneal scar. Thus a character in theater or on television who is blind from cataracts might have white instead of clear corneas, covering over the iris and pupil. Since the lens is behind the pupil, real cataracts are difficult to see without special instrumentation, so people with cataracts have rather normally appearing eyes.
## Age-related Macular Degeneration (AMD)
Age-related macular degeneration (AMD) is the leading cause of visual impairment and blindness in the United States and the developed world among people 65 years and older. It has been shown that vitamin E alone does not attenuate the development or progression of AMD.
However, studies focusing on efficacy of Vitamin E combined with other antioxidants, like zinc and vitamin C, indicate a protective effect against the onset and progression of AMD
## Glaucoma
A 2007 study published in the European Journal of Ophthalmology found that, along with other treatments for glaucoma, adding alpha-tocopherol appeared to help protect the retina from glaucomatous damage. Groups receiving 300 mg and 600 mg per day of alpha-tocopherol, delivered orally, showed statistically significant decreases in the resistivity index in the posterior ciliary arteries and in the pulsatility index in the ophthalmic arteries, after six and twelve months of therapy. Alpha-tocopherol-treated patients also had significantly lower differences in mean visual field deviations."
## Alzheimer's Disease
Alzheimer's disease is a wasting disease of the brain. As oxidative stress may be involved in the pathogenesis of Alzheimer's, tocopherols have been tested as both a means of preventing and treating this disease. The results of these studies have been mixed, with some research suggesting that high levels of vitamin E in the diet may reduce the risk of Alzheimer's, while other studies found no such link. Similarly, studies on if tocopherols could slow the progression of Alzheimer's have also been contradictory, with the Alzheimer’s Disease Cooperative Study suggesting that vitamin E supplementation might be beneficial, but a later trial finding no clinical benefit. Due to this contradictory and confusing evidence, vitamin E or tocopherol supplements are not currently recommended for treating or preventing Alzheimer's disease.
## Parkinson's Disease
In May 2005, The Lancet Neurology published a study suggesting that vitamin E may help protect against Parkinson's disease. Individuals with moderate to high intakes of dietary vitamin E were found to have a lower risk of Parkinson's. No conclusion was drawn about whether supplemental vitamin E has the same effect, however.
# Related Chapters
- Alkylresorcinols | Tocopherol
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [3]; Associate Editor(s)-in-Chief: Cafer Zorkun, M.D., Ph.D. [4]; Raviteja Guddeti, M.B.B.S. [5]
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# Overview
Tocopherol, a class of chemical compounds of which many have vitamin E activity, describes a series of organic compounds consisting of various methylated phenols. Because the vitamin activity was first identified in 1936 from a dietary fertility factor in rats, it was given the name "tocopherol" from the Greek words “τοκος” [birth], and “φορειν”, [to bear or carry] meaning in sum "to carry a pregnancy," with the ending "-ol" signifying its status as a chemical alcohol.
Tocotrienols, which are related compounds, may also have vitamin E activity. All of these various derivatives with vitamin activity, may correctly be referred to as "vitamin E". Tocopherols and tocotrienols are fat-soluble antioxidants.
The compound α-tocopherol, a common form of tocopherol added to food products, is denoted by the E number "E307".
# Forms
Natural vitamin E exists in eight different forms, four tocopherols and four tocotrienols. All feature a chromanol ring, with a hydroxyl group that can donate a hydrogen atom to reduce free radicals and a hydrophobic side chain which allows for penetration into biological membranes. Both the tocopherols and tocotrienols occur in alpha, beta, gamma and delta forms, determined by the number of methyl groups on the chromanol ring. Each form has slightly different biological activity.[1]
As a food additive, tocopherol is labeled with these E numbers: "E307" (α-tocopherol), "E308" (γ-tocopherol), and "E309" (δ-tocopherol). Vitamin E capsules are sometimes used as visible markers in magnetic resonance imaging.
## Alpha-Tocopherol
Alpha-tocopherol is traditionally considered the most active biological antioxidant in humans. The measurement of "vitamin E" activity in international units (IU) was based on fertility enhancement by the prevention of spontaneous abortions in pregnant rats relative to alpha tocopherol. It increases naturally to about 150% of normal in the maternal circulation during human pregnancies.
1 IU of tocopherol is defined as ⅔ milligrams of RRR-alpha-tocopherol (formerly named d-alpha-tocopherol or sometimes ddd-alpha-tocopherol). 1 IU is also defined as 1 milligram of the 8-isomer mix all-rac-alpha-tocopheryl acetate (commercially now "called" dl-alpha-tocopheryl acetate, even though it is more precisely dl,dl,dl-alpha-tocopherol acetate). However, 1 IU of this racemic mixture is not now considered equivalent to 1 IU of natural (RRR) α-tocopherol, and the Institute of Medicine and the USDA now convert IU's of the racemic mixture to milligrams of equivalent RRR using 1 IU racemic mixture = 0.45 "milligrams α-tocopherol".[2]
The original dl,l,l semi-synthetic molecular mix, originally called dl-alpha-tocopherol acetate also, but actually more precisely known as 2-ambo-alpha-tocopherol, is no longer manufactured.
### Pill Images
## Other R, R, R Tocopherol
The other R, R, R tocopherol vitamins are slowly being recognized as research begins to elucidate their additional roles in the human body. Many naturopathic and orthomolecular medicine advocates suggest that vitamin E supplements contain at least 20% by weight of the other natural vitamin E isomers.
## Tocotrienols
Tocotrienols, with four d- isomers, also belong to the vitamin E family. The four tocotrienols have structures corresponding to the four tocopherols, except with an unsaturated bond in each of the three isoprene units that form the hydrocarbon tail. Tocopherols have a saturated phytyl tail.
# History
During feeding experiments with rats Herbert McLean Evans concluded in 1922 that besides vitamins B and C, an unknown vitamin existed.[3] Although every other nutrition was present, the rats were not fertile. This condition could be changed by additional feeding with wheat germ. It took several years until 1936 when the substance was isolated from wheat germ and the formula C29H50O2 was determined. Evans also found that the compound reacted like an alcohol and concluded that one of the oxygen atoms was part of an OH (hydroxyl) group. As noted in the introduction, the vitamin was given its name by Evans from Greek words meaning "to bear young" with the addition of the -ol as an alcohol.[4]
The structure was determined shortly thereafter in 1938.[5]
# Recommended Amounts
The U.S. Dietary Reference Intake (DRI) Recommended Daily Amount (RDA) for a 25-year old male for Vitamin E is 15 mg/day. The DRI for vitamin E is based on the alpha-tocopherol form because it is the most active form as originally tested. Results of two national surveys, the National Health and Nutrition Examination Survey (NHANES III 1988-91) and the Continuing Survey of Food Intakes of Individuals (1994 CSFII) indicated that the dietary intakes of most Americans do not provide the recommended amounts of vitamin E. However, a 2000 Institute of Medicine (IOM) report on vitamin E states that intake estimates of vitamin E may be low because energy and fat intake is often underreported in national surveys and because the kind and amount of fat added during cooking is often not known. The IOM states that most North American adults get enough vitamin E from their normal diets to meet current recommendations. However, they do caution individuals who consume low fat diets because vegetable oils are such a good dietary source of vitamin E. "Low-fat diets can substantially decrease vitamin E intakes if food choices are not carefully made to enhance alpha-tocopherol intakes". Vitamin E supplements are absorbed best when taken with meals.[6]
Because vitamin E can act as an anticoagulant and may increase the risk of bleeding problems, many agencies have set an upper tolerable intake level (UL) for vitamin E at 1,000 mg (1,500 IU) per day.[7]
# Sources
In foods, the most abundant sources of vitamin E are vegetable oils such as palm oil, sunflower, corn, soybean, and olive oil. Nuts, sunflower seeds, seabuckthorn berries, kiwi fruit, and wheat germ are also good sources. Other sources of vitamin E are whole grains, fish, peanut butter, goats milk, and green leafy vegetables. Fortified breakfast cereals are also an important source of vitamin E in the United States. Although originally extracted from wheat germ oil, most natural vitamin E supplements are now derived from vegetable oils, usually soybean oil.
The content of Vitamin E for rich sources follows:[8]
- Wheat germ oil (215.4 mg/100 g)
- Sunflower oil (55.8 mg/100 g)
- Hazelnut (26.0 mg/100 g)
- Walnut oil (20.0 mg/100 g)
- Peanut oil (17.2 mg/100 g)
- Olive oil (12.0 mg/100 g)
- Peanut (9.0 mg/100 g)
- Pollard (2.4 mg/100 g)
- Corn (2.0 mg/100 g)
- Asparagus (1.5 mg/100 g)
- Oats (1.5 mg/100 g)
- Chestnut (1.2 mg/100 g)
- Coconut (1.0 mg/100 g)
- Tomatoes (0.9 mg/100 g)
- Carrots (0.6 mg/100 g)
- Goat's milk (0.1 mg/100ml)
# Deficiency
There are three specific situations when a vitamin E deficiency is likely to occur. It is seen in persons who cannot absorb dietary fat, has been found in premature, very low birth weight infants (birth weights less than 1500 grams, or 3.5 pounds), and is seen in individuals with rare disorders of fat metabolism. A vitamin E deficiency is usually characterized by neurological problems due to poor nerve conduction.
Individuals who cannot absorb fat may require a vitamin E supplement because some dietary fat is needed for the absorption of vitamin E from the gastrointestinal tract. Anyone diagnosed with cystic fibrosis, individuals who have had part or all of their stomach removed, and individuals with malabsorptive problems such as Crohn's disease, liver disease or pancreatic insufficiency may not absorb fat and should discuss the need for supplemental vitamin E with their physician (3). People who cannot absorb fat often pass greasy stools or have chronic diarrhea and bloating.
Very low birth weight infants may be deficient in vitamin E. A neonatologist, a pediatrician specializing in the care of newborns, typically evaluates the nutritional needs of premature infants.
Abetalipoproteinemia is a rare inherited disorder of fat metabolism that results in poor absorption of dietary fat and vitamin E. The vitamin E deficiency associated with this disease causes problems such as poor transmission of nerve impulses, muscle weakness, and degeneration of the retina that can cause blindness. Individuals with abetalipoproteinemia may be prescribed special vitamin E supplements by a physician to treat this disorder. In addition, there is a rare genetic condition termed isolated vitamin E deficiency or ataxia with isolated with vitamin E deficiency, caused by mutations in the tocopherol transfer protein gene. These individuals have an extremely poor capacity to absorb vitamin E and develop neurological complications that are reversible by supplementation with high doses of vitamin E.
Also, in adults, erythrocyte membrane fragility results as the erythrocytes are oxidized.
# Supplements
Commercial vitamin E supplements can be classified into several distinct categories:
- Fully synthetic vitamin E, "dl-alpha-tocopherol", the most inexpensive, most commonly sold supplement form usually as the acetate ester;
- Semi-synthetic "natural source" vitamin E esters, the "natural source" forms used in tablets and multiple vitamins. These are highly fractionated d-alpha tocopherol or its esters, often made by synthetic methylation of gamma and beta d,d,d tocopherol vitamers extracted from plant oils.
- Less fractionated "natural mixed tocopherols" and high d-gamma-tocopherol fraction supplements
## Synthetic All-racemic
Synthetic vitamin E derived from petroleum products is manufactured as all-racemic alpha tocopheryl acetate with three chiral centers. This mixture has only one alpha tocopherol molecule (moiety) in 8 molecules as actual R, R,R-alpha tocopherol.
The 8-isomer "all-rac" vitamin E is always marked on labels simply as "dl-tocopherol" or "dl-tocopheryl acetate", even though it is (if fully written out) actually dl,dl,dl-tocopherol. The present largest manufacturers of this type are DSM and BASF.
(An earlier semisynthetic vitamin E actually contained 50% d,d,d-alpha tocopherol moiety and 50% l,d,d-alpha-tocopherol moiety, as synthesized by an earlier process which started with a plant sterol intermediate with the correct chirality in the tail, and thus resulted in a racemic mixture at only one chiral center. This form, known as 2-ambo tocopherol, is no longer made.)
Natural alpha-tocopherol is the RRR-alpha (or ddd-alpha) form. The synthetic dl,dl,dl-alpha ("dl-alpha") form is not as active as the natural ddd-alpha ("d-alpha") tocopherol form. This is mainly due to nearly complete vitamin inactivity of the 4 possible chiral alpha epimers which are represented by the "l" or "S" enantiomer at the first chiral center (an S or l configuration between the chromanol ring and the tail, i.e., the SRR, SRS, SSR, and SSS epimers). Unnatural 2R chiral forms with natural R configuration at this key center, but S at the other centers in the tail (RSR, RRS), appear to retain substantial RRR vitamin activity because they are recognized by the alpha tocopherol transport protein, and thus maintained in the plasma, where the other four epimers are not. Thus, the synthetic all-rac-α-tocopherol probably has only about half the vitamin activity of RRR-α-tocopherol in humans, even though the ratio of activities of the 8 isomer sythetic mixture to the natural vitamin is 1 to 1.36 in the rat pregnancy model. [9]
Although it is clear that synthetic form is not as active as the natural alpha tocopherol form, in the ratios discussed above, specific information on any side effects of the seven synthetic vitamin E epimers is not readily available. Naturopathic and orthomolecular medicine advocates have held that none of the synthetic vitamin E forms have merit for cancer, circulatory and heart diseases, but hold this opinion without being able to point to definitive studies of the matter.
## Natural and Semi-synthetic
Semisynthetic "natural source" vitamin E, manufacturers convert the common natural beta, gamma and delta tocopherol isomers into the alpha form by adding methyl groups to yield d-alpha tocopherol. The largest manufacturers of this form are presently Cognis,Cargill and Archer Daniels Midland. Manufacturers also commonly convert the alcohol form of the vitamins to esters using acetic or succinic acid. These tocopheryl esters are more stable and are easy to use in tablets and multiple vitamin pills.
Because only alpha tocopherols were officially counted as "vitamin E" in supplements, refiners and manufacturers faced enormous economic pressure to esterify and methylate the other natural tocopherol isomers, d-beta-, d-gamma- and d-delta-tocopherol into d-alpha tocopheryl acetate or succinate. However, these alpha tocopheryl esters have been shown to be variably and less efficiently absorbed in humans than in the original normative tests using rats.[10] In the healthy human body, the semisynthetic forms are easily de-esterified over several days, primarily in the liver, but not for common problems in premature babies, aged or ill patients.
Tocopheryl nicotinate and tocopheryl linolate esters are used in cosmetics and some pharmaceuticals.
## Mixed Tocopherols
"Mixed tocopherols" in the US contain at least 20% w/w other natural R, R,R- tocopherols, i.e. R, R,R-alpha-tocopherol content plus at least 25% R, R,R-beta-, R, R,R-gamma-, R, R,R-delta-tocopherols.
Some premium brands may contain 200% w/w or more of the other tocopherols and measurable tocotrienols. Some mixed tocopherols with higher gamma-tocopherol content are marketed as "High Gamma-Tocopherol". The label should report each component in milligrams, except R, R,R-alpha-tocopherol may still be reported in IU. Mixed tocopherols can also be found in various nutritional supplements manufactured by high end supplement companies.
# Other Uses
Conventional medical studies on vitamin E, as of 2006 and as below, use either a synthetic all-racemic ("d, l-") alpha tocopheryl ester (acetate or succinate) or a semi-synthetic d-alpha tocopheryl ester (acetate or succinate). Proponents of megavitamin, orthomolecular and naturally based therapies have advocated, for the last two thirds of a century, and have used the natural tocopherols, often mixed tocopherols with an additional 25% - 200% w/w d-beta-, d-gamma-,[11][12] and d-delta-tocopherol. Based on various clinical, experimental, patent, and individual data, natural health proponents have long held[13][14] that the other poorly studied tocopherols, especially the abundant d-gamma-tocopherol,[15] in combination with other antioxidants such as selenium, coQ10, vitamin C, vitamin K2, mixed carotenoids, and lipoic acid, provide unique biochemical benefits.[16] The methodology, interpretation and reporting of conventional vitamin E studies have even become contentious within conventional medicine circles.[17]
## Controversy
"Megadoses" of Vitamin E are not recommended by many government agencies, due to a possible increased risk of bleeding. Two meta-analyses have concluded that synthetic and semisynthetic vitamin E supplements (alpha tocopheryl esters) increase mortality, although these meta-analyses have been repeatedly challenged in the nutrition literature for cofounders and selection bias.
A 2005 meta-analysis by Miller found that high-dosage vitamin E supplements may increase all-cause mortality.[18] "High dose" vitamin E esters (>400 units/day) were also associated with an increased risk in all-cause mortality of 39 per 10,000 persons, and a statistically significant relation existed between dose and mortality, with increased risk at doses exceeding 150 units per day. These trials included synthetic beta-carotene and other cofounders.
The Miller study was rebutted by Houston in the Journal of the American Nutraceutical Association.[16] Furthermore, Rosenberg concluded that "toxicity symptoms have not been reported even at intakes of 800 IU per kilogram of body weight daily for 5 months" according to the Food and Nutrition Board (Rosenberg, et al), an amount that corresponds to 60,000 IU per day for a 75 kg adult.
A review of a number of randomized controlled trials in the scientific literature by the Cochrane Collaboration published in JAMA in 2007 also found an increase in mortality, of 4% (Relative Risk 1.04, 95% confidence interval 1.01-1.07), or 400 per 10,000 persons.[19]
## As a Preservative
Vitamin E is widely used in industry as an inexpensive preservative (namely for cosmetics and foods). Vitamin E containing products are commonly used in the belief that vitamin E is good for the skin; many cosmetics include it, often labeled as tocopherol acetate, tocopheryl linoleate or tocopheryl nicotinate. Individuals can still experience allergic reactions to some tocopheryl esters or develop a rash and hives that may spread over the entire body from the use of topical products with alpha tocopheryl esters.[20]
## Reduce Scarring
Topical use of Vitamin E is often claimed by manufacturers of skin creams and lotions to play a role in encouraging skin healing and reducing scarring after injuries such as burns on the basis of limited research,[21] but the weak evidence of a benefit of silicon gel sheeting with or without added Vitamin E is limited by the poor quality of the research.[22] Indeed one study found that it did not improve or worsened the cosmetic appearance in 90% of patients, with a third developing contact dermatitis.[23]
## During Pregnancy
Recent studies into the use of both vitamin C and the single isomer vitamin E esters as possible help in preventing oxidative stress leading to pre-eclampsia has failed to show significant benefits,[24] but did increase the rate of babies born with a low birthweight in one study.[25] However, earlier work that suggested vitamin K (similar structures to natural E isomers) and C together have 91% benefit in nausea and vomiting remains unaddressed.[26]
## Heart Disease
Preliminary research has led to a widely held belief that vitamin E may help prevent or delay coronary heart disease, but larger controlled studies have not shown any benefit. Many researchers advance the belief that oxidative modification of LDL (also called "bad" cholesterol) promotes blockages in coronary arteries that may lead to atherosclerosis and heart attacks. Vitamin E may help prevent or delay coronary heart disease by limiting the oxidation of LDL. Vitamin E also may help prevent the formation of blood clots, which could lead to a heart attack. Observational studies have associated lower rates of heart disease with higher vitamin E intake. A study of approximately 90,000 nurses suggested that the incidence of heart disease was 30% to 40% lower among nurses with the highest intake of vitamin E from diet and supplements. The range of intakes from both diet and supplements in this group was 21.6 to 1,000 IU (32 to 1,500 mg), with the median intake being 208 IU (139 mg). A 1994 review of 5,133 Finnish men and women aged 30 - 69 years suggested that increased dietary intake of vitamin E was associated with decreased mortality (death) from heart disease.
But even though these observations are promising, randomized clinical trials have consistently shown lack of benefit to the role of vitamin E supplements in heart disease.
### Supportive Trial Data
- The Heart Outcomes Prevention Evaluation (HOPE) study followed almost 10,000 patients for 4.5 years who were at high risk for heart attack or stroke. In this intervention study the subjects who received 265 mg (400) IU of vitamin E daily did not experience significantly fewer cardiovascular events or hospitalizations for heart failure or chest pain when compared to those who received a sugar pill. The researchers suggested that it is unlikely that the vitamin E supplement provided any protection against cardiovascular disease in the HOPE study. The HOPE study was extended to evaluate whether long-term supplementation with vitamin E decreases the risk of cancer, cancer death, and major cardiovascular events (HOPE-The Ongoing Outcomes [HOPE-TOO]). Nearly 4500 patients were followed for a median time period of 7 years. This study did not find any significant differences in cancer incidence, cancer deaths, and major cardiovascular events, but found a higher rate of heart failure (17%) and hospitalizations for heart failure (21%) among the subjects.
- The Women's Angiographic Vitamin and Estrogen trial was a randomized, double-blind, placebo-controlled study which enrolled 423 postmenopausal women with some degree of coronary stenosis, to study the efficacy of estrogen replacement and antioxidant vitamins (vitamin C and vitamin E) in preventing angiographic progression of coronary artery disease. The study reported no cardiovascular benefit in women taking supplements compared to those on placebo. Moreover all-cause mortality was significantly higher in women taking the supplements. [27][28]
- The Women's Health study was a randomized, placebo-controlled, 2×2 factorial study in which 39,876 apparently healthy US women aged ≥45 years were enrolled to assess whether vitamin E supplementation decreases risks of cardiovascular disease and cancer among healthy women. All the women were randomly assigned to receive vitamin E or placebo and aspirin or placebo. After a mean follow-up period of 10.1 years, the study reported no significant benefit on the incidences of cardiovascular events, cancer and all-cause mortality in the group taking vitamin E. However a significant reduction of 24% was observed in cardiovascular mortality.[29]
- The Physicians' Health Study II was a randomized, double-blind, placebo-controlled factorial trial designed to evaluate whether long-term vitamin E or vitamin C supplementation decreases the risk of major cardiovascular events among men. 14,641 US male physicians ≥50 years of age were enrolled in this study. The subjects were randomly assigned to receive either alternate day vitamin E and daily vitamin C or a placebo. After a mean follow-up of 8 years the study found that neither vitamin E nor vitamin C supplementation reduced the risk of major cardiovascular events.[30]
Furthermore, meta analysis of several trials of antioxidants, including vitamin E, have not shown any benefit to vitamin E supplementation for preventing coronary heart disease.[31] One study suggested that Vitamin E (as alpha-tocopherol only) supplementation may increase the risk for heart failure.[32] Supplementing alpha-tocopherol without gamma-tocopherol is known to lead to reduced serum gamma- and delta-tocopherol concentrations.[33]
Orthomolecular and naturopathic medicine use much different types of vitamin E, the natural mixed tocopherols, and other supportive cofactors such as, selenium, vitamin C, carnitine, lysine, and co-Q10 for various cardiovascular diseases.[34][35] See also Orthomolecular medicine:Vitamin E controversy.
On September 10, 2007, the American Heart Association (in its journal Circulation) stated that women taking regular doses of vitamin E or Tocopherol were 21% less likely to suffer a blood clot. Dr. Robert Glynn of Harvard Medical School said it was an interesting finding but not yet proven and further research must confirm the link in the prevention of venous thromboembolism, and patients must not stop taking prescribed blood thinners.[36]
## Cancer
Antioxidants such as vitamin E help protect against the damaging effects of free radicals, which may contribute to the development of chronic diseases such as cancer. Vitamin E also may block the formation of nitrosamines, which are carcinogens formed in the stomach from nitrites consumed in the diet. It also may protect against the development of cancers by enhancing immune function. To date, human trials and surveys that have tried to associate vitamin E with incidence of cancer remain generally inconclusive.
Some evidence associates higher intake of vitamin E with a decreased incidence of prostate cancer (see ATBC study) and breast cancer. Some studies correlate additional cofactors, such as specific vitamin E isomers, e.g. gamma-tocopherol, and other nutrients, e.g. selenium, with dramatic risk reductions in prostate cancer.[37] However, an examination of the effect of dietary factors, including vitamin E, on incidence of postmenopausal breast cancer in over 18,000 women from New York State did not associate a greater vitamin E intake with a reduced risk of developing breast cancer. A study of the effect on lung cancer in smokers also showed no benefit.[38]
A study of women in Iowa provided evidence that an increased dietary intake of vitamin E may decrease the risk of colon cancer, especially in women under 65 years of age. On the other hand, vitamin E intake was not statistically associated with risk of colon cancer in almost 2,000 adults with cancer who were compared to controls without cancer. At this time there is limited evidence to recommend vitamin E supplements for the prevention of cancer.
Recent studies have found that increased intake of vitamin E, especially among smokers may be responsible for an increase in the incidence of lung cancer, with one study finding an increase in the incidence of lung cancer by 7% for each 100IU of vitamin E taken daily.[39][40][41]
## Cataracts
A cataract is a condition of clouding of the tissue of the lens of the eye. They increase the risk of disability and blindness in aging adults. Antioxidants are being studied to determine whether they can help prevent or delay cataract growth. Observational studies have found that lens clarity, which is used to diagnose cataracts, was better in regular users of vitamin E supplements and in persons with higher blood levels of vitamin E. A study of middle aged male smokers, however, did not demonstrate any effect from vitamin E supplements on the incidence of cataract formation. The effects of smoking, a major risk factor for developing cataracts, may have overridden any potential benefit from the vitamin E, but the conflicting results also indicate a need for further studies before researchers can confidently recommend extra vitamin E for the prevention of cataracts.
It is important to note that the term "cataract" may be used in common parlance for an opacity involving any tissue of the eye, for example a corneal scar. Thus a character in theater or on television who is blind from cataracts might have white instead of clear corneas, covering over the iris and pupil. Since the lens is behind the pupil, real cataracts are difficult to see without special instrumentation, so people with cataracts have rather normally appearing eyes.
## Age-related Macular Degeneration (AMD)
Age-related macular degeneration (AMD) is the leading cause of visual impairment and blindness in the United States and the developed world among people 65 years and older. It has been shown that vitamin E alone does not attenuate the development or progression of AMD.[42]
However, studies focusing on efficacy of Vitamin E combined with other antioxidants, like zinc and vitamin C, indicate a protective effect against the onset and progression of AMD[43][44][45]
## Glaucoma
A 2007 study published in the European Journal of Ophthalmology found that, along with other treatments for glaucoma, adding alpha-tocopherol appeared to help protect the retina from glaucomatous damage. Groups receiving 300 mg and 600 mg per day of alpha-tocopherol, delivered orally, showed statistically significant decreases in the resistivity index in the posterior ciliary arteries and in the pulsatility index in the ophthalmic arteries, after six and twelve months of therapy. Alpha-tocopherol-treated patients also had significantly lower differences in mean visual field deviations."[46]
## Alzheimer's Disease
Alzheimer's disease is a wasting disease of the brain. As oxidative stress may be involved in the pathogenesis of Alzheimer's, tocopherols have been tested as both a means of preventing and treating this disease. The results of these studies have been mixed, with some research suggesting that high levels of vitamin E in the diet may reduce the risk of Alzheimer's, while other studies found no such link.[47] Similarly, studies on if tocopherols could slow the progression of Alzheimer's have also been contradictory, with the Alzheimer’s Disease Cooperative Study suggesting that vitamin E supplementation might be beneficial, but a later trial finding no clinical benefit.[48] Due to this contradictory and confusing evidence, vitamin E or tocopherol supplements are not currently recommended for treating or preventing Alzheimer's disease.[49]
## Parkinson's Disease
In May 2005, The Lancet Neurology published a study suggesting that vitamin E may help protect against Parkinson's disease.[50] Individuals with moderate to high intakes of dietary vitamin E were found to have a lower risk of Parkinson's. No conclusion was drawn about whether supplemental vitamin E has the same effect, however.[51]
# Related Chapters
- Alkylresorcinols
# External Links
- US Office of Dietary Supplements article on Vitamin E
- Vitamin E risk assessment, Expert Group on Vitamins and Minerals, UK Food Standards Agency, 2003 | https://www.wikidoc.org/index.php/Alpha-tocopherol | |
fe44d8cf1c0bac47d088f727f81a6aaec9f7804e | wikidoc | Amino acid | Amino acid
# Overview
In chemistry, an amino acid is a molecule that contains both amine and carboxyl functional groups. In biochemistry, this term refers to alpha-amino acids with the general formula H2NCHRCOOH, where R is an organic substituent. In the alpha amino acids, the amino and carboxylate groups are attached to the same carbon, which is called the α–carbon. The various alpha amino acids differ in which side chain (R group) is attached to their alpha carbon. They can vary in size from just a hydrogen atom in glycine, through a methyl group in alanine, to a large heterocyclic group in tryptophan.
Beyond the amino acids that are found in all forms of life, many non-natural amino acids have vital roles in technology and industry. For example, the chelating agents EDTA and nitriloacetic acid are alpha amino acids that are important in the chemical industry.
Alpha-amino acids are the building blocks of proteins. A protein forms via the condensation of amino acids to form a chain of amino acid "residues" linked by peptide bonds. Proteins are defined by their unique sequence of amino acid residues; this sequence is the primary structure of the protein. Just as the letters of the alphabet can be combined to form an almost endless variety of words, amino acids can be linked in varying sequences to form a huge variety of proteins.
Twenty standard amino acids are used by cells in protein biosynthesis, and these are specified by the general genetic code. These twenty amino acids are biosynthesized from other molecules, but organisms differ in which ones they can synthesize and which ones must be provided in their diet. The ones that cannot be synthesized by an organism are called essential amino acids.
## Functions in proteins
Amino acids are the basic structural building units of proteins. They form short polymer chains called peptides or longer chains either called polypeptides or proteins. The process of such formation from an mRNA template is known as translation which is part of protein biosynthesis. Twenty amino acids are encoded by the standard genetic code and are called proteinogenic or standard amino acids. Other amino acids contained in proteins are usually formed by post-translational modification, which is modification after translation in protein synthesis. These modifications are often essential for the function or regulation of a protein; for example, the carboxylation of glutamate allows for better binding of calcium cations, and the hydroxylation of proline is critical for maintaining connective tissues and responding to oxygen starvation. Such modifications can also determine the localization of the protein, e.g., the addition of long hydrophobic groups can cause a protein to bind to a phospholipid membrane.
## Non-protein functions
The twenty standard amino acids are either used to synthesize proteins and other biomolecules, or oxidized to urea and carbon dioxide as a source of energy. The oxidation pathway starts with the removal of the amino group by a transaminase, the amino group is then fed into the urea cycle. The other product of transamidation is a keto acid that enters the citric acid cycle. Glucogenic amino acids can also be converted into glucose, through gluconeogenesis.
Hundreds of types of non-protein amino acids have been found in nature and they have multiple functions in living organisms. Microorganisms and plants can produce uncommon amino acids. In microbes, examples include 2-aminoisobutyric acid and lanthionine, which is a sulfide-bridged alanine dimer. Both these amino acids are both found in peptidic lantibiotics such as alamethicin. While in plants, 1-Aminocyclopropane-1-carboxylic acid is a small disubstituted cyclic amino acid that is a key intermediate in the production of the plant hormone ethylene.
In humans, non-protein amino acids also have biologically-important roles. Glycine, gamma-aminobutyric acid and glutamate are neurotransmitters and many amino acids are used to synthesize other molecules, for example:
- Tryptophan is a precursor of the neurotransmitter serotonin
- Glycine is a precursor of porphyrins such as heme
- Arginine is a precursor of nitric oxide
- Carnitine is used in lipid transport within a cell,
- Ornithine and S-adenosylmethionine are precursors of polyamines,
- Homocysteine is an intermediate in S-adenosylmethionine recycling
Also present are hydroxyproline, hydroxylysine, and sarcosine. The thyroid hormones are also alpha-amino acids.
Some amino acids have even been detected in meteorites, especially in a type known as carbonaceous chondrites. This observation has prompted the suggestion that life may have arrived on earth from an extraterrestrial source.
# General structure
In the structure shown to the right, the R represents a side chain specific to each amino acid. The central carbon atom called Cα is a chiral central carbon atom (with the exception of glycine) to which the two termini and the R-group are attached. Amino acids are usually classified by the properties of the side chain into four groups. The side chain can make them behave like a weak acid, a weak base, a hydrophile if they are polar, and hydrophobe if they are nonpolar. The chemical structures of the 20 standard amino acids, along with their chemical properties, are catalogued in the list of standard amino acids.
The phrase "branched-chain amino acids" or BCAA is sometimes used to refer to the amino acids having aliphatic side-chains that are non-linear, these are leucine, isoleucine and valine. Proline is the only proteinogenic amino acid whose side group links to the α-amino group, and thus is also the only proteinogenic amino acid containing a secondary amine at this position. Proline has sometimes been termed an imino acid, but this is not correct in the current nomenclature.
## Isomerism
Most amino acids can exist in either of two optical isomers, called D and L. The L-amino acids represent the vast majority of amino acids found in proteins. D-amino acids are found in some proteins produced by exotic sea-dwelling organisms, such as cone snails. They are also abundant components of the peptidoglycan cell walls of bacteria.
The L and D conventions for amino acid configuration do not refer to the optical activity of the amino acid itself, but rather to the optical activity of the isomer of glyceraldehyde having the same stereochemistry as the amino acid. S-Glyceraldehyde is levorotary, and R-glyceraldehyde is dexterorotary, and so S-amino acids are called L- even if they are not levorotary, and R-amino acids are likewise called D- even if they are not dexterorotary.
There are two exceptions to these general rules of amino acid isomerism. Firstly, glycine, where R = H, no isomerism is possible because the alpha-carbon bears two identical groups (hydrogen). Secondly, in cysteine, the L = S and D = R assignment is reversed to L = R and D = S. Cysteine is structured similarly (with respect to glyceraldehyde) to the other amino acids but the sulfur atom alters the interpretation of the Cahn-Ingold-Prelog priority rule.
# Reactions
As amino acids have both a primary amine group and a primary carboxyl group, these chemicals can undergo most of the reactions associated with these functional groups. These include nucleophilic addition, amide bond formation and imine formation for the amine group and esterification, amide bond formation and decarboxylation for the carboxylic acid group. The multiple side chains of amino acids can also undergo chemical reactions. The types of these reactions are determined by the groups on these side chains and are discussed in the articles dealing with each specific type of amino acid.
## Peptide bond formation
As both the amine and carboxylic acid groups of amino acids can react to form amide bonds, one amino acid molecule can react with another and become joined through an amide linkage. This polymerization of amino acids is what creates proteins. This condensation reaction yields the newly formed peptide bond and a molecule of water. In cells, this reaction does not occur directly, instead the amino acid is activated by attachment to a transfer RNA molecule through an ester bond. This aminoacyl-tRNA is produced in an ATP-dependent reaction carried out by an aminoacyl tRNA synthetase. This aminoacyl-tRNA is then a substrate for the ribosome, which catalyzes the attack of the amino group of the elongating protein chain on the ester bond. As a result of this mechanism, all proteins are synthesized starting at their N-terminus and moving towards their C-terminus.
However, not all peptide bonds are formed in this way. In a few cases peptides are synthesized by specific enzymes. For example, the tripeptide glutathione is an essential part of the defenses of cells against oxidative stress. This peptide is synthesized in two steps from free amino acids. In the first step gamma-glutamylcysteine synthetase condenses cysteine and glutamic acid through a peptide bond formed between the side-chain carboxyl of the glutamate (the gamma carbon of this side chain) and the amino group of the cysteine. This dipeptide is then condensed with glycine by glutathione synthetase to form glutathione.
In chemistry, peptides are synthesized by a variety of reactions. One of the most used in solid-phase peptide synthesis, which uses the aromatic oxime derivatives of amino acids as activated units. These are added in sequence onto the growing peptide chain, which is attached to a solid resin support.
## Zwitterions
As amino acids have both the active groups of an amine and a carboxylic acid they can be considered both acid and base (though their natural pH is usually influenced by the R group). At a certain pH known as the isoelectric point, the amine group gains a positive charge (is protonated) and the acid group a negative charge (is deprotonated). The exact value is specific to each different amino acid. This ion is known as a zwitterion, which comes from the German word Zwitter meaning "hybrid". A zwitterion can be extracted from the solution as a white crystalline structure with a very high melting point, due to its dipolar nature. Near-neutral physiological pH allows most free amino acids to exist as zwitterions.
# Hydrophilic and hydrophobic amino acids
Depending on the polarity of the side chain, amino acids vary in their hydrophilic or hydrophobic character. These properties are important in protein structure and protein-protein interactions. The importance of the physical properties of the side chains comes from the influence this has on the amino acid residues' interactions with other structures, both within a single protein and between proteins. The distribution of hydrophilic and hydrophobic amino acids determines the tertiary structure of the protein, and their physical location on the outside structure of the proteins influences their quaternary structure. For example, soluble proteins have surfaces rich with polar amino acids like serine and threonine, while integral membrane proteins tend to have outer ring of hydrophobic amino acids that anchors them into the lipid bilayer, and proteins anchored to the membrane have a hydrophobic end that locks into the membrane. Similarly, proteins that have to bind to positively-charged molecules have surfaces rich with negatively charged amino acids like glutamate and aspartate, while proteins binding to negatively-charged molecules have surfaces rich with positively charged chains like lysine and arginine. Recently a new scale of hydrophobicity based on the free energy of hydrophobic association has been proposed.
Hydrophilic and hydrophobic interactions of the proteins do not have to rely only on the sidechains of amino acids themselves. By various posttranslational modifications other chains can be attached to the proteins, forming hydrophobic lipoproteins or hydrophilic glycoproteins.
# Table of standard amino acid abbreviations and side chain properties
In addition to the normal amino acid codes, placeholders were used historically in cases where chemical or crystallographic analysis of a peptide or protein could not completely establish the identity of a certain residue in a structure. The ones they could not resolve between are these pairs of amino-acids:
Unk is sometimes used instead of Xaa, but is less standard.
# Nonstandard amino acids
Aside from the twenty standard amino acids, there are a vast number of "non-standard" amino acids. Two of these can be specified by the genetic code, but are rather rare in proteins. Selenocysteine is incorporated into some proteins at a UGA codon, which is normally a stop codon. Pyrrolysine is used by some methanogenic archaea in enzymes that they use to produce methane. It is coded for with the codon UAG.
Examples of nonstandard amino acids that are not found in proteins include lanthionine, 2-aminoisobutyric acid, dehydroalanine and the neurotransmitter gamma-aminobutyric acid. Nonstandard amino acids often occur as intermediates in the metabolic pathways for standard amino acids — for example ornithine and citrulline occur in the urea cycle, part of amino acid catabolism.
Nonstandard amino acids are usually formed through modifications to standard amino acids. For example, homocysteine is formed through the transsulfuration pathway or by the demethylation of methionine via the intermediate metabolite S-adenosyl methionine, while dopamine is synthesized from l-DOPA, and hydroxyproline is made by a posttranslational modification of proline.
# Uses in technology
# Nutritional importance
Of the 20 standard proteinogenic amino acids, 8 are called essential amino acids because the human body cannot synthesize them from other compounds at the level needed for normal growth, so they must be obtained from food. However, the situation is a little more complicated since cysteine, tyrosine, histidine and arginine are semiessential amino acids in children, because the metabolic pathways that synthesize these amino acids are not fully developed. The amounts required also depend on the age and health of the individual, so it is hard to make general statements about the dietary requirement for some amino acids.
(*) Essential only in certain cases.
Several common mnemonics have evolved for remembering the ten amino acids often described as essential. PVT TIM HALL ("Private Tim Hall") uses the first letter of each of these amino acids. Another mnemonic that frequently occurs in student practice materials beneath "TV TILL Past Midnight", which just includes the 8 essential amino acids, is "These ten valuable amino acids have long preserved life in man". | Amino acid
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Template:Otheruses4
# Overview
In chemistry, an amino acid is a molecule that contains both amine and carboxyl functional groups. In biochemistry, this term refers to alpha-amino acids with the general formula H2NCHRCOOH, where R is an organic substituent.[1] In the alpha amino acids, the amino and carboxylate groups are attached to the same carbon, which is called the α–carbon. The various alpha amino acids differ in which side chain (R group) is attached to their alpha carbon. They can vary in size from just a hydrogen atom in glycine, through a methyl group in alanine, to a large heterocyclic group in tryptophan.
Beyond the amino acids that are found in all forms of life, many non-natural amino acids have vital roles in technology and industry. For example, the chelating agents EDTA and nitriloacetic acid are alpha amino acids that are important in the chemical industry.
Alpha-amino acids are the building blocks of proteins. A protein forms via the condensation of amino acids to form a chain of amino acid "residues" linked by peptide bonds. Proteins are defined by their unique sequence of amino acid residues; this sequence is the primary structure of the protein. Just as the letters of the alphabet can be combined to form an almost endless variety of words, amino acids can be linked in varying sequences to form a huge variety of proteins.
Twenty standard amino acids are used by cells in protein biosynthesis, and these are specified by the general genetic code. These twenty amino acids are biosynthesized from other molecules, but organisms differ in which ones they can synthesize and which ones must be provided in their diet. The ones that cannot be synthesized by an organism are called essential amino acids.
## Functions in proteins
Amino acids are the basic structural building units of proteins. They form short polymer chains called peptides or longer chains either called polypeptides or proteins. The process of such formation from an mRNA template is known as translation which is part of protein biosynthesis. Twenty amino acids are encoded by the standard genetic code and are called proteinogenic or standard amino acids. Other amino acids contained in proteins are usually formed by post-translational modification, which is modification after translation in protein synthesis. These modifications are often essential for the function or regulation of a protein; for example, the carboxylation of glutamate allows for better binding of calcium cations, and the hydroxylation of proline is critical for maintaining connective tissues and responding to oxygen starvation. Such modifications can also determine the localization of the protein, e.g., the addition of long hydrophobic groups can cause a protein to bind to a phospholipid membrane.
## Non-protein functions
The twenty standard amino acids are either used to synthesize proteins and other biomolecules, or oxidized to urea and carbon dioxide as a source of energy.[2] The oxidation pathway starts with the removal of the amino group by a transaminase, the amino group is then fed into the urea cycle. The other product of transamidation is a keto acid that enters the citric acid cycle.[3] Glucogenic amino acids can also be converted into glucose, through gluconeogenesis.[4]
Hundreds of types of non-protein amino acids have been found in nature and they have multiple functions in living organisms. Microorganisms and plants can produce uncommon amino acids. In microbes, examples include 2-aminoisobutyric acid and lanthionine, which is a sulfide-bridged alanine dimer. Both these amino acids are both found in peptidic lantibiotics such as alamethicin.[5] While in plants, 1-Aminocyclopropane-1-carboxylic acid is a small disubstituted cyclic amino acid that is a key intermediate in the production of the plant hormone ethylene.[6]
In humans, non-protein amino acids also have biologically-important roles. Glycine, gamma-aminobutyric acid and glutamate are neurotransmitters and many amino acids are used to synthesize other molecules, for example:
- Tryptophan is a precursor of the neurotransmitter serotonin
- Glycine is a precursor of porphyrins such as heme
- Arginine is a precursor of nitric oxide
- Carnitine is used in lipid transport within a cell,
- Ornithine and S-adenosylmethionine are precursors of polyamines,
- Homocysteine is an intermediate in S-adenosylmethionine recycling
Also present are hydroxyproline, hydroxylysine, and sarcosine. The thyroid hormones are also alpha-amino acids.
Some amino acids have even been detected in meteorites, especially in a type known as carbonaceous chondrites.[7] This observation has prompted the suggestion that life may have arrived on earth from an extraterrestrial source.
# General structure
In the structure shown to the right, the R represents a side chain specific to each amino acid. The central carbon atom called Cα is a chiral central carbon atom (with the exception of glycine) to which the two termini and the R-group are attached. Amino acids are usually classified by the properties of the side chain into four groups. The side chain can make them behave like a weak acid, a weak base, a hydrophile if they are polar, and hydrophobe if they are nonpolar. The chemical structures of the 20 standard amino acids, along with their chemical properties, are catalogued in the list of standard amino acids.
The phrase "branched-chain amino acids" or BCAA is sometimes used to refer to the amino acids having aliphatic side-chains that are non-linear, these are leucine, isoleucine and valine. Proline is the only proteinogenic amino acid whose side group links to the α-amino group, and thus is also the only proteinogenic amino acid containing a secondary amine at this position. Proline has sometimes been termed an imino acid, but this is not correct in the current nomenclature.[8]
## Isomerism
Most amino acids can exist in either of two optical isomers, called D and L. The L-amino acids represent the vast majority of amino acids found in proteins. D-amino acids are found in some proteins produced by exotic sea-dwelling organisms, such as cone snails.[9] They are also abundant components of the peptidoglycan cell walls of bacteria.[10]
The L and D conventions for amino acid configuration do not refer to the optical activity of the amino acid itself, but rather to the optical activity of the isomer of glyceraldehyde having the same stereochemistry as the amino acid. S-Glyceraldehyde is levorotary, and R-glyceraldehyde is dexterorotary, and so S-amino acids are called L- even if they are not levorotary, and R-amino acids are likewise called D- even if they are not dexterorotary.
There are two exceptions to these general rules of amino acid isomerism. Firstly, glycine, where R = H, no isomerism is possible because the alpha-carbon bears two identical groups (hydrogen). Secondly, in cysteine, the L = S and D = R assignment is reversed to L = R and D = S. Cysteine is structured similarly (with respect to glyceraldehyde) to the other amino acids but the sulfur atom alters the interpretation of the Cahn-Ingold-Prelog priority rule.
# Reactions
As amino acids have both a primary amine group and a primary carboxyl group, these chemicals can undergo most of the reactions associated with these functional groups. These include nucleophilic addition, amide bond formation and imine formation for the amine group and esterification, amide bond formation and decarboxylation for the carboxylic acid group. The multiple side chains of amino acids can also undergo chemical reactions. The types of these reactions are determined by the groups on these side chains and are discussed in the articles dealing with each specific type of amino acid.
## Peptide bond formation
As both the amine and carboxylic acid groups of amino acids can react to form amide bonds, one amino acid molecule can react with another and become joined through an amide linkage. This polymerization of amino acids is what creates proteins. This condensation reaction yields the newly formed peptide bond and a molecule of water. In cells, this reaction does not occur directly, instead the amino acid is activated by attachment to a transfer RNA molecule through an ester bond. This aminoacyl-tRNA is produced in an ATP-dependent reaction carried out by an aminoacyl tRNA synthetase.[11] This aminoacyl-tRNA is then a substrate for the ribosome, which catalyzes the attack of the amino group of the elongating protein chain on the ester bond.[12] As a result of this mechanism, all proteins are synthesized starting at their N-terminus and moving towards their C-terminus.
However, not all peptide bonds are formed in this way. In a few cases peptides are synthesized by specific enzymes. For example, the tripeptide glutathione is an essential part of the defenses of cells against oxidative stress. This peptide is synthesized in two steps from free amino acids.[13] In the first step gamma-glutamylcysteine synthetase condenses cysteine and glutamic acid through a peptide bond formed between the side-chain carboxyl of the glutamate (the gamma carbon of this side chain) and the amino group of the cysteine. This dipeptide is then condensed with glycine by glutathione synthetase to form glutathione.[14]
In chemistry, peptides are synthesized by a variety of reactions. One of the most used in solid-phase peptide synthesis, which uses the aromatic oxime derivatives of amino acids as activated units. These are added in sequence onto the growing peptide chain, which is attached to a solid resin support.[15]
## Zwitterions
As amino acids have both the active groups of an amine and a carboxylic acid they can be considered both acid and base (though their natural pH is usually influenced by the R group). At a certain pH known as the isoelectric point, the amine group gains a positive charge (is protonated) and the acid group a negative charge (is deprotonated). The exact value is specific to each different amino acid. This ion is known as a zwitterion, which comes from the German word Zwitter meaning "hybrid". A zwitterion can be extracted from the solution as a white crystalline structure with a very high melting point, due to its dipolar nature. Near-neutral physiological pH allows most free amino acids to exist as zwitterions.
# Hydrophilic and hydrophobic amino acids
Depending on the polarity of the side chain, amino acids vary in their hydrophilic or hydrophobic character. These properties are important in protein structure and protein-protein interactions. The importance of the physical properties of the side chains comes from the influence this has on the amino acid residues' interactions with other structures, both within a single protein and between proteins. The distribution of hydrophilic and hydrophobic amino acids determines the tertiary structure of the protein, and their physical location on the outside structure of the proteins influences their quaternary structure. For example, soluble proteins have surfaces rich with polar amino acids like serine and threonine, while integral membrane proteins tend to have outer ring of hydrophobic amino acids that anchors them into the lipid bilayer, and proteins anchored to the membrane have a hydrophobic end that locks into the membrane. Similarly, proteins that have to bind to positively-charged molecules have surfaces rich with negatively charged amino acids like glutamate and aspartate, while proteins binding to negatively-charged molecules have surfaces rich with positively charged chains like lysine and arginine. Recently a new scale of hydrophobicity based on the free energy of hydrophobic association has been proposed.[16]
Hydrophilic and hydrophobic interactions of the proteins do not have to rely only on the sidechains of amino acids themselves. By various posttranslational modifications other chains can be attached to the proteins, forming hydrophobic lipoproteins or hydrophilic glycoproteins.
# Table of standard amino acid abbreviations and side chain properties
In addition to the normal amino acid codes, placeholders were used historically in cases where chemical or crystallographic analysis of a peptide or protein could not completely establish the identity of a certain residue in a structure. The ones they could not resolve between are these pairs of amino-acids:
Unk is sometimes used instead of Xaa, but is less standard.
# Nonstandard amino acids
Aside from the twenty standard amino acids, there are a vast number of "non-standard" amino acids. Two of these can be specified by the genetic code, but are rather rare in proteins. Selenocysteine is incorporated into some proteins at a UGA codon, which is normally a stop codon.[18] Pyrrolysine is used by some methanogenic archaea in enzymes that they use to produce methane. It is coded for with the codon UAG.[19]
Examples of nonstandard amino acids that are not found in proteins include lanthionine, 2-aminoisobutyric acid, dehydroalanine and the neurotransmitter gamma-aminobutyric acid. Nonstandard amino acids often occur as intermediates in the metabolic pathways for standard amino acids — for example ornithine and citrulline occur in the urea cycle, part of amino acid catabolism.[20]
Nonstandard amino acids are usually formed through modifications to standard amino acids. For example, homocysteine is formed through the transsulfuration pathway or by the demethylation of methionine via the intermediate metabolite S-adenosyl methionine, [21] while dopamine is synthesized from l-DOPA, and hydroxyproline is made by a posttranslational modification of proline.[22]
# Uses in technology
# Nutritional importance
Of the 20 standard proteinogenic amino acids, 8 are called essential amino acids because the human body cannot synthesize them from other compounds at the level needed for normal growth, so they must be obtained from food.[23] However, the situation is a little more complicated since cysteine, tyrosine, histidine and arginine are semiessential amino acids in children, because the metabolic pathways that synthesize these amino acids are not fully developed.[24] The amounts required also depend on the age and health of the individual, so it is hard to make general statements about the dietary requirement for some amino acids.
(*) Essential only in certain cases.[25][26]
Several common mnemonics have evolved for remembering the ten amino acids often described as essential. PVT TIM HALL ("Private Tim Hall") uses the first letter of each of these amino acids.[27] Another mnemonic that frequently occurs in student practice materials beneath "TV TILL Past Midnight", which just includes the 8 essential amino acids, is "These ten valuable amino acids have long preserved life in man".[28] | https://www.wikidoc.org/index.php/Alpha_amino_acid | |
8388264cb403c3448f1c25de4e94e2781f3cdedb | wikidoc | Altanserin | Altanserin
Altanserin is a compound that binds to the 5-HT2A receptor (serotonin 2A receptor).
It is a yellowish solid.
Labeled with the isotope fluorine-18 it is used as a radioligand in positron emission tomography (PET) studies of the brain, i.e., studies of the serotonin-2A neuroreceptors.
Besides human neuroimaging studies altanserin has also been used in the study of rats.
An alternative for PET imaging the 5-HT2A receptor is the
MDL 100,907 radioligand.
Fluorine-18-altanserin and tritium-MDL 100,907 have shown very comparable binding.
Both altanserin and MDL 100,907 are 5-HT2A receptor antagonists.
-setoperone can also be used in PET.
An alternative SPECT radioligand is the -5-I-R91150 receptor antagonist.
A rapid chemical synthesis of fluorine-18 and H-2 dual-labeled altanserin has been described.
Other ligands for other parts of the serotonin system used in PET studies are, e.g., DASB, ketanserin and WAY-100635.
# Human brain mapping studies with altanserin
As of 2007 altanserin is probably not used in clinical routine.
However, there have been performed several research-based neuroimaging studies with the compound in humans since the 1990s.
Some of these studies have considered methodogical issues such as the reproducibility of the method
-r whether to use constant infusion or bolus-infusion delivery of altanserin.
Other studies have compared altanserin binding to subject variables such as age, personality trait and neuropsychiatric disorder.
The altanserin PET scan shows high binding in neocortex.
The cerebellum is often regarded as a region with no specific 5-HT2A binding and the brain region is used as a reference in some studies, even though an autoradiography study has found nonnegligible levels of 5-HT2A binding in the human cerebellum,
and another type of study have observed strong immunoreaction against 5-HT2A receptor protein in rat Purkinje cells.
In the table below is an overview of the results of altanserin binding seen in human PET-studies.
A consistent finding across altanserin studies has been that the binding decreases with age.
This is in line with in vitro studies of the 5-HT2A receptor,
as well as PET studies with other radioligands that binds to the receptor.
The result for recovered bulimia-type anorexia nervosa
is in line with a SPECT study of anorexia nervosa patients, that found a decrease in frontal, occipital and parietal cortices.
The results of PET studies of the 5-HT2A in depression has been mixed.
Altanserin binding has also been examine in twins, where one study showed higher correlation between monozygotic twin pairs than between dizygotic twin pairs, giving evidence that the binding is "strongly genetically determined". | Altanserin
Altanserin is a compound that binds to the 5-HT2A receptor (serotonin 2A receptor).
It is a yellowish solid.[1]
Labeled with the isotope fluorine-18 it is used as a radioligand in positron emission tomography (PET) studies of the brain, i.e., studies of the serotonin-2A neuroreceptors.
Besides human neuroimaging studies altanserin has also been used in the study of rats.[2][3]
An alternative for PET imaging the 5-HT2A receptor is the
[11C]MDL 100,907 radioligand.
Fluorine-18-altanserin and tritium-MDL 100,907 have shown very comparable binding.[4]
Both altanserin and MDL 100,907 are 5-HT2A receptor antagonists.[4]
[18F]-setoperone can also be used in PET.
An alternative SPECT radioligand is the [123I]-5-I-R91150 receptor antagonist.[5]
A rapid chemical synthesis of fluorine-18 and H-2 dual-labeled altanserin has been described.[6]
Other ligands for other parts of the serotonin system used in PET studies are, e.g., DASB, ketanserin and WAY-100635.
# Human brain mapping studies with altanserin
As of 2007[update] altanserin is probably not used in clinical routine.
However, there have been performed several research-based neuroimaging studies with the compound in humans since the 1990s.[7][8]
Some of these studies have considered methodogical issues such as the reproducibility of the method[9][10]
or whether to use constant infusion[11] or bolus-infusion[12] delivery of altanserin.
Other studies have compared altanserin binding to subject variables such as age, personality trait and neuropsychiatric disorder.
The altanserin PET scan shows high binding in neocortex.
The cerebellum is often regarded as a region with no specific 5-HT2A binding and the brain region is used as a reference in some studies, even though an autoradiography study has found nonnegligible levels of 5-HT2A binding in the human cerebellum,[13]
and another type of study have observed strong immunoreaction against 5-HT2A receptor protein in rat Purkinje cells.[14]
In the table below is an overview of the results of altanserin binding seen in human PET-studies.
A consistent finding across altanserin studies has been that the binding decreases with age.
This is in line with in vitro studies of the 5-HT2A receptor,[15]
as well as PET studies with other radioligands that binds to the receptor.[16]
The result for recovered bulimia-type anorexia nervosa[17]
is in line with a SPECT study of anorexia nervosa patients, that found a decrease in frontal, occipital and parietal cortices.[5]
The results of PET studies of the 5-HT2A in depression has been mixed.[18]
Altanserin binding has also been examine in twins, where one study showed higher correlation between monozygotic twin pairs than between dizygotic twin pairs, giving evidence that the binding is "strongly genetically determined".[19] | https://www.wikidoc.org/index.php/Altanserin | |
56fd93fb56c4de70a9670a565fb79e8e17d5cd45 | wikidoc | Amantadine | Amantadine
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# Overview
Amantadine is a adamantane, anticholinergic and antiparkinsonian agent that is FDA approved for the treatment of Influenza A, Influenza A prophylaxis, Parkinson's syndrome, drug-Induced extrapyramidal reactions. Common adverse reactions include orthostatic hypotension, peripheral edema, constipation, diarrhea, loss of appetite, nausea, xerostomia, ataxia, confusion, dizziness, headache, insomnia, somnolence, agitation, anxiety, depression. dream disorder, feeling nervous, hallucinations, irritability and fatigue..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Amantadine hydrochloride capsules are indicated for the prophylaxis and treatment of signs and symptoms of infection caused by various strains of influenza A virus. Amantadine hydrochloride capsules are also indicated in the treatment of parkinsonism and drug-Induced extrapyramidal reactions.
- Amantadine hydrochloride capsules are indicated for chemoprophylaxis against signs and symptoms of influenza A virus infection. Because amantadine does not completely prevent the host immune response to influenza A infection, individuals who take this drug may still develop immune responses to natural disease or vaccination and may be protected when later exposed to antigenically related viruses. Following vaccination during an influenza A outbreak, amantadine prophylaxis should be considered for the 2- to 4-week time period required to develop an antibody response.
- Amantadine hydrochloride capsules are also indicated in the treatment of uncomplicated respiratory tract illness caused by influenza A virus strains especially when administered early in the course of illness. There are no well-controlled clinical studies demonstrating that treatment with amantadine hydrochloride capsules will avoid the development of influenza A virus pneumonitis or other complications in high risk patients.
- There is no clinical evidence indicating that amantadine hydrochloride capsules are effective in the prophylaxis or treatment of viral respiratory tract illnesses other than those caused by influenza A virus strains.
- The following points should be considered before initiating treatment or prophylaxis with amantadine hydrochloride capsules.
- Amantadine hydrochloride capsules are not a substitute for early vaccination on an annual basis as recommended by the Centers for Disease Control and Prevention Advisory Committee on Immunization Practices.
- Influenza viruses change over time. Emergence of resistance mutations could decrease drug effectiveness. Other factors (for example, changes in viral virulence) might also diminish clinical benefit of antiviral drugs. Prescribers should consider available information on influenza drug susceptibility patterns and treatment effects when deciding whether to use amantadine hydrochloride capsules.
- Amantadine hydrochloride capsules are indicated in the treatment of idiopathic Parkinson’s disease (Paralysis Agitans), postencephalitic parkinsonism and symptomatic parkinsonism which may follow injury to the nervous system by carbon monoxide intoxication. It is indicated in those elderly patients believed to develop parkinsonism in association with cerebral arteriosclerosis. In the treatment of Parkinson’s disease, amantadine is less effective than levodopa, (-)-3-(3,4-dihydroxyphenyl)-L-alanine, and its efficacy in comparison with the anticholinergic antiparkinson drugs has not yet been established.
- Amantadine hydrochloride is indicated in the treatment of drug-induced extrapyramidal reactions. Although anticholinergic-type side effects have been noted with amantadine when used in patients with drug-induced extrapyramidal reactions, there is a lower incidence of these side effects than that observed with the anticholinergic antiparkinson drugs.
- The dose of amantadine hydrochloride capsules may need reduction in patients with congestive heart failure, peripheral edema, orthostatic hypotension, or impaired renal function.
- The adult daily dosage of amantadine hydrochloride capsules is 200 mg; two 100 mg capsules as a single daily dose. The daily dosage may be split into one capsule of 100 mg twice a day. If central nervous system effects develop in once-a-day dosage, a split dosage schedule may reduce such complaints. In persons 65 years of age or older, the daily dosage of amantadine hydrochloride capsules is 100 mg.
- A 100 mg daily dose has also been shown in experimental challenge studies to be effective as prophylaxis in healthy adults who are not at high risk for influenza-related complications. However, it has not been demonstrated that a 100 mg daily dose is as effective as a 200 mg daily dose for prophylaxis, nor has the 100 mg daily dose been studied in the treatment of acute influenza illness. In recent clinical trials, the incidence of central nervous system (CNS) side effects associated with the 100 mg daily dose was at or near the level of placebo. The 100 mg dose is recommended for persons who have demonstrated intolerance to 200 mg of amantadine hydrochloride daily because of CNS or other toxicities.
- The usual dose of amantadine hydrochloride capsules is 100 mg twice a day when used alone. Amantadine has an onset of action usually within 48 hours.
- The initial dose of amantadine hydrochloride capsules is 100 mg daily for patients with serious associated medical illnesses or who are receiving high doses of other antiparkinson drugs. After one to several weeks at 100 mg once daily, the dose may be increased to 100 mg twice daily, if necessary.
- Occasionally, patients whose responses are not optimal with amantadine hydrochloride capsules at 200 mg daily may benefit from an increase up to 400 mg daily in divided doses. However, such patients should be supervised closely by their physicians.
- Patients initially deriving benefit from amantadine hydrochloride capsules not uncommonly experience a fall-off of effectiveness after a few months. Benefit may be regained by increasing the dose to 300 mg daily. Alternatively, temporary discontinuation of amantadine hydrochloride capsules for several weeks, followed by reinitiation of the drug, may result in regaining benefit in some patients. A decision to use other antiparkinson drugs may be necessary.
- Some patients who do not respond to anticholinergic antiparkinson drugs may respond to amantadine hydrochloride capsules. When amantadine hydrochloride capsules or anticholinergic antiparkinson drugs are each used with marginal benefit, concomitant use may produce additional benefit.
- When amantadine and levodopa are initiated concurrently, the patient can exhibit rapid therapeutic benefits. Amantadine hydrochloride capsules should be held constant at 100 mg daily or twice daily while the daily dose of levodopa is gradually increased to optimal benefit.
- When amantadine is added to optimal well-tolerated doses of levodopa, additional benefit may result, including smoothing out the fluctuations in improvement which sometimes occur in patients on levodopa alone. Patients who require a reduction in their usual dose of levodopa because of development of side effects may possibly regain lost benefit with the addition of amantadine hydrochloride capsules.
- The usual dose of amantadine hydrochloride capsules is 100 mg twice a day. Occasionally, patients whose responses are not optimal with amantadine hydrochloride capsules at 200 mg daily may benefit from an increase up to 300 mg daily in divided doses.
- Depending upon creatinine clearance, the following dosage adjustments are recommended:
- The recommended dosage for patients on hemodialysis is 200 mg every 7 days.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- Brain injury
- Cocaine withdrawal
- Drug-induced dyskinesia - Levodopa adverse reaction
- Hepatitis C, chronic
- Nocturnal enuresis
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Amantadine hydrochloride in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- The total daily dose should be calculated on the basis of 2 to 4 mg/lb/day (4.4 to 8.8 mg/kg/day), but not to exceed 150 mg per day.
- The total daily dose is 200 mg given as one capsule of 100 mg twice a day. The 100 mg daily dose has not been studied in this pediatric population. Therefore, there are no data which demonstrate that this dose is as effective as or is safer than the 200 mg daily dose in this patient population.
- Prophylactic dosing should be started in anticipation of an influenza A outbreak and before or after contact with individuals with influenza A virus respiratory tract illness.
- Amantadine hydrochloride capsules should be continued daily for at least 10 days following a known exposure. If amantadine is used chemoprophylactically in conjunction with inactivated influenza A virus vaccine until protective antibody responses develop, then it should be administered for 2 to 4 weeks after the vaccine has been given. When inactivated influenza A virus vaccine is unavailable or contraindicated, amantadine hydrochloride capsules should be administered for the duration of known influenza A in the community because of repeated and unknown exposure.
- Treatment of influenza A virus illness should be started as soon as possible, preferably within 24 to 48 hours after onset of signs and symptoms, and should be continued for 24 to 48 hours after the disappearance of signs and symptoms.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Amantadine hydrochloride in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Amantadine hydrochloride in pediatric patients.
# Contraindications
- Amantadine hydrochloride capsules, USP are contraindicated in patients with known hypersensitivity to amantadine hydrochloride or to any of the other ingredients in Amantadine hydrochloride capsules, USP.
# Warnings
### Deaths=
- Deaths have been reported from overdose with amantadine. The lowest reported acute lethal dose was 1 gram. Acute toxicity may be attributable to the anticholinergic effects of amantadine. Drug overdose has resulted in cardiac, respiratory, renal or central nervous system toxicity. Cardiac dysfunction includes arrhythmia, tachycardia and hypertension.
- Suicide attempts, some of which have been fatal, have been reported in patients treated with amantadine, many of whom received short courses for influenza treatment or prophylaxis. The incidence of suicide attempts is not known and the pathophysiologic mechanism is not understood. Suicide attempts and suicidal ideation have been reported in patients with and without prior history of psychiatric illness. Amantadine can exacerbate mental problems in patients with a history of psychiatric disorders or substance abuse. Patients who attempt suicide may exhibit abnormal mental states which include disorientation, confusion, depression, personality changes, agitation, aggressive behavior, hallucinations, paranoia, other psychotic reactions and somnolence or insomnia. Because of the possibility of serious adverse effects, caution should be observed when prescribing amantadine hydrochloride capsules to patients being treated with drugs having CNS effects, or for whom the potential risks outweigh the benefit of treatment.
- Patients with a history of epilepsy or other “seizures” should be observed closely for possible increased seizure activity.
- Patients receiving amantadine hydrochloride capsules who note central nervous system effects or blurring of vision should be cautioned against driving or working in situations where alertness and adequate motor coordination are important.
- Patients with a history of congestive heart failure or peripheral edema should be followed closely as there are patients who developed congestive heart failure while receiving amantadine hydrochloride capsules.
- Patients with Parkinson’s disease improving on amantadine hydrochloride capsules should resume normal activities gradually and cautiously, consistent with other medical considerations, such as the presence of osteoporosis or phlebothrombosis.
- Because Amantadine Hydrochloride Capsules, USP has anticholinergic effects and may cause mydriasis, it should not be given to patients with untreated angle closure glaucoma.
- Amantadine should not be discontinued abruptly in patients with Parkinson’s disease since a few patients have experienced a parkinsonian crisis, i.e., a sudden marked clinical deterioration, when this medication was suddenly stopped. The dose of anticholinergic drugs or of amantadine should be reduced if atropine-like effects appear when these drugs are used concurrently. Abrupt discontinuation may also precipitate delirium, agitation, delusions, hallucinations, paranoid reaction, stupor, anxiety, depression and slurred speech.
- Sporadic cases of possible Neuroleptic Malignant Syndrome (NMS) have been reported in association with dose reduction or withdrawal of amantadine therapy. Therefore, patients should be observed carefully when the dosage of amantadine is reduced abruptly or discontinued, especially if the patient is receiving neuroleptics.
- NMS is an uncommon but life-threatening syndrome characterized by fever or hyperthermia; neurologic findings including muscle rigidity, involuntary movements, altered consciousness; mental status changes; other disturbances such as autonomic dysfunction, tachycardia, tachypnea, hyper- or hypotension; laboratory findings such as creatine phosphokinase elevation, leukocytosis, myoglobinuria, and increased serum myoglobin.
- The early diagnosis of this condition is important for the appropriate management of these patients. Considering NMS as a possible diagnosis and ruling out other acute illnesses (e.g., pneumonia, systemic infection, etc.) is essential. This may be especially complex if the clinical presentation includes both serious medical illness and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology.
- The management of NMS should include: 1) intensive symptomatic treatment and medical monitoring, and 2) treatment of any concomitant serious medical problems for which specific treatments are available. Dopamine agonists, such as bromocriptine, and muscle relaxants, such as dantrolene are often used in the treatment of NMS, however, their effectiveness has not been demonstrated in controlled studies.
# Adverse Reactions
## Clinical Trials Experience
- The adverse reactions reported most frequently at the recommended dose of amantadine (5 to 10%) are: nausea, dizziness (lightheadedness), and insomnia.
- Less frequently (1 to 5%) reported adverse reactions are: depression, anxiety and irritability, hallucinations, confusion, anorexia, dry mouth, constipation, ataxia, livedo reticularis, peripheral edema, orthostatic hypotension, headache, somnolence, nervousness, dream abnormality, agitation, dry nose, diarrhea and fatigue.
- Infrequently (0.1 to 1%) occurring adverse reactions are: congestive heart failure, psychosis, urinary retention, dyspnea, skin rash, vomiting, weakness, slurred speech, euphoria, thinking abnormality, amnesia, hyperkinesia, hypertension, decreased libido, and visual disturbance, including punctate subepithelial or other corneal opacity, corneal edema, decreased visual acuity, sensitivity to light, and optic nerve palsy.
- Rare (less than 0.1%) occurring adverse reactions are: instances of convulsion, leukopenia, neutropenia, eczematoid dermatitis, oculogyric episodes, suicidal attempt, suicide, and suicidal ideation.
- Other adverse reactions reported during postmarketing experience with amantadine usage include:
- Coma, stupor, delirium, hypokinesia, hypertonia, delusions, aggressive behavior, paranoid reaction, manic reaction, involuntary muscle contractions, gait abnormalities, paresthesia, EEG changes, and tremor. Abrupt discontinuation may also precipitate delirium, agitation, delusions, hallucinations, paranoid reaction, stupor, anxiety, depression and slurred speech.
- Cardiac arrest, arrhythmias including malignant arrhythmias, hypotension, and tachycardia
- Acute respiratory failure, pulmonary edema, and tachypnea
- Dysphagia
- Leukocytosis, agranulocytosis
- Keratitis and mydriasis
- Pruritus and diaphoresis
- Neuroleptic malignant syndrome, allergic reactions including anaphylactic reactions, edema, fever, pathological gambling, increased libido including hypersexuality, and impulse control symptoms.
- Elevated: CPK, BUN, serum creatinine, alkaline phosphatase, LDH, bilirubin, GGT, SGOT, and SGPT.
## Postmarketing Experience
There is limited information regarding Clinical Trial Experience of Amantadine hydrochloride in the drug label.
# Drug Interactions
- Careful observation is required when amantadine is administered concurrently with central nervous system stimulants. Agents with anticholinergic properties may potentiate the anticholinergic-like side effects of amantadine.
- Coadministration of thioridazine has been reported to worsen the tremor in elderly patients with Parkinson’s disease, however, it is not known if other phenothiazines produce a similar response. Coadministration of triamterene and hydrochlorothiazide capsules resulted in a higher plasma amantadine concentration in a 61-year-old man receiving amantadine (hydrochloride capsules) 100 mg t.i.d. for Parkinson’s disease.1 It is not known which of the components of triamterene and hydrochlorothiazide capsules contributed to the observation or if related drugs produce a similar response.
- Coadministration of quinine or quinidine with amantadine was shown to reduce the renal clearance of amantadine by about 30%.
- The concurrent use of amantadine with live attenuated influenza vaccine (LAIV) intranasal has not been evaluated. However, because of the potential for interference between these products, LAIV should not be administered within 2 weeks before or 48 hours after administration of amantadine, unless medically indicated. The concern about possible interference arises from the potential for antiviral drugs to inhibit replication of live vaccine virus. inactivated influenza vaccine can be administered at any time relative to use of amantadine.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- The effect of amantadine on embryofetal and peri-postnatal development has not been adequately tested, that is, in studies conducted under Good Laboratory Practice (GLP) and according to current recommended methodology. However, in two non-GLP studies in rats in which females were dosed from 5 days prior to mating to Day 6 of gestation or on Days 7 to 14 of gestation, amantadine produced increases in embryonic death at an oral dose of 100 mg/kg (or 3 times the maximum recommended human dose on a mg/m2 basis). In the non-GLP rat study in which females were dosed on Days 7 to 14 of gestation, there was a marked increase in severe visceral and skeletal malformations at oral doses of 50 and 100 mg/kg (or 1.5 and 3 times, respectively, the maximum recommended human dose on a mg/m2 basis). The no-effect dose for teratogenicity was 37 mg/kg (equal to the maximum recommended human dose on a mg/m2 basis). The safety margins reported may not accurately reflect the risk considering the questionable quality of the study on which they are based. There are no adequate and well-controlled studies in pregnant women. Human data regarding teratogenicity after maternal use of amantadine is scarce. Tetralogy of Fallot and tibial hemimelia (normal karyotype) occurred in an infant exposed to amantadine during the first trimester of pregnancy (100 mg P.O. for 7 days during the 6th and 7th week of gestation). Cardiovascular maldevelopment (single ventricle with pulmonary atresia) was associated with maternal exposure to amantadine (100 mg/d) administered during the first 2 weeks of pregnancy.
- Amantadine should be used during pregnancy only if the potential benefit justifies the potential risk to the embryo or fetus.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Amantadine hydrochloride in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Amantadine hydrochloride during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Amantadine hydrochloride with respect to nursing mothers.
### Pediatric Use
There is no FDA guidance on the use of Amantadine hydrochloride with respect to pediatric patients.
### Geriatic Use
- Because amantadine is primarily excreted in the urine, it accumulates in the plasma and in the body when renal function declines. Thus, the dose of amantadine should be reduced in patients with renal impairment and in individuals who are 65 years of age or older. The dose of amantadine hydrochloride capsules may need reduction in patients with congestive heart failure, peripheral edema, or orthostatic hypotension.
### Gender
There is no FDA guidance on the use of Amantadine hydrochloride with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Amantadine hydrochloride with respect to specific racial populations.
### Renal Impairment
- Because amantadine is mainly excreted in the urine, it accumulates in the plasma and in the body when renal function declines. Thus, the dose of amantadine should be reduced in patients with renal impairment and in individuals who are 65 years of age or older.
### Hepatic Impairment
- Care should be exercised when administering amantadine to patients with liver disease. Rare instances of reversible elevation of liver enzymes have been reported in patients receiving amantadine, though a specific relationship between the drug and such changes has not been established.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Amantadine hydrochloride in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Amantadine hydrochloride in patients who are immunocompromised.
### Others
- The dose of amantadine may need careful adjustment in patients with congestive heart failure, peripheral edema, or orthostatic hypotension. Care should be exercised when administering amantadine to patients with a history of recurrent eczematoid rash, or to patients with psychosis or severe psychoneurosis not controlled by chemotherapeutic agents.
- Serious bacterial infections may begin with influenza-like symptoms or may coexist with or occur as complications during the course of influenza. Amantadine has not been shown to prevent such complications.
- Epidemiological studies have shown that patients with Parkinson’s disease have a higher risk (2- to approximately 6-fold higher) of developing melanoma than the general population. Whether the increased risk observed was due to Parkinson’s disease or other factors, such as drugs used to treat Parkinson’s disease, is unclear.
- For the reasons stated above, patients and providers are advised to monitor for melanomas frequently and on a regular basis when using amantadine for any indication. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists).
# Administration and Monitoring
### Administration
- Oral
### Monitoring
### Neuroleptic Malignant Syndrome (NMS)=
- Sporadic cases of possible Neuroleptic Malignant Syndrome (NMS) have been reported in association with dose reduction or withdrawal of amantadine therapy. Therefore, patients should be observed carefully when the dosage of amantadine is reduced abruptly or discontinued, especially if the patient is receiving neuroleptics.
- NMS is an uncommon but life-threatening syndrome characterized by fever or hyperthermia; neurologic findings including muscle rigidity, involuntary movements, altered consciousness; mental status changes; other disturbances such as autonomic dysfunction, tachycardia, tachypnea, hyper- or hypotension; laboratory findings such as creatine phosphokinase elevation, leukocytosis, myoglobinuria, and increased serum myoglobin.
- The early diagnosis of this condition is important for the appropriate management of these patients. Considering NMS as a possible diagnosis and ruling out other acute illnesses (e.g., pneumonia, systemic infection, etc.) is essential. This may be especially complex if the clinical presentation includes both serious medical illness and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology.
- The management of NMS should include: 1) intensive symptomatic treatment and medical monitoring, and 2) treatment of any concomitant serious medical problems for which specific treatments are available. Dopamine agonists, such as bromocriptine, and muscle relaxants, such as dantrolene are often used in the treatment of NMS, however, their effectiveness has not been demonstrated in controlled studies.
- Epidemiological studies have shown that patients with Parkinson’s disease have a higher risk (2- to approximately 6-fold higher) of developing melanoma than the general population. Whether the increased risk observed was due to Parkinson’s disease or other factors, such as drugs used to treat Parkinson’s disease, is unclear.
- For the reasons stated above, patients and providers are advised to monitor for melanomas frequently and on a regular basis when using amantadine for any indication. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists).
# IV Compatibility
There is limited information regarding IV Compatibility of Amantadine hydrochloride in the drug label.
# Overdosage
- Deaths have been reported from overdose with amantadine. The lowest reported acute lethal dose was 1 gram. Because some patients have attempted suicide by overdosing with amantadine, prescriptions should be written for the smallest quantity consistent with good patient management.
- Acute toxicity may be attributable to the anticholinergic effects of amantadine. Drug overdose has resulted in cardiac, respiratory, renal or central nervous system toxicity. Cardiac dysfunction includes arrhythmia, tachycardia and hypertension. Pulmonary edema and respiratory distress (including adult respiratory distress syndrome – ARDS) have been reported; renal dysfunction including increased BUN, decreased creatinine clearance and renal insufficiency can occur. Central nervous system effects that have been reported include insomnia, anxiety, agitation, aggressive behavior, hypertonia, hyperkinesia, ataxia, gait abnormality, tremor, confusion, disorientation, depersonalization, fear, delirium, hallucinations, psychotic reactions, lethargy, somnolence and coma. Seizures may be exacerbated in patients with prior history of seizure disorders. Hyperthermia has also been observed in cases where a drug overdose has occurred.
- There is no specific antidote for an overdose of amantadine. However, slowly administered intravenous physostigmine in 1 and 2 mg doses in an adult2 at 1- to 2-hour intervals and 0.5 mg doses in a child3 at 5- to 10-minute intervals up to a maximum of 2 mg/hour have been reported to be effective in the control of central nervous system toxicity caused by amantadine hydrochloride. For acute overdosing, general supportive measures should be employed along with immediate gastric lavage or induction of emesis. Fluids should be forced, and if necessary, given intravenously. The pH of the urine has been reported to influence the excretion rate of amantadine. Since the excretion rate of amantadine increases rapidly when the urine is acidic, the administration of urine acidacidifying drugs may increase the elimination of the drug from the body. The blood pressure, pulse, respiration and temperature should be monitored. The patient should be observed for hyperactivity and convulsions; if required, sedation, and anticonvulsant therapy should be administered. The patient should be observed for the possible development of arrhythmias and hypotension; if required, appropriate antiarrhythmic and antihypotensive therapy should be given.
- Electrocardiographic monitoring may be required after ingestion, since malignant tachyarrhythmias can appear after overdose.
- Care should be exercised when administering adrenergic agents, such as isoproterenol, to patients with an amantadine overdose, since the dopaminergic activity of amantadine has been reported to induce malignant arrhythmias.
- The blood electrolytes, urine pH and urinary output should be monitored. If there is no record of recent voiding, catheterization should be done.
# Pharmacology
## Mechanism of Action
- The mechanism by which amantadine exerts its antiviral activity is not clearly understood. It appears to mainly prevent the release of infectious viral nucleic acid into the host cell by interfering with the function of the transmembrane domain of the viral M2 protein. In certain cases, amantadine is also known to prevent virus assembly during virus replication. It does not appear to interfere with the immunogenicity of inactivated influenza A virus vaccine.
- The mechanism of action of amantadine in the treatment of Parkinson’s disease and drug-induced extrapyramidal reactions is not known. Data from earlier animal studies suggest that amantadine may have direct and indirect effects on dopamine neurons. More recent studies have demonstrated that amantadine is a weak, non-competitive NMDA receptor antagonist (K1 = 10µM). Although amantadine has not been shown to possess direct anticholinergic activity in animal studies, clinically, it exhibits anticholinergic-like side effects such as dry mouth, urinary retention, and constipation.
## Structure
- Amantadine hydrochloride is designated chemically as 1-adamantanamine hydrochloride. Its molecular weight is 187.71 with a molecular formula C10H18NCl. It has the following structural formula:
## Pharmacodynamics
### Antiviral Activity=
- Amantadine inhibits the replication of influenza A virus isolates from each of the subtypes, i.e., H1N1, H2N2 and H3N2. It has very little or no activity against influenza B virus isolates. A quantitative relationship between the in vitro susceptibility of influenza A virus to amantadine and the clinical response to therapy has not been established in man. Sensitivity test results, expressed as the concentration of amantadine required to inhibit by 50% the growth of virus (ED50) in tissue culture vary greatly (from 0.1 mcg/mL to 25.0 mcg/mL) depending upon the assay protocol used, size of virus inoculum, isolates of influenza A virus strains tested, and the cell type used. Host cells in tissue culture readily tolerated amantadine up to a concentration of 100 mcg/mL.
- Influenza A variants with reduced in vitro sensitivity to amantadine have been isolated from epidemic strains in areas where adamantane derivatives are being used. Influenza viruses with reduced in vitro sensitivity have been shown to be transmissible and to cause typical influenza illness. The quantitative relationship between the in vitro sensitivity of Influenza A variants to amantadine and the clinical response to therapy has not been established.
## Pharmacokinetics
- Amantadine is well absorbed orally. Maximum plasma concentrations are directly related to dose for doses up to 200 mg/day. Doses above 200 mg/day may result in a greater than proportional increase in maximum plasma concentrations. It is primarily excreted unchanged in the urine by glomerular filtration and tubular secretion. Eight metabolites of amantadine have been identified in human urine. One metabolite, an N-acetylated compound, was quantified in human urine and accounted for 5 to 15% of the administered dose. Plasma acetylamantadine accounted for up to 80% of the concurrent amantadine plasma concentration in 5 of 12 healthy volunteers following the ingestion of a 200 mg dose of amantadine. Acetylamantadine was not detected in the plasma of the remaining seven volunteers. The contribution of this metabolite to efficacy or toxicity is not known.
- There appears to be a relationship between plasma amantadine concentrations and toxicity. As concentration increases, toxicity seems to be more prevalent, however, absolute values of amantadine concentrations associated with adverse effects have not been fully defined.
- Amantadine pharmacokinetics were determined in 24 normal adult male volunteers after the oral administration of a single amantadine hydrochloride 100 mg soft gel capsule. The mean ± SD maximum plasma concentration was 0.22 ± 0.03 mcg/mL (range: 0.18 to 0.32 mcg/mL). The time to peak concentration was 3.3 ± 1.5 hours (range 1.5 to 8.0 hours). The apparent oral clearance was 0.28 ± 0.11 L/hr/kg (range: 0.14 to 0.62 L/hr/kg). The half-life was 17 ± 4 hours (range: 10 to 25 hours). Across other studies, amantadine plasma half-life has averaged 16 ± 6 hours (range: 9 to 31 hours) in 19 healthy volunteers.
- After oral administration of a single dose of 100 mg amantadine syrup to five healthy volunteers, the mean ± SD maximum plasma concentration Cmax was 0.24 ± 0.04 mcg/mL and ranged from 0.18 to 0.28 mcg/mL. After 15 days of amantadine 100 mg b.i.d., the Cmax was 0.47 ± 0.11 mcg/mL in four of the five volunteers. The administration of amantadine tablets as a 200 mg single dose to 6 healthy subjects resulted in a Cmax of 0.51 ± 0.14 mcg/mL. Across studies, the time to Cmax (Tmax) averaged about 2 to 4 hours.
- Plasma amantadine clearance ranged from 0.2 to 0.3 L/hr/kg after the administration of 5 mg to 25 mg intravenous doses of amantadine to 15 healthy volunteers.
- In six healthy volunteers, the ratio of amantadine renal clearance to apparent oral plasma clearance was 0.79 ± 0.17 (mean ± SD).
- The volume of distribution determined after the intravenous administration of amantadine to 15 healthy subjects was 3 to 8 L/kg, suggesting tissue binding. Amantadine, after single oral 200 mg doses to 6 healthy young subjects and to 6 healthy elderly subjects has been found in nasal mucus at mean ± SD concentrations of 0.15 ± 0.16, 0.28 ± 0.26, and 0.39 ± 0.34 mcg/g at 1, 4 and 8 hours after dosing, respectively. These concentrations represented 31 ± 33%, 59 ± 61% and 95 ± 86% of the corresponding plasma amantadine concentrations. Amantadine is approximately 67% bound to plasma proteins over a concentration range of 0.1 to 2.0 mcg/mL. Following the administration of amantadine 100 mg as a single dose, the mean ± SD red blood cell to plasma ratio ranged from 2.7 ± 0.5 in 6 healthy subjects to 1.4 ± 0.2 in 8 patients with renal insufficiency.
- The apparent oral plasma clearance of amantadine is reduced and the plasma half-life and plasma concentrations are increased in healthy elderly individuals age 60 and older. After single dose administration of 25 to 75 mg to 7 healthy, elderly male volunteers, the apparent plasma clearance of amantadine was 0.10 ± 0.04 L/hr/kg (range 0.06 to 0.17 L/hr/kg) and the half-life was 29 ± 7 hours (range 20 to 41 hours). Whether these changes are due to decline in renal function or other age related factors is not known.
- In a study of young healthy subjects (n=20), mean renal clearance of amantadine, normalized for body mass index, was 1.5 fold higher in males compared to females (p<0.032).
- Compared with otherwise healthy adult individuals, the clearance of amantadine is significantly reduced in adult patients with renal insufficiency. The elimination half-life increases two to three fold or greater when creatinine clearance is less than 40 mL/min/1.73 m2 and averages eight days in patients on chronic maintenance hemodialysis. Amantadine is removed in negligible amounts by hemodialysis.
- The pH of the urine has been reported to influence the excretion rate of amantadine. Since the excretion rate of amantadine increases rapidly when the urine is acidic, the administration of urine acidifying drugs may increase the elimination of the drug from the body.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Amantadine hydrochloride in the drug label.
# Clinical Studies
- Long-term in vivo animal studies designed to evaluate the carcinogenic potential of amantadine have not been performed. In several in vitro assays for gene mutation, amantadine did not increase the number of spontaneously observed mutations in four strains of Salmonella typhimurium (Ames Test) or in a mammalian cell line (Chinese Hamster Ovary cells) when incubations were performed either with or without a liver metabolic activation extract.
- Further, there was no evidence of chromosome damage observed in an in vitro test using freshly derived and stimulated human peripheral blood lymphocytes (with and without metabolic activation) or in an in vivo mouse bone marrow micronucleus test (140 to 550 mg/kg; estimated human equivalent doses of 11.7 to 45.8 mg/kg based on body surface area conversion).
- The effect of amantadine on fertility has not been adequately tested, that is, in a study conducted under Good Laboratory Practice (GLP) and according to current recommended methodology. In a three litter, non-GLP, reproduction study in rats, amantadine at a dose of 32 mg/kg/day (equal to the maximum recommended human dose on a mg/m2 basis) administered to both males and females slightly impaired fertility. There were no effects on fertility at a dose level of 10 mg/kg/day (or 0.3 times the maximum recommended human dose on a mg/m2 basis); intermediate doses were not tested.
- Failed fertility has been reported during human in vitro fertilization (IVF) when the sperm donor ingested amantadine 2 weeks prior to, and during the IVF cycle.
# How Supplied
- Amantadine hydrochloride capsules, USP for oral administration are available as:
- 100 mg: Red capsules imprinted GG 634 and supplied as:
- NDC 51079-247-20 - Unit dose blister packages of 100 (10 cards of 10 capsules each).
- NDC 51079-247-20 - Unit dose blister packages of 100 (10 cards of 10 capsules each).
## Storage
- Store at 20° to 25°C (68° to 77°F).
# Images
## Drug Images
## Package and Label Display Panel
NDC 51079-247-20
AMANTADINE
HYDROCHLORIDE
CAPSULES, USP
100 mg
100 Capsules (10 x 10)
Each capsule contains:
Amantadine Hydrochloride, USP 100 mg
Usual Dosage: See accompanying
prescribing information.
Store at 20° to 25°C (68° to 77°F). [See USP
Controlled Room Temperature].
Manufactured by:
Sandoz Inc.
Princeton, NJ 08540
Rx only
S-11371
Packaged and Distributed by:
UDL LABORATORIES, INC.
ROCKFORD, IL 61103
This unit dose package is not child resistant.
For institutional use only.
Keep this and all drugs out of the reach of children.
This container provides light-resistance.
See window for lot number and expiration date.
# Patient Counseling Information
Patients should be advised of the following information:
- Blurry vision and/or impaired mental acuity may occur.
- Gradually increase physical activity as the symptoms of Parkinson’s disease improve.
- Avoid excessive alcohol usage, since it may increase the potential for CNS effects such as dizziness, confusion, light-headedness and orthostatic hypotension.
- Avoid getting up suddenly from a sitting or lying position. If dizziness or lightheadedness occurs, notify physician.
- Notify physician if mood/mental changes, swelling of extremities, difficulty urinating and/or shortness of breath occur.
- Do not take more medication than prescribed because of the risk of overdose. If there is no improvement in a few days, or if medication appears less effective after a few weeks, discuss with a physician.
- Consult physician before discontinuing medication.
- Seek medical attention immediately if it is suspected that an overdose of medication has been taken.
- There have been reports of patients experiencing intense urges to gamble, increased sexual urges, and other intense urges, and the inability to control these urges while taking one or more of the medications that increase central dopaminergic tone and that are generally used for the treatment of Parkinson’s disease, including amantadine. Although it is not proven that the medications caused these events, these urges were reported to have stopped in some cases when the dose was reduced or the medication was stopped. Prescribers should ask patients about the development of new or increased gambling urges, sexual urges or other urges while being treated with amantadine. Patients should inform their physician if they experience new or increased gambling urges, increased sexual urges or other intense urges while taking amantadine. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking amantadine.
# Precautions with Alcohol
Alcohol-Amantadine hydrochloride interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Symmetrel®
# Look-Alike Drug Names
- amantadine® - amiodarone®
# Drug Shortage Status
# Price | Amantadine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Adeel Jamil, M.D. [2]
# Disclaimer
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# Overview
Amantadine is a adamantane, anticholinergic and antiparkinsonian agent that is FDA approved for the treatment of Influenza A, Influenza A prophylaxis, Parkinson's syndrome, drug-Induced extrapyramidal reactions. Common adverse reactions include orthostatic hypotension, peripheral edema, constipation, diarrhea, loss of appetite, nausea, xerostomia, ataxia, confusion, dizziness, headache, insomnia, somnolence, agitation, anxiety, depression. dream disorder, feeling nervous, hallucinations, irritability and fatigue..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Amantadine hydrochloride capsules are indicated for the prophylaxis and treatment of signs and symptoms of infection caused by various strains of influenza A virus. Amantadine hydrochloride capsules are also indicated in the treatment of parkinsonism and drug-Induced extrapyramidal reactions.
- Amantadine hydrochloride capsules are indicated for chemoprophylaxis against signs and symptoms of influenza A virus infection. Because amantadine does not completely prevent the host immune response to influenza A infection, individuals who take this drug may still develop immune responses to natural disease or vaccination and may be protected when later exposed to antigenically related viruses. Following vaccination during an influenza A outbreak, amantadine prophylaxis should be considered for the 2- to 4-week time period required to develop an antibody response.
- Amantadine hydrochloride capsules are also indicated in the treatment of uncomplicated respiratory tract illness caused by influenza A virus strains especially when administered early in the course of illness. There are no well-controlled clinical studies demonstrating that treatment with amantadine hydrochloride capsules will avoid the development of influenza A virus pneumonitis or other complications in high risk patients.
- There is no clinical evidence indicating that amantadine hydrochloride capsules are effective in the prophylaxis or treatment of viral respiratory tract illnesses other than those caused by influenza A virus strains.
- The following points should be considered before initiating treatment or prophylaxis with amantadine hydrochloride capsules.
- Amantadine hydrochloride capsules are not a substitute for early vaccination on an annual basis as recommended by the Centers for Disease Control and Prevention Advisory Committee on Immunization Practices.
- Influenza viruses change over time. Emergence of resistance mutations could decrease drug effectiveness. Other factors (for example, changes in viral virulence) might also diminish clinical benefit of antiviral drugs. Prescribers should consider available information on influenza drug susceptibility patterns and treatment effects when deciding whether to use amantadine hydrochloride capsules.
- Amantadine hydrochloride capsules are indicated in the treatment of idiopathic Parkinson’s disease (Paralysis Agitans), postencephalitic parkinsonism and symptomatic parkinsonism which may follow injury to the nervous system by carbon monoxide intoxication. It is indicated in those elderly patients believed to develop parkinsonism in association with cerebral arteriosclerosis. In the treatment of Parkinson’s disease, amantadine is less effective than levodopa, (-)-3-(3,4-dihydroxyphenyl)-L-alanine, and its efficacy in comparison with the anticholinergic antiparkinson drugs has not yet been established.
- Amantadine hydrochloride is indicated in the treatment of drug-induced extrapyramidal reactions. Although anticholinergic-type side effects have been noted with amantadine when used in patients with drug-induced extrapyramidal reactions, there is a lower incidence of these side effects than that observed with the anticholinergic antiparkinson drugs.
- The dose of amantadine hydrochloride capsules may need reduction in patients with congestive heart failure, peripheral edema, orthostatic hypotension, or impaired renal function.
- The adult daily dosage of amantadine hydrochloride capsules is 200 mg; two 100 mg capsules as a single daily dose. The daily dosage may be split into one capsule of 100 mg twice a day. If central nervous system effects develop in once-a-day dosage, a split dosage schedule may reduce such complaints. In persons 65 years of age or older, the daily dosage of amantadine hydrochloride capsules is 100 mg.
- A 100 mg daily dose has also been shown in experimental challenge studies to be effective as prophylaxis in healthy adults who are not at high risk for influenza-related complications. However, it has not been demonstrated that a 100 mg daily dose is as effective as a 200 mg daily dose for prophylaxis, nor has the 100 mg daily dose been studied in the treatment of acute influenza illness. In recent clinical trials, the incidence of central nervous system (CNS) side effects associated with the 100 mg daily dose was at or near the level of placebo. The 100 mg dose is recommended for persons who have demonstrated intolerance to 200 mg of amantadine hydrochloride daily because of CNS or other toxicities.
- The usual dose of amantadine hydrochloride capsules is 100 mg twice a day when used alone. Amantadine has an onset of action usually within 48 hours.
- The initial dose of amantadine hydrochloride capsules is 100 mg daily for patients with serious associated medical illnesses or who are receiving high doses of other antiparkinson drugs. After one to several weeks at 100 mg once daily, the dose may be increased to 100 mg twice daily, if necessary.
- Occasionally, patients whose responses are not optimal with amantadine hydrochloride capsules at 200 mg daily may benefit from an increase up to 400 mg daily in divided doses. However, such patients should be supervised closely by their physicians.
- Patients initially deriving benefit from amantadine hydrochloride capsules not uncommonly experience a fall-off of effectiveness after a few months. Benefit may be regained by increasing the dose to 300 mg daily. Alternatively, temporary discontinuation of amantadine hydrochloride capsules for several weeks, followed by reinitiation of the drug, may result in regaining benefit in some patients. A decision to use other antiparkinson drugs may be necessary.
- Some patients who do not respond to anticholinergic antiparkinson drugs may respond to amantadine hydrochloride capsules. When amantadine hydrochloride capsules or anticholinergic antiparkinson drugs are each used with marginal benefit, concomitant use may produce additional benefit.
- When amantadine and levodopa are initiated concurrently, the patient can exhibit rapid therapeutic benefits. Amantadine hydrochloride capsules should be held constant at 100 mg daily or twice daily while the daily dose of levodopa is gradually increased to optimal benefit.
- When amantadine is added to optimal well-tolerated doses of levodopa, additional benefit may result, including smoothing out the fluctuations in improvement which sometimes occur in patients on levodopa alone. Patients who require a reduction in their usual dose of levodopa because of development of side effects may possibly regain lost benefit with the addition of amantadine hydrochloride capsules.
- The usual dose of amantadine hydrochloride capsules is 100 mg twice a day. Occasionally, patients whose responses are not optimal with amantadine hydrochloride capsules at 200 mg daily may benefit from an increase up to 300 mg daily in divided doses.
- Depending upon creatinine clearance, the following dosage adjustments are recommended:
- The recommended dosage for patients on hemodialysis is 200 mg every 7 days.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- Brain injury
- Cocaine withdrawal
- Drug-induced dyskinesia - Levodopa adverse reaction
- Hepatitis C, chronic
- Nocturnal enuresis
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Amantadine hydrochloride in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- The total daily dose should be calculated on the basis of 2 to 4 mg/lb/day (4.4 to 8.8 mg/kg/day), but not to exceed 150 mg per day.
- The total daily dose is 200 mg given as one capsule of 100 mg twice a day. The 100 mg daily dose has not been studied in this pediatric population. Therefore, there are no data which demonstrate that this dose is as effective as or is safer than the 200 mg daily dose in this patient population.
- Prophylactic dosing should be started in anticipation of an influenza A outbreak and before or after contact with individuals with influenza A virus respiratory tract illness.
- Amantadine hydrochloride capsules should be continued daily for at least 10 days following a known exposure. If amantadine is used chemoprophylactically in conjunction with inactivated influenza A virus vaccine until protective antibody responses develop, then it should be administered for 2 to 4 weeks after the vaccine has been given. When inactivated influenza A virus vaccine is unavailable or contraindicated, amantadine hydrochloride capsules should be administered for the duration of known influenza A in the community because of repeated and unknown exposure.
- Treatment of influenza A virus illness should be started as soon as possible, preferably within 24 to 48 hours after onset of signs and symptoms, and should be continued for 24 to 48 hours after the disappearance of signs and symptoms.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Amantadine hydrochloride in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Amantadine hydrochloride in pediatric patients.
# Contraindications
- Amantadine hydrochloride capsules, USP are contraindicated in patients with known hypersensitivity to amantadine hydrochloride or to any of the other ingredients in Amantadine hydrochloride capsules, USP.
# Warnings
### Deaths=
- Deaths have been reported from overdose with amantadine. The lowest reported acute lethal dose was 1 gram. Acute toxicity may be attributable to the anticholinergic effects of amantadine. Drug overdose has resulted in cardiac, respiratory, renal or central nervous system toxicity. Cardiac dysfunction includes arrhythmia, tachycardia and hypertension.
- Suicide attempts, some of which have been fatal, have been reported in patients treated with amantadine, many of whom received short courses for influenza treatment or prophylaxis. The incidence of suicide attempts is not known and the pathophysiologic mechanism is not understood. Suicide attempts and suicidal ideation have been reported in patients with and without prior history of psychiatric illness. Amantadine can exacerbate mental problems in patients with a history of psychiatric disorders or substance abuse. Patients who attempt suicide may exhibit abnormal mental states which include disorientation, confusion, depression, personality changes, agitation, aggressive behavior, hallucinations, paranoia, other psychotic reactions and somnolence or insomnia. Because of the possibility of serious adverse effects, caution should be observed when prescribing amantadine hydrochloride capsules to patients being treated with drugs having CNS effects, or for whom the potential risks outweigh the benefit of treatment.
- Patients with a history of epilepsy or other “seizures” should be observed closely for possible increased seizure activity.
- Patients receiving amantadine hydrochloride capsules who note central nervous system effects or blurring of vision should be cautioned against driving or working in situations where alertness and adequate motor coordination are important.
- Patients with a history of congestive heart failure or peripheral edema should be followed closely as there are patients who developed congestive heart failure while receiving amantadine hydrochloride capsules.
- Patients with Parkinson’s disease improving on amantadine hydrochloride capsules should resume normal activities gradually and cautiously, consistent with other medical considerations, such as the presence of osteoporosis or phlebothrombosis.
- Because Amantadine Hydrochloride Capsules, USP has anticholinergic effects and may cause mydriasis, it should not be given to patients with untreated angle closure glaucoma.
- Amantadine should not be discontinued abruptly in patients with Parkinson’s disease since a few patients have experienced a parkinsonian crisis, i.e., a sudden marked clinical deterioration, when this medication was suddenly stopped. The dose of anticholinergic drugs or of amantadine should be reduced if atropine-like effects appear when these drugs are used concurrently. Abrupt discontinuation may also precipitate delirium, agitation, delusions, hallucinations, paranoid reaction, stupor, anxiety, depression and slurred speech.
- Sporadic cases of possible Neuroleptic Malignant Syndrome (NMS) have been reported in association with dose reduction or withdrawal of amantadine therapy. Therefore, patients should be observed carefully when the dosage of amantadine is reduced abruptly or discontinued, especially if the patient is receiving neuroleptics.
- NMS is an uncommon but life-threatening syndrome characterized by fever or hyperthermia; neurologic findings including muscle rigidity, involuntary movements, altered consciousness; mental status changes; other disturbances such as autonomic dysfunction, tachycardia, tachypnea, hyper- or hypotension; laboratory findings such as creatine phosphokinase elevation, leukocytosis, myoglobinuria, and increased serum myoglobin.
- The early diagnosis of this condition is important for the appropriate management of these patients. Considering NMS as a possible diagnosis and ruling out other acute illnesses (e.g., pneumonia, systemic infection, etc.) is essential. This may be especially complex if the clinical presentation includes both serious medical illness and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology.
- The management of NMS should include: 1) intensive symptomatic treatment and medical monitoring, and 2) treatment of any concomitant serious medical problems for which specific treatments are available. Dopamine agonists, such as bromocriptine, and muscle relaxants, such as dantrolene are often used in the treatment of NMS, however, their effectiveness has not been demonstrated in controlled studies.
# Adverse Reactions
## Clinical Trials Experience
- The adverse reactions reported most frequently at the recommended dose of amantadine (5 to 10%) are: nausea, dizziness (lightheadedness), and insomnia.
- Less frequently (1 to 5%) reported adverse reactions are: depression, anxiety and irritability, hallucinations, confusion, anorexia, dry mouth, constipation, ataxia, livedo reticularis, peripheral edema, orthostatic hypotension, headache, somnolence, nervousness, dream abnormality, agitation, dry nose, diarrhea and fatigue.
- Infrequently (0.1 to 1%) occurring adverse reactions are: congestive heart failure, psychosis, urinary retention, dyspnea, skin rash, vomiting, weakness, slurred speech, euphoria, thinking abnormality, amnesia, hyperkinesia, hypertension, decreased libido, and visual disturbance, including punctate subepithelial or other corneal opacity, corneal edema, decreased visual acuity, sensitivity to light, and optic nerve palsy.
- Rare (less than 0.1%) occurring adverse reactions are: instances of convulsion, leukopenia, neutropenia, eczematoid dermatitis, oculogyric episodes, suicidal attempt, suicide, and suicidal ideation.
- Other adverse reactions reported during postmarketing experience with amantadine usage include:
- Coma, stupor, delirium, hypokinesia, hypertonia, delusions, aggressive behavior, paranoid reaction, manic reaction, involuntary muscle contractions, gait abnormalities, paresthesia, EEG changes, and tremor. Abrupt discontinuation may also precipitate delirium, agitation, delusions, hallucinations, paranoid reaction, stupor, anxiety, depression and slurred speech.
- Cardiac arrest, arrhythmias including malignant arrhythmias, hypotension, and tachycardia
- Acute respiratory failure, pulmonary edema, and tachypnea
- Dysphagia
- Leukocytosis, agranulocytosis
- Keratitis and mydriasis
- Pruritus and diaphoresis
- Neuroleptic malignant syndrome, allergic reactions including anaphylactic reactions, edema, fever, pathological gambling, increased libido including hypersexuality, and impulse control symptoms.
- Elevated: CPK, BUN, serum creatinine, alkaline phosphatase, LDH, bilirubin, GGT, SGOT, and SGPT.
## Postmarketing Experience
There is limited information regarding Clinical Trial Experience of Amantadine hydrochloride in the drug label.
# Drug Interactions
- Careful observation is required when amantadine is administered concurrently with central nervous system stimulants. Agents with anticholinergic properties may potentiate the anticholinergic-like side effects of amantadine.
- Coadministration of thioridazine has been reported to worsen the tremor in elderly patients with Parkinson’s disease, however, it is not known if other phenothiazines produce a similar response. Coadministration of triamterene and hydrochlorothiazide capsules resulted in a higher plasma amantadine concentration in a 61-year-old man receiving amantadine (hydrochloride capsules) 100 mg t.i.d. for Parkinson’s disease.1 It is not known which of the components of triamterene and hydrochlorothiazide capsules contributed to the observation or if related drugs produce a similar response.
- Coadministration of quinine or quinidine with amantadine was shown to reduce the renal clearance of amantadine by about 30%.
- The concurrent use of amantadine with live attenuated influenza vaccine (LAIV) intranasal has not been evaluated. However, because of the potential for interference between these products, LAIV should not be administered within 2 weeks before or 48 hours after administration of amantadine, unless medically indicated. The concern about possible interference arises from the potential for antiviral drugs to inhibit replication of live vaccine virus. inactivated influenza vaccine can be administered at any time relative to use of amantadine.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- The effect of amantadine on embryofetal and peri-postnatal development has not been adequately tested, that is, in studies conducted under Good Laboratory Practice (GLP) and according to current recommended methodology. However, in two non-GLP studies in rats in which females were dosed from 5 days prior to mating to Day 6 of gestation or on Days 7 to 14 of gestation, amantadine produced increases in embryonic death at an oral dose of 100 mg/kg (or 3 times the maximum recommended human dose on a mg/m2 basis). In the non-GLP rat study in which females were dosed on Days 7 to 14 of gestation, there was a marked increase in severe visceral and skeletal malformations at oral doses of 50 and 100 mg/kg (or 1.5 and 3 times, respectively, the maximum recommended human dose on a mg/m2 basis). The no-effect dose for teratogenicity was 37 mg/kg (equal to the maximum recommended human dose on a mg/m2 basis). The safety margins reported may not accurately reflect the risk considering the questionable quality of the study on which they are based. There are no adequate and well-controlled studies in pregnant women. Human data regarding teratogenicity after maternal use of amantadine is scarce. Tetralogy of Fallot and tibial hemimelia (normal karyotype) occurred in an infant exposed to amantadine during the first trimester of pregnancy (100 mg P.O. for 7 days during the 6th and 7th week of gestation). Cardiovascular maldevelopment (single ventricle with pulmonary atresia) was associated with maternal exposure to amantadine (100 mg/d) administered during the first 2 weeks of pregnancy.
- Amantadine should be used during pregnancy only if the potential benefit justifies the potential risk to the embryo or fetus.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Amantadine hydrochloride in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Amantadine hydrochloride during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Amantadine hydrochloride with respect to nursing mothers.
### Pediatric Use
There is no FDA guidance on the use of Amantadine hydrochloride with respect to pediatric patients.
### Geriatic Use
- Because amantadine is primarily excreted in the urine, it accumulates in the plasma and in the body when renal function declines. Thus, the dose of amantadine should be reduced in patients with renal impairment and in individuals who are 65 years of age or older. The dose of amantadine hydrochloride capsules may need reduction in patients with congestive heart failure, peripheral edema, or orthostatic hypotension.
### Gender
There is no FDA guidance on the use of Amantadine hydrochloride with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Amantadine hydrochloride with respect to specific racial populations.
### Renal Impairment
- Because amantadine is mainly excreted in the urine, it accumulates in the plasma and in the body when renal function declines. Thus, the dose of amantadine should be reduced in patients with renal impairment and in individuals who are 65 years of age or older.
### Hepatic Impairment
- Care should be exercised when administering amantadine to patients with liver disease. Rare instances of reversible elevation of liver enzymes have been reported in patients receiving amantadine, though a specific relationship between the drug and such changes has not been established.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Amantadine hydrochloride in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Amantadine hydrochloride in patients who are immunocompromised.
### Others
- The dose of amantadine may need careful adjustment in patients with congestive heart failure, peripheral edema, or orthostatic hypotension. Care should be exercised when administering amantadine to patients with a history of recurrent eczematoid rash, or to patients with psychosis or severe psychoneurosis not controlled by chemotherapeutic agents.
- Serious bacterial infections may begin with influenza-like symptoms or may coexist with or occur as complications during the course of influenza. Amantadine has not been shown to prevent such complications.
- Epidemiological studies have shown that patients with Parkinson’s disease have a higher risk (2- to approximately 6-fold higher) of developing melanoma than the general population. Whether the increased risk observed was due to Parkinson’s disease or other factors, such as drugs used to treat Parkinson’s disease, is unclear.
- For the reasons stated above, patients and providers are advised to monitor for melanomas frequently and on a regular basis when using amantadine for any indication. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists).
# Administration and Monitoring
### Administration
- Oral
### Monitoring
### Neuroleptic Malignant Syndrome (NMS)=
- Sporadic cases of possible Neuroleptic Malignant Syndrome (NMS) have been reported in association with dose reduction or withdrawal of amantadine therapy. Therefore, patients should be observed carefully when the dosage of amantadine is reduced abruptly or discontinued, especially if the patient is receiving neuroleptics.
- NMS is an uncommon but life-threatening syndrome characterized by fever or hyperthermia; neurologic findings including muscle rigidity, involuntary movements, altered consciousness; mental status changes; other disturbances such as autonomic dysfunction, tachycardia, tachypnea, hyper- or hypotension; laboratory findings such as creatine phosphokinase elevation, leukocytosis, myoglobinuria, and increased serum myoglobin.
- The early diagnosis of this condition is important for the appropriate management of these patients. Considering NMS as a possible diagnosis and ruling out other acute illnesses (e.g., pneumonia, systemic infection, etc.) is essential. This may be especially complex if the clinical presentation includes both serious medical illness and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology.
- The management of NMS should include: 1) intensive symptomatic treatment and medical monitoring, and 2) treatment of any concomitant serious medical problems for which specific treatments are available. Dopamine agonists, such as bromocriptine, and muscle relaxants, such as dantrolene are often used in the treatment of NMS, however, their effectiveness has not been demonstrated in controlled studies.
- Epidemiological studies have shown that patients with Parkinson’s disease have a higher risk (2- to approximately 6-fold higher) of developing melanoma than the general population. Whether the increased risk observed was due to Parkinson’s disease or other factors, such as drugs used to treat Parkinson’s disease, is unclear.
- For the reasons stated above, patients and providers are advised to monitor for melanomas frequently and on a regular basis when using amantadine for any indication. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists).
# IV Compatibility
There is limited information regarding IV Compatibility of Amantadine hydrochloride in the drug label.
# Overdosage
- Deaths have been reported from overdose with amantadine. The lowest reported acute lethal dose was 1 gram. Because some patients have attempted suicide by overdosing with amantadine, prescriptions should be written for the smallest quantity consistent with good patient management.
- Acute toxicity may be attributable to the anticholinergic effects of amantadine. Drug overdose has resulted in cardiac, respiratory, renal or central nervous system toxicity. Cardiac dysfunction includes arrhythmia, tachycardia and hypertension. Pulmonary edema and respiratory distress (including adult respiratory distress syndrome – ARDS) have been reported; renal dysfunction including increased BUN, decreased creatinine clearance and renal insufficiency can occur. Central nervous system effects that have been reported include insomnia, anxiety, agitation, aggressive behavior, hypertonia, hyperkinesia, ataxia, gait abnormality, tremor, confusion, disorientation, depersonalization, fear, delirium, hallucinations, psychotic reactions, lethargy, somnolence and coma. Seizures may be exacerbated in patients with prior history of seizure disorders. Hyperthermia has also been observed in cases where a drug overdose has occurred.
- There is no specific antidote for an overdose of amantadine. However, slowly administered intravenous physostigmine in 1 and 2 mg doses in an adult2 at 1- to 2-hour intervals and 0.5 mg doses in a child3 at 5- to 10-minute intervals up to a maximum of 2 mg/hour have been reported to be effective in the control of central nervous system toxicity caused by amantadine hydrochloride. For acute overdosing, general supportive measures should be employed along with immediate gastric lavage or induction of emesis. Fluids should be forced, and if necessary, given intravenously. The pH of the urine has been reported to influence the excretion rate of amantadine. Since the excretion rate of amantadine increases rapidly when the urine is acidic, the administration of urine acidacidifying drugs may increase the elimination of the drug from the body. The blood pressure, pulse, respiration and temperature should be monitored. The patient should be observed for hyperactivity and convulsions; if required, sedation, and anticonvulsant therapy should be administered. The patient should be observed for the possible development of arrhythmias and hypotension; if required, appropriate antiarrhythmic and antihypotensive therapy should be given.
- Electrocardiographic monitoring may be required after ingestion, since malignant tachyarrhythmias can appear after overdose.
- Care should be exercised when administering adrenergic agents, such as isoproterenol, to patients with an amantadine overdose, since the dopaminergic activity of amantadine has been reported to induce malignant arrhythmias.
- The blood electrolytes, urine pH and urinary output should be monitored. If there is no record of recent voiding, catheterization should be done.
# Pharmacology
## Mechanism of Action
- The mechanism by which amantadine exerts its antiviral activity is not clearly understood. It appears to mainly prevent the release of infectious viral nucleic acid into the host cell by interfering with the function of the transmembrane domain of the viral M2 protein. In certain cases, amantadine is also known to prevent virus assembly during virus replication. It does not appear to interfere with the immunogenicity of inactivated influenza A virus vaccine.
- The mechanism of action of amantadine in the treatment of Parkinson’s disease and drug-induced extrapyramidal reactions is not known. Data from earlier animal studies suggest that amantadine may have direct and indirect effects on dopamine neurons. More recent studies have demonstrated that amantadine is a weak, non-competitive NMDA receptor antagonist (K1 = 10µM). Although amantadine has not been shown to possess direct anticholinergic activity in animal studies, clinically, it exhibits anticholinergic-like side effects such as dry mouth, urinary retention, and constipation.
## Structure
- Amantadine hydrochloride is designated chemically as 1-adamantanamine hydrochloride. Its molecular weight is 187.71 with a molecular formula C10H18NCl. It has the following structural formula:
## Pharmacodynamics
### Antiviral Activity=
- Amantadine inhibits the replication of influenza A virus isolates from each of the subtypes, i.e., H1N1, H2N2 and H3N2. It has very little or no activity against influenza B virus isolates. A quantitative relationship between the in vitro susceptibility of influenza A virus to amantadine and the clinical response to therapy has not been established in man. Sensitivity test results, expressed as the concentration of amantadine required to inhibit by 50% the growth of virus (ED50) in tissue culture vary greatly (from 0.1 mcg/mL to 25.0 mcg/mL) depending upon the assay protocol used, size of virus inoculum, isolates of influenza A virus strains tested, and the cell type used. Host cells in tissue culture readily tolerated amantadine up to a concentration of 100 mcg/mL.
- Influenza A variants with reduced in vitro sensitivity to amantadine have been isolated from epidemic strains in areas where adamantane derivatives are being used. Influenza viruses with reduced in vitro sensitivity have been shown to be transmissible and to cause typical influenza illness. The quantitative relationship between the in vitro sensitivity of Influenza A variants to amantadine and the clinical response to therapy has not been established.
## Pharmacokinetics
- Amantadine is well absorbed orally. Maximum plasma concentrations are directly related to dose for doses up to 200 mg/day. Doses above 200 mg/day may result in a greater than proportional increase in maximum plasma concentrations. It is primarily excreted unchanged in the urine by glomerular filtration and tubular secretion. Eight metabolites of amantadine have been identified in human urine. One metabolite, an N-acetylated compound, was quantified in human urine and accounted for 5 to 15% of the administered dose. Plasma acetylamantadine accounted for up to 80% of the concurrent amantadine plasma concentration in 5 of 12 healthy volunteers following the ingestion of a 200 mg dose of amantadine. Acetylamantadine was not detected in the plasma of the remaining seven volunteers. The contribution of this metabolite to efficacy or toxicity is not known.
- There appears to be a relationship between plasma amantadine concentrations and toxicity. As concentration increases, toxicity seems to be more prevalent, however, absolute values of amantadine concentrations associated with adverse effects have not been fully defined.
- Amantadine pharmacokinetics were determined in 24 normal adult male volunteers after the oral administration of a single amantadine hydrochloride 100 mg soft gel capsule. The mean ± SD maximum plasma concentration was 0.22 ± 0.03 mcg/mL (range: 0.18 to 0.32 mcg/mL). The time to peak concentration was 3.3 ± 1.5 hours (range 1.5 to 8.0 hours). The apparent oral clearance was 0.28 ± 0.11 L/hr/kg (range: 0.14 to 0.62 L/hr/kg). The half-life was 17 ± 4 hours (range: 10 to 25 hours). Across other studies, amantadine plasma half-life has averaged 16 ± 6 hours (range: 9 to 31 hours) in 19 healthy volunteers.
- After oral administration of a single dose of 100 mg amantadine syrup to five healthy volunteers, the mean ± SD maximum plasma concentration Cmax was 0.24 ± 0.04 mcg/mL and ranged from 0.18 to 0.28 mcg/mL. After 15 days of amantadine 100 mg b.i.d., the Cmax was 0.47 ± 0.11 mcg/mL in four of the five volunteers. The administration of amantadine tablets as a 200 mg single dose to 6 healthy subjects resulted in a Cmax of 0.51 ± 0.14 mcg/mL. Across studies, the time to Cmax (Tmax) averaged about 2 to 4 hours.
- Plasma amantadine clearance ranged from 0.2 to 0.3 L/hr/kg after the administration of 5 mg to 25 mg intravenous doses of amantadine to 15 healthy volunteers.
- In six healthy volunteers, the ratio of amantadine renal clearance to apparent oral plasma clearance was 0.79 ± 0.17 (mean ± SD).
- The volume of distribution determined after the intravenous administration of amantadine to 15 healthy subjects was 3 to 8 L/kg, suggesting tissue binding. Amantadine, after single oral 200 mg doses to 6 healthy young subjects and to 6 healthy elderly subjects has been found in nasal mucus at mean ± SD concentrations of 0.15 ± 0.16, 0.28 ± 0.26, and 0.39 ± 0.34 mcg/g at 1, 4 and 8 hours after dosing, respectively. These concentrations represented 31 ± 33%, 59 ± 61% and 95 ± 86% of the corresponding plasma amantadine concentrations. Amantadine is approximately 67% bound to plasma proteins over a concentration range of 0.1 to 2.0 mcg/mL. Following the administration of amantadine 100 mg as a single dose, the mean ± SD red blood cell to plasma ratio ranged from 2.7 ± 0.5 in 6 healthy subjects to 1.4 ± 0.2 in 8 patients with renal insufficiency.
- The apparent oral plasma clearance of amantadine is reduced and the plasma half-life and plasma concentrations are increased in healthy elderly individuals age 60 and older. After single dose administration of 25 to 75 mg to 7 healthy, elderly male volunteers, the apparent plasma clearance of amantadine was 0.10 ± 0.04 L/hr/kg (range 0.06 to 0.17 L/hr/kg) and the half-life was 29 ± 7 hours (range 20 to 41 hours). Whether these changes are due to decline in renal function or other age related factors is not known.
- In a study of young healthy subjects (n=20), mean renal clearance of amantadine, normalized for body mass index, was 1.5 fold higher in males compared to females (p<0.032).
- Compared with otherwise healthy adult individuals, the clearance of amantadine is significantly reduced in adult patients with renal insufficiency. The elimination half-life increases two to three fold or greater when creatinine clearance is less than 40 mL/min/1.73 m2 and averages eight days in patients on chronic maintenance hemodialysis. Amantadine is removed in negligible amounts by hemodialysis.
- The pH of the urine has been reported to influence the excretion rate of amantadine. Since the excretion rate of amantadine increases rapidly when the urine is acidic, the administration of urine acidifying drugs may increase the elimination of the drug from the body.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Amantadine hydrochloride in the drug label.
# Clinical Studies
- Long-term in vivo animal studies designed to evaluate the carcinogenic potential of amantadine have not been performed. In several in vitro assays for gene mutation, amantadine did not increase the number of spontaneously observed mutations in four strains of Salmonella typhimurium (Ames Test) or in a mammalian cell line (Chinese Hamster Ovary cells) when incubations were performed either with or without a liver metabolic activation extract.
- Further, there was no evidence of chromosome damage observed in an in vitro test using freshly derived and stimulated human peripheral blood lymphocytes (with and without metabolic activation) or in an in vivo mouse bone marrow micronucleus test (140 to 550 mg/kg; estimated human equivalent doses of 11.7 to 45.8 mg/kg based on body surface area conversion).
- The effect of amantadine on fertility has not been adequately tested, that is, in a study conducted under Good Laboratory Practice (GLP) and according to current recommended methodology. In a three litter, non-GLP, reproduction study in rats, amantadine at a dose of 32 mg/kg/day (equal to the maximum recommended human dose on a mg/m2 basis) administered to both males and females slightly impaired fertility. There were no effects on fertility at a dose level of 10 mg/kg/day (or 0.3 times the maximum recommended human dose on a mg/m2 basis); intermediate doses were not tested.
- Failed fertility has been reported during human in vitro fertilization (IVF) when the sperm donor ingested amantadine 2 weeks prior to, and during the IVF cycle.
# How Supplied
- Amantadine hydrochloride capsules, USP for oral administration are available as:
- 100 mg: Red capsules imprinted GG 634 and supplied as:
- NDC 51079-247-20 - Unit dose blister packages of 100 (10 cards of 10 capsules each).
- NDC 51079-247-20 - Unit dose blister packages of 100 (10 cards of 10 capsules each).
## Storage
- Store at 20° to 25°C (68° to 77°F).
# Images
## Drug Images
## Package and Label Display Panel
NDC 51079-247-20
AMANTADINE
HYDROCHLORIDE
CAPSULES, USP
100 mg
100 Capsules (10 x 10)
Each capsule contains:
Amantadine Hydrochloride, USP 100 mg
Usual Dosage: See accompanying
prescribing information.
Store at 20° to 25°C (68° to 77°F). [See USP
Controlled Room Temperature].
Manufactured by:
Sandoz Inc.
Princeton, NJ 08540
Rx only
S-11371
Packaged and Distributed by:
UDL LABORATORIES, INC.
ROCKFORD, IL 61103
This unit dose package is not child resistant.
For institutional use only.
Keep this and all drugs out of the reach of children.
This container provides light-resistance.
See window for lot number and expiration date.
# Patient Counseling Information
Patients should be advised of the following information:
- Blurry vision and/or impaired mental acuity may occur.
- Gradually increase physical activity as the symptoms of Parkinson’s disease improve.
- Avoid excessive alcohol usage, since it may increase the potential for CNS effects such as dizziness, confusion, light-headedness and orthostatic hypotension.
- Avoid getting up suddenly from a sitting or lying position. If dizziness or lightheadedness occurs, notify physician.
- Notify physician if mood/mental changes, swelling of extremities, difficulty urinating and/or shortness of breath occur.
- Do not take more medication than prescribed because of the risk of overdose. If there is no improvement in a few days, or if medication appears less effective after a few weeks, discuss with a physician.
- Consult physician before discontinuing medication.
- Seek medical attention immediately if it is suspected that an overdose of medication has been taken.
- There have been reports of patients experiencing intense urges to gamble, increased sexual urges, and other intense urges, and the inability to control these urges while taking one or more of the medications that increase central dopaminergic tone and that are generally used for the treatment of Parkinson’s disease, including amantadine. Although it is not proven that the medications caused these events, these urges were reported to have stopped in some cases when the dose was reduced or the medication was stopped. Prescribers should ask patients about the development of new or increased gambling urges, sexual urges or other urges while being treated with amantadine. Patients should inform their physician if they experience new or increased gambling urges, increased sexual urges or other intense urges while taking amantadine. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking amantadine.
# Precautions with Alcohol
Alcohol-Amantadine hydrochloride interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Symmetrel®
# Look-Alike Drug Names
- amantadine® - amiodarone®
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Amantadine | |
25f1bc865dbd88e1373cae778d508480f4640c63 | wikidoc | Ambenonium | Ambenonium
# 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
Ambenonium is a cholinesterase inhibitor that is FDA approved for the treatment of myasthenia gravis. Common adverse reactions include excessive salivation, abdominal cramps, diarrhea, miosis, urinary urgency, sweating, nausea, increase in bronchial and lachrymal secretions, vomiting, anxiety, vertigo, bradycardia and cardiac conduction disorders.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- This drug is indicated for the treatment of myasthenia gravis.
- The oral dose must be individualized according to the patient's response because the disease varies widely in its severity in different patients and because patients vary in their sensitivity to cholinergic drugs. Since the point of maximum therapeutic effectiveness with optimal muscle strength and no gastrointestinal disturbances is a highly critical one, the close supervision of a physician familiar with the disease is necessary.
- Because its action is longer, administration of MYTELASE is necessary only every three or four hours, depending on the clinical response. Usually medication is not required throughout the night, so that the patient can sleep uninterruptedly.
- For the patient with moderately severe myasthenia, from 5 mg to 25 mg of MYTELASE three or four times daily is an effective dose. In some patients a 5 mg dose is effective, whereas other patients require as much as from 50 mg to 75 mg per dose. The physician should start with a 5 mg dose, carefully observing the effect of the drug on the patient. The dosage may then be increased gradually to determine the effective and safe dose. The longer duration of action of MYTELASE makes it desirable to adjust dosage at intervals of one to two days to avoid drug accumulation and overdosage.
- In addition to individual variations in dosage requirements, the amount of cholinergic medication necessary to control symptoms may fluctuate in each patient, depending on his activity and the current status of the disease, including spontaneous remission. A few patients have required greater doses for adequate control of myasthenic symptoms, but increasing the dosage above 200 mg daily requires exacting supervision of a physician well aware of the signs and treatment of overdosage with cholinergic medication.
- Edrophonium (Tensilon®) may be used to evaluate the adequacy of the maintenance dose of anti-cholinesterase medication. Two mg edrophonium are administered intravenously one hour after the last anticholinesterase dose. A transient increase in strength occurring about 30 seconds later and lasting 3 to 5 minutes indicates insufficient maintenance dose. If the dose is adequate or excessive, no change or a transient decrease in strength will occur, sometimes accompanied by muscarinic symptoms.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ambenonium in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ambenonium in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Ambenonium in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ambenonium in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ambenonium in pediatric patients.
# Contraindications
- Routine administration of atropine with MYTELASE is contraindicated since belladonna derivatives may suppress the parasympathomimetic (muscarinic) symptoms of excessive gastrointestinal stimulation, leaving only the more serious symptoms of fasciculation and paralysis of voluntary muscles as signs of overdosage.
- MYTELASE should not be administered to patients receiving mecamylamine, or any other ganglionic blocking agents. MYTELASE should also not be administered to patients with a known hypersensitivity to ambenonium chloride or any other ingredients of MYTELASE.
# Warnings
- Because this drug has a more prolonged action than other antimyasthenic drugs, simultaneous administration with other cholinergics is contraindicated except under strict medical supervision. The overlap in duration of action of several drugs complicates dosage schedules. Therefore, when a patient is to be given the drug, the administration of all other cholinergics should be suspended until the patient has been stabilized. In most instances the myasthenic symptoms are effectively controlled by its use alone.
# Adverse Reactions
## Clinical Trials Experience
There is limited information regarding Clinical Trial Experience of Ambenonium in the drug label.
## Postmarketing Experience
- Adverse effects of anticholinesterase agents such as MYTELASE usually result from overdosage and include muscarinic effects such as excessive salivation, abdominal cramps, diarrhea, miosis, urinary urgency, sweating, nausea, increase in bronchial and lachrymal secretions, and vomiting, nicotinic effects such as muscle cramps, fasciculation of voluntary muscles, and rarely generalized malaise with anxiety and vertigo, and bradycardia and cardiac conduction disorders.
# Drug Interactions
There is limited information regarding Ambenonium Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Safe use of this drug during pregnancy has not been established. Therefore, before use of MYTELASE in pregnant women or women of childbearing potential, the potential benefits should be weighed against possible risks to mother and fetus.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ambenonium in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Ambenonium during labor and delivery.
### Nursing Mothers
- It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from MYTELASE, 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
There is no FDA guidance on the use of Ambenonium with respect to pediatric patients.
### Geriatic Use
- Clinical Studies of MYTELASE 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 Ambenonium with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Ambenonium with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Ambenonium in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Ambenonium in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ambenonium in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Ambenonium in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
- Intravenous
### Monitoring
There is limited information regarding Monitoring of Ambenonium in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Ambenonium in the drug label.
# Overdosage
- When the drug produces overstimulation, the clinical picture is one of increasing parasympathomimetic action that is more or less characteristic when not masked by the use of atropine.
- Signs and symptoms of overdosage, including cholinergic crises, vary considerably. They are usually manifested by increasing gastrointestinal stimulation with epigastric distress, abdominal cramps, diarrhea and vomiting, excessive salivation, pallor, pollakiuria, cold sweating, urinary urgency, blurring of vision, and eventually fasciculation and paralysis of voluntary muscles, including those of the tongue (thick tongue and difficulty in swallowing), shoulder, neck, and arms. Rarely, generalized malaise and vertigo may occur.
- Miosis, increase in blood pressure with or without bradycardia, bradycardia, cardiac conduction disorders, and finally, subjective sensations of internal trembling, and often severe anxiety and panic may complete the picture. A cholinergic crisis is usually differentiated from the weakness and paralysis of myasthenia gravis insufficiently treated by cholinergic drugs by the fact that myasthenic weakness is not accompanied by any of the above signs and symptoms, except the last two subjective ones (anxiety and panic).
- Since the warning of overdosage is minimal, the existence of a narrow margin between the first appearance of side effects and serious toxic effects must be borne in mind constantly. If signs of overdosage occur (excessive gastrointestinal stimulation, excessive salivation, miosis, and more serious fasciculations of voluntary muscles) discontinue temporarily all cholinergic medication and administer from 0.5 mg to 1 mg (1/120 to 1/60 grain) of atropine intravenously. It must be noted that atropine reverses effects of excessive acetylcholine due to overdosage at the muscarinic receptors but not the effects at the nicotinic receptors such as fasciculations and paralysis of respiratory muscles. Pralidoxime chloride may be used to alleviate these effects at the nicotinic receptors since pralidoxime has its most critical effect in relieving paralysis of the muscles of respiration. However, because pralidoxime is less effective in relieving depression of the respiratory center, atropine is always required concomitantly to block the effect of accumulated acetylcholine at this site. Give other supportive treatment as indicated (e.g. artificial respiration, tracheotomy, oxygen, and hospitalization).
# Pharmacology
There is limited information regarding Ambenonium Pharmacology in the drug label.
## Mechanism of Action
There is limited information regarding Ambenonium Mechanism of Action in the drug label.
## Structure
There is limited information regarding Ambenonium Structure in the drug label.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Ambenonium in the drug label.
## Pharmacokinetics
There is limited information regarding Pharmacokinetics of Ambenonium in the drug label.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Ambenonium in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Ambenonium in the drug label.
# How Supplied
- Scored, white, capsule – shaped tablets (caplets) with a stylized "W" on one side and "M" score "87" on the other side, 10 mg, bottles of 100 (NDC 0024-1287-04)
## Storage
- Store at room temperature up to 25° C (77° F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Ambenonium in the drug label.
# Precautions with Alcohol
- Alcohol-Ambenonium interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- MYTELASE ®
# Look-Alike Drug Names
There is limited information regarding Ambenonium Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Ambenonium
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Ambenonium is a cholinesterase inhibitor that is FDA approved for the treatment of myasthenia gravis. Common adverse reactions include excessive salivation, abdominal cramps, diarrhea, miosis, urinary urgency, sweating, nausea, increase in bronchial and lachrymal secretions, vomiting, anxiety, vertigo, bradycardia and cardiac conduction disorders.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- This drug is indicated for the treatment of myasthenia gravis.
- The oral dose must be individualized according to the patient's response because the disease varies widely in its severity in different patients and because patients vary in their sensitivity to cholinergic drugs. Since the point of maximum therapeutic effectiveness with optimal muscle strength and no gastrointestinal disturbances is a highly critical one, the close supervision of a physician familiar with the disease is necessary.
- Because its action is longer, administration of MYTELASE is necessary only every three or four hours, depending on the clinical response. Usually medication is not required throughout the night, so that the patient can sleep uninterruptedly.
- For the patient with moderately severe myasthenia, from 5 mg to 25 mg of MYTELASE three or four times daily is an effective dose. In some patients a 5 mg dose is effective, whereas other patients require as much as from 50 mg to 75 mg per dose. The physician should start with a 5 mg dose, carefully observing the effect of the drug on the patient. The dosage may then be increased gradually to determine the effective and safe dose. The longer duration of action of MYTELASE makes it desirable to adjust dosage at intervals of one to two days to avoid drug accumulation and overdosage.
- In addition to individual variations in dosage requirements, the amount of cholinergic medication necessary to control symptoms may fluctuate in each patient, depending on his activity and the current status of the disease, including spontaneous remission. A few patients have required greater doses for adequate control of myasthenic symptoms, but increasing the dosage above 200 mg daily requires exacting supervision of a physician well aware of the signs and treatment of overdosage with cholinergic medication.
- Edrophonium (Tensilon®) may be used to evaluate the adequacy of the maintenance dose of anti-cholinesterase medication. Two mg edrophonium are administered intravenously one hour after the last anticholinesterase dose. A transient increase in strength occurring about 30 seconds later and lasting 3 to 5 minutes indicates insufficient maintenance dose. If the dose is adequate or excessive, no change or a transient decrease in strength will occur, sometimes accompanied by muscarinic symptoms.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ambenonium in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ambenonium in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Ambenonium in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ambenonium in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ambenonium in pediatric patients.
# Contraindications
- Routine administration of atropine with MYTELASE is contraindicated since belladonna derivatives may suppress the parasympathomimetic (muscarinic) symptoms of excessive gastrointestinal stimulation, leaving only the more serious symptoms of fasciculation and paralysis of voluntary muscles as signs of overdosage.
- MYTELASE should not be administered to patients receiving mecamylamine, or any other ganglionic blocking agents. MYTELASE should also not be administered to patients with a known hypersensitivity to ambenonium chloride or any other ingredients of MYTELASE.
# Warnings
- Because this drug has a more prolonged action than other antimyasthenic drugs, simultaneous administration with other cholinergics is contraindicated except under strict medical supervision. The overlap in duration of action of several drugs complicates dosage schedules. Therefore, when a patient is to be given the drug, the administration of all other cholinergics should be suspended until the patient has been stabilized. In most instances the myasthenic symptoms are effectively controlled by its use alone.
# Adverse Reactions
## Clinical Trials Experience
There is limited information regarding Clinical Trial Experience of Ambenonium in the drug label.
## Postmarketing Experience
- Adverse effects of anticholinesterase agents such as MYTELASE usually result from overdosage and include muscarinic effects such as excessive salivation, abdominal cramps, diarrhea, miosis, urinary urgency, sweating, nausea, increase in bronchial and lachrymal secretions, and vomiting, nicotinic effects such as muscle cramps, fasciculation of voluntary muscles, and rarely generalized malaise with anxiety and vertigo, and bradycardia and cardiac conduction disorders.
# Drug Interactions
There is limited information regarding Ambenonium Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Safe use of this drug during pregnancy has not been established. Therefore, before use of MYTELASE in pregnant women or women of childbearing potential, the potential benefits should be weighed against possible risks to mother and fetus.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ambenonium in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Ambenonium during labor and delivery.
### Nursing Mothers
- It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from MYTELASE, 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
There is no FDA guidance on the use of Ambenonium with respect to pediatric patients.
### Geriatic Use
- Clinical Studies of MYTELASE 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 Ambenonium with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Ambenonium with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Ambenonium in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Ambenonium in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ambenonium in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Ambenonium in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
- Intravenous
### Monitoring
There is limited information regarding Monitoring of Ambenonium in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Ambenonium in the drug label.
# Overdosage
- When the drug produces overstimulation, the clinical picture is one of increasing parasympathomimetic action that is more or less characteristic when not masked by the use of atropine.
- Signs and symptoms of overdosage, including cholinergic crises, vary considerably. They are usually manifested by increasing gastrointestinal stimulation with epigastric distress, abdominal cramps, diarrhea and vomiting, excessive salivation, pallor, pollakiuria, cold sweating, urinary urgency, blurring of vision, and eventually fasciculation and paralysis of voluntary muscles, including those of the tongue (thick tongue and difficulty in swallowing), shoulder, neck, and arms. Rarely, generalized malaise and vertigo may occur.
- Miosis, increase in blood pressure with or without bradycardia, bradycardia, cardiac conduction disorders, and finally, subjective sensations of internal trembling, and often severe anxiety and panic may complete the picture. A cholinergic crisis is usually differentiated from the weakness and paralysis of myasthenia gravis insufficiently treated by cholinergic drugs by the fact that myasthenic weakness is not accompanied by any of the above signs and symptoms, except the last two subjective ones (anxiety and panic).
- Since the warning of overdosage is minimal, the existence of a narrow margin between the first appearance of side effects and serious toxic effects must be borne in mind constantly. If signs of overdosage occur (excessive gastrointestinal stimulation, excessive salivation, miosis, and more serious fasciculations of voluntary muscles) discontinue temporarily all cholinergic medication and administer from 0.5 mg to 1 mg (1/120 to 1/60 grain) of atropine intravenously. It must be noted that atropine reverses effects of excessive acetylcholine due to overdosage at the muscarinic receptors but not the effects at the nicotinic receptors such as fasciculations and paralysis of respiratory muscles. Pralidoxime chloride may be used to alleviate these effects at the nicotinic receptors since pralidoxime has its most critical effect in relieving paralysis of the muscles of respiration. However, because pralidoxime is less effective in relieving depression of the respiratory center, atropine is always required concomitantly to block the effect of accumulated acetylcholine at this site. Give other supportive treatment as indicated (e.g. artificial respiration, tracheotomy, oxygen, and hospitalization).
# Pharmacology
There is limited information regarding Ambenonium Pharmacology in the drug label.
## Mechanism of Action
There is limited information regarding Ambenonium Mechanism of Action in the drug label.
## Structure
There is limited information regarding Ambenonium Structure in the drug label.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Ambenonium in the drug label.
## Pharmacokinetics
There is limited information regarding Pharmacokinetics of Ambenonium in the drug label.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Ambenonium in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Ambenonium in the drug label.
# How Supplied
- Scored, white, capsule – shaped tablets (caplets) with a stylized "W" on one side and "M" score "87" on the other side, 10 mg, bottles of 100 (NDC 0024-1287-04)
## Storage
- Store at room temperature up to 25° C (77° F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Ambenonium in the drug label.
# Precautions with Alcohol
- Alcohol-Ambenonium interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- MYTELASE ®[1]
# Look-Alike Drug Names
There is limited information regarding Ambenonium Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Ambenonium | |
d24467d5fb6b612a3f6178c41ef77e5fbcc3b8c0 | wikidoc | Amcinonide | Amcinonide
# 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
Amcinonide is a corticosteroid that is FDA approved for the treatment of inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses. Common adverse reactions include burning sensation, itching, skin irritation, soreness, stinging of skin.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Topical corticosteroids are indicated for the relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses.
- Topical corticosteroids are generally applied to the affected area as a thin film from two to three times daily depending on the severity of the condition.
- Occlusive dressings may be a valuable therapeutic adjunct for the management of psoriasis or recalcitrant conditions.
- If an infection develops, the use of occlusive dressings should be discontinued and appropriate antimicrobial therapy instituted.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Amcinonide in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Amcinonide in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Pediatric patients may demonstrate greater susceptibility to topical corticosteroid-induced HPA axis suppression and Cushing's syndrome than mature patients because of a larger skin surface area to body weight ratio.
- Hypothalamic-pituitary-adrenal (HPA) axis suppression, Cushing's syndrome, and intracranial hypertension have been reported in pediatric patients receiving topical corticosteroids. Manifestations of adrenal suppression in pediatric patients include linear growth retardation, delayed weight gain, low plasma cortisol levels, and absence of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema.
- Administration of topical corticosteroids to pediatric patients should be limited to the least amount compatible with an effective therapeutic regimen. Chronic corticosteroid therapy may interfere with the growth and development of pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Amcinonide in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Amcinonide in pediatric patients.
# Contraindications
- Topical corticosteroids are contraindicated in those patients with a history of hypersensitivity to any of the components of the preparation.
# Warnings
- Systemic absorption of topical corticosteroids has produced reversible hypothalamic-pituitary-adrenal (HPA) axis suppression, manifestations of cushing's syndrome, hyperglycemia and glucosuria in some patients.
- Conditions that augment systemic absorption include the application of the more potent steroids, use over large surface areas, prolonged use and the addition of occlusive dressings. Therefore, patients receiving a large dose of a potent topical steroid applied to a large surface area or under an occlusive dressing should be evaluated periodically for evidence of HPA axis suppression by using the urinary free cortisol and ACTH stimulation tests. If HPA axis suppression is noted, an attempt should be made to withdraw the drug, to reduce the frequency of application, or to substitute with a less potent steroid.
- Recovery of HPA axis function is generally prompt and complete upon discontinuation of the drug.
- Infrequently, signs and symptoms of steroid withdrawal may occur, requiring supplemental systemic corticosteroids.
- Pediatric patients may absorb proportionally larger amounts of topical corticosteroids and thus be more susceptible to systemic toxicity.
- If irritation develops, topical corticosteroids should be discontinued and appropriate therapy instituted.
- In the presence of dermatological infections, the use of an appropriate antifungal or antibacterial agent should be instituted. If a favorable response does not occur promptly, the corticosteroid should be discontinued until the infection has been adequately controlled.
- These products are not for ophthalmic use.
# Adverse Reactions
## Clinical Trials Experience
There is limited information regarding Clinical Trial Experience of Amcinonide in the drug label.
## Postmarketing Experience
- Systemic absorption of topical corticosteroids has produced reversible hypothalamic-pituitary-adrenal (HPA) axis suppression, manifestations of Cushing's syndrome, hyperglycemia and glucosuria in some patients.
- Conditions that augment systemic absorption include the application of the more potent steroids, use over large surface areas, prolonged use and the addition of occlusive dressings. Therefore, patients receiving a large dose of a potent topical steroid applied to a large surface area or under an occlusive dressing should be evaluated periodically for evidence of HPA axis suppression by using the urinary free cortisol and ACTH stimulation tests. If HPA axis suppression is noted, an attempt should be made to withdraw the drug, to reduce the frequency of application, or to substitute with a less potent steroid.
- Recovery of HPA axis function is generally prompt and complete upon discontinuation of the drug.
- Infrequently, signs and symptoms of steroid withdrawal may occur, requiring supplemental systemic corticosteroids.
- Pediatric patients may absorb proportionally larger amounts of topical corticosteroids and thus be more susceptible to systemic toxicity.
- If irritation develops, topical corticosteroids should be discontinued and appropriate therapy instituted.
- In the presence of dermatological infections, the use of an appropriate antifungal or antibacterial agent should be instituted. If a favorable response does not occur promptly, the corticosteroid should be discontinued until the infection has been adequately controlled.
- These products are not for ophthalmic use.
# Drug Interactions
There is limited information regarding Amcinonide Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Corticosteroids are generally teratogenic in laboratory animals when administered systemically at relatively low dosage levels. The more potent corticosteroids have been shown to be teratogenic after dermal application in laboratory animals. There are no adequate and well-controlled studies in pregnant women on teratogenic effects from topically applied ]. Therefore, topical corticosteroids should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Drugs of this class should not be used extensively on pregnant patients, in large amounts, or for prolonged periods of time.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Amcinonide in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Amcinonide during labor and delivery.
### Nursing Mothers
- It is not known whether topical administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in breast milk. Systemically administered corticosteroids are secreted into breast milk in quantities not likely to have a deleterious effect on the infant. Nevertheless, 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
- Pediatric patients may demonstrate greater susceptibility to topical corticosteroid-induced HPA axis suppression and Cushing's syndrome than mature patients because of a larger skin surface area to body weight ratio.
- Hypothalamic-pituitary-adrenal (HPA) axis suppression, Cushing's syndrome, and intracranial hypertension have been reported in pediatric patients receiving topical corticosteroids. Manifestations of adrenal suppression in pediatric patients include linear growth retardation, delayed weight gain, low plasma cortisol levels, and absence of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema.
- Administration of topical corticosteroids to pediatric patients should be limited to the least amount compatible with an effective therapeutic regimen. Chronic corticosteroid therapy may interfere with the growth and development of pediatric patients.
### Geriatic Use
There is no FDA guidance on the use of Amcinonide with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Amcinonide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Amcinonide with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Amcinonide in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Amcinonide in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Amcinonide in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Amcinonide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
- Intravenous
### Monitoring
There is limited information regarding Monitoring of Amcinonide in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Amcinonide in the drug label.
# Overdosage
- Topically applied corticosteroids can be absorbed in sufficient amounts to produce systemic effects
# Pharmacology
## Mechanism of Action
- Topical corticosteroids share anti-inflammatory, antipruritic and vasoconstrictive actions.
- The mechanism of anti-inflammatory activity of the topical corticosteroids is unclear. Various laboratory methods, including vasoconstrictor assays, are used to compare and predict potencies and/or clinical efficacies of the topical corticosteroids. There is some evidence to suggest that a recognizable correlation exists between vasoconstrictor potency and therapeutic efficacy in man.
## Structure
- The topical corticosteroids constitute a class of primarily synthetic steroids used as anti-inflammatory and antipruritic agents.
- TOPICAL CREAM USP, 0.1%
- Each gram of Amcinonide Cream contains 1 mg of the active steroid amcinonide in a white, smooth, homogeneous, opaque emulsion composed of benzyl alcohol (as preservative), emulsifying wax, glycerin, isopropyl palmitate, lactic acid, purified water and sorbitol solution 70%.
- TOPICAL OINTMENT USP, 0.1%
- Each gram of Amcinonide Ointment contains 1 mg of the active steroid amcinonide in a specially formulated base composed of benzyl alcohol 2.2% (wt/wt) as preservative, butylated hydroxyanisole, citric acid anhydrous, emulsifying wax, propyl gallate, propylene glycol, and white petrolatum.
- Chemically, amcinonide is:
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Amcinonide in the drug label.
## Pharmacokinetics
- The extent of percutaneous absorption of topical corticosteroids is determined by many factors, including the vehicle, the integrity of the epidermal barrier, and the use of occlusive dressings.
- Topical corticosteroids can be absorbed from normal intact skin. Inflammation and/or other disease processes in the skin increase percutaneous absorption. Occlusive dressings substantially increase the percutaneous absorption of topical corticosteroids.
- Once absorbed through the skin, topical corticosteroids are handled through pharmacokinetic pathways similar to systemically administered corticosteroids. Corticosteroids are bound to plasma proteins in varying degrees.
- Corticosteroids are metabolized primarily in the liver and are then excreted by the kidneys. Some of the topical corticosteroids and their metabolites are also excreted into the bile.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Amcinonide in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Amcinonide in the drug label.
# How Supplied
- Amcinonide Topical Cream USP, 0.1% (1 mg/g) is supplied in 4 gm, 15 gm, 30 gm and 60 gm tubes.
- Amcinonide Topical Ointment USP, 0.1% (1 mg/g) is supplied in 15 gm, 30 gm and 60 gm tubes.
## Storage
- Store at 20° -25°C (68°-77°F)
- DO NOT FREEZE.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients using topical corticosteroids should receive the following information and instructions:
- This medication is to be used as directed by the physician. It is for external use only. Avoid contact with the eyes.
- Patients should be advised not to use this medication for any disorder other than that for which it was prescribed.
- The treated skin area should not be bandaged or otherwise covered or wrapped as to be occlusive unless directed by the physician.
- Patients should report any signs of local adverse reactions especially under occlusive dressing.
- Parents of pediatric patients should be advised not to use tight-fitting diapers or plastic pants on a child being treated in the diaper area since these garments may constitute occlusive dressings.
# Precautions with Alcohol
- Alcohol-Amcinonide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- AMCINONIDE®
# Look-Alike Drug Names
There is limited information regarding Amcinonide Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Amcinonide
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Amcinonide is a corticosteroid that is FDA approved for the treatment of inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses. Common adverse reactions include burning sensation, itching, skin irritation, soreness, stinging of skin.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Topical corticosteroids are indicated for the relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses.
- Topical corticosteroids are generally applied to the affected area as a thin film from two to three times daily depending on the severity of the condition.
- Occlusive dressings may be a valuable therapeutic adjunct for the management of psoriasis or recalcitrant conditions.
- If an infection develops, the use of occlusive dressings should be discontinued and appropriate antimicrobial therapy instituted.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Amcinonide in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Amcinonide in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Pediatric patients may demonstrate greater susceptibility to topical corticosteroid-induced HPA axis suppression and Cushing's syndrome than mature patients because of a larger skin surface area to body weight ratio.
- Hypothalamic-pituitary-adrenal (HPA) axis suppression, Cushing's syndrome, and intracranial hypertension have been reported in pediatric patients receiving topical corticosteroids. Manifestations of adrenal suppression in pediatric patients include linear growth retardation, delayed weight gain, low plasma cortisol levels, and absence of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema.
- Administration of topical corticosteroids to pediatric patients should be limited to the least amount compatible with an effective therapeutic regimen. Chronic corticosteroid therapy may interfere with the growth and development of pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Amcinonide in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Amcinonide in pediatric patients.
# Contraindications
- Topical corticosteroids are contraindicated in those patients with a history of hypersensitivity to any of the components of the preparation.
# Warnings
- Systemic absorption of topical corticosteroids has produced reversible hypothalamic-pituitary-adrenal (HPA) axis suppression, manifestations of cushing's syndrome, hyperglycemia and glucosuria in some patients.
- Conditions that augment systemic absorption include the application of the more potent steroids, use over large surface areas, prolonged use and the addition of occlusive dressings. Therefore, patients receiving a large dose of a potent topical steroid applied to a large surface area or under an occlusive dressing should be evaluated periodically for evidence of HPA axis suppression by using the urinary free cortisol and ACTH stimulation tests. If HPA axis suppression is noted, an attempt should be made to withdraw the drug, to reduce the frequency of application, or to substitute with a less potent steroid.
- Recovery of HPA axis function is generally prompt and complete upon discontinuation of the drug.
- Infrequently, signs and symptoms of steroid withdrawal may occur, requiring supplemental systemic corticosteroids.
- Pediatric patients may absorb proportionally larger amounts of topical corticosteroids and thus be more susceptible to systemic toxicity.
- If irritation develops, topical corticosteroids should be discontinued and appropriate therapy instituted.
- In the presence of dermatological infections, the use of an appropriate antifungal or antibacterial agent should be instituted. If a favorable response does not occur promptly, the corticosteroid should be discontinued until the infection has been adequately controlled.
- These products are not for ophthalmic use.
# Adverse Reactions
## Clinical Trials Experience
There is limited information regarding Clinical Trial Experience of Amcinonide in the drug label.
## Postmarketing Experience
- Systemic absorption of topical corticosteroids has produced reversible hypothalamic-pituitary-adrenal (HPA) axis suppression, manifestations of Cushing's syndrome, hyperglycemia and glucosuria in some patients.
- Conditions that augment systemic absorption include the application of the more potent steroids, use over large surface areas, prolonged use and the addition of occlusive dressings. Therefore, patients receiving a large dose of a potent topical steroid applied to a large surface area or under an occlusive dressing should be evaluated periodically for evidence of HPA axis suppression by using the urinary free cortisol and ACTH stimulation tests. If HPA axis suppression is noted, an attempt should be made to withdraw the drug, to reduce the frequency of application, or to substitute with a less potent steroid.
- Recovery of HPA axis function is generally prompt and complete upon discontinuation of the drug.
- Infrequently, signs and symptoms of steroid withdrawal may occur, requiring supplemental systemic corticosteroids.
- Pediatric patients may absorb proportionally larger amounts of topical corticosteroids and thus be more susceptible to systemic toxicity.
- If irritation develops, topical corticosteroids should be discontinued and appropriate therapy instituted.
- In the presence of dermatological infections, the use of an appropriate antifungal or antibacterial agent should be instituted. If a favorable response does not occur promptly, the corticosteroid should be discontinued until the infection has been adequately controlled.
- These products are not for ophthalmic use.
# Drug Interactions
There is limited information regarding Amcinonide Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Corticosteroids are generally teratogenic in laboratory animals when administered systemically at relatively low dosage levels. The more potent corticosteroids have been shown to be teratogenic after dermal application in laboratory animals. There are no adequate and well-controlled studies in pregnant women on teratogenic effects from topically applied [corticosteroids]]. Therefore, topical corticosteroids should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Drugs of this class should not be used extensively on pregnant patients, in large amounts, or for prolonged periods of time.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Amcinonide in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Amcinonide during labor and delivery.
### Nursing Mothers
- It is not known whether topical administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in breast milk. Systemically administered corticosteroids are secreted into breast milk in quantities not likely to have a deleterious effect on the infant. Nevertheless, 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
- Pediatric patients may demonstrate greater susceptibility to topical corticosteroid-induced HPA axis suppression and Cushing's syndrome than mature patients because of a larger skin surface area to body weight ratio.
- Hypothalamic-pituitary-adrenal (HPA) axis suppression, Cushing's syndrome, and intracranial hypertension have been reported in pediatric patients receiving topical corticosteroids. Manifestations of adrenal suppression in pediatric patients include linear growth retardation, delayed weight gain, low plasma cortisol levels, and absence of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema.
- Administration of topical corticosteroids to pediatric patients should be limited to the least amount compatible with an effective therapeutic regimen. Chronic corticosteroid therapy may interfere with the growth and development of pediatric patients.
### Geriatic Use
There is no FDA guidance on the use of Amcinonide with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Amcinonide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Amcinonide with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Amcinonide in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Amcinonide in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Amcinonide in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Amcinonide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
- Intravenous
### Monitoring
There is limited information regarding Monitoring of Amcinonide in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Amcinonide in the drug label.
# Overdosage
- Topically applied corticosteroids can be absorbed in sufficient amounts to produce systemic effects
# Pharmacology
## Mechanism of Action
- Topical corticosteroids share anti-inflammatory, antipruritic and vasoconstrictive actions.
- The mechanism of anti-inflammatory activity of the topical corticosteroids is unclear. Various laboratory methods, including vasoconstrictor assays, are used to compare and predict potencies and/or clinical efficacies of the topical corticosteroids. There is some evidence to suggest that a recognizable correlation exists between vasoconstrictor potency and therapeutic efficacy in man.
## Structure
- The topical corticosteroids constitute a class of primarily synthetic steroids used as anti-inflammatory and antipruritic agents.
- TOPICAL CREAM USP, 0.1%
- Each gram of Amcinonide Cream contains 1 mg of the active steroid amcinonide in a white, smooth, homogeneous, opaque emulsion composed of benzyl alcohol (as preservative), emulsifying wax, glycerin, isopropyl palmitate, lactic acid, purified water and sorbitol solution 70%.
- TOPICAL OINTMENT USP, 0.1%
- Each gram of Amcinonide Ointment contains 1 mg of the active steroid amcinonide in a specially formulated base composed of benzyl alcohol 2.2% (wt/wt) as preservative, butylated hydroxyanisole, citric acid anhydrous, emulsifying wax, propyl gallate, propylene glycol, and white petrolatum.
- Chemically, amcinonide is:
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Amcinonide in the drug label.
## Pharmacokinetics
- The extent of percutaneous absorption of topical corticosteroids is determined by many factors, including the vehicle, the integrity of the epidermal barrier, and the use of occlusive dressings.
- Topical corticosteroids can be absorbed from normal intact skin. Inflammation and/or other disease processes in the skin increase percutaneous absorption. Occlusive dressings substantially increase the percutaneous absorption of topical corticosteroids.
- Once absorbed through the skin, topical corticosteroids are handled through pharmacokinetic pathways similar to systemically administered corticosteroids. Corticosteroids are bound to plasma proteins in varying degrees.
- Corticosteroids are metabolized primarily in the liver and are then excreted by the kidneys. Some of the topical corticosteroids and their metabolites are also excreted into the bile.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Amcinonide in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Amcinonide in the drug label.
# How Supplied
- Amcinonide Topical Cream USP, 0.1% (1 mg/g) is supplied in 4 gm, 15 gm, 30 gm and 60 gm tubes.
- Amcinonide Topical Ointment USP, 0.1% (1 mg/g) is supplied in 15 gm, 30 gm and 60 gm tubes.
## Storage
- Store at 20° -25°C (68°-77°F)
- DO NOT FREEZE.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients using topical corticosteroids should receive the following information and instructions:
- This medication is to be used as directed by the physician. It is for external use only. Avoid contact with the eyes.
- Patients should be advised not to use this medication for any disorder other than that for which it was prescribed.
- The treated skin area should not be bandaged or otherwise covered or wrapped as to be occlusive unless directed by the physician.
- Patients should report any signs of local adverse reactions especially under occlusive dressing.
- Parents of pediatric patients should be advised not to use tight-fitting diapers or plastic pants on a child being treated in the diaper area since these garments may constitute occlusive dressings.
# Precautions with Alcohol
- Alcohol-Amcinonide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- AMCINONIDE®[1]
# Look-Alike Drug Names
There is limited information regarding Amcinonide Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Amcinonide | |
795b77ae912ba380ff541a6b14d9f2e1ad2dc72c | wikidoc | Amelogenin | Amelogenin
Amelogenin is the name for a series of closely related proteins involved in amelogenesis, the development of enamel. They are a type of extracellular matrix (ECM) protein, which, together with ameloblastins, enamelins, and tuftelins direct the mineralization of enamel to form a highly organized matrix of rods, interrod crystal, and protein. Although the precise role of amelogenin(s) in regulating the mineralization process is unknown, it is known that amelogenins are abundant during amelogenesis. Developing human enamel contains about 70% protein, 90% of which are amelogenins.
# Function
Amelogenins are believed to be involved in the organizing of enamel rods during tooth development. The latest research indicates that these proteins regulate the initiation and growth of hydroxyapatite crystals during the mineralization of enamel. In addition, amelogenins appear to aid in the development of cementum by directing cementoblasts to the tooth's root surface.
# Variants
The amelogenin gene has been most widely studied in humans, where it is a single copy gene, located on the X and Y chromosomes at Xp22.1-Xp22.3 and Yp 11.2 . The amelogenin gene’s location on sex chromosomes has implications for variability both between the X chromosome form (AMELX) and the Y chromosome form (AMELY), and between alleles of AMELY among different populations. This is because AMELY exists in the non-recombining region of chromosome Y, effectively isolating it from normal selection pressures. Other sources of amelogenin variation arise from the various isoforms of AMELX obtained from alternative splicing of mRNA transcripts. Specific roles for isoforms have yet to be established. Among other organisms, amelogenin is well conserved among eutherians, and has homologs in monotremes, reptiles and amphibians.
# Application in sex determination
Differences between the X chromosome and Y chromosome versions of the amelogenin gene (AMELX and AMELY respectively) enable it to be used in sex determination of unknown human samples. AMELX’s intron 1 contains a 6 bp deletion relative to intron 1 of AMELY. This can be detected at low cost using polymerase chain reaction (PCR) of intron 1, followed by gel electrophoresis. Two bands of DNA, at 106bps and 112bps, are resolved if both the AMELX and AMELY versions of the gene are present (i.e. the sample is from a male) or one band of DNA, at 106bps, if the AMELX version only is present (i.e. the sample is from a female).
However because of AMELY variation among individuals and populations, this method of sex determination is not 100% accurate. Mutation in regions of AMELY intron 1 commonly used as primer annealing sites may disable PCR amplification. A 6bp insertion to AMELY intron 1 results in an amplicon identical in length to that of AMELX. In some males AMELY may be deleted entirely. In any of these cases only one band is visualized during gel electrophoresis of PCR products, causing misidentification of the sample as female. The misidentification rate may vary among populations, but in general appears to be low. In one study in Spain, the amelogenin sex determination test using AMELX (977bps) and AMELY (790bps) bands was performed for 1224 individuals of known gender with a 99.84% (1222/1224) accuracy rate. Another study in India, however, found 5 of its 270 men studied (1.85%) possessed an AMELY deletion, terming them “deleted-amelogenin males” (DAMs). In response the authors suggested that while the amelogenin sex test may be accurate in general, other Y chromosome markers such as SRY, STR, or 50f2 can be used for less ambiguous gender identification.
# Clinical significance
Mutations in AMELX can cause amelogenesis imperfecta, a disorder of tooth enamel development. | Amelogenin
Amelogenin is the name for a series of closely related proteins involved in amelogenesis, the development of enamel.[1] They are a type of extracellular matrix (ECM) protein, which, together with ameloblastins, enamelins, and tuftelins direct the mineralization of enamel to form a highly organized matrix of rods, interrod crystal, and protein. Although the precise role of amelogenin(s) in regulating the mineralization process is unknown, it is known that amelogenins are abundant during amelogenesis. Developing human enamel contains about 70% protein, 90% of which are amelogenins.
# Function
Amelogenins are believed to be involved in the organizing of enamel rods during tooth development. The latest research indicates that these proteins regulate the initiation and growth of hydroxyapatite crystals during the mineralization of enamel. In addition, amelogenins appear to aid in the development of cementum by directing cementoblasts to the tooth's root surface.
# Variants
The amelogenin gene has been most widely studied in humans, where it is a single copy gene, located on the X and Y chromosomes at Xp22.1-Xp22.3 and Yp 11.2 [5].[2] The amelogenin gene’s location on sex chromosomes has implications for variability both between the X chromosome form (AMELX) and the Y chromosome form (AMELY), and between alleles of AMELY among different populations. This is because AMELY exists in the non-recombining region of chromosome Y, effectively isolating it from normal selection pressures. Other sources of amelogenin variation arise from the various isoforms of AMELX obtained from alternative splicing of mRNA transcripts. Specific roles for isoforms have yet to be established. Among other organisms, amelogenin is well conserved among eutherians, and has homologs in monotremes, reptiles and amphibians.
# Application in sex determination
Differences between the X chromosome and Y chromosome versions of the amelogenin gene (AMELX and AMELY respectively) enable it to be used in sex determination of unknown human samples. AMELX’s intron 1 contains a 6 bp deletion relative to intron 1 of AMELY. This can be detected at low cost using polymerase chain reaction (PCR) of intron 1, followed by gel electrophoresis. Two bands of DNA, at 106bps and 112bps, are resolved if both the AMELX and AMELY versions of the gene are present (i.e. the sample is from a male) or one band of DNA, at 106bps, if the AMELX version only is present (i.e. the sample is from a female).[3]
However because of AMELY variation among individuals and populations, this method of sex determination is not 100% accurate. Mutation in regions of AMELY intron 1 commonly used as primer annealing sites may disable PCR amplification. A 6bp insertion to AMELY intron 1 results in an amplicon identical in length to that of AMELX. In some males AMELY may be deleted entirely. In any of these cases only one band is visualized during gel electrophoresis of PCR products, causing misidentification of the sample as female.[3] The misidentification rate may vary among populations, but in general appears to be low. In one study in Spain, the amelogenin sex determination test using AMELX (977bps) and AMELY (790bps) bands was performed for 1224 individuals of known gender with a 99.84% (1222/1224) accuracy rate.[4] Another study in India, however, found 5 of its 270 men studied (1.85%) possessed an AMELY deletion, terming them “deleted-amelogenin males” (DAMs). In response the authors suggested that while the amelogenin sex test may be accurate in general, other Y chromosome markers such as SRY, STR, or 50f2 can be used for less ambiguous gender identification.[5]
# Clinical significance
Mutations in AMELX can cause amelogenesis imperfecta, a disorder of tooth enamel development.[6] | https://www.wikidoc.org/index.php/Amelogenin | |
e24e37b848db86688e9b2a3f91f0a8d921ffef33 | wikidoc | Amifostine | Amifostine
# 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
Amifostine is an cytoprotective agent that is FDA approved for the treatment of reducing the cumulative renal toxicity associated with repeated administration of cisplatin in patients with advanced ovarian cancer and also to reduce the incidence of moderate to severe xerostomia in patients undergoing post-operative radiation treatment for head and neck cancer, where the radiation port includes a substantial portion of the parotid glands. Common adverse reactions include hypotension, nausea and/or vomiting, flushing/feeling of warmth, chills/feeling of coldness, malaise, fever, rash, dizziness, somnolence, hiccups, sneezing, and decrease in serum calcium concentrations.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Amifostine for Injection is indicated to reduce the cumulative renal toxicity associated with repeated administration of cisplatin in patients with advanced ovarian cancer.
- The recommended starting dose of Amifostine for Injection is 910 mg/m2 administered once daily as a 15-minute i.v. infusion, starting 30 minutes prior to chemotherapy.
- The 15-minute infusion is better tolerated than more extended infusions. Further reductions in infusion times for chemotherapy regimens have not been systematically investigated.
- Patients should be adequately hydrated prior to Amifostine for Injection infusion and kept in a supine position during the infusion. Blood pressure should be monitored every 5 minutes during the infusion, and thereafter as clinically indicated.
- The infusion of Amifostine for Injection should be interrupted if the systolic blood pressure decreases significantly from the baseline value as listed in the guideline below:
- If the blood pressure returns to normal within 5 minutes and the patient is asymptomatic, the infusion may be restarted so that the full dose of Amifostine for Injection may be administered. If the full dose of amifostine cannot be administered, the dose of amifostine for subsequent chemotherapy cycles should be 740 mg/m2.
- It is recommended that antiemetic medication, including dexamethasone 20 mg i.v. and a serotonin 5HT3 receptor antagonist, be administered prior to and in conjunction with Amifostine for Injection. Additional antiemetics may be required based on the chemotherapy drugs administered.
- Amifostine for Injection is indicated to reduce the incidence of moderate to severe xerostomia in patients undergoing post-operative radiation treatment for head and neck cancer, where the radiation port includes a substantial portion of the parotid glands .
- For the approved indications, the clinical data do not suggest that the effectiveness of cisplatin based chemotherapy regimens or radiation therapy is altered by Amifostine for Injection. There are at present only limited data on the effects of amifostine on the efficacy of chemotherapy or radiotherapy in other settings.
- Amifostine should not be administered to patients in other settings where chemotherapy can produce a significant survival benefit or cure, or in patients receiving definitive radiotherapy, except in the context of a clinical study.
- The recommended dose of Amifostine for Injection is 200 mg/m2 administered once daily as a 3-minute i.v. infusion, starting 15-30 minutes prior to standard fraction radiation therapy (1.8-2.0 Gy).
- Patients should be adequately hydrated prior to Amifostine for Injection infusion. Blood pressure should be monitored at least before and immediately after the infusion, and thereafter as clinically indicated.
- It is recommended that antiemetic medication be administered prior to and in conjunction with Amifostine for Injection. Oral 5HT3 receptor antagonists, alone or in combination with other antiemetics, have been used effectively in the radiotherapy setting.
- Amifostine for Injection is supplied as a sterile lyophilized powder requiring reconstitution for intravenous infusion. Each single-use vial contains 500 mg of amifostine on the anhydrous basis.
- Prior to intravenous injection, Amifostine for Injection is reconstituted with 9.7 mL of sterile 0.9% Sodium Chloride Injection, USP. The reconstituted solution (500 mg amifostine/10 mL) is chemically stable for up to 5 hours at room temperature (approximately 25°C) or up to 24 hours under refrigeration (2°C to 8°C).
- Amifostine for Injection prepared in polyvinylchloride (PVC) bags at concentrations ranging from 5 mg/mL to 40 mg/mL is chemically stable for up to 5 hours when stored at room temperature (approximately 25°C) or up to 24 hours when stored under refrigeration (2°C to 8°C).
CAUTION: Parenteral products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not use if cloudiness or precipitate is observed.
- The compatibility of Amifostine for Injection with solutions other than 0.9% Sodium Chloride for Injection, or Sodium Chloride solutions with other additives, has not been examined. The use of other solutions is not recommended.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Amifostine in adult patients.
### Non–Guideline-Supported Use
- Amifostine (500 mg/m(2))
- 2 doses of amifostine 910 mg/m(2)
- Amifostine (910 mg/m(2), days 1-3)
- Intravenous amifostine 100 mg, 200 mg, or 400 mg/m(2) 3 times per week or 740 mg/m(2) weekly for 3 consecutive weeks
- Higher doses of amifostine (750 to 900 mg/m(2)
- Amifostine 740 or 910 mg/m(2)
- Amifostine 500 mg IV before each radiotherapy session
- 340 mg/m(2) over 10 minutes daily
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- The safety and effectiveness in pediatric patients have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
The safety and effectiveness in pediatric patients have not been established.
### Non–Guideline-Supported Use
The safety and effectiveness in pediatric patients have not been established.
# Contraindications
- Amifostine for Injection is contraindicated in patients with known hypersensitivity to aminothiol compounds.
# Warnings
- Limited data are currently available regarding the preservation of antitumor efficacy when Amifostine for Injection is administered prior to cisplatin therapy in settings other than advanced ovarian cancer. Although some animal data suggest interference is possible, in most tumor models the antitumor effects of chemotherapy are not altered by amifostine. Amifostine should not be used in patients receiving chemotherapy for other malignancies in which chemotherapy can produce a significant survival benefit or cure (e.g., certain malignancies of germ cell origin), except in the context of a clinical study.
- Amifostine for Injection should not be administered in patients receiving definitive radiotherapy, except in the context of a clinical trial, since there are at present insufficient data to exclude a tumor-protective effect in this setting. Amifostine was studied only with standard fractionated radiotherapy and only when ≥75% of both parotid glands were exposed to radiation. The effects of amifostine on the incidence of xerostomia and on toxicity in the setting of combined chemotherapy and radiotherapy and in the setting of accelerated and hyperfractionated therapy have not been systematically studied.
- Patients who are hypotensive or in a state of dehydration should not receive Amifostine for Injection. Patients receiving amifostine at doses recommended for chemotherapy should have antihypertensive therapy interrupted 24 hours preceding administration of amifostine. Patients receiving amifostine at doses recommended for chemotherapy who are taking antihypertensive therapy that cannot be stopped for 24 hours preceding amifostine treatment, should not receive amifostine.
- Prior to Amifostine for Injection infusion patients should be adequately hydrated. During amifostine infusion patients should be kept in a supine position. Blood pressure should be monitored every 5 minutes during the infusion, and thereafter as clinically indicated. It is important that the duration of the 910 mg/m2 infusion not exceed 15 minutes, as administration of amifostine as a longer infusion is associated with a higher incidence of side effects. For infusion durations less than 5 minutes, blood pressure should be monitored at least before and immediately after the infusion, and thereafter as clinically indicated. If hypotension occurs, patients should be placed in the Trendelenburg position and be given an infusion of normal saline using a separate i.v. line. During and after amifostine infusion, care should be taken to monitor the blood pressure of patients whose antihypertensive medication has been interrupted since hypertension may be exacerbated by discontinuation of antihypertensive medication and other causes such as i.v. hydration.
- Guidelines for interrupting and restarting Amifostine for Injection infusion if a decrease in systolic blood pressure should occur are provided . Hypotension may occur during or shortly after amifostine infusion, despite adequate hydration and positioning of the patient . Hypotension has been reported to be associated with dyspnea, apnea, hypoxia, and in rare cases seizures, unconsciousness, respiratory arrest and renal failure.
- Serious cutaneous reactions have been associated with Amifostine for Injection administration. Serious cutaneous reactions have included erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, toxoderma and exfoliative dermatitis. These reactions have been reported more frequently when amifostine is used as a radioprotectant . Some of these reactions have been fatal or have required hospitalization and/or discontinuance of therapy. Patients should be carefully monitored prior to, during and after amifostine administration. Serious cutaneous reactions may develop weeks after initiation of amifostine administration .
- Allergic manifestations including anaphylaxis and severe cutaneous reactions have been associated with Amifostine for Injection administration.
- Antiemetic medication should be administered prior to and in conjunction with Amifostine for Injection . When amifostine is administered with highly emetogenic chemotherapy, the fluid balance of the patient should be carefully monitored.
- Serum calcium levels should be monitored in patients at risk of hypocalcemia, such as those with nephrotic syndrome or patients receiving multiple doses of Amifostine for Injection. If necessary, calcium supplements can be administered.
### Precautions
- Patients should be adequately hydrated prior to the Amifostine for Injection infusion and blood pressure should be monitored .
- The safety of Amifostine for Injection administration has not been established in elderly patients, or in patients with preexisting cardiovascular or cerebrovascular conditions such as ischemic heart disease, arrhythmias, congestive heart failure, or history of stroke or transient ischemic attacks. *Amifostine should be used with particular care in these and other patients in whom the common amifostine adverse effects of nausea/vomiting and hypotension may be more likely to have serious consequences.
- Prior to chemotherapy, Amifostine for Injection should be administered as a 15-minute infusion. Blood pressure should be monitored every 5 minutes during the infusion, and thereafter as clinically indicated.
- Prior to radiation therapy, Amifostine for Injection should be administered as a 3-minute infusion . Blood pressure should be monitored at least before and immediately after the infusion, and thereafter as clinically indicated.
- Cutaneous reactions may require permanent discontinuation of Amifostine for Injection or urgent dermatologic consultation and biopsy.
- Cutaneous evaluation of the patient prior to each Amifostine for Injection administration should be performed with particular attention paid to the development of the following:
- Any rash involving the lips or involving mucosa not known to be due to another etiology (e.g., radiation mucositis, herpes simplex, etc.)
- Erythematous, edematous, or bullous lesions on the palms of the hands or soles of the feet and/or other cutaneous reactions on the trunk (front, back, abdomen)
- Cutaneous reactions with associated fever or other constitutional symptoms.
- Cutaneous reactions must be clearly differentiated from radiation-induced dermatitis and from cutaneous reactions related to an alternate etiology. Amifostine for Injection should be permanently discontinued for serious or severe cutaneous reactions or for cutaneous reactions associated with fever or other constitutional symptoms not known to be due to another etiology. Amifostine should be withheld and dermatologic consultation and biopsy considered for cutaneous reactions or mucosal lesions of unknown etiology appearing outside of the injection site or radiation port and for erythematous, edematous or bullous lesions on the palms of the hand or soles of the feet. *Reinitiation of amifostine should be at the physician’s discretion based on medical judgment and appropriate dermatologic evaluation.
- In case of severe acute allergic reactions Amifostine for Injection should be immediately and permanently discontinued. Epinephrine and other appropriate measures should be available for treatment of serious allergic events such as anaphylaxis.
# Adverse Reactions
## Clinical Trials Experience
- In the randomized study of patients with ovarian cancer given Amifostine for Injection at a dose of 910 mg/m2 prior to chemotherapy, transient hypotension was observed in 62% of patients treated. The mean time of onset was 14 minutes into the 15-minute period of amifostine infusion, and the mean duration was 6 minutes. In some cases, the infusion had to be prematurely terminated due to a more pronounced drop in systolic blood pressure. In general, the blood pressure returned to normal within 5-15 minutes. Fewer than 3% of patients discontinued amifostine due to blood pressure reductions. In the randomized study of patients with head and neck cancer given amifostine at a dose of 200 mg/m2 prior to radiotherapy, hypotension was observed in 15% of patients treated. (see TABLE 6)
- In the randomized study of patients with head and neck cancer, 17% (26/150) discontinued Amifostine for Injection due to adverse events. All but one of these patients continued to receive radiation treatment until completion.
- Hypotension that requires interruption of the Amifostine for Injection infusion should be treated with fluid infusion and postural management of the patient (supine or Trendelenburg position). If the blood pressure returns to normal within 5 minutes and the patient is asymptomatic, the infusion may be restarted, so that the full dose of amifostine can be administered. Short term, reversible loss of consciousness has been reported rarely.
- Nausea and/or vomiting occur frequently after Amifostine for Injection infusion and may be severe. In the ovarian cancer randomized study, the incidence of severe nausea/vomiting on day 1 of cyclophosphamide-cisplatin chemotherapy was 10% in patients who did not receive amifostine, and 19% in patients who did receive amifostine. In the randomized study of patients with head and neck cancer, the incidence of severe nausea/vomiting was 8% in patients who received amifostine and 1% in patients who did not receive amifostine.
- Decrease in serum calcium concentrations is a known pharmacological effect of Amifostine for Injection. At the recommended doses, clinically significant hypocalcemia was reported in 1% of patients in the randomized head and neck cancer study .
- Other effects, which have been described during, or following Amifostine for Injection infusion are flushing/feeling of warmth, chills/feeling of coldness, malaise, fever, rash, dizziness, somnolence, hiccups and sneezing. These effects have not generally precluded the completion of therapy.
- Allergic reactions characterized by one or more of the following manifestations have been observed during or after Amifostine for Injection administration: hypotension, fever, chills/rigors, dyspnea, hypoxia, chest tightness, cutaneous eruptions, pruritus, urticaria and laryngeal edema. Cutaneous eruptions have been commonly reported during clinical trials and were generally non-serious. Serious, sometimes fatal skin reactions including erythema multiforme, and in rare cases, exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis have also occurred. *The reported incidence of serious skin reactions associated with amifostine is higher in patients receiving amifostine as a radioprotectant than in patients receiving amifostine as a chemoprotectant. Rare anaphylactoid reactions and cardiac arrest have also been reported.
- Hypotension, usually brief systolic and diastolic, has been associated with one or more of the following adverse events: apnea, dyspnea, hypoxia, tachycardia, bradycardia, extrasystoles, chest pain, myocardial ischemia and convulsion. Rare cases of renal failure, myocardial infarction, respiratory and cardiac arrest have been observed during or after hypotension.
- Rare cases of arrhythmias such as atrial fibrillation/flutter and supraventricular tachycardia have been reported. These are sometimes associated with hypotension or allergic reactions.
- Transient hypertension and exacerbations of preexisting hypertension have been observed rarely after Amifostine for Injection administration.
- Seizures and syncope have been reported rarely.
## Postmarketing Experience
There is limited information regarding Amifostine Postmarketing Experience in the drug label.
# Drug Interactions
- Special consideration should be given to the administration of Amifostine for Injection in patients receiving antihypertensive medications or other drugs that could cause or potentiate hypotension.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Amifostine has been shown to be embryotoxic in rabbits at doses of 50 mg/kg, approximately sixty percent of the recommended dose in humans on a body surface area basis. There are no adequate and well-controlled studies in pregnant women. Amifostine for Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Amifostine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Amifostine during labor and delivery.
### Nursing Mothers
- No information is available on the excretion of amifostine or its metabolites into human milk. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants, it is recommended that breast feeding be discontinued if the mother is treated with Amifostine for Injection.
### Pediatric Use
- The safety and effectiveness in pediatric patients have not been established.
### Geriatic Use
- The clinical studies did not include sufficient number 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 elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy in elderly patients.
### Gender
There is no FDA guidance on the use of Amifostine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Amifostine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Amifostine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Amifostine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Amifostine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Amifostine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
### Monitoring
- Patients should be carefully monitored prior to, during and after amifostine administration. Serious cutaneous reactions may develop weeks after initiation of amifostine administration
- Serum calcium levels should be monitored in patients at risk of hypocalcemia, such as those with nephrotic syndrome or patients receiving multiple doses of Amifostine for Injection
- Patients should be adequately hydrated prior to the Amifostine for Injection infusion and blood pressure should be monitored
# IV Compatibility
There is limited information regarding IV Compatibility of Amifostine in the drug label.
# Overdosage
- In clinical trials, the maximum single dose of Amifostine for Injection was 1300 mg/m2. No information is available on single doses higher than this in adults. In the setting of a clinical trial, pediatric patients have received single amifostine doses of up to 2700 mg/m2. At the higher doses, anxiety and reversible urinary retention occurred.
- Administration of Amifostine for Injection at 2 and 4 hours after the initial dose has not led to increased nausea and vomiting or hypotension. The most likely symptom of overdosage is hypotension, which should be managed by infusion of normal saline and other supportive measures, as clinically indicated.
# Pharmacology
## Mechanism of Action
- Amifostine is a prodrug that is dephosphorylated by alkaline phosphatase in tissues to a pharmacologically active free thiol metabolite. This metabolite is believed to be responsible for the reduction of the cumulative renal toxicity of cisplatin and for the reduction of the toxic effects of radiation on normal oral tissues. The ability of amifostine to differentially protect normal tissues is attributed to the higher capillary alkaline phosphatase activity, higher pH and better vascularity of normal tissues relative to tumor tissue, which results in a more rapid generation of the active thiol metabolite as well as a higher rate constant for uptake into cells. The higher concentration of the thiol metabolite in normal tissues is available to bind to, and thereby detoxify, reactive metabolites of cisplatin. This thiol metabolite can also scavenge reactive oxygen species generated by exposure to either cisplatin or radiation.
## Structure
- Amifostine for Injection is an organic thiophosphate cytoprotective agent known chemically as 2-ethanethiol dihydrogen phosphate (ester) and has the following structural formula:
- H2N(CH2)3NH(CH2)2S-PO3H2
- Amifostine is a white crystalline powder which is freely soluble in water. Its empirical formula is C5H15N2O3PS and it has a molecular weight of 214.22.
- Amifostine for Injection is the trihydrate form of amifostine and is supplied as a sterile lyophilized powder requiring reconstitution for intravenous infusion. Each single-use 10 mL vial contains 500 mg of amifostine on the anhydrous basis.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Amifostine in the drug label.
## Pharmacokinetics
- Clinical pharmacokinetic studies show that amifostine is rapidly cleared from the plasma with a distribution half-life of < 1 minute and an elimination half-life of approximately 8 minutes. Less than 10% of amifostine remains in the plasma 6 minutes after drug administration. Amifostine is rapidly metabolized to an active free thiol metabolite. A disulfide metabolite is produced subsequently and is less active than the free thiol. After a 10-second bolus dose of 150 mg/m2 of amifostine, renal excretion of the parent drug and its two metabolites was low during the hour following drug administration, averaging 0.69%, 2.64% and 2.22% of the administered dose for the parent, thiol and disulfide, respectively. Measurable levels of the free thiol metabolite have been found in bone marrow cells 5-8 minutes after intravenous infusion of amifostine. Pretreatment with dexamethasone or metoclopramide has no effect on amifostine pharmacokinetics.
## Nonclinical Toxicology
- No long term animal studies have been performed to evaluate the carcinogenic potential of amifostine. Amifostine was negative in the Ames test and in the mouse micronucleus test. The free thiol metabolite was positive in the Ames test with S9 microsomal fraction in the TA1535 Salmonella typhimurium strain and at the TK locus in the mouse L5178Y cell assay. The metabolite was negative in the mouse micronucleus test and negative for clastogenicity in human lymphocytes.
# Clinical Studies
- A randomized controlled trial compared six cycles of cyclophosphamide 1000 mg/m2, and cisplatin 100 mg/m2 with or without Amifostine for Injection pretreatment at 910 mg/m2, in two successive cohorts of 121 patients with advanced ovarian cancer. *In both cohorts, after multiple cycles of chemotherapy, pretreatment with amifostine significantly reduced the cumulative renal toxicity associated with cisplatin as assessed by the proportion of patients who had ≥40% decrease in creatinine clearance from pretreatment values, protracted elevations in serum creatinine (>1.5 mg/dL), or severe hypomagnesemia. Subgroup analyses suggested that the effect of amifostine was present in patients who had received nephrotoxic antibiotics, or who had preexisting diabetes or hypertension (and thus may have been at increased risk for significant nephrotoxicity), as well as in patients who lacked these risks. Selected analyses of the effects of amifostine in reducing the cumulative renal toxicity of cisplatin in the randomized ovarian cancer study are provided in TABLES 1 and 2, below.
- In the randomized ovarian cancer study, Amifostine for Injection had no detectable effect on the antitumor efficacy of cisplatin-cyclophosphamide chemotherapy. Objective response rates (including pathologically confirmed complete remission rates), time to progression, and survival duration were all similar in the amifostine and control study groups. The table below summarizes the principal efficacy findings of the randomized ovarian cancer study.
- A randomized controlled trial of standard fractionated radiation (1.8 Gy - 2.0 Gy/day for 5 days/week for 5-7 weeks) with or without Amifostine for Injection, administered at 200 mg/m2 as a 3 minute i.v. infusion 15-30 minutes prior to each fraction of radiation, was conducted in 315 patients with head and neck cancer. Patients were required to have at least 75% of both parotid glands in the radiation field. The incidence of Grade 2 or higher acute (90 days or less from start of radiation) and late xerostomia (9-12 months following radiation) as assessed by RTOG Acute and Late Morbidity Scoring Criteria, was significantly reduced in patients receiving amifostine (TABLE 4).
- At one year following radiation, whole saliva collection following radiation showed that more patients given Amifostine for Injection produced >0.1 gm of saliva (72% vs. 49%). In addition, the median saliva production at one year was higher in those patients who received amifostine (0.26 gm vs. 0.1 gm). Stimulated saliva collections did not show a difference between treatment arms. These improvements in saliva production were supported by the patients' subjective responses to a questionnaire regarding oral dryness.
- In the randomized head and neck cancer study, locoregional control, disease-free survival and overall survival were all comparable in the two treatment groups after one year of follow-up (see TABLE 5).
# How Supplied
- Amifostine for Injection is supplied as a sterile lyophilized powder in 10 mL single-use vials (NDC 55390-308-03). Each single-use vial contains 500 mg of amifostine on the anhydrous basis. The vials are available packaged as follows:
- 3 pack - 3 vials per carton (NDC 55390-308-03)
## Storage
- Store the lyophilized dosage form at Controlled Room Temperature 20°-25°C (68°-77°F) .
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Amifostine in the drug label.
# Precautions with Alcohol
- Alcohol-Amifostine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Ethyol ®
# Look-Alike Drug Names
- A® — B®
# Drug Shortage Status
# Price | Amifostine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aparna Vuppala, M.B.B.S. [2]
# Disclaimer
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# Overview
Amifostine is an cytoprotective agent that is FDA approved for the treatment of reducing the cumulative renal toxicity associated with repeated administration of cisplatin in patients with advanced ovarian cancer and also to reduce the incidence of moderate to severe xerostomia in patients undergoing post-operative radiation treatment for head and neck cancer, where the radiation port includes a substantial portion of the parotid glands. Common adverse reactions include hypotension, nausea and/or vomiting, flushing/feeling of warmth, chills/feeling of coldness, malaise, fever, rash, dizziness, somnolence, hiccups, sneezing, and decrease in serum calcium concentrations.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Amifostine for Injection is indicated to reduce the cumulative renal toxicity associated with repeated administration of cisplatin in patients with advanced ovarian cancer.
- The recommended starting dose of Amifostine for Injection is 910 mg/m2 administered once daily as a 15-minute i.v. infusion, starting 30 minutes prior to chemotherapy.
- The 15-minute infusion is better tolerated than more extended infusions. Further reductions in infusion times for chemotherapy regimens have not been systematically investigated.
- Patients should be adequately hydrated prior to Amifostine for Injection infusion and kept in a supine position during the infusion. Blood pressure should be monitored every 5 minutes during the infusion, and thereafter as clinically indicated.
- The infusion of Amifostine for Injection should be interrupted if the systolic blood pressure decreases significantly from the baseline value as listed in the guideline below:
- If the blood pressure returns to normal within 5 minutes and the patient is asymptomatic, the infusion may be restarted so that the full dose of Amifostine for Injection may be administered. If the full dose of amifostine cannot be administered, the dose of amifostine for subsequent chemotherapy cycles should be 740 mg/m2.
- It is recommended that antiemetic medication, including dexamethasone 20 mg i.v. and a serotonin 5HT3 receptor antagonist, be administered prior to and in conjunction with Amifostine for Injection. Additional antiemetics may be required based on the chemotherapy drugs administered.
- Amifostine for Injection is indicated to reduce the incidence of moderate to severe xerostomia in patients undergoing post-operative radiation treatment for head and neck cancer, where the radiation port includes a substantial portion of the parotid glands .
- For the approved indications, the clinical data do not suggest that the effectiveness of cisplatin based chemotherapy regimens or radiation therapy is altered by Amifostine for Injection. There are at present only limited data on the effects of amifostine on the efficacy of chemotherapy or radiotherapy in other settings.
- Amifostine should not be administered to patients in other settings where chemotherapy can produce a significant survival benefit or cure, or in patients receiving definitive radiotherapy, except in the context of a clinical study.
- The recommended dose of Amifostine for Injection is 200 mg/m2 administered once daily as a 3-minute i.v. infusion, starting 15-30 minutes prior to standard fraction radiation therapy (1.8-2.0 Gy).
- Patients should be adequately hydrated prior to Amifostine for Injection infusion. Blood pressure should be monitored at least before and immediately after the infusion, and thereafter as clinically indicated.
- It is recommended that antiemetic medication be administered prior to and in conjunction with Amifostine for Injection. Oral 5HT3 receptor antagonists, alone or in combination with other antiemetics, have been used effectively in the radiotherapy setting.
- Amifostine for Injection is supplied as a sterile lyophilized powder requiring reconstitution for intravenous infusion. Each single-use vial contains 500 mg of amifostine on the anhydrous basis.
- Prior to intravenous injection, Amifostine for Injection is reconstituted with 9.7 mL of sterile 0.9% Sodium Chloride Injection, USP. The reconstituted solution (500 mg amifostine/10 mL) is chemically stable for up to 5 hours at room temperature (approximately 25°C) or up to 24 hours under refrigeration (2°C to 8°C).
- Amifostine for Injection prepared in polyvinylchloride (PVC) bags at concentrations ranging from 5 mg/mL to 40 mg/mL is chemically stable for up to 5 hours when stored at room temperature (approximately 25°C) or up to 24 hours when stored under refrigeration (2°C to 8°C).
CAUTION: Parenteral products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not use if cloudiness or precipitate is observed.
- The compatibility of Amifostine for Injection with solutions other than 0.9% Sodium Chloride for Injection, or Sodium Chloride solutions with other additives, has not been examined. The use of other solutions is not recommended.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Amifostine in adult patients.
### Non–Guideline-Supported Use
- Amifostine (500 mg/m(2))[1]
- 2 doses of amifostine 910 mg/m(2)[2]
- Amifostine (910 mg/m(2), days 1-3)[3]
- Intravenous amifostine 100 mg, 200 mg, or 400 mg/m(2) 3 times per week or 740 mg/m(2) weekly for 3 consecutive weeks[4]
- Higher doses of amifostine (750 to 900 mg/m(2)[5]
- Amifostine 740 or 910 mg/m(2)[6]
- Amifostine 500 mg IV before each radiotherapy session[7]
- 340 mg/m(2) over 10 minutes daily [8]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- The safety and effectiveness in pediatric patients have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
The safety and effectiveness in pediatric patients have not been established.
### Non–Guideline-Supported Use
The safety and effectiveness in pediatric patients have not been established.
# Contraindications
- Amifostine for Injection is contraindicated in patients with known hypersensitivity to aminothiol compounds.
# Warnings
- Limited data are currently available regarding the preservation of antitumor efficacy when Amifostine for Injection is administered prior to cisplatin therapy in settings other than advanced ovarian cancer. Although some animal data suggest interference is possible, in most tumor models the antitumor effects of chemotherapy are not altered by amifostine. Amifostine should not be used in patients receiving chemotherapy for other malignancies in which chemotherapy can produce a significant survival benefit or cure (e.g., certain malignancies of germ cell origin), except in the context of a clinical study.
- Amifostine for Injection should not be administered in patients receiving definitive radiotherapy, except in the context of a clinical trial, since there are at present insufficient data to exclude a tumor-protective effect in this setting. Amifostine was studied only with standard fractionated radiotherapy and only when ≥75% of both parotid glands were exposed to radiation. The effects of amifostine on the incidence of xerostomia and on toxicity in the setting of combined chemotherapy and radiotherapy and in the setting of accelerated and hyperfractionated therapy have not been systematically studied.
- Patients who are hypotensive or in a state of dehydration should not receive Amifostine for Injection. Patients receiving amifostine at doses recommended for chemotherapy should have antihypertensive therapy interrupted 24 hours preceding administration of amifostine. Patients receiving amifostine at doses recommended for chemotherapy who are taking antihypertensive therapy that cannot be stopped for 24 hours preceding amifostine treatment, should not receive amifostine.
- Prior to Amifostine for Injection infusion patients should be adequately hydrated. During amifostine infusion patients should be kept in a supine position. Blood pressure should be monitored every 5 minutes during the infusion, and thereafter as clinically indicated. It is important that the duration of the 910 mg/m2 infusion not exceed 15 minutes, as administration of amifostine as a longer infusion is associated with a higher incidence of side effects. For infusion durations less than 5 minutes, blood pressure should be monitored at least before and immediately after the infusion, and thereafter as clinically indicated. If hypotension occurs, patients should be placed in the Trendelenburg position and be given an infusion of normal saline using a separate i.v. line. During and after amifostine infusion, care should be taken to monitor the blood pressure of patients whose antihypertensive medication has been interrupted since hypertension may be exacerbated by discontinuation of antihypertensive medication and other causes such as i.v. hydration.
- Guidelines for interrupting and restarting Amifostine for Injection infusion if a decrease in systolic blood pressure should occur are provided . Hypotension may occur during or shortly after amifostine infusion, despite adequate hydration and positioning of the patient . Hypotension has been reported to be associated with dyspnea, apnea, hypoxia, and in rare cases seizures, unconsciousness, respiratory arrest and renal failure.
- Serious cutaneous reactions have been associated with Amifostine for Injection administration. Serious cutaneous reactions have included erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, toxoderma and exfoliative dermatitis. These reactions have been reported more frequently when amifostine is used as a radioprotectant . Some of these reactions have been fatal or have required hospitalization and/or discontinuance of therapy. Patients should be carefully monitored prior to, during and after amifostine administration. Serious cutaneous reactions may develop weeks after initiation of amifostine administration .
- Allergic manifestations including anaphylaxis and severe cutaneous reactions have been associated with Amifostine for Injection administration.
- Antiemetic medication should be administered prior to and in conjunction with Amifostine for Injection . When amifostine is administered with highly emetogenic chemotherapy, the fluid balance of the patient should be carefully monitored.
- Serum calcium levels should be monitored in patients at risk of hypocalcemia, such as those with nephrotic syndrome or patients receiving multiple doses of Amifostine for Injection. If necessary, calcium supplements can be administered.
### Precautions
- Patients should be adequately hydrated prior to the Amifostine for Injection infusion and blood pressure should be monitored .
- The safety of Amifostine for Injection administration has not been established in elderly patients, or in patients with preexisting cardiovascular or cerebrovascular conditions such as ischemic heart disease, arrhythmias, congestive heart failure, or history of stroke or transient ischemic attacks. *Amifostine should be used with particular care in these and other patients in whom the common amifostine adverse effects of nausea/vomiting and hypotension may be more likely to have serious consequences.
- Prior to chemotherapy, Amifostine for Injection should be administered as a 15-minute infusion. Blood pressure should be monitored every 5 minutes during the infusion, and thereafter as clinically indicated.
- Prior to radiation therapy, Amifostine for Injection should be administered as a 3-minute infusion . Blood pressure should be monitored at least before and immediately after the infusion, and thereafter as clinically indicated.
- Cutaneous reactions may require permanent discontinuation of Amifostine for Injection or urgent dermatologic consultation and biopsy.
- Cutaneous evaluation of the patient prior to each Amifostine for Injection administration should be performed with particular attention paid to the development of the following:
- Any rash involving the lips or involving mucosa not known to be due to another etiology (e.g., radiation mucositis, herpes simplex, etc.)
- Erythematous, edematous, or bullous lesions on the palms of the hands or soles of the feet and/or other cutaneous reactions on the trunk (front, back, abdomen)
- Cutaneous reactions with associated fever or other constitutional symptoms.
- Cutaneous reactions must be clearly differentiated from radiation-induced dermatitis and from cutaneous reactions related to an alternate etiology. Amifostine for Injection should be permanently discontinued for serious or severe cutaneous reactions or for cutaneous reactions associated with fever or other constitutional symptoms not known to be due to another etiology. Amifostine should be withheld and dermatologic consultation and biopsy considered for cutaneous reactions or mucosal lesions of unknown etiology appearing outside of the injection site or radiation port and for erythematous, edematous or bullous lesions on the palms of the hand or soles of the feet. *Reinitiation of amifostine should be at the physician’s discretion based on medical judgment and appropriate dermatologic evaluation.
- In case of severe acute allergic reactions Amifostine for Injection should be immediately and permanently discontinued. Epinephrine and other appropriate measures should be available for treatment of serious allergic events such as anaphylaxis.
# Adverse Reactions
## Clinical Trials Experience
- In the randomized study of patients with ovarian cancer given Amifostine for Injection at a dose of 910 mg/m2 prior to chemotherapy, transient hypotension was observed in 62% of patients treated. The mean time of onset was 14 minutes into the 15-minute period of amifostine infusion, and the mean duration was 6 minutes. In some cases, the infusion had to be prematurely terminated due to a more pronounced drop in systolic blood pressure. In general, the blood pressure returned to normal within 5-15 minutes. Fewer than 3% of patients discontinued amifostine due to blood pressure reductions. In the randomized study of patients with head and neck cancer given amifostine at a dose of 200 mg/m2 prior to radiotherapy, hypotension was observed in 15% of patients treated. (see TABLE 6)
- In the randomized study of patients with head and neck cancer, 17% (26/150) discontinued Amifostine for Injection due to adverse events. All but one of these patients continued to receive radiation treatment until completion.
- Hypotension that requires interruption of the Amifostine for Injection infusion should be treated with fluid infusion and postural management of the patient (supine or Trendelenburg position). If the blood pressure returns to normal within 5 minutes and the patient is asymptomatic, the infusion may be restarted, so that the full dose of amifostine can be administered. Short term, reversible loss of consciousness has been reported rarely.
- Nausea and/or vomiting occur frequently after Amifostine for Injection infusion and may be severe. In the ovarian cancer randomized study, the incidence of severe nausea/vomiting on day 1 of cyclophosphamide-cisplatin chemotherapy was 10% in patients who did not receive amifostine, and 19% in patients who did receive amifostine. In the randomized study of patients with head and neck cancer, the incidence of severe nausea/vomiting was 8% in patients who received amifostine and 1% in patients who did not receive amifostine.
- Decrease in serum calcium concentrations is a known pharmacological effect of Amifostine for Injection. At the recommended doses, clinically significant hypocalcemia was reported in 1% of patients in the randomized head and neck cancer study .
- Other effects, which have been described during, or following Amifostine for Injection infusion are flushing/feeling of warmth, chills/feeling of coldness, malaise, fever, rash, dizziness, somnolence, hiccups and sneezing. These effects have not generally precluded the completion of therapy.
- Allergic reactions characterized by one or more of the following manifestations have been observed during or after Amifostine for Injection administration: hypotension, fever, chills/rigors, dyspnea, hypoxia, chest tightness, cutaneous eruptions, pruritus, urticaria and laryngeal edema. Cutaneous eruptions have been commonly reported during clinical trials and were generally non-serious. Serious, sometimes fatal skin reactions including erythema multiforme, and in rare cases, exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis have also occurred. *The reported incidence of serious skin reactions associated with amifostine is higher in patients receiving amifostine as a radioprotectant than in patients receiving amifostine as a chemoprotectant. Rare anaphylactoid reactions and cardiac arrest have also been reported.
- Hypotension, usually brief systolic and diastolic, has been associated with one or more of the following adverse events: apnea, dyspnea, hypoxia, tachycardia, bradycardia, extrasystoles, chest pain, myocardial ischemia and convulsion. Rare cases of renal failure, myocardial infarction, respiratory and cardiac arrest have been observed during or after hypotension.
- Rare cases of arrhythmias such as atrial fibrillation/flutter and supraventricular tachycardia have been reported. These are sometimes associated with hypotension or allergic reactions.
- Transient hypertension and exacerbations of preexisting hypertension have been observed rarely after Amifostine for Injection administration.
- Seizures and syncope have been reported rarely.
## Postmarketing Experience
There is limited information regarding Amifostine Postmarketing Experience in the drug label.
# Drug Interactions
- Special consideration should be given to the administration of Amifostine for Injection in patients receiving antihypertensive medications or other drugs that could cause or potentiate hypotension.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Amifostine has been shown to be embryotoxic in rabbits at doses of 50 mg/kg, approximately sixty percent of the recommended dose in humans on a body surface area basis. There are no adequate and well-controlled studies in pregnant women. Amifostine for Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Amifostine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Amifostine during labor and delivery.
### Nursing Mothers
- No information is available on the excretion of amifostine or its metabolites into human milk. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants, it is recommended that breast feeding be discontinued if the mother is treated with Amifostine for Injection.
### Pediatric Use
- The safety and effectiveness in pediatric patients have not been established.
### Geriatic Use
- The clinical studies did not include sufficient number 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 elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy in elderly patients.
### Gender
There is no FDA guidance on the use of Amifostine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Amifostine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Amifostine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Amifostine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Amifostine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Amifostine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
### Monitoring
- Patients should be carefully monitored prior to, during and after amifostine administration. Serious cutaneous reactions may develop weeks after initiation of amifostine administration
- Serum calcium levels should be monitored in patients at risk of hypocalcemia, such as those with nephrotic syndrome or patients receiving multiple doses of Amifostine for Injection
- Patients should be adequately hydrated prior to the Amifostine for Injection infusion and blood pressure should be monitored
# IV Compatibility
There is limited information regarding IV Compatibility of Amifostine in the drug label.
# Overdosage
- In clinical trials, the maximum single dose of Amifostine for Injection was 1300 mg/m2. No information is available on single doses higher than this in adults. In the setting of a clinical trial, pediatric patients have received single amifostine doses of up to 2700 mg/m2. At the higher doses, anxiety and reversible urinary retention occurred.
- Administration of Amifostine for Injection at 2 and 4 hours after the initial dose has not led to increased nausea and vomiting or hypotension. The most likely symptom of overdosage is hypotension, which should be managed by infusion of normal saline and other supportive measures, as clinically indicated.
# Pharmacology
## Mechanism of Action
- Amifostine is a prodrug that is dephosphorylated by alkaline phosphatase in tissues to a pharmacologically active free thiol metabolite. This metabolite is believed to be responsible for the reduction of the cumulative renal toxicity of cisplatin and for the reduction of the toxic effects of radiation on normal oral tissues. The ability of amifostine to differentially protect normal tissues is attributed to the higher capillary alkaline phosphatase activity, higher pH and better vascularity of normal tissues relative to tumor tissue, which results in a more rapid generation of the active thiol metabolite as well as a higher rate constant for uptake into cells. The higher concentration of the thiol metabolite in normal tissues is available to bind to, and thereby detoxify, reactive metabolites of cisplatin. This thiol metabolite can also scavenge reactive oxygen species generated by exposure to either cisplatin or radiation.
## Structure
- Amifostine for Injection is an organic thiophosphate cytoprotective agent known chemically as 2-[(3-aminopropyl)amino]ethanethiol dihydrogen phosphate (ester) and has the following structural formula:
- H2N(CH2)3NH(CH2)2S-PO3H2
- Amifostine is a white crystalline powder which is freely soluble in water. Its empirical formula is C5H15N2O3PS and it has a molecular weight of 214.22.
- Amifostine for Injection is the trihydrate form of amifostine and is supplied as a sterile lyophilized powder requiring reconstitution for intravenous infusion. Each single-use 10 mL vial contains 500 mg of amifostine on the anhydrous basis.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Amifostine in the drug label.
## Pharmacokinetics
- Clinical pharmacokinetic studies show that amifostine is rapidly cleared from the plasma with a distribution half-life of < 1 minute and an elimination half-life of approximately 8 minutes. Less than 10% of amifostine remains in the plasma 6 minutes after drug administration. Amifostine is rapidly metabolized to an active free thiol metabolite. A disulfide metabolite is produced subsequently and is less active than the free thiol. After a 10-second bolus dose of 150 mg/m2 of amifostine, renal excretion of the parent drug and its two metabolites was low during the hour following drug administration, averaging 0.69%, 2.64% and 2.22% of the administered dose for the parent, thiol and disulfide, respectively. Measurable levels of the free thiol metabolite have been found in bone marrow cells 5-8 minutes after intravenous infusion of amifostine. Pretreatment with dexamethasone or metoclopramide has no effect on amifostine pharmacokinetics.
## Nonclinical Toxicology
- No long term animal studies have been performed to evaluate the carcinogenic potential of amifostine. Amifostine was negative in the Ames test and in the mouse micronucleus test. The free thiol metabolite was positive in the Ames test with S9 microsomal fraction in the TA1535 Salmonella typhimurium strain and at the TK locus in the mouse L5178Y cell assay. The metabolite was negative in the mouse micronucleus test and negative for clastogenicity in human lymphocytes.
# Clinical Studies
- A randomized controlled trial compared six cycles of cyclophosphamide 1000 mg/m2, and cisplatin 100 mg/m2 with or without Amifostine for Injection pretreatment at 910 mg/m2, in two successive cohorts of 121 patients with advanced ovarian cancer. *In both cohorts, after multiple cycles of chemotherapy, pretreatment with amifostine significantly reduced the cumulative renal toxicity associated with cisplatin as assessed by the proportion of patients who had ≥40% decrease in creatinine clearance from pretreatment values, protracted elevations in serum creatinine (>1.5 mg/dL), or severe hypomagnesemia. Subgroup analyses suggested that the effect of amifostine was present in patients who had received nephrotoxic antibiotics, or who had preexisting diabetes or hypertension (and thus may have been at increased risk for significant nephrotoxicity), as well as in patients who lacked these risks. Selected analyses of the effects of amifostine in reducing the cumulative renal toxicity of cisplatin in the randomized ovarian cancer study are provided in TABLES 1 and 2, below.
- In the randomized ovarian cancer study, Amifostine for Injection had no detectable effect on the antitumor efficacy of cisplatin-cyclophosphamide chemotherapy. Objective response rates (including pathologically confirmed complete remission rates), time to progression, and survival duration were all similar in the amifostine and control study groups. The table below summarizes the principal efficacy findings of the randomized ovarian cancer study.
- A randomized controlled trial of standard fractionated radiation (1.8 Gy - 2.0 Gy/day for 5 days/week for 5-7 weeks) with or without Amifostine for Injection, administered at 200 mg/m2 as a 3 minute i.v. infusion 15-30 minutes prior to each fraction of radiation, was conducted in 315 patients with head and neck cancer. Patients were required to have at least 75% of both parotid glands in the radiation field. The incidence of Grade 2 or higher acute (90 days or less from start of radiation) and late xerostomia (9-12 months following radiation) as assessed by RTOG Acute and Late Morbidity Scoring Criteria, was significantly reduced in patients receiving amifostine (TABLE 4).
- At one year following radiation, whole saliva collection following radiation showed that more patients given Amifostine for Injection produced >0.1 gm of saliva (72% vs. 49%). In addition, the median saliva production at one year was higher in those patients who received amifostine (0.26 gm vs. 0.1 gm). Stimulated saliva collections did not show a difference between treatment arms. These improvements in saliva production were supported by the patients' subjective responses to a questionnaire regarding oral dryness.
- In the randomized head and neck cancer study, locoregional control, disease-free survival and overall survival were all comparable in the two treatment groups after one year of follow-up (see TABLE 5).
# How Supplied
- Amifostine for Injection is supplied as a sterile lyophilized powder in 10 mL single-use vials (NDC 55390-308-03). Each single-use vial contains 500 mg of amifostine on the anhydrous basis. The vials are available packaged as follows:
- 3 pack - 3 vials per carton (NDC 55390-308-03)
## Storage
- Store the lyophilized dosage form at Controlled Room Temperature 20°-25°C (68°-77°F) [See USP].
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Amifostine in the drug label.
# Precautions with Alcohol
- Alcohol-Amifostine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Ethyol ®
# Look-Alike Drug Names
- A® — B®
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Amifostine | |
65f098886a807b7bccc0acc6a7886111a88ed49e | wikidoc | Hemiaminal | Hemiaminal
A hemiaminal is a functional group or type of chemical compound that has a hydroxyl group and an amine attached to the same carbon atom: -C(OH)(NR2)-. R can be hydrogen or an alkyl group. Hemiaminals are intermediates in imine formation from an amine and a carbonyl by alkylimino-de-oxo-bisubstitution.
An example is of an hemiaminal is that obtained from reaction of secondary amine carbazole and formaldehyde
reaction of carbazole with formaldehyde to Carbazol-9-yl-methanol
Those generated from primary amines are unstable to the extent that they have never been isolated and very rarely been observed directly. In a 2007 study a hemiaminal substructure trapped in the cavity of a host-guest complex was studied with a chemical half-life of 30 minutes. Because both amine and carbonyl group are isolated in a cavity, hemiaminal formation is favored due to a high forward reaction rate comparable to a intramolecular reaction and also due to restricted access of external base (another amine) to the same cavity which would favor elimination of water to the imine .
Hemiaminal formation is a key step in a asymmetric total synthesis of saxitoxin :
In this reaction step the alkene group is first oxidized to an intermediate acyloin by action of osmium(III) chloride, oxone (sacrificial catalyst) and sodium carbonate (base).
# Aminal
An aminal or aminoacetal is a functional group or type of chemical compound that has two amine groups attached to the same carbon atom: -C(NR2)(NR2)-. Again R can be hydrogen or an alkyl group.
The aminal and the hemiaminal groups are the cousins of hemiacetals and acetals with nitrogen replaced by oxygen. Aminals are encountered in for instance the Fischer indole synthesis.
# Reflist
- ↑ Carbazol-9-yl-methanol Milata Viktora, Kada Rudolfa, Lokaj J¨¢nb Molbank 2004, M354 open access publication
- ↑ Reaction in methanol in reflux with potassium carbonate. Acid catalysis turns the hemiaminal to the aminal N,N´-biscarbazol-9-yl-methane.
- ↑ Stabilization of Labile Carbonyl Addition Intermediates by a Synthetic Receptor Tetsuo Iwasawa, Richard J. Hooley, Julius Rebek Jr. Science 317, 493 (2007) doi:10.1126/science.1143272
- ↑ (+)-Saxitoxin: A First and Second Generation Stereoselective Synthesis James J. Fleming, Matthew D. McReynolds, and J. Du Bois J. Am. Chem. Soc., 129 (32), 9964 -9975, 2007. doi:10.1021/ja071501o
de:Aminoacetal | Hemiaminal
A hemiaminal is a functional group or type of chemical compound that has a hydroxyl group and an amine attached to the same carbon atom: -C(OH)(NR2)-. R can be hydrogen or an alkyl group. Hemiaminals are intermediates in imine formation from an amine and a carbonyl by alkylimino-de-oxo-bisubstitution.
An example is of an hemiaminal is that obtained from reaction of secondary amine carbazole and formaldehyde [1] [2]
reaction of carbazole with formaldehyde to Carbazol-9-yl-methanol
Those generated from primary amines are unstable to the extent that they have never been isolated and very rarely been observed directly. In a 2007 study a hemiaminal substructure trapped in the cavity of a host-guest complex was studied with a chemical half-life of 30 minutes. Because both amine and carbonyl group are isolated in a cavity, hemiaminal formation is favored due to a high forward reaction rate comparable to a intramolecular reaction and also due to restricted access of external base (another amine) to the same cavity which would favor elimination of water to the imine [3].
Hemiaminal formation is a key step in a asymmetric total synthesis of saxitoxin [4]:
In this reaction step the alkene group is first oxidized to an intermediate acyloin by action of osmium(III) chloride, oxone (sacrificial catalyst) and sodium carbonate (base).
# Aminal
An aminal or aminoacetal is a functional group or type of chemical compound that has two amine groups attached to the same carbon atom: -C(NR2)(NR2)-. Again R can be hydrogen or an alkyl group.
The aminal and the hemiaminal groups are the cousins of hemiacetals and acetals with nitrogen replaced by oxygen. Aminals are encountered in for instance the Fischer indole synthesis.
# Reflist
- ↑ Carbazol-9-yl-methanol Milata Viktora, Kada Rudolfa, Lokaj J¨¢nb Molbank 2004, M354 open access publication [1]
- ↑ Reaction in methanol in reflux with potassium carbonate. Acid catalysis turns the hemiaminal to the aminal N,N´-biscarbazol-9-yl-methane.
- ↑ Stabilization of Labile Carbonyl Addition Intermediates by a Synthetic Receptor Tetsuo Iwasawa, Richard J. Hooley, Julius Rebek Jr. Science 317, 493 (2007) doi:10.1126/science.1143272
- ↑ (+)-Saxitoxin: A First and Second Generation Stereoselective Synthesis James J. Fleming, Matthew D. McReynolds, and J. Du Bois J. Am. Chem. Soc., 129 (32), 9964 -9975, 2007. doi:10.1021/ja071501o
de:Aminoacetal
Template:WH
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Aminal | |
ba79e6a57520ba96e806dbc4f600eb0464700509 | wikidoc | Amineptine | Amineptine
# Oveview
Amineptine was developed by the French Society of Medical research in the 1960s. Under the trade-names (Survector, Maneon, Directim, Neolior, Provector, Viaspera) is used as an atypical tricyclic antidepressant (TCA) that selectively inhibits the reuptake of dopamine and to a lesser extent norepinephrine, in turn producing an antidepressant effect.
Introduced in France in 1978 by the pharmaceutical company Servier and marketed under the trade name Survector, amineptine soon gained a reputation for abuse due to its short-lived, but pleasant, stimulant effect experienced by some patients. (This is to be distinguished from its antidepressant effect, which appears in approximately seven days after commencing treatment.)
After its release into the European market, cases of hepatotoxicity emerged, some serious. This, along with the potential for abuse, led to the suspension of the French marketing authorization for Survector in 1999.
Amineptine was never approved by the U.S. Food and Drug Administration (FDA) for marketing in the United States, meaning that it is not legal to market or sell amineptine for any medical uses in the US.
# Therapeutic indications
## Approved
Amineptine was approved in France for severe clinical depression of endogenous origin in 1978.
## Unapproved/off-label/investigational
Parkinson's Disease, amotivational syndromes, ADHD (Attention Deficit Hyperactivity Disorder)
# Mechanism of action
- Reuptake inhibitor of dopamine and, to a lesser extent, norepinephrine.
- Very weak muscarinic and histaminic receptor antagonist.
# Side effects
## Dermatological
Severe acne due to amineptine was first reported in 1988 by various authors—Grupper, Thioly-Bensoussan, Vexiau, Fiet, Puissant, Gourmel, Teillac, Levigne, to name a few—simultaneously in the same issue of Annales de dermatologie et de vénéréologie and in 12 March 1988 of The Lancet. A year later, Dr Martin-Ortega and colleagues in Barcelona, Spain reported a case of "acneiform eruption" in a 54-year-old woman whose intake of amineptine was described as "excessive." One year after that, Vexiau and colleagues reported six women, one of whom never admitted to using amineptine, getting severe acne concentrated in the face, back and thorax, the severity of which varied with the dosage. Most of them were treated unsuccessfully with isotretinoin (Accutane) for about 18 months; two of the three that discontinued amineptine experienced a reduction in cutaneous symptoms, with the least affected patient going into remission.
This can be seen as a general side effect of central dopamine enhancement, due to the inhibitory effect of dopamine on prolactin, with the subsequent increase in testosterone output, leading in turn to the same potential for acne as is typical of pubescents.
## Psychiatric
Psychomotor excitation can very rarely occur with this drug.
- Insomnia
- Irritability
- Nervousness
- Suicidal ideation. Seen early in the treatment, by lifting of psychomotor inhibition. This is a common occurrence with most, if not all, antidepressants.
## Cardiovascular
Very rarely:
- Arterial hypotension
- Palpitations
- Vasomotor episode
## Hepatic
Amineptine can rarely cause hepatitis, of the cytolytic, cholestatic varieties. Amineptine-induced hepatitis, which is sometimes preceded by a rash, is believed to be due to an allergic reaction. It resolves upon discontinuation of the offending drug. The risk of getting this may or may not be genetically determined.
Additionally, amineptine is known to rarely elevate transaminases, alkaline phosphatase, and bilirubin.
Mixed hepatitis, which is very rare, generally occurs between the 15th and 30th day of treatment. Often preceded by sometimes intense abdominal pains, nausea, vomiting or a rash, the jaundice is variable. Hepatitis is either of mixed type or with cholestatic prevalence. The evolution was, in all the cases, favorable to the discontinuation of the drug. The mechanism is discussed (immunoallergic and/or toxic).
In circa 1994 Spain, there was a case associating acute pancreatitis and mixed hepatitis, after three weeks of treatment.
Lazaros and colleagues at the Western Attica General Hospital in Athens, Greece reported two cases of drug induced hepatitis 18 and 15 days of treatment.
One case of cytolytic hepatitis occurred after ingestion of only one tablet.
## Gastrointestinal
- Acute pancreatitis (very rare) A case associating acute pancreatitis and mixed hepatitis after three weeks of treatment.
## Immunological
In 1989, Sgro and colleagues at the Centre de Pharmacovigilance in Dijon reported a case of anaphylactic shock in a woman who had been taking amineptine.
## Withdrawal
Pharmacodependence is very common with amineptine compared to other antidepressants. A variety of psychological symptoms can occur during withdrawal from amineptine, such as anxiety and agitation.
# Effects on the fetus
- Lacking information in humans
- Non-teratogenic in rodents
# Abuse and dependence
The risk of addiction is low, but exists nonetheless. Between 1978 and 1988, there were 186 cases of amineptine addiction reported to the French Regional Centres of Pharmacovigilance; an analysis of 155 of those cases found that they were predominantly female, and that two-thirds of cases had known risk factors for addiction. However, a 1981 study of known opiate addicts and schizophrenia patients found no drug addiction in any of the subjects. In a 1990 study of eight amineptine dependence cases, the gradual withdrawal of amineptine could be achieved without problems in six people; in two others, anxiety, psychomotor agitation, and/or bulimia appeared.
# Precautions for use
Warnings and precautions before taking amineptine:
- Breast feeding
- Children less than 15 year of age
- General anaesthesia: Discontinue the drug 24 to 48 hours before anaesthesia.
- Official sports/Olympic Games: Prohibited substance.
7 March Official Journal 2000.
- 7 March Official Journal 2000.
- Pregnancy (first trimester)
# Contraindications
- Chorea
- Hypersensitivity: Known hypersensitivity to amineptine, in particular antecedents of hepatitis after dosage of the product.
- MAO inhibitors | Amineptine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Oveview
Amineptine was developed by the French Society of Medical research in the 1960s.[3] Under the trade-names (Survector, Maneon, Directim, Neolior, Provector, Viaspera) is used as an atypical tricyclic antidepressant (TCA) that selectively inhibits the reuptake of dopamine[4] and to a lesser extent norepinephrine, in turn producing an antidepressant effect.[5]
Introduced in France in 1978 by the pharmaceutical company Servier[6] and marketed under the trade name Survector, amineptine soon gained a reputation for abuse due to its short-lived, but pleasant, stimulant effect experienced by some patients. (This is to be distinguished from its antidepressant effect, which appears in approximately seven days after commencing treatment.)
After its release into the European market, cases of hepatotoxicity emerged, some serious. This, along with the potential for abuse, led to the suspension of the French marketing authorization for Survector in 1999.[7]
Amineptine was never approved by the U.S. Food and Drug Administration (FDA) for marketing in the United States, meaning that it is not legal to market or sell amineptine for any medical uses in the US.
# Therapeutic indications
## Approved
Amineptine was approved in France for severe clinical depression of endogenous origin in 1978.[8]
## Unapproved/off-label/investigational
Parkinson's Disease, amotivational syndromes, ADHD (Attention Deficit Hyperactivity Disorder)
# Mechanism of action
- Reuptake inhibitor of dopamine and, to a lesser extent, norepinephrine.
- Very weak muscarinic and histaminic receptor antagonist.
# Side effects
## Dermatological
Severe acne due to amineptine was first reported in 1988 by various authors—Grupper, Thioly-Bensoussan, Vexiau, Fiet, Puissant, Gourmel, Teillac, Levigne, to name a few—simultaneously[9][10][11][12][13] in the same issue of Annales de dermatologie et de vénéréologie and in 12 March 1988 of The Lancet.[14] A year later, Dr Martin-Ortega and colleagues in Barcelona, Spain reported a case of "acneiform eruption" in a 54-year-old woman whose intake of amineptine was described as "excessive."[15] One year after that, Vexiau and colleagues reported six women, one of whom never admitted to using amineptine, getting severe acne concentrated in the face, back and thorax, the severity of which varied with the dosage.[16] Most of them were treated unsuccessfully with isotretinoin (Accutane) for about 18 months; two of the three that discontinued amineptine experienced a reduction in cutaneous symptoms, with the least affected patient going into remission.[16]
This can be seen as a general side effect of central dopamine enhancement, due to the inhibitory effect of dopamine on prolactin, with the subsequent increase in testosterone output, leading in turn to the same potential for acne as is typical of pubescents.[citation needed]
## Psychiatric
Psychomotor excitation can very rarely occur with this drug.
- Insomnia
- Irritability
- Nervousness
- Suicidal ideation. Seen early in the treatment, by lifting of psychomotor inhibition. This is a common occurrence with most, if not all, antidepressants.
## Cardiovascular
Very rarely:
- Arterial hypotension
- Palpitations
- Vasomotor episode
## Hepatic
Amineptine can rarely cause hepatitis, of the cytolytic, cholestatic varieties.[17] Amineptine-induced hepatitis, which is sometimes preceded by a rash, is believed to be due to an allergic reaction.[18] It resolves upon discontinuation of the offending drug.[17] The risk of getting this may or may not be genetically determined.[19]
Additionally, amineptine is known to rarely elevate transaminases, alkaline phosphatase, and bilirubin.[20]
Mixed hepatitis, which is very rare, generally occurs between the 15th and 30th day of treatment. Often preceded by sometimes intense abdominal pains, nausea, vomiting or a rash, the jaundice is variable. Hepatitis is either of mixed type or with cholestatic prevalence. The evolution was, in all the cases, favorable to the discontinuation of the drug. The mechanism is discussed (immunoallergic and/or toxic).[21]
In circa 1994 Spain, there was a case associating acute pancreatitis and mixed hepatitis, after three weeks of treatment.[22]
Lazaros and colleagues at the Western Attica General Hospital in Athens, Greece reported two cases of drug induced hepatitis 18 and 15 days of treatment.[23]
One case of cytolytic hepatitis occurred after ingestion of only one tablet.[24]
## Gastrointestinal
- Acute pancreatitis (very rare) A case associating acute pancreatitis and mixed hepatitis after three weeks of treatment.[22]
## Immunological
In 1989, Sgro and colleagues at the Centre de Pharmacovigilance[25] in Dijon reported a case of anaphylactic shock in a woman who had been taking amineptine.[26]
## Withdrawal
Pharmacodependence is very common with amineptine compared to other antidepressants.[27] A variety of psychological symptoms can occur during withdrawal from amineptine,[28] such as anxiety and agitation.[29]
# Effects on the fetus
- Lacking information in humans
- Non-teratogenic in rodents
# Abuse and dependence
The risk of addiction is low, but exists nonetheless. Between 1978 and 1988, there were 186 cases of amineptine addiction reported to the French Regional Centres of Pharmacovigilance; an analysis of 155 of those cases found that they were predominantly female, and that two-thirds of cases had known risk factors for addiction.[30] However, a 1981 study of known opiate addicts and schizophrenia patients found no drug addiction in any of the subjects.[31] In a 1990 study of eight amineptine dependence cases, the gradual withdrawal of amineptine could be achieved without problems in six people; in two others, anxiety, psychomotor agitation, and/or bulimia appeared.[32]
# Precautions for use
Warnings and precautions before taking amineptine:[33]
- Breast feeding
- Children less than 15 year of age
- General anaesthesia: Discontinue the drug 24 to 48 hours before anaesthesia.[citation needed]
- Official sports/Olympic Games: Prohibited substance.
7 March Official Journal 2000.
- 7 March Official Journal 2000.
- Pregnancy (first trimester)[citation needed]
# Contraindications
- Chorea
- Hypersensitivity: Known hypersensitivity to amineptine, in particular antecedents of hepatitis after dosage of the product.
- MAO inhibitors | https://www.wikidoc.org/index.php/Amineptine | |
65a96ba457b6c7ca04b9951e5b8bb04909cbb7d5 | wikidoc | N-terminus | N-terminus
# Overview
The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) refers to the end of a protein or polypeptide terminated by an amino acid with a free amine group (-NH2). The convention for writing peptide sequences is to put the N-terminus on the left and write the sequence from N- to C-terminus. When the protein is translated from messenger RNA, it is created from N-terminus to C-terminus.
# Chemistry
Each amino acid has a carboxyl group and an amine group, and amino acids link to one another to form a chain by a dehydration reaction by joining the amine group of one amino acid to the carboxyl group of the next. Thus polypeptide chains have an end with an unbound carboxyl group, the C-terminus, and an end with an amine group, the N-terminus.
When the protein is translated from messenger RNA, it is created from N-terminus to C-terminus. The amino end of an amino acid (on a charged tRNA) during the elongation stage of translation, attaches to the carboxyl end of the growing or nascent chain. Since the start codon of the genetic code codes for the amino acid methionine, most protein sequences start with a methionine (more specifically: the modified version N-formylmethionine, fMet). However, some proteins are modified posttranslationally, for example by cleavage from a protein precursor, and therefore may have different amino acids at their N-terminus.
# Function
## N-terminal targeting signals
The N-terminus is the first part of the protein that exits the ribosome during protein biosynthesis. It often contains sequences that act as targeting signals, basically intracellular zip codes, that allow for the protein to be delivered to its designated location within the cell. The targeting signal is usually cleaved off after successful targeting by a processing peptidase
- Signal peptide
The N-terminal signal peptide is recognized by the signal recognition particle (SRP) and results in the targeting of the protein to the secretory pathway. In eukaryotic cells, these proteins are synthesized at the rough endoplasmic reticulum. In prokaryotic cells, the proteins are exported across the cell membrane. In chloroplasts, signal peptides target proteins to the thylakoids.
- Mitochondrial targeting peptide
The N-terminal mitochondrial targeting peptide (mtTP) allows for the protein to be imported into the mitochondrion.
- Chloroplast targeting peptide
The N-terminal chloroplast targeting peptide (cpTP) allows for the protein to be imported into the chloroplast.
## N-terminal modifications
Some proteins are modified posttranslationally by the addition of membrane anchors that allow the protein to associate with membrane without having a transmembrane domain. The N-terminus (as well as the C-terminus) of a protein can be modified this way.
- N-Myristoylation
The N-terminus can be modified by the addition of a myristoyl anchor. Proteins that are modified this way contain a consensus motif at their N-terminus as a modification signal.
- N-Acylation
The N-terminus can also be modified by the addition of a fatty acid anchor to form N-acylated proteins. The most common form of such modification is the addition of a palmitoyl group. | N-terminus
# Overview
The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) refers to the end of a protein or polypeptide terminated by an amino acid with a free amine group (-NH2). The convention for writing peptide sequences is to put the N-terminus on the left and write the sequence from N- to C-terminus. When the protein is translated from messenger RNA, it is created from N-terminus to C-terminus.
# Chemistry
Each amino acid has a carboxyl group and an amine group, and amino acids link to one another to form a chain by a dehydration reaction by joining the amine group of one amino acid to the carboxyl group of the next. Thus polypeptide chains have an end with an unbound carboxyl group, the C-terminus, and an end with an amine group, the N-terminus.
When the protein is translated from messenger RNA, it is created from N-terminus to C-terminus. The amino end of an amino acid (on a charged tRNA) during the elongation stage of translation, attaches to the carboxyl end of the growing or nascent chain. Since the start codon of the genetic code codes for the amino acid methionine, most protein sequences start with a methionine (more specifically: the modified version N-formylmethionine, fMet). However, some proteins are modified posttranslationally, for example by cleavage from a protein precursor, and therefore may have different amino acids at their N-terminus.
# Function
## N-terminal targeting signals
The N-terminus is the first part of the protein that exits the ribosome during protein biosynthesis. It often contains sequences that act as targeting signals, basically intracellular zip codes, that allow for the protein to be delivered to its designated location within the cell. The targeting signal is usually cleaved off after successful targeting by a processing peptidase
- Signal peptide
The N-terminal signal peptide is recognized by the signal recognition particle (SRP) and results in the targeting of the protein to the secretory pathway. In eukaryotic cells, these proteins are synthesized at the rough endoplasmic reticulum. In prokaryotic cells, the proteins are exported across the cell membrane. In chloroplasts, signal peptides target proteins to the thylakoids.
- Mitochondrial targeting peptide
The N-terminal mitochondrial targeting peptide (mtTP) allows for the protein to be imported into the mitochondrion.
- Chloroplast targeting peptide
The N-terminal chloroplast targeting peptide (cpTP) allows for the protein to be imported into the chloroplast.
## N-terminal modifications
Some proteins are modified posttranslationally by the addition of membrane anchors that allow the protein to associate with membrane without having a transmembrane domain. The N-terminus (as well as the C-terminus) of a protein can be modified this way.
- N-Myristoylation
The N-terminus can be modified by the addition of a myristoyl anchor. Proteins that are modified this way contain a consensus motif at their N-terminus as a modification signal.
- N-Acylation
The N-terminus can also be modified by the addition of a fatty acid anchor to form N-acylated proteins. The most common form of such modification is the addition of a palmitoyl group. | https://www.wikidoc.org/index.php/Amino-terminus | |
2d939022232c4f818144e384dfd414508e1d7cf6 | wikidoc | Urea cycle | Urea cycle
The urea cycle (also known as the ornithine cycle) is a cycle of biochemical reactions occurring in many animals that produces urea from ammonia (NH3). This cycle was the first metabolic cycle discovered (Krebs and Kurt Henseleit, 1932). In mammals, the urea cycle takes place only in the liver.
# Function
Organisms that cannot easily and quickly remove ammonia usually have to convert it to some other substance, like urea or uric acid, which are much less toxic. Insufficiency of the urea cycle occurs in some genetic disorders (inborn errors of metabolism), and in liver failure. The result of liver failure is accumulation of nitrogenous waste, mainly ammonia, which leads to hepatic encephalopathy.
# Reactions
The urea cycle consists of five reactions - two mitochondrial and three cytosolic. The cycle converts two amino groups, one from NH4+ and one from Aspartic acid, and a carbon atom from HCO3-, to relatively nontoxic excretion product, urea, at the cost of four "high-energy" phosphate bonds (3 ATP hydrolyzed to 2 ADP and one AMP). Ornithine is the carrier of these carbon and nitrogen atoms.
Reactions of cycle:
Shown below is an image depicting the different steps of the urea cycle.
Overall energy requirement:
- NH3 + CO2 + Aspartate + 3 ATP + 2 H2O → urea + Fumarate + 2 ADP + 4 Pi + AMP
Overall equation of the urea cycle:
- 2 NH3 + CO2 + 3 ATP + H2O → urea + 2 ADP + 4 Pi + AMP + 2 H
Note that reactions related to the urea cycle also causes the reduction of 2 NADH, so the urea cycle releases slightly more energy than it consumes. These NADH are produced in two ways:
- One NADH molecule is reduced by the enzyme glutamate dehydrogenase in the conversion of glutamate to ammonium and α-ketoglutarate. Recall that glutamate is the non-toxic carrier of amine groups. This provides the ammonium ion used in the initial synthesis of carbamoyl phosphate.
- The fumarate released in the cytosol is converted to malate by cytosolic fumarase. This malate is then converted to oxaloacetate by cytosolic malate dehydrogenase, generating a reduced NADH in the cytosol. Oxaloacetate is one of the keto acids preferred by transaminases, and so will be recycled to aspartate, maintained the flow of nitrogen into the urea cycle.
The two NADH produced can provide energy for the formation of 5 ATP, a net production of one high energy phosphate bond for the urea cycle. However, if gluconeogenesis is underway in the cytosol, the latter reducing equivalent is used to drive the reversal of the GAPDH step instead of generating ATP.
The fate of oxaloacetate is either to produce aspartate via oxidative deaminatin or to be converted to phosphoenyl pyruvate, which is a substrate to glucose.()
An excellent way to memorize the Urea Cycle is to remember the phrase "Ordinarily Careless Crappers Are Also Frivolous About Urination." The first letter of each word corresponds to the order in which reactants are combined to give products or intermediates that break apart as one progresses through the cycle.
# Regulation
## N-Acetylglutamic acid
The synthesis of carbamoyl phosphate and the urea cycle are dependent on the presence of NAcGlu, which allosterically activates CPS1. Synthesis of NAcGlu by NAGS, is stimulated by Arg - allosteric stimulator of NAGS, and Glu - a product in the transamination reactions and one of NAGS's substrates, both of which are elevated when free amino acids are elevated. So, Arg is not only a substrate for the urea cycle reactions but also serves as an activator for the urea cycle.
## Substrate concentrations
The remaining enzymes of the cycle are controlled by the concentrations of their substrates. Thus, inherited deficiencies in the cycle enzymes other than ARG1 do not result in significant decrease in urea production (the total lack of any cycle enzyme results in death shortly after birth). Rather, the deficient enzyme's substrate builds up, increasing the rate of the deficient reaction to normal.
The anomalous substrate buildup is not without cost, however. The substrate concentrations become elevated all the way back up the cycle to NH4+, resulting in hyperammonemia (elevated P).
Although the root cause of NH4+ toxicity is not completely understood, a high
# Pathology
Diseases associated with the urea cycle include:
- Citrullinemia
- Hyperammonemia
- Ornithine translocase deficiency
- N-Acetylglutamate synthase deficiency
# Additional images
- Urea cycle.
Urea cycle. | Urea cycle
The urea cycle (also known as the ornithine cycle) is a cycle of biochemical reactions occurring in many animals that produces urea from ammonia (NH3). This cycle was the first metabolic cycle discovered (Krebs and Kurt Henseleit, 1932). In mammals, the urea cycle takes place only in the liver.
# Function
Organisms that cannot easily and quickly remove ammonia usually have to convert it to some other substance, like urea or uric acid, which are much less toxic. Insufficiency of the urea cycle occurs in some genetic disorders (inborn errors of metabolism), and in liver failure. The result of liver failure is accumulation of nitrogenous waste, mainly ammonia, which leads to hepatic encephalopathy.
# Reactions
The urea cycle consists of five reactions - two mitochondrial and three cytosolic. The cycle converts two amino groups, one from NH4+ and one from Aspartic acid, and a carbon atom from HCO3-, to relatively nontoxic excretion product, urea, at the cost of four "high-energy" phosphate bonds (3 ATP hydrolyzed to 2 ADP and one AMP). Ornithine is the carrier of these carbon and nitrogen atoms.
Reactions of cycle:
Shown below is an image depicting the different steps of the urea cycle.
Overall energy requirement:
- NH3 + CO2 + Aspartate + 3 ATP + 2 H2O → urea + Fumarate + 2 ADP + 4 Pi + AMP
Overall equation of the urea cycle:
- 2 NH3 + CO2 + 3 ATP + H2O → urea + 2 ADP + 4 Pi + AMP + 2 H
Note that reactions related to the urea cycle also causes the reduction of 2 NADH, so the urea cycle releases slightly more energy than it consumes. These NADH are produced in two ways:
- One NADH molecule is reduced by the enzyme glutamate dehydrogenase in the conversion of glutamate to ammonium and α-ketoglutarate. Recall that glutamate is the non-toxic carrier of amine groups. This provides the ammonium ion used in the initial synthesis of carbamoyl phosphate.
- The fumarate released in the cytosol is converted to malate by cytosolic fumarase. This malate is then converted to oxaloacetate by cytosolic malate dehydrogenase, generating a reduced NADH in the cytosol. Oxaloacetate is one of the keto acids preferred by transaminases, and so will be recycled to aspartate, maintained the flow of nitrogen into the urea cycle.
The two NADH produced can provide energy for the formation of 5 ATP, a net production of one high energy phosphate bond for the urea cycle. However, if gluconeogenesis is underway in the cytosol, the latter reducing equivalent is used to drive the reversal of the GAPDH step instead of generating ATP.
The fate of oxaloacetate is either to produce aspartate via oxidative deaminatin or to be converted to phosphoenyl pyruvate, which is a substrate to glucose.()
An excellent way to memorize the Urea Cycle is to remember the phrase "Ordinarily Careless Crappers Are Also Frivolous About Urination." The first letter of each word corresponds to the order in which reactants are combined to give products or intermediates that break apart as one progresses through the cycle.
# Regulation
## N-Acetylglutamic acid
The synthesis of carbamoyl phosphate and the urea cycle are dependent on the presence of NAcGlu, which allosterically activates CPS1. Synthesis of NAcGlu by NAGS, is stimulated by Arg - allosteric stimulator of NAGS, and Glu - a product in the transamination reactions and one of NAGS's substrates, both of which are elevated when free amino acids are elevated. So, Arg is not only a substrate for the urea cycle reactions but also serves as an activator for the urea cycle.
## Substrate concentrations
The remaining enzymes of the cycle are controlled by the concentrations of their substrates. Thus, inherited deficiencies in the cycle enzymes other than ARG1 do not result in significant decrease in urea production (the total lack of any cycle enzyme results in death shortly after birth). Rather, the deficient enzyme's substrate builds up, increasing the rate of the deficient reaction to normal.
The anomalous substrate buildup is not without cost, however. The substrate concentrations become elevated all the way back up the cycle to NH4+, resulting in hyperammonemia (elevated [NH4+]P).
Although the root cause of NH4+ toxicity is not completely understood, a high [NH4+] puts an enormous strain on the NH4+-clearing system, especially in the brain (symptoms of urea cycle enzyme deficiencies include mental retardation and lethargy). This clearing system involves GLUD1 and GLUL, which decrease the 2OG and Glu pools. The brain is most sensitive to the depletion of these pools. Depletion of 2OG decreases the rate of TCAC, whereas Glu is both a neurotransmitter and a precursor to GABA, another neurotransmitter. [1](p.734)
# Pathology
Diseases associated with the urea cycle include:
- Citrullinemia
- Hyperammonemia
- Ornithine translocase deficiency
- N-Acetylglutamate synthase deficiency
# Additional images
- Urea cycle.
Urea cycle.
# External links
- The chemical logic behind the urea cycle
- Basic Neurochemistry - amino acid disorders
Template:Urea cycle
de:Harnstoffzyklus
it:Ciclo dell'urea
sl:Ciklus sečnine
sr:Уреа циклус
sv:Ureacykeln
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Amino_acid_catabolism | |
76d3cb5db22a9b0dc8994a8efb2529efafaaad99 | wikidoc | Amlodipine | Amlodipine
# 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
Amlodipine is a calcium channel blocker, dihydropirydine calcium channel blocker that is FDA approved for the treatment of hypertension, coronary artery disease. Common adverse reactions include flushing, palpitations, peripheral edema, abdominal pain, nausea, dizziness, headache, somnolence, fatigue.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- The usual initial antihypertensive oral dose of amlodipine is 5 mg once daily with a maximum dose of 10 mg once daily.
Small, fragile, or elderly patients, or patients with hepatic insufficiency may be started on 2.5 mg once daily and this dose may be used when adding amlodipine to other antihypertensive therapy.
Adjust dosage according to each patient's need. In general, titration should proceed over 7 to 14 days so that the physician can fully assess the patient's response to each dose level. Titration may proceed more rapidly, however, if clinically warranted, provided the patient is assessed frequently.
- Dosing Information
- The recommended dose for chronic stable or vasospastic angina is 5–10 mg, with the lower dose suggested in the elderly and in patients with hepatic insufficiency. Most patients will require 10 mg for adequate effect.
The recommended dose range for patients with coronary artery disease is 5–10 mg once daily. In clinical studies, the majority of patients required 10 mg
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Amlodipine in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- Monotherapy: 10 mg/daily.
- Combination therapy: amlodipine 5-15 mg/day + fosinopril 10-30 mg/day.
- Dosing Information
- 5-10 mg/day.
- Dosing Information
- Monotherapy: 5 mg/day, increase to 10 mg/day after first 14 days of treatment.
- Combination therapy: Amlodipine 5 mg/day for 14 days, then amlodipine 5 mg/day + benazepril 10 mg/day.
- Dosing Information
- 10 mg PO q24h.
- Dosing Information
- 10 mg/day.
- Dosing Information
- 5 mg PO q24h.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Dosing Information
- The effective antihypertensive oral dose in pediatric patients ages 6–17 years is 2.5 mg to 5 mg once daily. Doses in excess of 5 mg daily have not been studied in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Amlodipine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Amlodipine in pediatric patients.
# Contraindications
- Hypersensitivity to amlodipine.
# Warnings
Symptomatic hypotension is possible, particularly in patients with severe aortic stenosis. Because of the gradual onset of action, acute hypotension is unlikely.
Worsening angina and acute myocardial infarction can develop after starting or increasing the dose of amlodipine, particularly in patients with severe obstructive coronary artery disease.
Amlodipine is not a beta-blocker and therefore gives no protection against the dangers of abrupt beta-blocker withdrawal; any such withdrawal should be by gradual reduction of the dose of beta-blocker.
# 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.
Amlodipine has been evaluated for safety in more than 11,000 patients in U.S. and foreign clinical trials. In general, treatment with amlodipine was well-tolerated at doses up to 10 mg daily. Most adverse reactions reported during therapy with amlodipine were of mild or moderate severity. In controlled clinical trials directly comparing amlodipine (N=1730) at doses up to 10 mg to placebo (N=1250), discontinuation of amlodipine due to adverse reactions was required in only about 1.5% of patients and was not significantly different from placebo (about 1%). The most common side effects are headache and edema. The incidence (%) of side effects that occurred in a dose related manner are as follows:
Other adverse experiences that were not clearly dose related but were reported with an incidence greater than 1.0% in placebo-controlled clinical trials include the following:
For several adverse experiences that appear to be drug and dose related, there was a greater incidence in women than men associated with amlodipine treatment as shown in the following table:
The following events occurred in 0.1% of patients in controlled clinical trials or under conditions of open trials or marketing experience where a causal relationship is uncertain; they are listed to alert the physician to a possible relationship:
- Cardiovascular: Arrhythmia (including ventricular tachycardia and atrial fibrillation), bradycardia, chest pain, hypotension, peripheral ischemia, syncope, tachycardia, postural dizziness, postural hypotension, vasculitis.
- Central and Peripheral Nervous: Hypoesthesia, neuropathy peripheral, paresthesia, tremor, vertigo.
- Gastrointestinal: Anorexia, constipation, dyspepsia,1 dysphagia, diarrhea, flatulence, pancreatitis, vomiting, gingival hyperplasia.
- General: Allergic reaction, asthenia,2 back pain,hot flushes, malaise, pain, rigors, weight gain, weight decrease.
- Musculoskeletal System: Arthralgia, arthrosis, muscle cramps,3 myalgia.
- Psychiatric: Sexual dysfunction (male4 and female), insomnia, nervousness, depression, abnormal dreams, anxiety, depersonalization.
- Respiratory System: Dyspnea, epistaxis.
- Skin and Appendages: Angioedema, erythema multiforme, pruritus,6 rash,7 rash erythematous, rash maculopapular.
- Special Senses: Abnormal vision, conjunctivitis, diplopia, eye pain, tinnitus.
- Urinary System: Micturition frequency, micturition disorder, nocturia.
- Autonomic Nervous System: Dry mouth, sweating increased.
- Metabolic and Nutritional: Hyperglycemia, thirst.
- Hemopoietic: Leukopenia, purpura, thrombocytopenia.
Amlodipine therapy has not been associated with clinically significant changes in routine laboratory tests. No clinically relevant changes were noted in serum potassium, serum glucose, total triglycerides, total cholesterol, HDL cholesterol, uric acid, blood urea nitrogen, or creatinine.
In the CAMELOT and PREVENT studies, the adverse event profile was similar to that reported previously (see above), with the most common adverse event being peripheral edema.
## Postmarketing Experience
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 postmarketing event has been reported infrequently where a causal relationship is uncertain: gynecomastia. In postmarketing experience, jaundice and hepatic enzyme elevations (mostly consistent with cholestasis or hepatitis), in some cases severe enough to require hospitalization, have been reported in association with use of amlodipine.
Amlodipine has been used safely in patients with chronic obstructive pulmonary disease, well-compensated congestive heart failure, coronary artery disease, peripheral vascular disease, diabetes mellitus, and abnormal lipid profiles.
# Drug Interactions
In vitro data indicate that amlodipine has no effect on the human plasma protein binding of digoxin, phenytoin, warfarin, and indomethacin.
Co-administration of amlodipine with cimetidine did not alter the pharmacokinetics of amlodipine.
Co-administration of 240 mL of grapefruit juice with a single oral dose of amlodipine 10 mg in 20 healthy volunteers had no significant effect on the pharmacokinetics of amlodipine.
Co-administration of a magnesium and aluminum hydroxide antacid with a single dose of amlodipine had no significant effect on the pharmacokinetics of amlodipine .
A single 100 mg dose of sildenafil in subjects with essential hypertension had no effect on the pharmacokinetic parameters of amlodipine. When amlodipine and sildenafil were used in combination, each agent independently exerted its own blood pressure lowering effect.
Co-administration of multiple 10 mg doses of amlodipine with 80 mg of atorvastatin resulted in no significant change in the steady-state pharmacokinetic parameters of atorvastatin.
Co-administration of multiple doses of 10 mg of amlodipine with 80 mg simvastatin resulted in a 77% increase in exposure to simvastatin compared to simvastatin alone. Limit the dose of simvastatin in patients on amlodipine to 20 mg daily.
Co-administration of amlodipine with digoxin did not change serum digoxin levels or digoxin renal clearance in normal volunteers.
Single and multiple 10 mg doses of amlodipine had no significant effect on the pharmacokinetics of ethanol.
Co-administration of amlodipine with warfarin did not change the warfarin prothrombin response time.
Co-administration of a 180 mg daily dose of diltiazem with 5 mg amlodipine in elderly hypertensive patients resulted in a 60% increase in amlodipine systemic exposure. Erythromycin co-administration in healthy volunteers did not significantly change amlodipine systemic exposure. However, strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, ritonavir) may increase the plasma concentrations of amlodipine to a greater extent. Monitor for symptoms of hypotension and edema when amlodipine is co-administered with CYP3A4 inhibitors.
No information is available on the quantitative effects of CYP3A4 inducers on amlodipine. Blood pressure should be closely monitored when amlodipine is co-administered with CYP3A4 inducers.
None known.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
There are no adequate and well-controlled studies in pregnant women. Amlodipine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
No evidence of teratogenicity or other embryo/fetal toxicity was found when pregnant rats and rabbits were treated orally with amlodipine maleate at doses up to 10 mg amlodipine/kg/day (respectively, 8 times8 and 23 times8 the maximum recommended human dose of 10 mg on a mg/m2 basis) during their respective periods of major organogenesis. However, litter size was significantly decreased (by about 50%) and the number of intrauterine deaths was significantly increased (about 5-fold) in rats receiving amlodipine maleate at a dose equivalent to 10 mg amlodipine/kg/day for 14 days before mating and throughout mating and gestation. Amlodipine maleate has been shown to prolong both the gestation period and the duration of labor in rats at this dose.
- 8Based on patient weight of 50 kg.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Amlodipine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Amlodipine during labor and delivery.
### Nursing Mothers
It is not known whether amlodipine is excreted in human milk. In the absence of this information, it is recommended that nursing be discontinued while amlodipine is administered.
### Pediatric Use
Effect of amlodipine on blood pressure in patients less than 6 years of age is not known.
### Geriatic Use
Clinical studies of amlodipine 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. Elderly patients have decreased clearance of amlodipine with a resulting increase of AUC of approximately 40–60%, and a lower initial dose may be required
### Gender
There is no FDA guidance on the use of Amlodipine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Amlodipine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Amlodipine in patients with renal impairment.
### Hepatic Impairment
Because amlodipine is extensively metabolized by the liver and the plasma elimination half-life (t 1/2) is 56 hours in patients with impaired hepatic function, titrate slowly when administering amlodipine to patients with severe hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Amlodipine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Amlodipine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Oral
### Monitoring
There is limited information regarding Amlodipine Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Amlodipine and IV administrations.
# Overdosage
Overdosage might be expected to cause excessive peripheral vasodilation with marked hypotension and possibly a reflex tachycardia. In humans, experience with intentional overdosage of amlodipine is limited.
Single oral doses of amlodipine maleate equivalent to 40 mg amlodipine/kg and 100 mg amlodipine/kg in mice and rats, respectively, caused deaths. Single oral amlodipine maleate doses equivalent to 4 or more mg amlodipine/kg or higher in dogs (11 or more times the maximum recommended human dose on a mg/m2 basis) caused a marked peripheral vasodilation and hypotension.
If massive overdose should occur, initiate active cardiac and respiratory monitoring. Frequent blood pressure measurements are essential. Should hypotension occur, provide cardiovascular support including elevation of the extremities and the judicious administration of fluids. If hypotension remains unresponsive to these conservative measures, consider administration of vasopressors (such as phenylephrine) with attention to circulating volume and urine output. As amlodipine is highly protein bound, hemodialysis is not likely to be of benefit.
# Pharmacology
## Mechanism of Action
Amlodipine is a dihydropyridine calcium antagonist (calcium ion antagonist or slow-channel blocker) that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. Experimental data suggest that amlodipine binds to both dihydropyridine and nondihydropyridine binding sites. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. Amlodipine inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. Negative inotropic effects can be detected in vitro but such effects have not been seen in intact animals at therapeutic doses. Serum calcium concentration is not affected by amlodipine. Within the physiologic pH range, amlodipine is an ionized compound (pKa=8.6), and its kinetic interaction with the calcium channel receptor is characterized by a gradual rate of association and dissociation with the receptor binding site, resulting in a gradual onset of effect.
Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure.
The precise mechanisms by which amlodipine relieves angina have not been fully delineated, but are thought to include the following:
In patients with exertional angina, amlodipine reduces the total peripheral resistance (afterload) against which the heart works and reduces the rate pressure product, and thus myocardial oxygen demand, at any given level of exercise.
Amlodipine has been demonstrated to block constriction and restore blood flow in coronary arteries and arterioles in response to calcium, potassium epinephrine, serotonin, and thromboxane A2 analog in experimental animal models and in human coronary vessels in vitro. This inhibition of coronary spasm is responsible for the effectiveness of amlodipine in vasospastic (Prinzmetal's or variant) angina.
## Structure
NORVASC is the besylate salt of amlodipine, a long-acting calcium channel blocker.
Amlodipine besylate is chemically described as 3-Ethyl-5-methyl (±)-2--4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate, monobenzenesulphonate. Its empirical formula is C20H25CIN2O5C6H6O3S, and its structural formula is:
Amlodipine besylate is a white crystalline powder with a molecular weight of 567.1. It is slightly soluble in water and sparingly soluble in ethanol. Amlodipine tablets are formulated as white tablets equivalent to 2.5, 5, and 10 mg of amlodipine for oral administration. In addition to the active ingredient, amlodipine besylate, each tablet contains the following inactive ingredients: microcrystalline cellulose, dibasic calcium phosphate anhydrous, sodium starch glycolate, and magnesium stearate.
## Pharmacodynamics
Following administration of therapeutic doses to patients with hypertension, amlodipine produces vasodilation resulting in a reduction of supine and standing blood pressures. These decreases in blood pressure are not accompanied by a significant change in heart rate or plasma catecholamine levels with chronic dosing. Although the acute intravenous administration of amlodipine decreases arterial blood pressure and increases heart rate in hemodynamic studies of patients with chronic stable angina, chronic oral administration of amlodipine in clinical trials did not lead to clinically significant changes in heart rate or blood pressures in normotensive patients with angina.
With chronic once daily oral administration, antihypertensive effectiveness is maintained for at least 24 hours. Plasma concentrations correlate with effect in both young and elderly patients. The magnitude of reduction in blood pressure with amlodipine is also correlated with the height of pretreatment elevation; thus, individuals with moderate hypertension (diastolic pressure 105–114 mmHg) had about a 50% greater response than patients with mild hypertension (diastolic pressure 90–104 mmHg). Normotensive subjects experienced no clinically significant change in blood pressures (+1/–2 mmHg).
In hypertensive patients with normal renal function, therapeutic doses of amlodipine resulted in a decrease in renal vascular resistance and an increase in glomerular filtration rate and effective renal plasma flow without change in filtration fraction or proteinuria.
As with other calcium channel blockers, hemodynamic measurements of cardiac function at rest and during exercise (or pacing) in patients with normal ventricular function treated with amlodipine have generally demonstrated a small increase in cardiac index without significant influence on dP/dt or on left ventricular end diastolic pressure or volume. In hemodynamic studies, amlodipine has not been associated with a negative inotropic effect when administered in the therapeutic dose range to intact animals and man, even when co-administered with beta-blockers to man. Similar findings, however, have been observed in normal or well-compensated patients with heart failure with agents possessing significant negative inotropic effects.
Amlodipine does not change sinoatrial nodal function or atrioventricular conduction in intact animals or man. In patients with chronicstable angina, intravenous administration of 10 mg did not significantly alter A-H and H-V conduction and sinus node recovery time after pacing. Similar results were obtained in patients receiving amlodipine and concomitant beta-blockers. In clinical studies in which amlodipine was administered in combination with beta-blockers to patients with either hypertension or angina, no adverse effects on electrocardiographic parameters were observed. In clinical trials with angina patients alone, amlodipine therapy did not alter electrocardiographic intervals or produce higher degrees of AV blocks.
## Pharmacokinetics
After oral administration of therapeutic doses of amlodipine, absorption produces peak plasma concentrations between 6 and 12 hours. Absolute bioavailability has been estimated to be between 64 and 90%. The bioavailability of amlodipine is not altered by the presence of food.
Amlodipine is extensively (about 90%) converted to inactive metabolites via hepatic metabolism with 10% of the parent compound and 60% of the metabolites excreted in the urine. Ex vivo studies have shown that approximately 93% of the circulating drug is bound to plasma proteins in hypertensive patients. Elimination from the plasma is biphasic with a terminal elimination half-life of about 30–50 hours. Steady-state plasma levels of amlodipine are reached after 7 to 8 days of consecutive daily dosing.
The pharmacokinetics of amlodipine are not significantly influenced by renal impairment. Patients with renal failure may therefore receive the usual initial dose.
Elderly patients and patients with hepatic insufficiency have decreased clearance of amlodipine with a resulting increase in AUC of approximately 40–60%, and a lower initial dose may be required. A similar increase in AUC was observed in patients with moderate to severe heart failure.
Sixty-two hypertensive patients aged 6 to 17 years received doses of amlodipine between 1.25 mg and 20 mg. Weight-adjusted clearance and volume of distribution were similar to values in adults.
## Nonclinical Toxicology
Rats and mice treated with amlodipine maleate in the diet for up to two years, at concentrations calculated to provide daily dosage levels of 0.5, 1.25, and 2.5 amlodipine mg/kg/day, showed no evidence of a carcinogenic effect of the drug. For the mouse, the highest dose was, on a mg/m2 basis, similar to the maximum recommended human dose of 10 mg amlodipine/day.10 For the rat, the highest dose was, on a mg/m2 basis, about twice the maximum recommended human dose.10
Mutagenicity studies conducted with amlodipine maleate revealed no drug related effects at either the gene or chromosome level.
There was no effect on the fertility of rats treated orally with amlodipine maleate (males for 64 days and females for 14 days prior to mating) at doses up to 10 mg amlodipine/kg/day (8 times the maximum recommended human dose10 of 10 mg/day on a mg/m2 basis).
- 10Based on patient weight of 50 kg
# Clinical Studies
The antihypertensive efficacy of amlodipine has been demonstrated in a total of 15 double-blind, placebo-controlled, randomized studies involving 800 patients on amlodipine and 538 on placebo. Once daily administration produced statistically significant placebo-corrected reductions in supine and standing blood pressures at 24 hours postdose, averaging about 12/6 mmHg in the standing position and 13/7 mmHg in the supine position in patients with mild to moderate hypertension. Maintenance of the blood pressure effect over the 24-hour dosing interval was observed, with little difference in peak and trough effect. Tolerance was not demonstrated in patients studied for up to 1 year. The 3 parallel, fixed dose, dose response studies showed that the reduction in supine and standing blood pressures was dose-related within the recommended dosing range. Effects on diastolic pressure were similar in young and older patients. The effect on systolic pressure was greater in older patients, perhaps because of greater baseline systolic pressure. Effects were similar in black patients and in white patients.
Two hundred sixty-eight hypertensive patients aged 6 to 17 years were randomized first to amlodipine 2.5 or 5 mg once daily for 4 weeks and then randomized again to the same dose or to placebo for another 4 weeks. Patients receiving 2.5 mg or 5 mg at the end of 8 weeks had significantly lower systolic blood pressure than those secondarily randomized to placebo. The magnitude of the treatment effect is difficult to interpret, but it is probably less than 5 mmHg systolic on the 5 mg dose and 3.3 mmHg systolic on the 2.5 mg dose. Adverse events were similar to those seen in adults.
The effectiveness of 5–10 mg/day of amlodipine in exercise-induced angina has been evaluated in 8 placebo-controlled, double-blind clinical trials of up to 6 weeks duration involving 1038 patients (684 amlodipine, 354 placebo) with chronic stable angina. In 5 of the 8 studies, significant increases in exercise time (bicycle or treadmill) were seen with the 10 mg dose. Increases in symptom-limited exercise time averaged 12.8% (63 sec) for amlodipine 10 mg, and averaged 7.9% (38 sec) for amlodipine 5 mg. amlodipine 10 mg also increased time to 1 mm ST segment deviation in several studies and decreased angina attack rate. The sustained efficacy of amlodipine in angina patients has been demonstrated over long-term dosing. In patients with angina, there were no clinically significant reductions in blood pressures (4/1 mmHg) or changes in heart rate (+0.3 bpm).
In a double-blind, placebo-controlled clinical trial of 4 weeks duration in 50 patients, amlodipine therapy decreased attacks by approximately 4/week compared with a placebo decrease of approximately 1/week (p<0.01). Two of 23 amlodipine and 7 of 27 placebo patients discontinued from the study due to lack of clinical improvement.
In PREVENT, 825 patients with angiographically documented coronary artery disease were randomized to amlodipine (5–10 mg once daily) or placebo and followed for 3 years. Although the study did not show significance on the primary objective of change in coronary luminal diameter as assessed by quantitative coronary angiography, the data suggested a favorable outcome with respect to fewer hospitalizations for angina and revascularization procedures in patients with CAD.
CAMELOT enrolled 1318 patients with CAD recently documented by angiography, without left main coronary disease and without heart failure or an ejection fraction <40%. Patients (76% males, 89% Caucasian, 93% enrolled at US sites, 89% with a history of angina, 52% without PCI, 4% with PCI and no stent, and 44% with a stent) were randomized to double-blind treatment with either amlodipine (5–10 mg once daily) or placebo in addition to standard care that included aspirin (89%), statins (83%), beta-blockers (74%), nitroglycerin (50%),-coagulants (40%), and diuretics (32%), but excluded other calcium channel blockers. The mean duration of follow-up was 19 months. The primary endpoint was the time to first occurrence of one of the following events: hospitalization for angina pectoris, coronary revascularization, myocardial infarction, cardiovascular death, resuscitated cardiac arrest, hospitalization for heart failure, stroke/TIA, or peripheral vascular disease. A total of 110 (16.6%) and 151 (23.1%) first events occurred in the amlodipine and placebo groups, respectively, for a hazard ratio of 0.691 (95% CI: 0.540–0.884, p = 0.003). The primary endpoint is summarized in Figure 1 below. The outcome of this study was largely derived from the prevention of hospitalizations for angina and the prevention of revascularization procedures (see the table below). Effects in various subgroups are shown in Figure 2.
In an angiographic substudy (n=274) conducted within CAMELOT, there was no significant difference between amlodipine and placebo on the change of atheroma volume in the coronary artery as assessed by intravascular ultrasound.
The table below summarizes the significant composite endpoint and clinical outcomes from the composites of the primary endpoint. The other components of the primary endpoint including cardiovascular death, resuscitated cardiac arrest, myocardial infarction, hospitalization for heart failure, stroke/TIA, or peripheral vascular disease did not demonstrate a significant difference between amlodipine and placebo.
amlodipine has been compared to placebo in four 8–12 week studies of patients with NYHA Class II/III heart failure, involving a total of 697 patients. In these studies, there was no evidence of worsened heart failure based on measures of exercise tolerance, NYHA classification, symptoms, or left ventricular ejection fraction. In a long-term (follow-up at least 6 months, mean 13.8 months) placebo-controlled mortality/morbidity study of amlodipine 5–10 mg in 1153 patients with NYHA Classes III (n=931) or IV (n=222) heart failure on stable doses of diuretics, digoxin, and ACE inhibitors, amlodipine had no effect on the primary endpoint of the study which was the combined endpoint of all-cause mortality and cardiac morbidity (as defined by life-threatening arrhythmia, acute myocardial infarction, or hospitalization for worsened heart failure), or on NYHA classification, or symptoms of heart failure. Total combined all-cause mortality and cardiac morbidity events were 222/571 (39%) for patients on amlodipine and 246/583 (42%) for patients on placebo; the cardiac morbid events represented about 25% of the endpoints in the study.
Another study (PRAISE-2) randomized patients with NYHA Class III (80%) or IV (20%) heart failure without clinical symptoms or objective evidence of underlying ischemic disease, on stable doses of ACE inhibitors (99%), digitalis (99%), and diuretics (99%), to placebo (n=827) or amlodipine (n=827) and followed them for a mean of 33 months. There was no statistically significant difference between amlodipine and placebo in the primary endpoint of all-cause mortality (95% confidence limits from 8% reduction to 29% increase on amlodipine). With amlodipine there were more reports of pulmonary edema.
# How Supplied
- NORVASC – 2.5 mg Tablets (amlodipine besylate equivalent to 2.5 mg of amlodipine per tablet) are supplied as white, diamond, flat-faced, beveled edged engraved with "NORVASC" on one side and "2.5" on the other side and supplied as follows:
- Bottle of 90 (NDC 0069-1520-68)
NORVASC – 5 mg Tablets (amlodipine besylate equivalent to 5 mg of amlodipine per tablet) are white, elongated octagon, flat-faced, beveled edged engraved with both "NORVASC" and "5" on one side and plain on the other side and supplied as follows:
- Bottle of 90 (NDC 0069-1530-68)
- Unit Dose package of 100 (NDC 0069-1530-41)
- Bottle of 300 (NDC 0069-1530-72)
- NORVASC – 10 mg Tablets (amlodipine besylate equivalent to 10 mg of amlodipine per tablet) are white, round, flat-faced, beveled edged engraved with both "NORVASC" and "10" on one side and plain on the other side and supplied as follows:
- Bottle of 90 (NDC 0069-1540-68)
- Unit Dose package of 100 (NDC 0069-1540-41)
## Storage
Store bottles at controlled room temperature, 59° to 86°F (15° to 30°C) and dispense in tight, light-resistant containers (USP).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Amlodipine Patient Counseling Information in the drug label.
# Precautions with Alcohol
Single and multiple 10 mg doses of amlodipine had no significant effect on the pharmacokinetics of ethanol.
# Brand Names
- Norvasc
# Look-Alike Drug Names
- Amlodipineine - Amiloride
- Norvasc - Navane
# Drug Shortage Status
Drug Shortage
# Price | Amlodipine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alonso Alvarado, M.D. [2]
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# Overview
Amlodipine is a calcium channel blocker, dihydropirydine calcium channel blocker that is FDA approved for the treatment of hypertension, coronary artery disease. Common adverse reactions include flushing, palpitations, peripheral edema, abdominal pain, nausea, dizziness, headache, somnolence, fatigue.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- The usual initial antihypertensive oral dose of amlodipine is 5 mg once daily with a maximum dose of 10 mg once daily.
Small, fragile, or elderly patients, or patients with hepatic insufficiency may be started on 2.5 mg once daily and this dose may be used when adding amlodipine to other antihypertensive therapy.
Adjust dosage according to each patient's need. In general, titration should proceed over 7 to 14 days so that the physician can fully assess the patient's response to each dose level. Titration may proceed more rapidly, however, if clinically warranted, provided the patient is assessed frequently.
- Dosing Information
- The recommended dose for chronic stable or vasospastic angina is 5–10 mg, with the lower dose suggested in the elderly and in patients with hepatic insufficiency. Most patients will require 10 mg for adequate effect.
The recommended dose range for patients with coronary artery disease is 5–10 mg once daily. In clinical studies, the majority of patients required 10 mg
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Amlodipine in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- Monotherapy: 10 mg/daily.[1]
- Combination therapy: amlodipine 5-15 mg/day + fosinopril 10-30 mg/day.[2]
- Dosing Information
- 5-10 mg/day.[3]
- Dosing Information
- Monotherapy: 5 mg/day, increase to 10 mg/day after first 14 days of treatment.
- Combination therapy: Amlodipine 5 mg/day for 14 days, then amlodipine 5 mg/day + benazepril 10 mg/day.[4]
- Dosing Information
- 10 mg PO q24h.[5]
- Dosing Information
- 10 mg/day.[6][7][8]
- Dosing Information
- 5 mg PO q24h.[9]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Dosing Information
- The effective antihypertensive oral dose in pediatric patients ages 6–17 years is 2.5 mg to 5 mg once daily. Doses in excess of 5 mg daily have not been studied in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Amlodipine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Amlodipine in pediatric patients.
# Contraindications
- Hypersensitivity to amlodipine.
# Warnings
Symptomatic hypotension is possible, particularly in patients with severe aortic stenosis. Because of the gradual onset of action, acute hypotension is unlikely.
Worsening angina and acute myocardial infarction can develop after starting or increasing the dose of amlodipine, particularly in patients with severe obstructive coronary artery disease.
Amlodipine is not a beta-blocker and therefore gives no protection against the dangers of abrupt beta-blocker withdrawal; any such withdrawal should be by gradual reduction of the dose of beta-blocker.
# 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.
Amlodipine has been evaluated for safety in more than 11,000 patients in U.S. and foreign clinical trials. In general, treatment with amlodipine was well-tolerated at doses up to 10 mg daily. Most adverse reactions reported during therapy with amlodipine were of mild or moderate severity. In controlled clinical trials directly comparing amlodipine (N=1730) at doses up to 10 mg to placebo (N=1250), discontinuation of amlodipine due to adverse reactions was required in only about 1.5% of patients and was not significantly different from placebo (about 1%). The most common side effects are headache and edema. The incidence (%) of side effects that occurred in a dose related manner are as follows:
Other adverse experiences that were not clearly dose related but were reported with an incidence greater than 1.0% in placebo-controlled clinical trials include the following:
For several adverse experiences that appear to be drug and dose related, there was a greater incidence in women than men associated with amlodipine treatment as shown in the following table:
The following events occurred in <1% but >0.1% of patients in controlled clinical trials or under conditions of open trials or marketing experience where a causal relationship is uncertain; they are listed to alert the physician to a possible relationship:
- Cardiovascular: Arrhythmia (including ventricular tachycardia and atrial fibrillation), bradycardia, chest pain, hypotension, peripheral ischemia, syncope, tachycardia, postural dizziness, postural hypotension, vasculitis.
- Central and Peripheral Nervous: Hypoesthesia, neuropathy peripheral, paresthesia, tremor, vertigo.
- Gastrointestinal: Anorexia, constipation, dyspepsia,1 dysphagia, diarrhea, flatulence, pancreatitis, vomiting, gingival hyperplasia.
- General: Allergic reaction, asthenia,2 back pain,hot flushes, malaise, pain, rigors, weight gain, weight decrease.
- Musculoskeletal System: Arthralgia, arthrosis, muscle cramps,3 myalgia.
- Psychiatric: Sexual dysfunction (male4 and female), insomnia, nervousness, depression, abnormal dreams, anxiety, depersonalization.
- Respiratory System: Dyspnea, epistaxis.
- Skin and Appendages: Angioedema, erythema multiforme, pruritus,6 rash,7 rash erythematous, rash maculopapular.
- Special Senses: Abnormal vision, conjunctivitis, diplopia, eye pain, tinnitus.
- Urinary System: Micturition frequency, micturition disorder, nocturia.
- Autonomic Nervous System: Dry mouth, sweating increased.
- Metabolic and Nutritional: Hyperglycemia, thirst.
- Hemopoietic: Leukopenia, purpura, thrombocytopenia.
Amlodipine therapy has not been associated with clinically significant changes in routine laboratory tests. No clinically relevant changes were noted in serum potassium, serum glucose, total triglycerides, total cholesterol, HDL cholesterol, uric acid, blood urea nitrogen, or creatinine.
In the CAMELOT and PREVENT studies, the adverse event profile was similar to that reported previously (see above), with the most common adverse event being peripheral edema.
## Postmarketing Experience
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 postmarketing event has been reported infrequently where a causal relationship is uncertain: gynecomastia. In postmarketing experience, jaundice and hepatic enzyme elevations (mostly consistent with cholestasis or hepatitis), in some cases severe enough to require hospitalization, have been reported in association with use of amlodipine.
Amlodipine has been used safely in patients with chronic obstructive pulmonary disease, well-compensated congestive heart failure, coronary artery disease, peripheral vascular disease, diabetes mellitus, and abnormal lipid profiles.
# Drug Interactions
In vitro data indicate that amlodipine has no effect on the human plasma protein binding of digoxin, phenytoin, warfarin, and indomethacin.
Co-administration of amlodipine with cimetidine did not alter the pharmacokinetics of amlodipine.
Co-administration of 240 mL of grapefruit juice with a single oral dose of amlodipine 10 mg in 20 healthy volunteers had no significant effect on the pharmacokinetics of amlodipine.
Co-administration of a magnesium and aluminum hydroxide antacid with a single dose of amlodipine had no significant effect on the pharmacokinetics of amlodipine .
A single 100 mg dose of sildenafil in subjects with essential hypertension had no effect on the pharmacokinetic parameters of amlodipine. When amlodipine and sildenafil were used in combination, each agent independently exerted its own blood pressure lowering effect.
Co-administration of multiple 10 mg doses of amlodipine with 80 mg of atorvastatin resulted in no significant change in the steady-state pharmacokinetic parameters of atorvastatin.
Co-administration of multiple doses of 10 mg of amlodipine with 80 mg simvastatin resulted in a 77% increase in exposure to simvastatin compared to simvastatin alone. Limit the dose of simvastatin in patients on amlodipine to 20 mg daily.
Co-administration of amlodipine with digoxin did not change serum digoxin levels or digoxin renal clearance in normal volunteers.
Single and multiple 10 mg doses of amlodipine had no significant effect on the pharmacokinetics of ethanol.
Co-administration of amlodipine with warfarin did not change the warfarin prothrombin response time.
Co-administration of a 180 mg daily dose of diltiazem with 5 mg amlodipine in elderly hypertensive patients resulted in a 60% increase in amlodipine systemic exposure. Erythromycin co-administration in healthy volunteers did not significantly change amlodipine systemic exposure. However, strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, ritonavir) may increase the plasma concentrations of amlodipine to a greater extent. Monitor for symptoms of hypotension and edema when amlodipine is co-administered with CYP3A4 inhibitors.
No information is available on the quantitative effects of CYP3A4 inducers on amlodipine. Blood pressure should be closely monitored when amlodipine is co-administered with CYP3A4 inducers.
None known.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
There are no adequate and well-controlled studies in pregnant women. Amlodipine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
No evidence of teratogenicity or other embryo/fetal toxicity was found when pregnant rats and rabbits were treated orally with amlodipine maleate at doses up to 10 mg amlodipine/kg/day (respectively, 8 times8 and 23 times8 the maximum recommended human dose of 10 mg on a mg/m2 basis) during their respective periods of major organogenesis. However, litter size was significantly decreased (by about 50%) and the number of intrauterine deaths was significantly increased (about 5-fold) in rats receiving amlodipine maleate at a dose equivalent to 10 mg amlodipine/kg/day for 14 days before mating and throughout mating and gestation. Amlodipine maleate has been shown to prolong both the gestation period and the duration of labor in rats at this dose.
- 8Based on patient weight of 50 kg.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Amlodipine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Amlodipine during labor and delivery.
### Nursing Mothers
It is not known whether amlodipine is excreted in human milk. In the absence of this information, it is recommended that nursing be discontinued while amlodipine is administered.
### Pediatric Use
Effect of amlodipine on blood pressure in patients less than 6 years of age is not known.
### Geriatic Use
Clinical studies of amlodipine 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. Elderly patients have decreased clearance of amlodipine with a resulting increase of AUC of approximately 40–60%, and a lower initial dose may be required
### Gender
There is no FDA guidance on the use of Amlodipine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Amlodipine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Amlodipine in patients with renal impairment.
### Hepatic Impairment
Because amlodipine is extensively metabolized by the liver and the plasma elimination half-life (t 1/2) is 56 hours in patients with impaired hepatic function, titrate slowly when administering amlodipine to patients with severe hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Amlodipine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Amlodipine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Oral
### Monitoring
There is limited information regarding Amlodipine Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Amlodipine and IV administrations.
# Overdosage
Overdosage might be expected to cause excessive peripheral vasodilation with marked hypotension and possibly a reflex tachycardia. In humans, experience with intentional overdosage of amlodipine is limited.
Single oral doses of amlodipine maleate equivalent to 40 mg amlodipine/kg and 100 mg amlodipine/kg in mice and rats, respectively, caused deaths. Single oral amlodipine maleate doses equivalent to 4 or more mg amlodipine/kg or higher in dogs (11 or more times the maximum recommended human dose on a mg/m2 basis) caused a marked peripheral vasodilation and hypotension.
If massive overdose should occur, initiate active cardiac and respiratory monitoring. Frequent blood pressure measurements are essential. Should hypotension occur, provide cardiovascular support including elevation of the extremities and the judicious administration of fluids. If hypotension remains unresponsive to these conservative measures, consider administration of vasopressors (such as phenylephrine) with attention to circulating volume and urine output. As amlodipine is highly protein bound, hemodialysis is not likely to be of benefit.
# Pharmacology
## Mechanism of Action
Amlodipine is a dihydropyridine calcium antagonist (calcium ion antagonist or slow-channel blocker) that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. Experimental data suggest that amlodipine binds to both dihydropyridine and nondihydropyridine binding sites. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. Amlodipine inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. Negative inotropic effects can be detected in vitro but such effects have not been seen in intact animals at therapeutic doses. Serum calcium concentration is not affected by amlodipine. Within the physiologic pH range, amlodipine is an ionized compound (pKa=8.6), and its kinetic interaction with the calcium channel receptor is characterized by a gradual rate of association and dissociation with the receptor binding site, resulting in a gradual onset of effect.
Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure.
The precise mechanisms by which amlodipine relieves angina have not been fully delineated, but are thought to include the following:
In patients with exertional angina, amlodipine reduces the total peripheral resistance (afterload) against which the heart works and reduces the rate pressure product, and thus myocardial oxygen demand, at any given level of exercise.
Amlodipine has been demonstrated to block constriction and restore blood flow in coronary arteries and arterioles in response to calcium, potassium epinephrine, serotonin, and thromboxane A2 analog in experimental animal models and in human coronary vessels in vitro. This inhibition of coronary spasm is responsible for the effectiveness of amlodipine in vasospastic (Prinzmetal's or variant) angina.
## Structure
NORVASC is the besylate salt of amlodipine, a long-acting calcium channel blocker.
Amlodipine besylate is chemically described as 3-Ethyl-5-methyl (±)-2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate, monobenzenesulphonate. Its empirical formula is C20H25CIN2O5•C6H6O3S, and its structural formula is:
Amlodipine besylate is a white crystalline powder with a molecular weight of 567.1. It is slightly soluble in water and sparingly soluble in ethanol. Amlodipine tablets are formulated as white tablets equivalent to 2.5, 5, and 10 mg of amlodipine for oral administration. In addition to the active ingredient, amlodipine besylate, each tablet contains the following inactive ingredients: microcrystalline cellulose, dibasic calcium phosphate anhydrous, sodium starch glycolate, and magnesium stearate.
## Pharmacodynamics
Following administration of therapeutic doses to patients with hypertension, amlodipine produces vasodilation resulting in a reduction of supine and standing blood pressures. These decreases in blood pressure are not accompanied by a significant change in heart rate or plasma catecholamine levels with chronic dosing. Although the acute intravenous administration of amlodipine decreases arterial blood pressure and increases heart rate in hemodynamic studies of patients with chronic stable angina, chronic oral administration of amlodipine in clinical trials did not lead to clinically significant changes in heart rate or blood pressures in normotensive patients with angina.
With chronic once daily oral administration, antihypertensive effectiveness is maintained for at least 24 hours. Plasma concentrations correlate with effect in both young and elderly patients. The magnitude of reduction in blood pressure with amlodipine is also correlated with the height of pretreatment elevation; thus, individuals with moderate hypertension (diastolic pressure 105–114 mmHg) had about a 50% greater response than patients with mild hypertension (diastolic pressure 90–104 mmHg). Normotensive subjects experienced no clinically significant change in blood pressures (+1/–2 mmHg).
In hypertensive patients with normal renal function, therapeutic doses of amlodipine resulted in a decrease in renal vascular resistance and an increase in glomerular filtration rate and effective renal plasma flow without change in filtration fraction or proteinuria.
As with other calcium channel blockers, hemodynamic measurements of cardiac function at rest and during exercise (or pacing) in patients with normal ventricular function treated with amlodipine have generally demonstrated a small increase in cardiac index without significant influence on dP/dt or on left ventricular end diastolic pressure or volume. In hemodynamic studies, amlodipine has not been associated with a negative inotropic effect when administered in the therapeutic dose range to intact animals and man, even when co-administered with beta-blockers to man. Similar findings, however, have been observed in normal or well-compensated patients with heart failure with agents possessing significant negative inotropic effects.
Amlodipine does not change sinoatrial nodal function or atrioventricular conduction in intact animals or man. In patients with chronicstable angina, intravenous administration of 10 mg did not significantly alter A-H and H-V conduction and sinus node recovery time after pacing. Similar results were obtained in patients receiving amlodipine and concomitant beta-blockers. In clinical studies in which amlodipine was administered in combination with beta-blockers to patients with either hypertension or angina, no adverse effects on electrocardiographic parameters were observed. In clinical trials with angina patients alone, amlodipine therapy did not alter electrocardiographic intervals or produce higher degrees of AV blocks.
## Pharmacokinetics
After oral administration of therapeutic doses of amlodipine, absorption produces peak plasma concentrations between 6 and 12 hours. Absolute bioavailability has been estimated to be between 64 and 90%. The bioavailability of amlodipine is not altered by the presence of food.
Amlodipine is extensively (about 90%) converted to inactive metabolites via hepatic metabolism with 10% of the parent compound and 60% of the metabolites excreted in the urine. Ex vivo studies have shown that approximately 93% of the circulating drug is bound to plasma proteins in hypertensive patients. Elimination from the plasma is biphasic with a terminal elimination half-life of about 30–50 hours. Steady-state plasma levels of amlodipine are reached after 7 to 8 days of consecutive daily dosing.
The pharmacokinetics of amlodipine are not significantly influenced by renal impairment. Patients with renal failure may therefore receive the usual initial dose.
Elderly patients and patients with hepatic insufficiency have decreased clearance of amlodipine with a resulting increase in AUC of approximately 40–60%, and a lower initial dose may be required. A similar increase in AUC was observed in patients with moderate to severe heart failure.
Sixty-two hypertensive patients aged 6 to 17 years received doses of amlodipine between 1.25 mg and 20 mg. Weight-adjusted clearance and volume of distribution were similar to values in adults.
## Nonclinical Toxicology
Rats and mice treated with amlodipine maleate in the diet for up to two years, at concentrations calculated to provide daily dosage levels of 0.5, 1.25, and 2.5 amlodipine mg/kg/day, showed no evidence of a carcinogenic effect of the drug. For the mouse, the highest dose was, on a mg/m2 basis, similar to the maximum recommended human dose of 10 mg amlodipine/day.10 For the rat, the highest dose was, on a mg/m2 basis, about twice the maximum recommended human dose.10
Mutagenicity studies conducted with amlodipine maleate revealed no drug related effects at either the gene or chromosome level.
There was no effect on the fertility of rats treated orally with amlodipine maleate (males for 64 days and females for 14 days prior to mating) at doses up to 10 mg amlodipine/kg/day (8 times the maximum recommended human dose10 of 10 mg/day on a mg/m2 basis).
- 10Based on patient weight of 50 kg
# Clinical Studies
The antihypertensive efficacy of amlodipine has been demonstrated in a total of 15 double-blind, placebo-controlled, randomized studies involving 800 patients on amlodipine and 538 on placebo. Once daily administration produced statistically significant placebo-corrected reductions in supine and standing blood pressures at 24 hours postdose, averaging about 12/6 mmHg in the standing position and 13/7 mmHg in the supine position in patients with mild to moderate hypertension. Maintenance of the blood pressure effect over the 24-hour dosing interval was observed, with little difference in peak and trough effect. Tolerance was not demonstrated in patients studied for up to 1 year. The 3 parallel, fixed dose, dose response studies showed that the reduction in supine and standing blood pressures was dose-related within the recommended dosing range. Effects on diastolic pressure were similar in young and older patients. The effect on systolic pressure was greater in older patients, perhaps because of greater baseline systolic pressure. Effects were similar in black patients and in white patients.
Two hundred sixty-eight hypertensive patients aged 6 to 17 years were randomized first to amlodipine 2.5 or 5 mg once daily for 4 weeks and then randomized again to the same dose or to placebo for another 4 weeks. Patients receiving 2.5 mg or 5 mg at the end of 8 weeks had significantly lower systolic blood pressure than those secondarily randomized to placebo. The magnitude of the treatment effect is difficult to interpret, but it is probably less than 5 mmHg systolic on the 5 mg dose and 3.3 mmHg systolic on the 2.5 mg dose. Adverse events were similar to those seen in adults.
The effectiveness of 5–10 mg/day of amlodipine in exercise-induced angina has been evaluated in 8 placebo-controlled, double-blind clinical trials of up to 6 weeks duration involving 1038 patients (684 amlodipine, 354 placebo) with chronic stable angina. In 5 of the 8 studies, significant increases in exercise time (bicycle or treadmill) were seen with the 10 mg dose. Increases in symptom-limited exercise time averaged 12.8% (63 sec) for amlodipine 10 mg, and averaged 7.9% (38 sec) for amlodipine 5 mg. amlodipine 10 mg also increased time to 1 mm ST segment deviation in several studies and decreased angina attack rate. The sustained efficacy of amlodipine in angina patients has been demonstrated over long-term dosing. In patients with angina, there were no clinically significant reductions in blood pressures (4/1 mmHg) or changes in heart rate (+0.3 bpm).
In a double-blind, placebo-controlled clinical trial of 4 weeks duration in 50 patients, amlodipine therapy decreased attacks by approximately 4/week compared with a placebo decrease of approximately 1/week (p<0.01). Two of 23 amlodipine and 7 of 27 placebo patients discontinued from the study due to lack of clinical improvement.
In PREVENT, 825 patients with angiographically documented coronary artery disease were randomized to amlodipine (5–10 mg once daily) or placebo and followed for 3 years. Although the study did not show significance on the primary objective of change in coronary luminal diameter as assessed by quantitative coronary angiography, the data suggested a favorable outcome with respect to fewer hospitalizations for angina and revascularization procedures in patients with CAD.
CAMELOT enrolled 1318 patients with CAD recently documented by angiography, without left main coronary disease and without heart failure or an ejection fraction <40%. Patients (76% males, 89% Caucasian, 93% enrolled at US sites, 89% with a history of angina, 52% without PCI, 4% with PCI and no stent, and 44% with a stent) were randomized to double-blind treatment with either amlodipine (5–10 mg once daily) or placebo in addition to standard care that included aspirin (89%), statins (83%), beta-blockers (74%), nitroglycerin (50%),-coagulants (40%), and diuretics (32%), but excluded other calcium channel blockers. The mean duration of follow-up was 19 months. The primary endpoint was the time to first occurrence of one of the following events: hospitalization for angina pectoris, coronary revascularization, myocardial infarction, cardiovascular death, resuscitated cardiac arrest, hospitalization for heart failure, stroke/TIA, or peripheral vascular disease. A total of 110 (16.6%) and 151 (23.1%) first events occurred in the amlodipine and placebo groups, respectively, for a hazard ratio of 0.691 (95% CI: 0.540–0.884, p = 0.003). The primary endpoint is summarized in Figure 1 below. The outcome of this study was largely derived from the prevention of hospitalizations for angina and the prevention of revascularization procedures (see the table below). Effects in various subgroups are shown in Figure 2.
In an angiographic substudy (n=274) conducted within CAMELOT, there was no significant difference between amlodipine and placebo on the change of atheroma volume in the coronary artery as assessed by intravascular ultrasound.
The table below summarizes the significant composite endpoint and clinical outcomes from the composites of the primary endpoint. The other components of the primary endpoint including cardiovascular death, resuscitated cardiac arrest, myocardial infarction, hospitalization for heart failure, stroke/TIA, or peripheral vascular disease did not demonstrate a significant difference between amlodipine and placebo.
amlodipine has been compared to placebo in four 8–12 week studies of patients with NYHA Class II/III heart failure, involving a total of 697 patients. In these studies, there was no evidence of worsened heart failure based on measures of exercise tolerance, NYHA classification, symptoms, or left ventricular ejection fraction. In a long-term (follow-up at least 6 months, mean 13.8 months) placebo-controlled mortality/morbidity study of amlodipine 5–10 mg in 1153 patients with NYHA Classes III (n=931) or IV (n=222) heart failure on stable doses of diuretics, digoxin, and ACE inhibitors, amlodipine had no effect on the primary endpoint of the study which was the combined endpoint of all-cause mortality and cardiac morbidity (as defined by life-threatening arrhythmia, acute myocardial infarction, or hospitalization for worsened heart failure), or on NYHA classification, or symptoms of heart failure. Total combined all-cause mortality and cardiac morbidity events were 222/571 (39%) for patients on amlodipine and 246/583 (42%) for patients on placebo; the cardiac morbid events represented about 25% of the endpoints in the study.
Another study (PRAISE-2) randomized patients with NYHA Class III (80%) or IV (20%) heart failure without clinical symptoms or objective evidence of underlying ischemic disease, on stable doses of ACE inhibitors (99%), digitalis (99%), and diuretics (99%), to placebo (n=827) or amlodipine (n=827) and followed them for a mean of 33 months. There was no statistically significant difference between amlodipine and placebo in the primary endpoint of all-cause mortality (95% confidence limits from 8% reduction to 29% increase on amlodipine). With amlodipine there were more reports of pulmonary edema.
# How Supplied
- NORVASC – 2.5 mg Tablets (amlodipine besylate equivalent to 2.5 mg of amlodipine per tablet) are supplied as white, diamond, flat-faced, beveled edged engraved with "NORVASC" on one side and "2.5" on the other side and supplied as follows:
- Bottle of 90 (NDC 0069-1520-68)
NORVASC – 5 mg Tablets (amlodipine besylate equivalent to 5 mg of amlodipine per tablet) are white, elongated octagon, flat-faced, beveled edged engraved with both "NORVASC" and "5" on one side and plain on the other side and supplied as follows:
- Bottle of 90 (NDC 0069-1530-68)
- Unit Dose package of 100 (NDC 0069-1530-41)
- Bottle of 300 (NDC 0069-1530-72)
- NORVASC – 10 mg Tablets (amlodipine besylate equivalent to 10 mg of amlodipine per tablet) are white, round, flat-faced, beveled edged engraved with both "NORVASC" and "10" on one side and plain on the other side and supplied as follows:
- Bottle of 90 (NDC 0069-1540-68)
- Unit Dose package of 100 (NDC 0069-1540-41)
## Storage
Store bottles at controlled room temperature, 59° to 86°F (15° to 30°C) and dispense in tight, light-resistant containers (USP).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Amlodipine Patient Counseling Information in the drug label.
# Precautions with Alcohol
Single and multiple 10 mg doses of amlodipine had no significant effect on the pharmacokinetics of ethanol.
# Brand Names
- Norvasc
# Look-Alike Drug Names
- Amlodipineine - Amiloride
- Norvasc - Navane
# Drug Shortage Status
Drug Shortage
# Price | https://www.wikidoc.org/index.php/Amiodarone_precautions | |
f9b5b4b54c539a2b2c10324b96724e05e2e8336e | wikidoc | Amorolfine | Amorolfine
# Overview
Amorolfine (or amorolfin), is a morpholine antifungal drug that inhibits D14 reductase and D7-D8 isomerase, which depletes ergosterol and causes ignosterol to accumulate in the fungal cytoplasmic cell membranes. Marketed as Curanail, Loceryl, Locetar, and Odenil, amorolfine is commonly available in the form of a nail lacquer, containing 5% amorolfine as the active ingredient. It is used to treat onychomycosis (fungal infection of the toe- and fingernails). Amorolfine 5% nail lacquer in once-weekly or twice-weekly applications has been shown in two studies to be between 60% and 71% effective in treating toenail onychomycosis; complete cure rates three months after stopping treatment (after six months of treatment) were 38% and 46%. However, full experimental details of these trials were not available and since they were first reported in 1992 there have been no subsequent trials.
It is a topical solution for the treatment of toenail infections. Systemic treatments may be considered more effective.
It is approved for sale over the counter in Australia and the UK (recently re-classified to over the counter status), and is approved for the treatment of toenail fungus by prescription in other countries. It is not approved for the treatment of onychomycosis in the United States or Canada, but can be ordered from there by mail from other countries.
# Notes
- ↑ Jump up to: 1.0 1.1 Hywel C. Williams (2003). Evidence-Based Dermatology. Blackwell..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}
- ↑ It can readily be verified that Curanail is advertised on websites such as US Amazon.com, shipped from abroad. | Amorolfine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Amorolfine (or amorolfin), is a morpholine antifungal drug that inhibits D14 reductase and D7-D8 isomerase, which depletes ergosterol and causes ignosterol to accumulate in the fungal cytoplasmic cell membranes. Marketed as Curanail, Loceryl, Locetar, and Odenil, amorolfine is commonly available in the form of a nail lacquer, containing 5% amorolfine as the active ingredient. It is used to treat onychomycosis (fungal infection of the toe- and fingernails). Amorolfine 5% nail lacquer in once-weekly or twice-weekly applications has been shown in two studies to be between 60% and 71% effective in treating toenail onychomycosis; complete cure rates three months after stopping treatment (after six months of treatment) were 38% and 46%. However, full experimental details of these trials were not available and since they were first reported in 1992 there have been no subsequent trials.[1]
It is a topical solution for the treatment of toenail infections. Systemic treatments may be considered more effective.[1]
It is approved for sale over the counter in Australia and the UK (recently re-classified to over the counter status), and is approved for the treatment of toenail fungus by prescription in other countries. It is not approved for the treatment of onychomycosis in the United States or Canada, but can be ordered from there by mail from other countries.[2]
# Notes
- ↑ Jump up to: 1.0 1.1 Hywel C. Williams (2003). Evidence-Based Dermatology. Blackwell..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}
- ↑ It can readily be verified that Curanail is advertised on websites such as US Amazon.com, shipped from abroad. | https://www.wikidoc.org/index.php/Amorolfine | |
e319b2c3c5eb0edfc718d003dcfb5ef52a32f0f6 | wikidoc | Amphenicol | Amphenicol
Amphenicols are a class of antibiotics which include phenol and alcohol functional groups.
Medications in this class function by interfering with the 50S ribosome subunit.
Examples of medications in this class include chloramphenicol, thiamphenicol, and florfenicol. | Amphenicol
Amphenicols are a class of antibiotics which include phenol and alcohol functional groups.
Medications in this class function by interfering with the 50S ribosome subunit.[1]
Examples of medications in this class include chloramphenicol, thiamphenicol, and florfenicol. | https://www.wikidoc.org/index.php/Amphenicol | |
a2fd47ab840ddd8cacf514b742dc4b396c775fa8 | wikidoc | Zwitterion | Zwitterion
# Overview
A zwitterion (from German "Zwitter" — "hybrid," "hermaphrodite") is a chemical compound that is electrically neutral but carries formal positive and negative charges on different atoms. Zwitterions are polar and usually have a high solubility in water and a poor solubility in most organic solvents.
Ampholytes are molecules that contain both acidic and basic groups (and are therefore amphoteric) and will exist as zwitterions at a certain pH. This pH is known as the molecule's isoelectric point. Ampholytic molecules make good buffer solutions — they resist change to the pH of a solution by selective ionization. In the presence of acids, they will accept the hydrogen ions, removing them from the solution. In the presence of bases, they will donate hydrogen ions to the solution, again balancing the pH.
Typical examples of zwitterions are:
- Used as buffering agents most of which are included in Good's buffers:
The amino-sulfonic acid based MES, MOPS, HEPES, PIPES or CAPS
The amino-carboxylic acid (amino acid) based glycine, its derivatives bicine and tricine, and alanine
- The amino-sulfonic acid based MES, MOPS, HEPES, PIPES or CAPS
- The amino-carboxylic acid (amino acid) based glycine, its derivatives bicine and tricine, and alanine
- Used as detergents:
CHAPSO
- CHAPSO
- Natural products like the alkaloids psilocybin and lysergic acid.
- Betaines
Less common examples of zwitterions are:
- Quinonoid zwitterions.
- Drugs such as Fexofenadine (Allegra®). | Zwitterion
# Overview
A zwitterion (from German "Zwitter" — "hybrid," "hermaphrodite") is a chemical compound that is electrically neutral but carries formal positive and negative charges on different atoms.[1] Zwitterions are polar and usually have a high solubility in water and a poor solubility in most organic solvents.
Ampholytes are molecules that contain both acidic and basic groups (and are therefore amphoteric) and will exist as zwitterions at a certain pH. This pH is known as the molecule's isoelectric point. Ampholytic molecules make good buffer solutions — they resist change to the pH of a solution by selective ionization. In the presence of acids, they will accept the hydrogen ions, removing them from the solution. In the presence of bases, they will donate hydrogen ions to the solution, again balancing the pH.
Typical examples of zwitterions are:
- Used as buffering agents most of which are included in Good's buffers:
The amino-sulfonic acid based MES, MOPS, HEPES, PIPES or CAPS
The amino-carboxylic acid (amino acid) based glycine, its derivatives bicine and tricine, and alanine
- The amino-sulfonic acid based MES, MOPS, HEPES, PIPES or CAPS
- The amino-carboxylic acid (amino acid) based glycine, its derivatives bicine and tricine, and alanine
- Used as detergents:
CHAPSO
- CHAPSO
- Natural products like the alkaloids psilocybin and lysergic acid.
- Betaines
Less common examples of zwitterions are:
- Quinonoid zwitterions.
- Drugs such as Fexofenadine (Allegra®). | https://www.wikidoc.org/index.php/Ampholyte | |
20c67476b833698d80ca994304854204c01dd4ad | wikidoc | Amputation | Amputation
Amputation is the removal of a body extremity by trauma or surgery. As a surgical measure, it is used to control pain or a disease process in the affected limb, such as malignancy or gangrene. In some cases, it is carried out on individuals as a preventative surgery for such problems. A special case is the congenital amputation, a congenital disorder, where foetal limbs have been cut off by constrictive bands. In some countries, amputation of the hands or feet was or is used as a form of punishment for criminals. Amputation has also been used as a tactic in war and acts of terrorism. In some cultures and religions, minor amputations or mutilations are considered a ritual accomplishment. Unlike many non-mammalian animals, (such as lizards which shed their tails), once removed, human extremities do not grow back. A transplant or a prosthesis are the only options for recovering the loss.
# Overview
The history of human amputation can be divided into a number of periods. Initially the many thousands of years when limb loss was the result of trauma or 'nonsurgical' removal. This was followed by the hesitant beginnings of surgical intervention, mainly on gangrenous limbs or those already terribly damaged, which developed through to surgical amputations around the 15th century, the distinction is marked by the choice of the patient and the aim of saving a life and achieving a healed stump, despite the difficulties with infection and the lack of effective control for pain or blood loss. Improvements in surgical techniques were married with better haemorrhage control in the 19th century and in the 1840s with anaesthesia and around twenty years later efficient infection control. The 20th century noted marked improvements in surgical techniques and also a move to increasingly sophisticated prosthetic limbs.
# History
## Origins of the word
Amputation is derived from the Latin amputare, to cut away, from amb (about) and putare (to prune). The Latin word has never been recorded in a surgical context, being reserved to indicate punishment for criminals. The English word amputation was first applied to surgery in the 17th century, possibly first in Peter Lowe's A discourse of the Whole Art of Chirurgerie (published in either 1597 or 1612), his work was derived from 16th century French texts and early English writers also used the words "extirpation" (16th century French texts tended to use extirper), "disarticulation," and "dismemberment" (from the Old French desmembrer and a more common term before the 17th century for limb loss or removal), or simply "cutting." but by the end of the 17th century amputation had come to dominate as the accepted medical term.
# Types and causes
Types of amputation include:
- leg
amputation of digits
partial foot amputation (Chopart, Lisfranc)
ankle disarticulation (Syme, Pyrogoff)
below-knee amputation (transtibial)
knee-bearing amputation (knee disarticulation)
above knee amputation (transfemoral)
Van-ness rotation (Foot being turned around and reattached to allow the ankle joint to be used as a knee.)
hip disarticulation
hemipelvectomy
- amputation of digits
- partial foot amputation (Chopart, Lisfranc)
- ankle disarticulation (Syme, Pyrogoff)
- below-knee amputation (transtibial)
- knee-bearing amputation (knee disarticulation)
- above knee amputation (transfemoral)
- Van-ness rotation (Foot being turned around and reattached to allow the ankle joint to be used as a knee.)
- hip disarticulation
- hemipelvectomy
- arm
amputation of digits
metacarpal amputation
wrist disarticulation
forearm amputation (transradial)
elbow disarticulation
above-elbow amputation (transhumeral)
shoulder disarticulation and forequarter amputation
Krukenberg procedure
- amputation of digits
- metacarpal amputation
- wrist disarticulation
- forearm amputation (transradial)
- elbow disarticulation
- above-elbow amputation (transhumeral)
- shoulder disarticulation and forequarter amputation
- Krukenberg procedure
- teeth
The avulsion of some teeth (mainly incisives) is or was practiced by some cultures for ritual purposes (for instance in the Iberomaurusian culture of Neolithic North Africa).
- The avulsion of some teeth (mainly incisives) is or was practiced by some cultures for ritual purposes (for instance in the Iberomaurusian culture of Neolithic North Africa).
Hemicorporectomy, or amputation at the waist, is the most radical amputation.
Genital modification and mutilation may involve amputating tissue (as the case is with circumcision), although not necessarily as a result of injury or disease.
As a rule, partial amputations are preferred to preserve joint function, but in oncological surgery, disarticulation is favored.
Reasons for amputation
- Cancerous bone tumours (e.g. osteosarcoma, osteochondroma)
- Severe limb injuries in which the limb cannot be spared or attempts to spare the limb have failed
- Circulation problems
- Deformities of digits and/or limbs
- Any advanced cancers
- Gangrene
- Bone infection (osteomyelitis)
- Traumatic amputation (Amputation occurs actually at scene of accident, the limb can be partially or wholly severed)
- Amputation in utero (Amniotic band)
- Mastectomy (amputation of breast) for breast cancer
# Method
The first step is ligating the supplying artery and vein, to prevent hemorrhage. The muscles are transected, and finally the bone is sawed through with an oscillating saw. Skin and muscle flaps are then transposed over the stump, occasionally with the insertion of elements to attach a prosthesis.
# Self-amputation
In some rare cases when a person has become trapped in a deserted place, with no means of communication or hope of rescue, the victim has amputated his own limb:
- In 2007, 66-year old Al Hill amputated his leg below the knee using his pocketknife after the leg got stuck beneath a felled tree he was cutting in California.
- In 2003, 27-year old Aron Ralston amputated his forearm using his pocketknife and breaking and tearing the two bones, after the arm got stuck under a boulder when hiking in Utah.
- Also in 2003, an Australian coal miner amputated his own arm with a Stanley knife after it became trapped when the front-end loader he was driving overturned three kilometers underground.
- In the 1990s, a crab fisherman got his arm caught in the winch during a storm and had to amputate it at the shoulder, as reported in The New Englander.
Even rarer are cases where self-amputation is performed for criminal or political purposes:
- Documentary filmmaker Errol Morris was ordered to "leave town within twenty-four hours or leave in a casket" by the unnamed "king of the nubbies" of the town of Vernon, Florida (which Morris called "Nub City"), when he was researching a documentary about a bizarre scam wherein individuals would cut off their own limbs as a way to collect insurance money. The final version of Vernon, Florida contains no references to this scam.
- On March 7 1998, Daniel Rudolph, the elder brother of the 1996 Olympics bomber Eric Robert Rudolph, videotaped himself cutting off one of his own hands with an electric saw in order to "send a message to the FBI and the media."
Body Integrity Identity Disorder is a psychological condition in which an individual feels compelled to remove one or more of their body parts, usually a limb. In some cases, that individual may take drastic measures to remove the offending appendages, either by causing irreparable damage to the limb so that medical intervention can not save the limb, or by causing the limb to be severed.
# After-effects
A large proportion of amputees (50-80%) experience the phenomenon of phantom limbs; they feel body parts that are no longer there. These limbs can itch, ache, and feel as if they are moving. Some scientists believe it has to do with a kind of neural map that the brain has of the body, which sends information to the rest of the brain about limbs regardless of their existence. Phantom sensations and phantom pain may also occur after the removal of body parts other than the limbs, e.g. after amputation of the breast, extraction of a tooth (phantom tooth pain) or removal of an eye (phantom eye syndrome). A similar phenomenon is unexplained sensation in a body part unrelated to the amputated limb. It has been hypothesized that the portion of the brain responsible for processing stimulation from amputated limbs, being deprived of input, actually expands into the surrounding brain, such that an individual who has had an arm amputated will experience unexplained pressure or movement on their face or head. The individual may also experience some trauma as well as emotional discomfort.
In many cases, the phantom limb aids in adaptation to a prosthesis, as it permits the person to experience proprioception of the prosthetic limb.
Another side-effect can be heterotopic ossification, especially when a bone injury is combined with a head injury. The brain signals the bone to grow instead of scar tissue to form, and nodules and other growth can interfere with prosthetics and sometimes require further operations. This type of injury has been especially common among soldiers wounded by improvised explosive devices in the Iraq war. | Amputation
Amputation is the removal of a body extremity by trauma or surgery. As a surgical measure, it is used to control pain or a disease process in the affected limb, such as malignancy or gangrene. In some cases, it is carried out on individuals as a preventative surgery for such problems. A special case is the congenital amputation, a congenital disorder, where foetal limbs have been cut off by constrictive bands. In some countries, amputation of the hands or feet was or is used as a form of punishment for criminals. Amputation has also been used as a tactic in war and acts of terrorism. In some cultures and religions, minor amputations or mutilations are considered a ritual accomplishment. Unlike many non-mammalian animals, (such as lizards which shed their tails), once removed, human extremities do not grow back. A transplant or a prosthesis are the only options for recovering the loss.[1]
# Overview
The history of human amputation can be divided into a number of periods. Initially the many thousands of years when limb loss was the result of trauma or 'nonsurgical' removal. This was followed by the hesitant beginnings of surgical intervention, mainly on gangrenous limbs or those already terribly damaged, which developed through to surgical amputations around the 15th century, the distinction is marked by the choice of the patient and the aim of saving a life and achieving a healed stump, despite the difficulties with infection and the lack of effective control for pain or blood loss. Improvements in surgical techniques were married with better haemorrhage control in the 19th century and in the 1840s with anaesthesia and around twenty years later efficient infection control. The 20th century noted marked improvements in surgical techniques and also a move to increasingly sophisticated prosthetic limbs.
# History
## Origins of the word
Amputation is derived from the Latin amputare, to cut away, from amb (about) and putare (to prune). The Latin word has never been recorded in a surgical context, being reserved to indicate punishment for criminals. The English word amputation was first applied to surgery in the 17th century, possibly first in Peter Lowe's A discourse of the Whole Art of Chirurgerie (published in either 1597 or 1612), his work was derived from 16th century French texts and early English writers also used the words "extirpation" (16th century French texts tended to use extirper), "disarticulation," and "dismemberment" (from the Old French desmembrer and a more common term before the 17th century for limb loss or removal), or simply "cutting." but by the end of the 17th century amputation had come to dominate as the accepted medical term.
# Types and causes
Types of amputation include:
- leg
amputation of digits
partial foot amputation (Chopart, Lisfranc)
ankle disarticulation (Syme, Pyrogoff)
below-knee amputation (transtibial)
knee-bearing amputation (knee disarticulation)
above knee amputation (transfemoral)
Van-ness rotation (Foot being turned around and reattached to allow the ankle joint to be used as a knee.)
hip disarticulation
hemipelvectomy
- amputation of digits
- partial foot amputation (Chopart, Lisfranc)
- ankle disarticulation (Syme, Pyrogoff)
- below-knee amputation (transtibial)
- knee-bearing amputation (knee disarticulation)
- above knee amputation (transfemoral)
- Van-ness rotation (Foot being turned around and reattached to allow the ankle joint to be used as a knee.)
- hip disarticulation
- hemipelvectomy
- arm
amputation of digits
metacarpal amputation
wrist disarticulation
forearm amputation (transradial)
elbow disarticulation
above-elbow amputation (transhumeral)
shoulder disarticulation and forequarter amputation
Krukenberg procedure
- amputation of digits
- metacarpal amputation
- wrist disarticulation
- forearm amputation (transradial)
- elbow disarticulation
- above-elbow amputation (transhumeral)
- shoulder disarticulation and forequarter amputation
- Krukenberg procedure
- teeth
The avulsion of some teeth (mainly incisives) is or was practiced by some cultures for ritual purposes (for instance in the Iberomaurusian culture of Neolithic North Africa).
- The avulsion of some teeth (mainly incisives) is or was practiced by some cultures for ritual purposes (for instance in the Iberomaurusian culture of Neolithic North Africa).
Hemicorporectomy, or amputation at the waist, is the most radical amputation.
Genital modification and mutilation may involve amputating tissue (as the case is with circumcision), although not necessarily as a result of injury or disease.
As a rule, partial amputations are preferred to preserve joint function, but in oncological surgery, disarticulation is favored.
Reasons for amputation
- Cancerous bone tumours (e.g. osteosarcoma, osteochondroma)
- Severe limb injuries in which the limb cannot be spared or attempts to spare the limb have failed
- Circulation problems
- Deformities of digits and/or limbs
- Any advanced cancers
- Gangrene
- Bone infection (osteomyelitis)
- Traumatic amputation (Amputation occurs actually at scene of accident, the limb can be partially or wholly severed)
- Amputation in utero (Amniotic band)
- Mastectomy (amputation of breast) for breast cancer
# Method
The first step is ligating the supplying artery and vein, to prevent hemorrhage. The muscles are transected, and finally the bone is sawed through with an oscillating saw. Skin and muscle flaps are then transposed over the stump, occasionally with the insertion of elements to attach a prosthesis.
# Self-amputation
In some rare cases when a person has become trapped in a deserted place, with no means of communication or hope of rescue, the victim has amputated his own limb:
- In 2007, 66-year old Al Hill amputated his leg below the knee using his pocketknife after the leg got stuck beneath a felled tree he was cutting in California. [2]
- In 2003, 27-year old Aron Ralston amputated his forearm using his pocketknife and breaking and tearing the two bones, after the arm got stuck under a boulder when hiking in Utah.
- Also in 2003, an Australian coal miner amputated his own arm with a Stanley knife after it became trapped when the front-end loader he was driving overturned three kilometers underground. [3]
- In the 1990s, a crab fisherman got his arm caught in the winch during a storm and had to amputate it at the shoulder, as reported in The New Englander.
Even rarer are cases where self-amputation is performed for criminal or political purposes:
- Documentary filmmaker Errol Morris was ordered to "leave town within twenty-four hours or leave in a casket" by the unnamed "king of the nubbies" of the town of Vernon, Florida (which Morris called "Nub City"), when he was researching a documentary about a bizarre scam wherein individuals would cut off their own limbs as a way to collect insurance money.[4] The final version of Vernon, Florida contains no references to this scam.
- On March 7 1998, Daniel Rudolph, the elder brother of the 1996 Olympics bomber Eric Robert Rudolph, videotaped himself cutting off one of his own hands with an electric saw in order to "send a message to the FBI and the media." [5]
Body Integrity Identity Disorder is a psychological condition in which an individual feels compelled to remove one or more of their body parts, usually a limb. In some cases, that individual may take drastic measures to remove the offending appendages, either by causing irreparable damage to the limb so that medical intervention can not save the limb, or by causing the limb to be severed.
# After-effects
A large proportion of amputees (50-80%) experience the phenomenon of phantom limbs;[2] they feel body parts that are no longer there. These limbs can itch, ache, and feel as if they are moving. Some scientists believe it has to do with a kind of neural map that the brain has of the body, which sends information to the rest of the brain about limbs regardless of their existence. Phantom sensations and phantom pain may also occur after the removal of body parts other than the limbs, e.g. after amputation of the breast, extraction of a tooth (phantom tooth pain) or removal of an eye (phantom eye syndrome). A similar phenomenon is unexplained sensation in a body part unrelated to the amputated limb. It has been hypothesized that the portion of the brain responsible for processing stimulation from amputated limbs, being deprived of input, actually expands into the surrounding brain, such that an individual who has had an arm amputated will experience unexplained pressure or movement on their face or head. The individual may also experience some trauma as well as emotional discomfort.
In many cases, the phantom limb aids in adaptation to a prosthesis, as it permits the person to experience proprioception of the prosthetic limb.
Another side-effect can be heterotopic ossification, especially when a bone injury is combined with a head injury. The brain signals the bone to grow instead of scar tissue to form, and nodules and other growth can interfere with prosthetics and sometimes require further operations. This type of injury has been especially common among soldiers wounded by improvised explosive devices in the Iraq war. [6] | https://www.wikidoc.org/index.php/Amputated | |
52e751b1ee787ca5b20263987ef89ff6e101ad74 | wikidoc | Quinbolone | Quinbolone
# Overview
Quinbolone (Anabolicum Vister) is an anabolic steroid with weak androgenic effects. It was developed by Parke Davis in an attempt to create a viable orally-administered anabolic steroid with little or no liver toxicity.
The drug is atypical in that steroid molecules are usually only given officially distinct names when there is a permanent structural difference between the parent molecule and itself. Quinbolone, however, differs from its parent molecule (boldenone) solely by the addition of an easily removed cyclopentenyl ether group.
Most orally administered anabolic steroids function by having an alkylated 17α-carbon atom, which prevents first-pass metabolism by the liver. This approach does, however, give the drug a high hepatotoxicity. Quinbolone is not 17α-alkylated; instead it has increased oral bioavailability due to its cyclopentenyl ether group. This allows the drug to be fully dissolved in an oil base, which is then absorbed into the lymphatic system via the large intestine, from which it travels into the blood. Once there the ester group detaches and the relatively inactive quinbolone becomes boldenone, which then reacts with the androgen receptor of any muscles it comes into contact with.
Quinbolone itself has very few androgenic effects, and most of what it does have are a result of its conversion to boldenone and its metabolites. This, combined with its unusual route of absorption, provides the drug with highly variable results, meaning that large quantities of the drug (100-200mgs per day) must be taken in order to maintain high enough concentrations in the blood for noticeable and consistent effects. The cost and inconvenience of this meant that quinbolone never proved commercially successful, and its clinical applications were fulfilled by alternative, more effective, steroids. Its illicit usage in bodybuilding and athletics likewise proved limited, though drug tests are still used to detect its metabolites as it remains a banned substance for most competitive sports. | Quinbolone
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Quinbolone (Anabolicum Vister) is an anabolic steroid with weak androgenic effects. It was developed by Parke Davis in an attempt to create a viable orally-administered anabolic steroid with little or no liver toxicity.
The drug is atypical in that steroid molecules are usually only given officially distinct names when there is a permanent structural difference between the parent molecule and itself. Quinbolone, however, differs from its parent molecule (boldenone) solely by the addition of an easily removed cyclopentenyl ether group.
Most orally administered anabolic steroids function by having an alkylated 17α-carbon atom, which prevents first-pass metabolism by the liver. This approach does, however, give the drug a high hepatotoxicity. Quinbolone is not 17α-alkylated; instead it has increased oral bioavailability due to its cyclopentenyl ether group. This allows the drug to be fully dissolved in an oil base, which is then absorbed into the lymphatic system via the large intestine, from which it travels into the blood. Once there the ester group detaches and the relatively inactive quinbolone becomes boldenone, which then reacts with the androgen receptor of any muscles it comes into contact with.
Quinbolone itself has very few androgenic effects, and most of what it does have are a result of its conversion to boldenone and its metabolites. This, combined with its unusual route of absorption, provides the drug with highly variable results, meaning that large quantities of the drug (100-200mgs per day) must be taken in order to maintain high enough concentrations in the blood for noticeable and consistent effects. The cost and inconvenience of this meant that quinbolone never proved commercially successful, and its clinical applications were fulfilled by alternative, more effective, steroids. Its illicit usage in bodybuilding and athletics likewise proved limited, though drug tests are still used to detect its metabolites as it remains a banned substance for most competitive sports. | https://www.wikidoc.org/index.php/Anabolicum_Vister | |
51c8826c51f97d9609f4e4adc854a1e19c4c4257 | wikidoc | Anesthesia | Anesthesia
# Overview
Anesthesia or anaesthesia (from Greek αν- an- “without” + αἲσθησις aisthesis “sensation”) has traditionally meant the condition of having the feeling of pain and other sensations blocked. This allows patients to undergo surgery and other procedures without the distress and pain they would otherwise experience. The word was coined by Oliver Wendell Holmes, Sr. in 1846. Another definition is a "reversible lack of awareness", whether this is a total lack of awareness (e.g. a general anaesthestic) or a lack of awareness of a part of a the body such as a spinal anaesthetic or another nerve block would cause.
Today, the term general anesthesia in its most general form can include:
- Analgesia: blocking the conscious sensation of pain;
- Hypnosis: produces unconsciousness without analgesia;
- Amnesia: preventing memory formation;
- Relaxation: preventing unwanted movement or muscle tone;
- Obtundation of reflexes, preventing exaggerated autonomic reflexes.
Patients undergoing surgery usually undergo preoperative evaluation. It includes gathering history of previous anesthetics, and any other medical problems, physical examination, ordering required blood work and consultations prior to surgery.
There are several forms of anesthesia. The following forms refer to states achieved by anesthetics working on the brain:
- General anesthesia: "Drug-induced loss of consciousness during which patients are not arousable, even by painful stimulation." Patients undergoing general anesthesia often cannot maintain their own airway and breathe on their own. While usually administered with inhalational agents, general anesthesia can be achieved with intravenous agents, such as propofol.
- Deep sedation/analgesia: "Drug-induced depression of consciousness during which patients cannot be easily aroused but respond purposefully following repeated or painful stimulation." Patients may sometimes be unable to maintain their airway and breathe on their own.
- Moderate sedation/analgesia or conscious sedation: "Drug-induced depression of consciousness during which patients respond purposefully to verbal commands, either alone or accompanied by light tactile stimulation." In this state, patients can breathe on their own and need no help maintaining an airway.
- Minimal sedation or anxiolysis: "Drug-induced state during which patients respond normally to verbal commands." Though concentration, memory, and coordination may be impaired, patients need no help breathing or maintaining an airway.
The level of anesthesia achieved ranges on a continuum of depth of consciousness from minimal sedation to general anesthesia. The depth of consciousness of a patient may change from one minute to the next.
The following refer to states achieved by anesthetics working outside of the brain:
- Regional anesthesia: Loss of pain sensation, with varying degrees of muscle relaxation, in certain regions of the body. Administered with local anesthesia to peripheral nerve bundles, such as the brachial plexus in the neck. Examples include the interscalene block for shoulder surgery, axillary block for wrist surgery, and femoral nerve block for leg surgery. While traditionally administered as a single injection, newer techniques involve placement of indwelling catheters for continuous or intermittent administration of local anesthetics.
Spinal anesthesia: also known as subarachnoid block. Refers to a Regional block resulting from a small volume of local anesthetics being injected into the spinal canal. The spinal canal is covered by the dura mater, through which the spinal needle enters. The spinal canal contains cerebrospinal fluid and the spinal cord. The sub arachnoid block is usually injected between the 4th and 5th lumbar vertebrae, because the spinal cord usually stops at the 1st lumbar vertebra, while the canal continues to the sacral vertebrae. It results in a loss of pain sensation and muscle strength, usually up to the level of the chest (nipple line or 4th thoracic dermatome).
Epidural anesthesia: Regional block resulting from an injection of a large volume of local anesthetic into the epidural space. The epidural space is a potential space that lies underneath the ligamenta flava, and outside the dura mater (outside layer of the spinal canal). This is basically an injection around the spinal canal.
- Spinal anesthesia: also known as subarachnoid block. Refers to a Regional block resulting from a small volume of local anesthetics being injected into the spinal canal. The spinal canal is covered by the dura mater, through which the spinal needle enters. The spinal canal contains cerebrospinal fluid and the spinal cord. The sub arachnoid block is usually injected between the 4th and 5th lumbar vertebrae, because the spinal cord usually stops at the 1st lumbar vertebra, while the canal continues to the sacral vertebrae. It results in a loss of pain sensation and muscle strength, usually up to the level of the chest (nipple line or 4th thoracic dermatome).
- Epidural anesthesia: Regional block resulting from an injection of a large volume of local anesthetic into the epidural space. The epidural space is a potential space that lies underneath the ligamenta flava, and outside the dura mater (outside layer of the spinal canal). This is basically an injection around the spinal canal.
- Local anesthesia is similar to regional anesthesia, but exerts its effect on a smaller area of the body.
# History
## Herbal derivatives
The first herbal anesthesia was administered in prehistory. Opium poppy capsules were collected in 4200 BC, and opium poppies were farmed in Sumeria and succeeding empires. The use of opium-like preparations in anaesthesia is recorded in the Ebers Papyrus of 1500 BC. By 1100 BC poppies were scored for opium collection in Cyprus by methods similar to those used in the present day, and simple apparatus for smoking of opium were found in a Minoan temple. Opium was not introduced to India and China until 330 BC and 600–1200 AD, but these nations pioneered the use of cannabis incense and aconitum. In the second century, according to the Book of Later Han, the physician Hua Tuo performed abdominal surgery using an anesthetic substance called mafeisan (麻沸散 "cannabis boil powder") dissolved in wine. Throughout Europe, Asia, and the Americas a variety of Solanum species containing potent tropane alkaloids were used, such as mandrake, henbane, Datura metel, and Datura inoxia. Classic Greek and Roman medical texts by Hippocrates, Theophrastus, Aulus Cornelius Celsus, Pedanius Dioscorides, and Pliny the Elder discussed the use of opium and Solanum species, and treatment with the combined alkaloids proved a mainstay of anaesthesia until the nineteenth century. In the Americas coca was also an important anaesthetic used in trephining operations. Incan shamans chewed coca leaves and performed operations on the skull while spitting into the wounds they had inflicted to anaesthetize the site. Alcohol was also used, its vasodilatory properties being unknown. Ancient herbal anaesthetics have variously been called soporifics, anodynes, and narcotics, depending on whether the emphasis is on producing unconsciousness or relieving pain.
In Central Asia, in the 10th century work of Shahnameh, the author, Ferdowsi, describes a caesarean section performed on Rudaba when giving birth, in which a special wine agent was prepared as an anesthetic by a Zoroastrian priest, and used to produce unconsciousness for the operation. Although largely mythical in content, the passage does at least illustrate knowledge of anesthesia in ancient Persia.
The use of herbal anaesthesia had a crucial drawback compared to modern practice — as lamented by Fallopus, "When soporifics are weak they are useless, and when strong, they kill." To overcome this, production was typically standardized as much as feasible, with production occurring from specific famous locations (such as opium from the fields of Thebes in ancient Egypt). Anaesthetics were sometimes administered in the spongia somnifera, a sponge into which a large quantity of drug was allowed to dry, from which a saturated solution could be trickled into the nose of the patient. At least in more recent centuries, trade was often highly standardized, with the drying and packing of opium in standard chests, for example. In the 19th century, varying aconitum alkaloids from a variety of species were standardized by testing with guinea pigs. Despite these refinements, the discovery of morphine, a purified alkaloid that soon afterward could be injected by hypodermic for a consistent dosage, was enthusiastically received and led to the foundation of the modern pharmaceutical industry.
Another factor affecting ancient anaesthesia is that drugs used systemically in modern times were often administered locally, reducing the risk to the patient. Opium used directly in a wound acts on peripheral opioid receptors to serve as an analgesic, and a medicine containing willow leaves (salicylate, the predecessor of aspirin) would then be applied directly to the source of inflammation.
In 1804, the Japanese surgeon Hanaoka Seishū performed general anaesthesia for the operation of a breast cancer (mastectomy), by combining Chinese herbal medicine know-how and Western surgery techniques learned through "Rangaku", or "Dutch studies". His patient was a 60-year-old woman called Kan Aiya. He used a compound he called Tsusensan, based on the plants Datura metel, Aconitum and others.
## Non-pharmacological methods
Hypnotism and acupuncture have a long history of use as anesthetic techniques. In China, Taoist medical practitioners developed anesthesia by means of acupuncture. Chilling tissue (e.g. with ice) can temporarily cause nerve fibers (axons) to stop conducting sensation, while hyperventilation can cause brief alteration in conscious perception of stimuli including pain (see Lamaze).
In modern anesthetic practice, these techniques are seldom employed.
## Early gases and vapours
The works of Greek authors such as Dioscorides were well-known in the Islamic Empire, and physicians such as al-Razi, Avicenna, and Abu al-Qasim wrote medical textbooks of great importance in the development of medicine in Europe and the Middle East. Muslim anesthesiologists were the first to utilize oral as well as inhalant anesthetics. In Islamic Spain, Abu al-Qasim (Abulcasis) and Ibn Zuhr (Avenzoar), among other Muslim surgeons, performed hundreds of surgeries under inhalant anesthesia with the use of narcotic-soaked sponges which were placed over the face. Abulcasis and Ibn Sina (Avicenna) wrote about anasthesia in their influential medical encyclopedias, the al-Tasrif and The Canon of Medicine.
In the West, the development of effective anesthetics in the 19th century was, with Listerian techniques, one of the keys to successful surgery. Henry Hill Hickman experimented with carbon dioxide in the 1820s. The anesthetic qualities of nitrous oxide (isolated in 1773 by Joseph Priestley) were discovered by the British chemist Humphry Davy about 1799 when he was an assistant to Thomas Beddoes, and reported in a paper in 1800. But initially the medical uses of this so-called "laughing gas" were limited — its main role was in entertainment. It was used on 30 September 1846 for painless tooth extraction upon patient Eben Frost by American dentist William Thomas Green Morton. Horace Wells of Connecticut, a traveling dentist, had demonstrated it the previous year 1845, at Massachusetts General Hospital. Wells made a mistake, in choosing a particularly sturdy male volunteer, and the patient suffered considerable pain. This lost the colorful Wells any support. Later the patient told Wells he screamed in shock and not in pain. A subsequently drunk Wells died in jail, by cutting his femoral artery, after allegedly assaulting a prostitute with sulfuric acid.
Another dentist,William E. Clarke, performed an extraction in January 1842 using a different chemical, diethyl ether (discovered by Valerius Cordus in 1540). In March 1842 in Danielsville, Georgia, Dr. Crawford Long was the first to use anaesthesia during an operation, giving it to a boy (John Venables) before excising a cyst from his neck; however, he did not publicize this information until later.
On October 16, 1846, another dentist, William Thomas Green Morton, invited to the Massachusetts General Hospital, performed the first public demonstration of diethyl ether (then called sulfuric ether) as an anesthetic agent, for a patient (Edward Gilbert Abbott) undergoing an excision of a vascular tumor from his neck. In a letter to Morton shortly thereafter, Oliver Wendell Holmes, Sr. proposed naming the procedure anæsthesia.
Despite Morton's efforts to keep "his" compound a secret, which he named "Letheon" and for which he received a US patent, the news of the discovery and the nature of the compound spread very quickly to Europe in late 1846. Here, respected surgeons—including Liston, Dieffenbach, Pirogoff, and Syme—undertook numerous operations with ether.
An American-born physician, Boott — who had traveled to London — encouraged a leading dentist, Mr James Robinson, to perform a dental procedure on a Miss Lonsdale. This was the first case of an operator-anesthetist. On the same day, 19 December 1846 in Dumfries Royal Infirmary, Scotland, a Dr. Scott used ether for a surgical procedure. The first use of anesthesia in the Southern Hemisphere took place in Launceston, Tasmania, that same year. Ether has a number of drawbacks, such as its tendency to induce vomiting and its flammability. In England it was quickly replaced with chloroform.
Discovered in 1831, the use of chloroform in anesthesia is usually linked to James Young Simpson, who, in a wide-ranging study of organic compounds, found chloroform's efficacy on 4 November 1847. Its use spread quickly and gained royal approval in 1853 when John Snow gave it to Queen Victoria during the birth of Prince Leopold. Unfortunately, chloroform is not as safe an agent as ether, especially when administered by an untrained practitioner (medical students, nurses, and occasionally members of the public were often pressed into giving anesthetics at this time). This led to many deaths from the use of chloroform that (with hindsight) might have been preventable. The first fatality directly attributed to chloroform anesthesia (Hannah Greener) was recorded on 28 January 1848.
John Snow of London published articles from May 1848 onwards 'On Narcotism by the Inhalation of Vapours' in the London Medical Gazette. Snow also involved himself in the production of equipment needed for inhalational anesthesia.
The surgical amphitheatre at Massachusetts General Hospital, or "ether dome" still exists today, although it is used for lectures and not surgery. The public can visit the amphitheater on weekdays when it is not in use.
## Early local anesthetics
The first effective local anesthetic was cocaine. Isolated in 1859, it was first used by Karl Koller, at the suggestion of Sigmund Freud, in ophthalmic surgery in 1884. Before that doctors had used a salt and ice mix for the numbing effects of cold, which could only have limited application. Similar numbing was also induced by a spray of ether or ethyl chloride. A number of cocaine derivatives and safer replacements were soon produced, including procaine (1905), Eucaine (1900), Stovaine (1904), and lidocaine (1943).
Opioids were first used by Racoviceanu-Piteşti, who reported his work in 1901.
# Anesthesia providers
Physicians specialising in peri-operative care, development of an anesthetic plan, and the administration of anesthetics are known in the United States as anesthesiologists and in the UK and Canada as anaesthetists or anaesthesiologists. All anaesthetics in the UK, Australia, New Zealand and Japan are administered by physicians. Nurse anesthetists also administer anesthesia in 109 nations. In the US, 35% of anesthetics are provided by physicians in solo practice, about 55% are provided by ACTs with anesthesiologists medically directing Anesthesiologist Assistants, CRNAs, and about 10% are provided by CRNAs in solo practice.
## Physician anesthesiologists/anaesthetists/anaesthesiologists
In the US, medical doctors who specialize in anesthesiology are called anesthesiologists. Such physicians in the UK and Canada are called anaesthetists or anaesthesiologists.
In the U.S., a physician specializing in anesthesiology completes 4 years of college, 4 years of medical school, 1 year of internship, and 3 years of residency. According to the American Society of Anesthesiologists, anesthesiologists provide or participate in more than 90 percent of the 40 million anesthetics delivered annually.
In the UK this training lasts a minimum of seven years after the awarding of a medical degree and two years of basic residency, and takes place under the supervision of the Royal College of Anaesthetists. In Australia and New Zealand, it lasts five years after the awarding of a medical degree and two years of basic residency, under the supervision of the Australian and New Zealand College of Anaesthetists. Other countries have similar systems, including Ireland (the Faculty of Anaesthetists of the Royal College of Surgeons in Ireland), Canada and South Africa (the College of Anaesthetists of South Africa).
In the UK, completion of the examinations set by the Royal College of Anaesthetists leads to award of the Diploma of Fellowship of the Royal College of Anaesthetists (FRCA). In the US, completion of the written and oral Board examinations by a physician anesthesiologist allows one to be called "Board Certified" or a "Diplomate" of the American Board of Anesthesiology.
Other specialties within medicine are closely affiliated to anaesthetics. These include intensive care medicine and pain medicine. Specialists in these disciplines have usually done some training in anaesthetics. The role of the anaesthetist is changing. It is no longer limited to the operation itself. Many anaesthetists consider themselves to be peri-operative physicians, and will involve themselves in optimizing the patient's health before surgery (colloquially called "work-up"), performing the anaesthetic, following up the patient in the post anesthesia care unit and post-operative wards, and ensuring optimal analgesia throughout.
It is important to note that the term anesthetist in the United States usually refers to registered nurses who have completed specialized education and training in nurse anesthesia to become certified registered nurse anesthetists (CRNAs). As noted above, the term anaesthetist in the UK and Cananda refers to medical doctors who specialize in anesthesiology.
## Nurse Anesthetists
In the United States, advance practice nurses specializing in the provision of anesthesia care are known as Certified Registered Nurse Anesthetists (CRNAs). CRNAs provide 27 million hands-on anesthetics each year, roughly two thirds of the US total and are the sole providers of anesthesia in more than 70 percent of rural area hospitals. According to the American Association of Nurse Anesthetists, the 36,000 CRNAs in the US administer approximately 27 million anesthetics each year.] CRNAs are the sole providers of anesthesia in more than 70 percent of rural area hospitals. Thirty-four percent of nurse anesthetists practice in communities of less than 50,000. CRNAs start school with a bachelors degree and at least 1 year of acute care nursing experience], and gain a masters degree in nurse anesthesia before passing the mandatory Certification Exam. The average CRNA student has 5-7 years of nursing experience before entering a 27-36 month masters level anesthesia program.
CRNAs may work with podiatrists, dentists, anesthesiologists, surgeons, obstetricians and other professionals requiring their services. CRNAs administer anesthesia in all types of surgical cases, and are able to apply all the accepted anesthetic techniques -- general, regional, local, or sedation. Nurse Anesthetists are licensed to practice anesthesia independently, as well as in Anesthesia Care Teams. CRNAs may also practice in parallel with their physician colleagues in certain institutions, both types of provider caring for their own patients independently and consulting whenever collaboration is appropriate to patient outcome. CRNAs may also practice in parallel with their physician colleagues in certain institutions, both types of provider caring for their own patients independently and consulting whenever collaboration is appropriate to patient outcome.
## Anesthesiology assistants
In the US, anesthesiologist assistants (AAs) are physician assistants who have undertaken specialized education and training to provide anesthesia care. AAs typically hold a masters degree and practice under physician supervision in sixteen states through licensing, certification or physician delegation.
In the UK, a similar group of assistants are currently being evaluated. In Scotland they are named Physician's Assistant - Anaesthesia and in the rest of the UK, they are called anaesthesia practitioners. Their background can be nursing, operating department professional or another profession allied to medicine or a science graduate. Training takes 27 months and to date, the first five have graduated in England.
Anesthesiology Assistants should be distinguished from Anesthesia Technicians.
## Anesthesia technicians
Anesthesia technicians are specially trained biomedical technicians who assist anesthesiologists, nurse anesthetists, and anesthesiology assistants with monitoring equipment, supplies, and patient care procedures in the operating room.
In New Zealand, anaesthetic technicians complete a course of study recognized by the New Zealand Association of Anaesthetic Technicians and Nurses.
In the United Kingdom, personnel known as ODPs (operating department practitioners) or anaesthetic nurses provide support to the physician anaesthetist (anaesthesiologist).
## Veterinary Anesthetists/anesthesiologists
Veterinary anesthetists utilize much the same equipment and drugs as those who provide anesthesia to human patients. In the case of animals, the anesthesia must be tailored to fit the species ranging from large land animals like horses or elephants to birds to aquatic animals like fish. For each species there are ideal, or at least less problematic, methods of safely inducing anesthesia. For wild animals, anesthetic drugs must often be delivered from a distance by means of remote projector systems ("dart guns") before the animal can even be approached. Large domestic animals, like cattle, can often be anesthetized for standing surgery using only local anesthetics and sedative drugs. While most clinical veterinarians and veterinary technicians routinely function as anesthetists in the course of their professional duties, veterinary anesthesiologists in the U.S. are veterinarians who have completed a two-year residency in anesthesia and have qualified for certification by the American College of Veterinary Anesthesiologists.
# Anesthetic agents
## Local anesthetics
- procaine
- amethocaine
- cocaine
- lidocaine
- prilocaine
- bupivicaine
- levobupivacaine
- ropivacaine
- dibucaine
Local anesthetics are agents which prevent transmission of nerve impulses without causing unconsciousness. They act by binding to fast sodium channels from within (in an open state). Local anesthetics can be either ester or amide based.
Ester local anesthetics (e.g., procaine, amethocaine, cocaine) are generally unstable in solution and fast-acting, and allergic reactions are common.
Amide local anesthetics (e.g., lidocaine, prilocaine, bupivicaine, levobupivacaine, ropivacaine and dibucaine) are generally heat-stable, with a long shelf life (around 2 years). They have a slower onset and longer half-life than ester anaesthetics, and are usually racemic mixtures, with the exception of levobupivacaine (which is S(-) -bupivacaine) and ropivacaine (S(-)-ropivacaine). These agents are generally used within regional and epidural or spinal techniques, due to their longer duration of action, which provides adequate analgesia for surgery, labor, and symptomatic relief.
Only preservative-free local anesthetic agents may be injected intrathecally.
### Adverse effects of local anaesthesia
Adverse effects of local anesthesia are generally referred to as Local Anesthetic Toxicity.
Effects may be localized or systemic.
Examples of systemic effects of local anesthesia:
Local anesthetic drugs are toxic to the heart (where they cause arrhythmia) and brain (where they may cause unconsciousness and seizures). Arrhythmias may be resistant to defibrillation and other standard treatments, and may lead to loss of heart function and death.
The first evidence of local anesthetic toxicity involves the nervous system, including agitation, confusion, dizziness, blurred vision, tinnitus, a metallic taste in the mouth, and nausea that can quickly progress to seizures and cardiovascular collapse.
Toxicity can occur with any local anesthetic as an individual reaction by that patient. Possible toxicity can be tested with pre-operative procedures to avoid toxic reactions during surgery.
An example of localized effect of local anesthesia:
Direct infiltration of local anesthetic into skeletal muscle will cause temporary paralysis of the muscle.
## Current inhaled general anesthetic agents
- Nitrous oxide
- Halothane
- Enflurane
- Isoflurane
- Sevoflurane
- Desflurane
- Xenon (rarely used)
Volatile agents are specially formulated organic liquids that evaporate readily into vapors, and are given by inhalation for induction and/or maintenance of general anesthesia. Nitrous oxide and xenon are gases at room temperature rather than liquids, so they are not considered volatile agents. The ideal anesthetic vapor or gas should be non-flammable, non-explosive, lipid-soluble, and should possess low blood gas solubility, have no end organ (heart, liver, kidney) toxicity or side-effects, should not be metabolized, and should be non-irritant when inhaled by patients.
No anesthetic agent currently in use meets all these requirements. The agents in widespread current use are isoflurane, desflurane, sevoflurane, and nitrous oxide. Nitrous oxide is a common adjuvant gas, making it one of the most long-lived drugs still in current use. Because of its low potency, it cannot produce anesthesia on its own but is frequently combined with other agents. Halothane, an agent introduced in the 1950s, has been almost completely replaced in modern anesthesia practice by newer agents because of its shortcomings. Partly because of its side effects, enflurane never gained widespread popularity.
In theory, any inhaled anesthetic agent can be used for induction of general anesthesia. However, most of the halogenated anesthetics are irritating to the airway, perhaps leading to coughing, laryngospasm and overall difficult inductions. For this reason, the most frequently used agent for inhalational induction is sevoflurane. All of the volatile agents can be used alone or in combination with other medications to maintain anesthesia (nitrous oxide is not potent enough to be used as a sole agent).
As of 2007, research into the use of xenon as an anesthetic is underway, but the gas is very expensive to produce and requires special equipment for delivery, as well as special monitoring and scavenging of waste gas.
Volatile agents are frequently compared in terms of potency, which is inversely proportional to the minimum alveolar concentration. Potency is directly related to lipid solubility. This is known as the Meyer-Overton hypothesis. However, certain pharmacokinetic properties of volatile agents have become another point of comparison. Most important of those properties is known as the blood:gas partition coefficient. This concept refers to the relative solubilty of a given agent in blood. Those agents with a lower blood solubility (i.e., a lower blood–gas partition coefficient; e.g., desflurane) give the anesthesia provider greater rapidity in titrating the depth of anesthesia, and permit a more rapid emergence from the anesthetic state upon discontinuing their administration. In fact, newer volatile agents (e.g., sevoflurane, desflurane) have been popular not due to their potency (minimum alveolar concentration), but due to their versatility for a faster emergence from anesthesia, thanks to their lower blood–gas partition coefficient.
## Current intravenous anesthetic agents (non-opioid)
While there are many drugs that can be used intravenously to produce anesthesia or sedation, the most common are:
- Barbiturates
Thiopental
Methohexital
- Thiopental
- Methohexital
- Benzodiazepines
Midazolam
Lorazepam
Diazepam
- Midazolam
- Lorazepam
- Diazepam
- Propofol
- Etomidate
- Ketamine
The two barbiturates mentioned above, thiopental and methohexital, are ultra-short-acting, and are used to induce and maintain anesthesia. However, though they produce unconsciousness, they provide no analgesia (pain relief) and must be used with other agents. Benzodiazepines can be used for sedation before or after surgery and can be used to induce and maintain general anesthesia. When benzodiazepines are used to induce general anesthesia, midazolam is preferred. Benzodiazepines are also used for sedation during procedures that do not require general anesthesia. Like barbiturates, benzodiazepines have no pain-relieving properties. Propofol is one of the most commonly used intravenous drugs employed to induce and maintain general anesthesia. It can also be used for sedation during procedures or in the ICU. Like the other agents mentioned above, it renders patients unconscious without producing pain relief. Because of its favorable physiological effects, "etomidate has been primarily used in sick patients". Ketamine is infrequently used in anesthesia practice because of the unpleasant experiences which sometimes occur upon emergence from anesthesia, which include "vivid dreaming, extracorporeal experiences, and illusions." However, like etomidate it is frequently used in emergency settings and with sick patients because it produces fewer adverse physiological effects. Unlike the intravenous anesthetic drugs previously mentioned, ketamine produces profound pain relief, even in doses lower than those which induce general anesthesia. Also unlike the other anesthetic agents in this section, "patients who receive ketamine alone appear to be in a cataleptic state, unlike other states of anesthesia that resemble normal sleep. Ketamine-anesthetized patients have profound analgesia but keep their eyes open and maintain many reflexes."
## Current intravenous opioid analgesic agents
While opioids can produce unconsciousness, they do so unreliably and with significant side effects. So, while they are rarely used to induce anesthesia, they are frequently used along with other agents such as intravenous non-opioid anesthetics or inhalational anesthetics. Furthermore, they are used to relieve pain of patients before, during, or after surgery. The following opioids have short onset and duration of action and are frequently used during general anesthesia:
- Fentanyl
- Alfentanil
- Sufentanil
- Remifentanil
The following agents have longer onset and duration of action and are frequently used for post-operative pain relief:
- Buprenorphine
- Butorphanol
- Diamorphine, (diacetyl morphine, also known as heroin, not available in U.S.)
- Hydromorphone
- Levorphanol
- Meperidine, also called pethidine in the UK, New Zealand, Australia and other countries
- Methadone
- Morphine
- Nalbuphine
- Oxycodone, (not available intravenously in U.S.)
- Oxymorphone
- Pentazocine
## Current muscle relaxants
Muscle relaxants do not render patients unconscious or relieve pain. Instead, they are sometimes used after a patient is rendered unconscious (induction of anesthesia) to facilitate intubation or surgery by paralyzing skeletal muscle.
- Depolarizing muscle relaxants
Succinylcholine (also known as suxamethonium in the UK, New Zealand, Australia and other countries)
- Succinylcholine (also known as suxamethonium in the UK, New Zealand, Australia and other countries)
- Non-depolarizing muscle relaxants
Short acting
Mivacurium
Rapacuronium
Intermediate acting
Atracurium
Cisatracurium
Vecuronium
Rocuronium
Long acting
Pancuronium
Metocurine
d-Tubocurarine
Gallamine
Alcuronium
Doxacurium
Pipecuronium
- Short acting
Mivacurium
Rapacuronium
- Mivacurium
- Rapacuronium
- Intermediate acting
Atracurium
Cisatracurium
Vecuronium
Rocuronium
- Atracurium
- Cisatracurium
- Vecuronium
- Rocuronium
- Long acting
Pancuronium
Metocurine
d-Tubocurarine
Gallamine
Alcuronium
Doxacurium
Pipecuronium
- Pancuronium
- Metocurine
- d-Tubocurarine
- Gallamine
- Alcuronium
- Doxacurium
- Pipecuronium
### Adverse effects of muscle relaxants
Succinylcholine may cause hyperkalemia if given to burn patients, or paralyzed (quadraplegic, paraplegic) patients. The mechanism is reported to be through upregulation of acetylcholine receptors in those patient populations. Succinylcholine may also trigger malignant hyperthermia in susceptible patients.
Another potentially disturbing complication can be 'anesthesia awareness'. In this situation, patients paralyzed with muscle relaxants may awaken during their anesthesia, due to decrease in the levels of drugs providing sedation and/or pain relief. If this fact is missed by the anaesthesia provider, the patient may be aware of his surroundings, but be incapable of moving or communicating that fact. Neurological monitors are becoming increasingly available which may help decrease the incidence of awareness. Most of these monitors use proprietary algorithms monitoring brain activity via evoked potentials. Despite the widespread marketing of these devices many case reports exist in which awareness under anesthesia has occurred despite apparently adequate anesthesia as measured by the neurologic monitor.
## Current intravenous reversal agents
- Naloxone, reverses the effects of opioids
- Flumazenil, reverses the effects of benzodiazepines
- Neostigmine, reverses the effects of non-depolarizing muscle relaxants
- Suggamadex, more effectively reverses rocuronium and norcuronium
# Anesthetic equipment
In modern anesthesia, a wide variety of medical equipment is desirable depending on the necessity for portable field use, surgical operations or intensive care support. Anesthesia practitioners must possess a comprehensive and intricate knowledge of the production and use of various medical gases, anaesthetic agents and vapours, medical breathing circuits and the variety of anaesthetic machines (including vaporizers, ventilators and pressure gauges) and their corresponding safety features, hazards and limitations of each piece of equipment, for the safe, clinical competence and practical application for day to day practice.
# Anesthetic monitoring
Patients being treated under general anesthetics must be monitored continuously to ensure the patient's safety. For minor surgery, this generally includes monitoring of heart rate (via ECG or pulse oximetry), oxygen saturation (via pulse oximetry), non-invasive blood pressure, inspired and expired gases (for oxygen, carbon dioxide, nitrous oxide, and volatile agents). For moderate to major surgery, monitoring may also include temperature, urine output, invasive blood measurements (arterial blood pressure, central venous pressure), pulmonary artery pressure and pulmonary artery occlusion pressure, cerebral activity (via EEG analysis), neuromuscular function (via peripheral nerve stimulation monitoring), and cardiac output. In addition, the operating room's environment must be monitored for temperature and humidity and for buildup of exhaled inhalational anesthetics which might impair the health of operating room personnel.
# Anesthesia record
The anesthesia record is the medical and legal documentation of events during an anesthetic. It reflects a detailed and continuous account of drugs, fluids, and blood products administered and procedures undertaken, and also includes the observation of cardiovascular responses, estimated blood loss, urinary body fluids and data from physiologic monitors (Anesthetic monitoring, see above) during the course of an anesthetic. The anesthesia record may be written manually on paper; however, the paper record is increasingly replaced by an electronic record as part of an Anesthesia Information Management System (AIMS).
# Anesthesia Information Management System (AIMS)
An AIMS refers to any information system that is used as an automated electronic anesthesia record keeper (i.e., connection to patient physiologic monitors and/or the Anaesthetic machine) and which also may allow the collection and analysis of anesthesia-related perioperative patient data. | Anesthesia
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Anesthesia or anaesthesia (from Greek αν- an- “without” + αἲσθησις aisthesis “sensation”) has traditionally meant the condition of having the feeling of pain and other sensations blocked. This allows patients to undergo surgery and other procedures without the distress and pain they would otherwise experience. The word was coined by Oliver Wendell Holmes, Sr. in 1846. Another definition is a "reversible lack of awareness", whether this is a total lack of awareness (e.g. a general anaesthestic) or a lack of awareness of a part of a the body such as a spinal anaesthetic or another nerve block would cause.
Today, the term general anesthesia in its most general form can include:
- Analgesia: blocking the conscious sensation of pain;
- Hypnosis: produces unconsciousness without analgesia;
- Amnesia: preventing memory formation;
- Relaxation: preventing unwanted movement or muscle tone;
- Obtundation of reflexes, preventing exaggerated autonomic reflexes.
Patients undergoing surgery usually undergo preoperative evaluation. It includes gathering history of previous anesthetics, and any other medical problems, physical examination, ordering required blood work and consultations prior to surgery.
There are several forms of anesthesia. The following forms refer to states achieved by anesthetics working on the brain:
- General anesthesia: "Drug-induced loss of consciousness during which patients are not arousable, even by painful stimulation." Patients undergoing general anesthesia often cannot maintain their own airway and breathe on their own. While usually administered with inhalational agents, general anesthesia can be achieved with intravenous agents, such as propofol.[1]
- Deep sedation/analgesia: "Drug-induced depression of consciousness during which patients cannot be easily aroused but respond purposefully following repeated or painful stimulation." Patients may sometimes be unable to maintain their airway and breathe on their own.[1]
- Moderate sedation/analgesia or conscious sedation: "Drug-induced depression of consciousness during which patients respond purposefully to verbal commands, either alone or accompanied by light tactile stimulation." In this state, patients can breathe on their own and need no help maintaining an airway.[1]
- Minimal sedation or anxiolysis: "Drug-induced state during which patients respond normally to verbal commands." Though concentration, memory, and coordination may be impaired, patients need no help breathing or maintaining an airway.[1]
The level of anesthesia achieved ranges on a continuum of depth of consciousness from minimal sedation to general anesthesia. The depth of consciousness of a patient may change from one minute to the next.
The following refer to states achieved by anesthetics working outside of the brain:
- Regional anesthesia: Loss of pain sensation, with varying degrees of muscle relaxation, in certain regions of the body. Administered with local anesthesia to peripheral nerve bundles, such as the brachial plexus in the neck. Examples include the interscalene block for shoulder surgery, axillary block for wrist surgery, and femoral nerve block for leg surgery. While traditionally administered as a single injection, newer techniques involve placement of indwelling catheters for continuous or intermittent administration of local anesthetics.
Spinal anesthesia: also known as subarachnoid block. Refers to a Regional block resulting from a small volume of local anesthetics being injected into the spinal canal. The spinal canal is covered by the dura mater, through which the spinal needle enters. The spinal canal contains cerebrospinal fluid and the spinal cord. The sub arachnoid block is usually injected between the 4th and 5th lumbar vertebrae, because the spinal cord usually stops at the 1st lumbar vertebra, while the canal continues to the sacral vertebrae. It results in a loss of pain sensation and muscle strength, usually up to the level of the chest (nipple line or 4th thoracic dermatome).
Epidural anesthesia: Regional block resulting from an injection of a large volume of local anesthetic into the epidural space. The epidural space is a potential space that lies underneath the ligamenta flava, and outside the dura mater (outside layer of the spinal canal). This is basically an injection around the spinal canal.
- Spinal anesthesia: also known as subarachnoid block. Refers to a Regional block resulting from a small volume of local anesthetics being injected into the spinal canal. The spinal canal is covered by the dura mater, through which the spinal needle enters. The spinal canal contains cerebrospinal fluid and the spinal cord. The sub arachnoid block is usually injected between the 4th and 5th lumbar vertebrae, because the spinal cord usually stops at the 1st lumbar vertebra, while the canal continues to the sacral vertebrae. It results in a loss of pain sensation and muscle strength, usually up to the level of the chest (nipple line or 4th thoracic dermatome).
- Epidural anesthesia: Regional block resulting from an injection of a large volume of local anesthetic into the epidural space. The epidural space is a potential space that lies underneath the ligamenta flava, and outside the dura mater (outside layer of the spinal canal). This is basically an injection around the spinal canal.
- Local anesthesia is similar to regional anesthesia, but exerts its effect on a smaller area of the body.
# History
## Herbal derivatives
The first herbal anesthesia was administered in prehistory. Opium poppy capsules were collected in 4200 BC, and opium poppies were farmed in Sumeria and succeeding empires. The use of opium-like preparations in anaesthesia is recorded in the Ebers Papyrus of 1500 BC. By 1100 BC poppies were scored for opium collection in Cyprus by methods similar to those used in the present day, and simple apparatus for smoking of opium were found in a Minoan temple. Opium was not introduced to India and China until 330 BC and 600–1200 AD, but these nations pioneered the use of cannabis incense and aconitum. In the second century, according to the Book of Later Han, the physician Hua Tuo performed abdominal surgery using an anesthetic substance called mafeisan (麻沸散 "cannabis boil powder") dissolved in wine. Throughout Europe, Asia, and the Americas a variety of Solanum species containing potent tropane alkaloids were used, such as mandrake, henbane, Datura metel, and Datura inoxia. Classic Greek and Roman medical texts by Hippocrates, Theophrastus, Aulus Cornelius Celsus, Pedanius Dioscorides, and Pliny the Elder discussed the use of opium and Solanum species, and treatment with the combined alkaloids proved a mainstay of anaesthesia until the nineteenth century. In the Americas coca was also an important anaesthetic used in trephining operations. Incan shamans chewed coca leaves and performed operations on the skull while spitting into the wounds they had inflicted to anaesthetize the site. Alcohol was also used, its vasodilatory properties being unknown. Ancient herbal anaesthetics have variously been called soporifics, anodynes, and narcotics, depending on whether the emphasis is on producing unconsciousness or relieving pain.
In Central Asia, in the 10th century work of Shahnameh, the author, Ferdowsi, describes a caesarean section performed on Rudaba when giving birth, in which a special wine agent was prepared as an anesthetic[2] by a Zoroastrian priest, and used to produce unconsciousness for the operation. Although largely mythical in content, the passage does at least illustrate knowledge of anesthesia in ancient Persia.
The use of herbal anaesthesia had a crucial drawback compared to modern practice — as lamented by Fallopus, "When soporifics are weak they are useless, and when strong, they kill." To overcome this, production was typically standardized as much as feasible, with production occurring from specific famous locations (such as opium from the fields of Thebes in ancient Egypt). Anaesthetics were sometimes administered in the spongia somnifera, a sponge into which a large quantity of drug was allowed to dry, from which a saturated solution could be trickled into the nose of the patient. At least in more recent centuries, trade was often highly standardized, with the drying and packing of opium in standard chests, for example. In the 19th century, varying aconitum alkaloids from a variety of species were standardized by testing with guinea pigs. Despite these refinements, the discovery of morphine, a purified alkaloid that soon afterward could be injected by hypodermic for a consistent dosage, was enthusiastically received and led to the foundation of the modern pharmaceutical industry.
Another factor affecting ancient anaesthesia is that drugs used systemically in modern times were often administered locally, reducing the risk to the patient. Opium used directly in a wound acts on peripheral opioid receptors to serve as an analgesic, and a medicine containing willow leaves (salicylate, the predecessor of aspirin) would then be applied directly to the source of inflammation.
In 1804, the Japanese surgeon Hanaoka Seishū performed general anaesthesia for the operation of a breast cancer (mastectomy), by combining Chinese herbal medicine know-how and Western surgery techniques learned through "Rangaku", or "Dutch studies". His patient was a 60-year-old woman called Kan Aiya.[3] He used a compound he called Tsusensan, based on the plants Datura metel, Aconitum and others.
## Non-pharmacological methods
Hypnotism and acupuncture have a long history of use as anesthetic techniques. In China, Taoist medical practitioners developed anesthesia by means of acupuncture. Chilling tissue (e.g. with ice) can temporarily cause nerve fibers (axons) to stop conducting sensation, while hyperventilation can cause brief alteration in conscious perception of stimuli including pain (see Lamaze).
In modern anesthetic practice, these techniques are seldom employed.
## Early gases and vapours
The works of Greek authors such as Dioscorides were well-known in the Islamic Empire, and physicians such as al-Razi, Avicenna, and Abu al-Qasim wrote medical textbooks of great importance in the development of medicine in Europe and the Middle East. Muslim anesthesiologists were the first to utilize oral as well as inhalant anesthetics. In Islamic Spain, Abu al-Qasim (Abulcasis) and Ibn Zuhr (Avenzoar), among other Muslim surgeons, performed hundreds of surgeries under inhalant anesthesia with the use of narcotic-soaked sponges which were placed over the face. Abulcasis and Ibn Sina (Avicenna) wrote about anasthesia in their influential medical encyclopedias, the al-Tasrif and The Canon of Medicine.[4][5]
In the West, the development of effective anesthetics in the 19th century was, with Listerian techniques, one of the keys to successful surgery. Henry Hill Hickman experimented with carbon dioxide in the 1820s. The anesthetic qualities of nitrous oxide (isolated in 1773 by Joseph Priestley) were discovered by the British chemist Humphry Davy about 1799 when he was an assistant to Thomas Beddoes, and reported in a paper in 1800. But initially the medical uses of this so-called "laughing gas" were limited — its main role was in entertainment. It was used on 30 September 1846 for painless tooth extraction upon patient Eben Frost by American dentist William Thomas Green Morton. Horace Wells of Connecticut, a traveling dentist, had demonstrated it the previous year 1845, at Massachusetts General Hospital. Wells made a mistake, in choosing a particularly sturdy male volunteer, and the patient suffered considerable pain. This lost the colorful Wells any support. Later the patient told Wells he screamed in shock and not in pain. A subsequently drunk Wells died in jail, by cutting his femoral artery, after allegedly assaulting a prostitute with sulfuric acid.
Another dentist,William E. Clarke, performed an extraction in January 1842 using a different chemical, diethyl ether (discovered by Valerius Cordus in 1540). In March 1842 in Danielsville, Georgia, Dr. Crawford Long was the first to use anaesthesia during an operation, giving it to a boy (John Venables) before excising a cyst from his neck; however, he did not publicize this information until later.
On October 16, 1846, another dentist, William Thomas Green Morton, invited to the Massachusetts General Hospital, performed the first public demonstration of diethyl ether (then called sulfuric ether) as an anesthetic agent, for a patient (Edward Gilbert Abbott) undergoing an excision of a vascular tumor from his neck. In a letter to Morton shortly thereafter, Oliver Wendell Holmes, Sr. proposed naming the procedure anæsthesia.
Despite Morton's efforts to keep "his" compound a secret, which he named "Letheon" and for which he received a US patent, the news of the discovery and the nature of the compound spread very quickly to Europe in late 1846. Here, respected surgeons—including Liston, Dieffenbach, Pirogoff, and Syme—undertook numerous operations with ether.
An American-born physician, Boott — who had traveled to London — encouraged a leading dentist, Mr James Robinson, to perform a dental procedure on a Miss Lonsdale. This was the first case of an operator-anesthetist. On the same day, 19 December 1846 in Dumfries Royal Infirmary, Scotland, a Dr. Scott used ether for a surgical procedure. The first use of anesthesia in the Southern Hemisphere took place in Launceston, Tasmania, that same year. Ether has a number of drawbacks, such as its tendency to induce vomiting and its flammability. In England it was quickly replaced with chloroform.
Discovered in 1831, the use of chloroform in anesthesia is usually linked to James Young Simpson, who, in a wide-ranging study of organic compounds, found chloroform's efficacy on 4 November 1847. Its use spread quickly and gained royal approval in 1853 when John Snow gave it to Queen Victoria during the birth of Prince Leopold. Unfortunately, chloroform is not as safe an agent as ether, especially when administered by an untrained practitioner (medical students, nurses, and occasionally members of the public were often pressed into giving anesthetics at this time). This led to many deaths from the use of chloroform that (with hindsight) might have been preventable. The first fatality directly attributed to chloroform anesthesia (Hannah Greener) was recorded on 28 January 1848.
John Snow of London published articles from May 1848 onwards 'On Narcotism by the Inhalation of Vapours' in the London Medical Gazette. Snow also involved himself in the production of equipment needed for inhalational anesthesia.
The surgical amphitheatre at Massachusetts General Hospital, or "ether dome" still exists today, although it is used for lectures and not surgery. The public can visit the amphitheater on weekdays when it is not in use.
## Early local anesthetics
The first effective local anesthetic was cocaine. Isolated in 1859, it was first used by Karl Koller, at the suggestion of Sigmund Freud, in ophthalmic surgery in 1884. Before that doctors had used a salt and ice mix for the numbing effects of cold, which could only have limited application. Similar numbing was also induced by a spray of ether or ethyl chloride. A number of cocaine derivatives and safer replacements were soon produced, including procaine (1905), Eucaine (1900), Stovaine (1904), and lidocaine (1943).
Opioids were first used by Racoviceanu-Piteşti, who reported his work in 1901.
# Anesthesia providers
Physicians specialising in peri-operative care, development of an anesthetic plan, and the administration of anesthetics are known in the United States as anesthesiologists and in the UK and Canada as anaesthetists or anaesthesiologists. All anaesthetics in the UK, Australia, New Zealand and Japan are administered by physicians. Nurse anesthetists also administer anesthesia in 109 nations.[6] In the US, 35% of anesthetics are provided by physicians in solo practice, about 55% are provided by ACTs with anesthesiologists medically directing Anesthesiologist Assistants, CRNAs, and about 10% are provided by CRNAs in solo practice. [7] [8] [9]
- [10]
- [11]
## Physician anesthesiologists/anaesthetists/anaesthesiologists
In the US, medical doctors who specialize in anesthesiology are called anesthesiologists. Such physicians in the UK and Canada are called anaesthetists or anaesthesiologists.
In the U.S., a physician specializing in anesthesiology completes 4 years of college, 4 years of medical school, 1 year of internship, and 3 years of residency. According to the American Society of Anesthesiologists, anesthesiologists provide or participate in more than 90 percent of the 40 million anesthetics delivered annually.[12]
In the UK this training lasts a minimum of seven years after the awarding of a medical degree and two years of basic residency, and takes place under the supervision of the Royal College of Anaesthetists. In Australia and New Zealand, it lasts five years after the awarding of a medical degree and two years of basic residency, under the supervision of the Australian and New Zealand College of Anaesthetists. Other countries have similar systems, including Ireland (the Faculty of Anaesthetists of the Royal College of Surgeons in Ireland), Canada and South Africa (the College of Anaesthetists of South Africa).
In the UK, completion of the examinations set by the Royal College of Anaesthetists leads to award of the Diploma of Fellowship of the Royal College of Anaesthetists (FRCA). In the US, completion of the written and oral Board examinations by a physician anesthesiologist allows one to be called "Board Certified" or a "Diplomate" of the American Board of Anesthesiology.
Other specialties within medicine are closely affiliated to anaesthetics. These include intensive care medicine and pain medicine. Specialists in these disciplines have usually done some training in anaesthetics. The role of the anaesthetist is changing. It is no longer limited to the operation itself. Many anaesthetists consider themselves to be peri-operative physicians, and will involve themselves in optimizing the patient's health before surgery (colloquially called "work-up"), performing the anaesthetic, following up the patient in the post anesthesia care unit and post-operative wards, and ensuring optimal analgesia throughout.
It is important to note that the term anesthetist in the United States usually refers to registered nurses who have completed specialized education and training in nurse anesthesia to become certified registered nurse anesthetists (CRNAs). As noted above, the term anaesthetist in the UK and Cananda refers to medical doctors who specialize in anesthesiology.
## Nurse Anesthetists
In the United States, advance practice nurses specializing in the provision of anesthesia care are known as Certified Registered Nurse Anesthetists (CRNAs). CRNAs provide 27 million hands-on anesthetics each year, roughly two thirds of the US total and are the sole providers of anesthesia in more than 70 percent of rural area hospitals. According to the American Association of Nurse Anesthetists, the 36,000 CRNAs in the US administer approximately 27 million anesthetics each year.[[2]] CRNAs are the sole providers of anesthesia in more than 70 percent of rural area hospitals. Thirty-four percent of nurse anesthetists practice in communities of less than 50,000. CRNAs start school with a bachelors degree and at least 1 year of acute care nursing experience[[3]], and gain a masters degree in nurse anesthesia before passing the mandatory Certification Exam. The average CRNA student has 5-7 years of nursing experience before entering a 27-36 month masters level anesthesia program.[13]
CRNAs may work with podiatrists, dentists, anesthesiologists, surgeons, obstetricians and other professionals requiring their services. CRNAs administer anesthesia in all types of surgical cases, and are able to apply all the accepted anesthetic techniques -- general, regional, local, or sedation. Nurse Anesthetists are licensed to practice anesthesia independently, as well as in Anesthesia Care Teams.[14] CRNAs may also practice in parallel with their physician colleagues in certain institutions, both types of provider caring for their own patients independently and consulting whenever collaboration is appropriate to patient outcome. CRNAs may also practice in parallel with their physician colleagues in certain institutions, both types of provider caring for their own patients independently and consulting whenever collaboration is appropriate to patient outcome.
## Anesthesiology assistants
In the US, anesthesiologist assistants (AAs) are physician assistants who have undertaken specialized education and training to provide anesthesia care. AAs typically hold a masters degree and practice under physician supervision in sixteen states through licensing, certification or physician delegation.[15]
In the UK, a similar group of assistants are currently being evaluated. In Scotland they are named Physician's Assistant - Anaesthesia and in the rest of the UK, they are called anaesthesia practitioners. Their background can be nursing, operating department professional or another profession allied to medicine or a science graduate. Training takes 27 months and to date, the first five have graduated in England.
Anesthesiology Assistants should be distinguished from Anesthesia Technicians.
## Anesthesia technicians
Anesthesia technicians are specially trained biomedical technicians who assist anesthesiologists, nurse anesthetists, and anesthesiology assistants with monitoring equipment, supplies, and patient care procedures in the operating room.
In New Zealand, anaesthetic technicians complete a course of study recognized by the New Zealand Association of Anaesthetic Technicians and Nurses.
In the United Kingdom, personnel known as ODPs (operating department practitioners) or anaesthetic nurses provide support to the physician anaesthetist (anaesthesiologist).
## Veterinary Anesthetists/anesthesiologists
Veterinary anesthetists utilize much the same equipment and drugs as those who provide anesthesia to human patients. In the case of animals, the anesthesia must be tailored to fit the species ranging from large land animals like horses or elephants to birds to aquatic animals like fish. For each species there are ideal, or at least less problematic, methods of safely inducing anesthesia. For wild animals, anesthetic drugs must often be delivered from a distance by means of remote projector systems ("dart guns") before the animal can even be approached. Large domestic animals, like cattle, can often be anesthetized for standing surgery using only local anesthetics and sedative drugs. While most clinical veterinarians and veterinary technicians routinely function as anesthetists in the course of their professional duties, veterinary anesthesiologists in the U.S. are veterinarians who have completed a two-year residency in anesthesia and have qualified for certification by the American College of Veterinary Anesthesiologists.
# Anesthetic agents
## Local anesthetics
- procaine
- amethocaine
- cocaine
- lidocaine
- prilocaine
- bupivicaine
- levobupivacaine
- ropivacaine
- dibucaine
Local anesthetics are agents which prevent transmission of nerve impulses without causing unconsciousness. They act by binding to fast sodium channels from within (in an open state). Local anesthetics can be either ester or amide based.
Ester local anesthetics (e.g., procaine, amethocaine, cocaine) are generally unstable in solution and fast-acting, and allergic reactions are common.
Amide local anesthetics (e.g., lidocaine, prilocaine, bupivicaine, levobupivacaine, ropivacaine and dibucaine) are generally heat-stable, with a long shelf life (around 2 years). They have a slower onset and longer half-life than ester anaesthetics, and are usually racemic mixtures, with the exception of levobupivacaine (which is S(-) -bupivacaine) and ropivacaine (S(-)-ropivacaine). These agents are generally used within regional and epidural or spinal techniques, due to their longer duration of action, which provides adequate analgesia for surgery, labor, and symptomatic relief.
Only preservative-free local anesthetic agents may be injected intrathecally.
### Adverse effects of local anaesthesia
Adverse effects of local anesthesia are generally referred to as Local Anesthetic Toxicity.
Effects may be localized or systemic.
Examples of systemic effects of local anesthesia:
Local anesthetic drugs are toxic to the heart (where they cause arrhythmia) and brain (where they may cause unconsciousness and seizures). Arrhythmias may be resistant to defibrillation and other standard treatments, and may lead to loss of heart function and death.
The first evidence of local anesthetic toxicity involves the nervous system, including agitation, confusion, dizziness, blurred vision, tinnitus, a metallic taste in the mouth, and nausea that can quickly progress to seizures and cardiovascular collapse.
Toxicity can occur with any local anesthetic as an individual reaction by that patient. Possible toxicity can be tested with pre-operative procedures to avoid toxic reactions during surgery.
An example of localized effect of local anesthesia:
Direct infiltration of local anesthetic into skeletal muscle will cause temporary paralysis of the muscle.
## Current inhaled general anesthetic agents
- Nitrous oxide
- Halothane
- Enflurane
- Isoflurane
- Sevoflurane
- Desflurane
- Xenon (rarely used)
Volatile agents are specially formulated organic liquids that evaporate readily into vapors, and are given by inhalation for induction and/or maintenance of general anesthesia. Nitrous oxide and xenon are gases at room temperature rather than liquids, so they are not considered volatile agents. The ideal anesthetic vapor or gas should be non-flammable, non-explosive, lipid-soluble, and should possess low blood gas solubility, have no end organ (heart, liver, kidney) toxicity or side-effects, should not be metabolized, and should be non-irritant when inhaled by patients.
No anesthetic agent currently in use meets all these requirements. The agents in widespread current use are isoflurane, desflurane, sevoflurane, and nitrous oxide. Nitrous oxide is a common adjuvant gas, making it one of the most long-lived drugs still in current use. Because of its low potency, it cannot produce anesthesia on its own but is frequently combined with other agents. Halothane, an agent introduced in the 1950s, has been almost completely replaced in modern anesthesia practice by newer agents because of its shortcomings.[16] Partly because of its side effects, enflurane never gained widespread popularity. [16]
In theory, any inhaled anesthetic agent can be used for induction of general anesthesia. However, most of the halogenated anesthetics are irritating to the airway, perhaps leading to coughing, laryngospasm and overall difficult inductions. For this reason, the most frequently used agent for inhalational induction is sevoflurane. All of the volatile agents can be used alone or in combination with other medications to maintain anesthesia (nitrous oxide is not potent enough to be used as a sole agent).
As of 2007, research into the use of xenon as an anesthetic is underway, but the gas is very expensive to produce and requires special equipment for delivery, as well as special monitoring and scavenging of waste gas.
Volatile agents are frequently compared in terms of potency, which is inversely proportional to the minimum alveolar concentration. Potency is directly related to lipid solubility. This is known as the Meyer-Overton hypothesis. However, certain pharmacokinetic properties of volatile agents have become another point of comparison. Most important of those properties is known as the blood:gas partition coefficient. This concept refers to the relative solubilty of a given agent in blood. Those agents with a lower blood solubility (i.e., a lower blood–gas partition coefficient; e.g., desflurane) give the anesthesia provider greater rapidity in titrating the depth of anesthesia, and permit a more rapid emergence from the anesthetic state upon discontinuing their administration. In fact, newer volatile agents (e.g., sevoflurane, desflurane) have been popular not due to their potency (minimum alveolar concentration), but due to their versatility for a faster emergence from anesthesia, thanks to their lower blood–gas partition coefficient.
## Current intravenous anesthetic agents (non-opioid)
While there are many drugs that can be used intravenously to produce anesthesia or sedation, the most common are:
- Barbiturates
Thiopental
Methohexital
- Thiopental
- Methohexital
- Benzodiazepines
Midazolam
Lorazepam
Diazepam
- Midazolam
- Lorazepam
- Diazepam
- Propofol
- Etomidate
- Ketamine
The two barbiturates mentioned above, thiopental and methohexital, are ultra-short-acting, and are used to induce and maintain anesthesia.[17] However, though they produce unconsciousness, they provide no analgesia (pain relief) and must be used with other agents.[17] Benzodiazepines can be used for sedation before or after surgery and can be used to induce and maintain general anesthesia.[17] When benzodiazepines are used to induce general anesthesia, midazolam is preferred.[17] Benzodiazepines are also used for sedation during procedures that do not require general anesthesia.[17] Like barbiturates, benzodiazepines have no pain-relieving properties.[17] Propofol is one of the most commonly used intravenous drugs employed to induce and maintain general anesthesia.[17] It can also be used for sedation during procedures or in the ICU.[17] Like the other agents mentioned above, it renders patients unconscious without producing pain relief.[17] Because of its favorable physiological effects, "etomidate has been primarily used in sick patients".[17] Ketamine is infrequently used in anesthesia practice because of the unpleasant experiences which sometimes occur upon emergence from anesthesia, which include "vivid dreaming, extracorporeal experiences, and illusions."[18] However, like etomidate it is frequently used in emergency settings and with sick patients because it produces fewer adverse physiological effects.[17] Unlike the intravenous anesthetic drugs previously mentioned, ketamine produces profound pain relief, even in doses lower than those which induce general anesthesia.[17] Also unlike the other anesthetic agents in this section, "patients who receive ketamine alone appear to be in a cataleptic state, unlike other states of anesthesia that resemble normal sleep. Ketamine-anesthetized patients have profound analgesia but keep their eyes open and maintain many reflexes."[17]
## Current intravenous opioid analgesic agents
While opioids can produce unconsciousness, they do so unreliably and with significant side effects.[19][20] So, while they are rarely used to induce anesthesia, they are frequently used along with other agents such as intravenous non-opioid anesthetics or inhalational anesthetics.[17] Furthermore, they are used to relieve pain of patients before, during, or after surgery. The following opioids have short onset and duration of action and are frequently used during general anesthesia:
- Fentanyl
- Alfentanil
- Sufentanil
- Remifentanil
The following agents have longer onset and duration of action and are frequently used for post-operative pain relief:
- Buprenorphine
- Butorphanol
- Diamorphine, (diacetyl morphine, also known as heroin, not available in U.S.)
- Hydromorphone
- Levorphanol
- Meperidine, also called pethidine in the UK, New Zealand, Australia and other countries
- Methadone
- Morphine
- Nalbuphine
- Oxycodone, (not available intravenously in U.S.)
- Oxymorphone
- Pentazocine
## Current muscle relaxants
Muscle relaxants do not render patients unconscious or relieve pain. Instead, they are sometimes used after a patient is rendered unconscious (induction of anesthesia) to facilitate intubation or surgery by paralyzing skeletal muscle.
- Depolarizing muscle relaxants
Succinylcholine (also known as suxamethonium in the UK, New Zealand, Australia and other countries)
- Succinylcholine (also known as suxamethonium in the UK, New Zealand, Australia and other countries)
- Non-depolarizing muscle relaxants
Short acting
Mivacurium
Rapacuronium
Intermediate acting
Atracurium
Cisatracurium
Vecuronium
Rocuronium
Long acting
Pancuronium
Metocurine
d-Tubocurarine
Gallamine
Alcuronium
Doxacurium
Pipecuronium
- Short acting
Mivacurium
Rapacuronium
- Mivacurium
- Rapacuronium
- Intermediate acting
Atracurium
Cisatracurium
Vecuronium
Rocuronium
- Atracurium
- Cisatracurium
- Vecuronium
- Rocuronium
- Long acting
Pancuronium
Metocurine
d-Tubocurarine
Gallamine
Alcuronium
Doxacurium
Pipecuronium
- Pancuronium
- Metocurine
- d-Tubocurarine
- Gallamine
- Alcuronium
- Doxacurium
- Pipecuronium
### Adverse effects of muscle relaxants
Succinylcholine may cause hyperkalemia if given to burn patients, or paralyzed (quadraplegic, paraplegic) patients. The mechanism is reported to be through upregulation of acetylcholine receptors in those patient populations. Succinylcholine may also trigger malignant hyperthermia in susceptible patients.
Another potentially disturbing complication can be 'anesthesia awareness'. In this situation, patients paralyzed with muscle relaxants may awaken during their anesthesia, due to decrease in the levels of drugs providing sedation and/or pain relief. If this fact is missed by the anaesthesia provider, the patient may be aware of his surroundings, but be incapable of moving or communicating that fact. Neurological monitors are becoming increasingly available which may help decrease the incidence of awareness. Most of these monitors use proprietary algorithms monitoring brain activity via evoked potentials. Despite the widespread marketing of these devices many case reports exist in which awareness under anesthesia has occurred despite apparently adequate anesthesia as measured by the neurologic monitor.
## Current intravenous reversal agents
- Naloxone, reverses the effects of opioids
- Flumazenil, reverses the effects of benzodiazepines
- Neostigmine, reverses the effects of non-depolarizing muscle relaxants
- Suggamadex, more effectively reverses rocuronium and norcuronium
# Anesthetic equipment
In modern anesthesia, a wide variety of medical equipment is desirable depending on the necessity for portable field use, surgical operations or intensive care support. Anesthesia practitioners must possess a comprehensive and intricate knowledge of the production and use of various medical gases, anaesthetic agents and vapours, medical breathing circuits and the variety of anaesthetic machines (including vaporizers, ventilators and pressure gauges) and their corresponding safety features, hazards and limitations of each piece of equipment, for the safe, clinical competence and practical application for day to day practice.
# Anesthetic monitoring
Patients being treated under general anesthetics must be monitored continuously to ensure the patient's safety. For minor surgery, this generally includes monitoring of heart rate (via ECG or pulse oximetry), oxygen saturation (via pulse oximetry), non-invasive blood pressure, inspired and expired gases (for oxygen, carbon dioxide, nitrous oxide, and volatile agents). For moderate to major surgery, monitoring may also include temperature, urine output, invasive blood measurements (arterial blood pressure, central venous pressure), pulmonary artery pressure and pulmonary artery occlusion pressure, cerebral activity (via EEG analysis), neuromuscular function (via peripheral nerve stimulation monitoring), and cardiac output. In addition, the operating room's environment must be monitored for temperature and humidity and for buildup of exhaled inhalational anesthetics which might impair the health of operating room personnel.
# Anesthesia record
The anesthesia record is the medical and legal documentation of events during an anesthetic.[21] It reflects a detailed and continuous account of drugs, fluids, and blood products administered and procedures undertaken, and also includes the observation of cardiovascular responses, estimated blood loss, urinary body fluids and data from physiologic monitors (Anesthetic monitoring, see above) during the course of an anesthetic. The anesthesia record may be written manually on paper; however, the paper record is increasingly replaced by an electronic record as part of an Anesthesia Information Management System (AIMS).
# Anesthesia Information Management System (AIMS)
An AIMS refers to any information system that is used as an automated electronic anesthesia record keeper (i.e., connection to patient physiologic monitors and/or the Anaesthetic machine) and which also may allow the collection and analysis of anesthesia-related perioperative patient data. | https://www.wikidoc.org/index.php/Anaesthesia | |
29133226a9de25a1d1cf119d42c3e061836b07fb | wikidoc | Anagrelide | Anagrelide
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# Overview
Anagrelide is a platelet reducing agent that is FDA approved for the treatment of thrombocythemia, secondary to myeloproliferative neoplasms. Common adverse reactions include .
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- AGRYLIN Capsules are indicated for the treatment of patients with thrombocythemia, secondary to myeloproliferative neoplasms, to reduce the elevated platelet count and the risk of thrombosis and to ameliorate associated symptoms including thrombo-hemorrhagic events
### Dosage
- Adults: The recommended starting dosage of AGRYLIN is 0.5 mg four times daily or 1 mg twice daily.
- Pediatric Patients: The recommended starting dosage of AGRYLIN is 0.5 mg daily.
- Continue the starting dose for at least one week and then titrate to reduce and maintain the platelet count below 600,000/µL, and ideally between 150,000/µL and 400,000/µL. The dose increment should not exceed 0.5 mg/day in any one week. Dosage should not exceed 10 mg/day or 2.5 mg in a single dose. Most patients will experience an adequate response at a dose of 1.5 to 3.0 mg/day. Monitor platelet counts weekly during titration then monthly or as necessary.
- In patients with moderate hepatic impairment (Child Pugh score 7-9) start AGRYLIN therapy at a dose of 0.5 mg/day and monitor frequently for cardiovascular events. Patients with moderate hepatic impairment who have tolerated AGRYLIN therapy for one week may have their dose increased. The dose increase increment should not exceed 0.5 mg/day in any one week. Avoid use of AGRYLIN in patients with severe hepatic impairment.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Anagrelide in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Anagrelide in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
### Dosage
- The recommended starting dosage of AGRYLIN is 0.5 mg daily.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Anagrelide in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Anagrelide in pediatric patients.
# Contraindications
- none
# Warnings
- Torsades de pointes and ventricular tachycardia have been reported with anagrelide. Obtain a pre-treatment cardiovascular examination including an ECG in all patients. During treatment with AGRYLIN monitor patients for cardiovascular effects and evaluate as necessary.
- Anagrelide increases the QTc interval of the electrocardiogram and increases the heart rate in healthy volunteers .
- Do not use AGRYLIN in patients with known risk factors for QT interval prolongation, such as congenital long QT syndrome, a known history of acquired QTc prolongation, medicinal products that can prolong QTc interval and hypokalemia
- Hepatic impairment increases anagrelide exposure and could increase the risk of QTc prolongation. Monitor patients with hepatic impairment for QTc prolongation and other cardiovascular adverse reactions. The potential risks and benefits of anagrelide therapy in a patient with mild and moderate hepatic impairment should be assessed before treatment is commenced. Reduce AGRYLIN dose in patients with moderate hepatic impairment. Use of AGRYLIN in patients with severe hepatic impairment has not been studied.
- In patients with heart failure, bradyarrhythmias, or electrolyte abnormalities, consider periodic monitoring with electrocardiogram.
- Anagrelide is a phosphodiesterase 3 (PDE3) inhibitor and may cause vasodilation, tachycardia, palpitations, and congestive heart failure. Other drugs that inhibit PDE3 have caused decreased survival when compared with placebo in patients with Class III-IV congestive heart failure.
- In patients with cardiac disease, use AGRYLIN only when the benefits outweigh the risks.
- Use of concomitant anagrelide and aspirin increased major hemorrhagic events in a postmarketing study. Assess the potential risks and benefits for concomitant use of anagrelide with aspirin, since bleeding risks may be increased. Monitor patients for bleeding, including those receiving concomitant therapy with other drugs known to cause bleeding (e.g., anticoagulants, PDE3 inhibitors, NSAIDs, antiplatelet agents, selective serotonin reuptake inhibitors).
- Interstitial lung diseases (including allergic alveolitis, eosinophilic pneumonia and interstitial pneumonitis) have been reported to be associated with the use of anagrelide in post-marketing reports. Most cases presented with progressive dyspnea with lung infiltrations. The time of onset ranged from 1 week to several years after initiating anagrelide. If suspected, discontinue AGRYLIN and evaluate. Symptoms may improve after discontinuation
# Adverse Reactions
## Clinical Trials Experience
### Clinical Trial Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- In three single-arm clinical studies, 942 patients diagnosed with myeloproliferative neoplasms of varying etiology (ET: 551; PV: 117; OMPN: 274) were exposed to anagrelide with a mean duration of approximately 65 weeks. Serious adverse reactions reported in these patients included the following: congestive heart failure, myocardial infarction, cardiomyopathy, cardiomegaly, complete heart block, atrial fibrillation, cerebrovascular accident, pericardial effusion, pleural effusion, pulmonary infiltrates, pulmonary fibrosis, pulmonary hypertension, and pancreatitis. Of the 942 patients treated with anagrelide, 161 (17%) were discontinued from the study because of adverse reactions or abnormal laboratory test results. The most common adverse reactions for treatment discontinuation were headache, diarrhea, edema, palpitations, and abdominal pain.
- The most frequently reported adverse reactions to anagrelide (in 5% or greater of 942 patients with myeloproliferative neoplasms) in clinical trials were listed in Table 1.
- General disorders and administration site conditions: Flu symptoms, chills.
- Cardiac Disorders: Arrhythmia, angina pectoris, heart failure, syncope.
- Vascular disorders: Hemorrhage, hypertension, postural hypotension, vasodilatation.
- Gastrointestinal disorders: Constipation, gastrointestinal hemorrhage, gastritis.
- Blood and lymphatic system disorders: Anemia, thrombocytopenia, ecchymosis.
- Hepatobiliary disorders: Elevated liver enzymes.
- Musculoskeletal and connective tissue disorders: Arthralgia, myalgia.
- Psychiatric disorders: Depression, confusion, nervousness.
- Nervous system disorders: Somnolence, insomnia, amnesia, migraine headache.
- Respiratory, thoracic and mediastinal disorders: Epistaxis, pneumonia.
- Skin and subcutaneous tissue disorders: Alopecia.
- Eye disorders: Abnormal vision, diplopia.
- Ear and labyrinth disorders: Tinnitus
- Renal and urinary disorders: Hematuria, renal failure.
- The frequency of adverse events observed in pediatric patients was similar to adult patients. The most common adverse events observed in pediatric patients were fever, epistaxis, headache, and fatigue during the 3-month anagrelide treatment in the study. Episodes of increased pulse and decreased systolic or diastolic blood pressure beyond the normal ranges in the absence of clinical symptoms were observed. Adverse events that had been reported in these pediatric patients prior to the study and were considered to be related to anagrelide treatment based on retrospective review were; palpitations, headache, nausea, vomiting, abdominal pain, back pain, anorexia, fatigue, and muscle cramps.
## Postmarketing Experience
- The following adverse reactions have been identified during post-marketing use of AGRYLIN. 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 torsades de pointes, ventricular tachycardia, interstitial lung diseases (including allergic alveolitis, eosinophilic pneumonia and interstitial pneumonitis), tubulointerstitial nephritis and clinically significant hepatotoxicity (including symptomatic ALT and AST elevations and elevations greater than three times the ULN) have been reported.
- Other adverse events in pediatric patients reported in spontaneous reports and literature reviews include anemia, cutaneous photosensitivity and elevated leukocyte count.
# Drug Interactions
- Do not use AGRYLIN in patients taking medications that may prolong QT interval (including, but not limited to, chloroquine, clarithromycin, haloperidol, methadone, moxifloxacin, amiodarone, disopyramide, procainamide and pimozide).
- Anagrelide is a phosphodiesterase 3 (PDE3) inhibitor. The effects of drug products with similar properties such as inotropes and other PDE3 inhibitors (e.g., cilostazol, milrinone) should be avoided.
- Co-administration of single-dose or repeat-dose anagrelide and aspirin showed greater ex vivo anti-platelet aggregation effects than administration of aspirin alone. Results from an observational study in patients with essential thrombocythemia suggest the rate of major hemorrhagic events (MHEs) in patients treated with anagrelide is higher than in those subjects treated with another cytoreductive treatment. The majority of the major hemorrhagic events occurred in patients who were also receiving concomitant anti-aggregatory treatment (primarily, aspirin). Therefore, the potential risks of the concomitant use of anagrelide with aspirin should be assessed, particularly in patients with a high risk profile for hemorrhage, before treatment is initiated .
- Monitor patients for bleeding, particularly those receiving concomitant therapy with other drugs known to cause bleeding (e.g., anticoagulants, PDE3 inhibitors, NSAIDs, antiplatelet agents, selective serotonin reuptake inhibitors).
- CYP1A2 inhibitors: Anagrelide and its active metabolite are primarily metabolized by CYP1A2. Drugs that inhibit CYP1A2 (e.g., fluvoxamine, ciprofloxacin) could increase the exposure of anagrelide. Monitor patients for cardiovascular events and titrate doses accordingly when CYP1A2 inhibitors are co-administered.
- CYP1A2 inducers: CYP1A2 inducers could decrease the exposure of anagrelide. Patients taking concomitant CYP1A2 inducers (e.g., omeprazole) may need to have their dose titrated to compensate for the decrease in anagrelide exposure.
- CYP1A2 substrates: Anagrelide demonstrates limited inhibitory activity towards CYP1A2 in vitro and may alter the exposure of concomitant CYP1A2 substrates (e.g. theophylline, fluvoxamine, ondansetron).
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- There are no adequate and well-controlled studies with AGRYLIN in pregnant women. In animal embryo-fetal studies, delayed development (delayed skeletal ossification and reduced body weight) was observed in rats administered anagrelide hydrochloride during organogenesis at doses substantially higher than the maximum clinical dose of 10 mg/day. AGRYLIN should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Anagrelide hydrochloride was administered orally to pregnant rats and rabbits during the period of organogenesis at doses up to 900 mg/kg/day in rats and up to 20 mg/kg/day in rabbits (875 and 39 times, respectively, the maximum clinical dose of 10 mg/day based on body surface area). In rats, developmental delays were observed including reductions in fetal weight at 300 and 900 mg/kg/day and delays in skeletal ossification at doses of 100 mg/kg/day and higher. The dose of 100 mg/kg/day (600 mg/m2/day) in rats is approximately 97 times the maximum clinical dose based on body surface area. No adverse embryo-fetal effects were detected in rabbits at the highest dose of 20 mg/kg/day (39 times the maximal clinical dose based on body surface area).
- In a pre- and post-natal study conducted in female rats, anagrelide hydrochloride at oral doses of 60 mg/kg/day (58 times the maximum clinical dose based on body surface area) or higher produced delay or blockage of parturition, deaths of non-delivering pregnant dams and their fully developed fetuses, and increased mortality in the pups born.
- In a placental transfer study, a single oral dose of -anagrelide hydrochloride was administered to pregnant rats on gestation Day 17. Drug-related radioactivity was detected in maternal and fetal tissue.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Anagrelide in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Anagrelide during labor and delivery.
### Nursing Mothers
Risk Summary
- It is not known whether anagrelide is excreted in human milk. Anagrelide or its metabolites have been detected in the milk of lactating rats. Because many drugs are excreted into human milk and because of the potential for serious adverse reaction in nursing infants from anagrelide, 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.
- In a rat milk secretion study, a single oral dose of -anagrelide hydrochloride was administered to lactating female rats on postnatal Day 10. Drug-related radioactivity was detected in the maternal milk and blood.
### Pediatric Use
- Experience with AGRYLIN in pediatric patients was based on an open label safety and PK/PD study conducted in 18 pediatric patients aged 7-16 years with thrombocytopenia secondary to ET.
- There were no apparent trends or differences in the types of adverse events observed between the pediatric patients compared with those of the adult patients
### Geriatic Use
- Of the 942 subjects in clinical studies of AGRYLIN, 42.1% were 65 years and over, while 14.9% were 75 years 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 response 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 Anagrelide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Anagrelide with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Anagrelide in patients with renal impairment.
### Hepatic Impairment
- Hepatic metabolism is the major route of anagrelide clearance. Exposure to anagrelide is increased 8-fold in patients with moderate hepatic impairment and dose reduction is required. Use of AGRYLIN in patients with severe hepatic impairment has not been studied. The potential risks and benefits of anagrelide therapy in a patient with mild and moderate hepatic impairment should be assessed before treatment is commenced. Assess hepatic function before and during anagrelide treatment
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Anagrelide in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Anagrelide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
- Intravenous
### Monitoring
- AGRYLIN therapy requires clinical monitoring, including complete blood counts, assessment of hepatic and renal function, and electrolytes.
- To prevent the occurrence of thrombocytopenia, monitor platelet counts every two days during the first week of treatment and at least weekly thereafter until the maintenance dosage is reached. Typically, platelet counts begin to respond within 7 to 14 days at the proper dosage. In the clinical trials, the time to complete response, defined as platelet count ≤ 600,000/µL, ranged from 4 to 12 weeks. In the event of dosage interruption or treatment withdrawal, the rebound in platelet count is variable, but platelet counts typically will start to rise within 4 days and return to baseline levels in one to two weeks, possibly rebounding above baseline values. Monitor platelet counts frequently.
# IV Compatibility
There is limited information regarding IV Compatibility of Anagrelide in the drug label.
# Overdosage
- At higher than recommended doses, this medicine has been shown to cause hypotension. There have been postmarketing case reports of intentional overdose with anagrelide hydrochloride. Reported symptoms include sinus tachycardia and vomiting. Symptoms resolved with supportive management. Platelet reduction from anagrelide therapy is dose-related; therefore, thrombocytopenia, which can potentially cause bleeding, is expected from overdosage.
- In case of overdosage, close clinical supervision of the patient is required; this especially includes monitoring of the platelet count for thrombocytopenia. Dosage should be stopped, as appropriate, until the platelet count returns to within the normal range.
# Pharmacology
## Mechanism of Action
- The precise mechanism by which anagrelide reduces blood platelet count is unknown. In cell culture studies, anagrelide suppressed expression of transcription factors including GATA-1 and FOG-1 required for megakaryocytopoiesis, ultimately leading to reduced platelet production.
## Structure
- AGRYLIN (anagrelide hydrochloride) is a platelet-reducing agent. Its chemical name is 6,7-dichloro-1,5-dihydroimidazoquinazolin-2(3H)-one monohydrochloride monohydrate. The molecular formula is C10H7Cl2N3O∙HCl∙H2O which corresponds to a molecular weight of 310.55. The structural formula is:
## Pharmacodynamics
- In blood withdrawn from normal volunteers treated with anagrelide, a disruption was found in the postmitotic phase of megakaryocyte development and a reduction in megakaryocyte size and ploidy. At therapeutic doses, anagrelide does not produce significant changes in white cell counts or coagulation parameters, and may have a small, but clinically insignificant effect on red cell parameters. The active metabolite, 3-hydroxy anagrelide, has similar potency and efficacy to that of anagrelide in the platelet lowering effect; however, exposure (measured by plasma AUC) to 3-hydroxy anagrelide is approximately 2-fold higher compared to anagrelide. Anagrelide and 3-hydroxy anagrelide inhibit cyclic AMP phosphodiesterase 3 (PDE3) and 3-hydroxy anagrelide is approximately forty times more potent than anagrelide (IC50s = 0.9 and 36nM, respectively). PDE3 inhibition does not alter platelet production. PDE3 inhibitors, as a class can inhibit platelet aggregation. However, significant inhibition of platelet aggregation is observed only at doses of anagrelide higher than those typically required to reduce platelet count. PDE3 inhibitors have cardiovascular (CV) effects including vasodilation, positive inotropy and chronotropy.
- The effect of anagrelide dose (0.5 mg and 2.5 mg single doses) on the heart rate and QTc interval prolongation potential was evaluated in a double-blind, randomized, placebo- and active-controlled, cross-over study in 60 healthy adult men and women.
- A dose-related increase in heart rate was observed, with the maximum increase occurring around the time of maximal drug concentration (0.5 – 4 hours). The maximum change in mean heart rate occurred at 2 hours after administration and was +7.8 beats per minute (bpm) for 0.5 mg and +29.1 bpm for 2.5 mg.
- Dose-related increase in mean QTc was observed. The maximum mean (95% upper confidence bound) change in QTcI (individual subject correction) from placebo after baseline-correction was 7.0 (9.8) ms and 13.0 (15.7) ms following anagrelide doses of 0.5 mg and 2.5 mg, respectively.
## Pharmacokinetics
- Dose proportionality has been found in the dose range 0.5 mg to 2.5 mg.
- Following oral administration of AGRYLIN, at least 70% is absorbed from the gastrointestinal tract. In fasted subjects, anagrelide peak plasma concentrations occur within about 1 hour after administration.
- Pharmacokinetic data obtained from healthy volunteers comparing the pharmacokinetics of anagrelide in the fed and fasted states showed that administration of a 1 mg dose of anagrelide with food decreased the Cmax by 14%, but increased the AUC by 20%. Food decreased the Cmax of the active metabolite 3-hydroxy-anagrelide by 29%, although it had no effect on the AUC.
- Anagrelide is primarily metabolized by CYP1A2 to the active metabolite, 3-hydroxy-anagrelide, which is subsequently metabolized by CYP1A2 to the inactive metabolite, RL603. Less than 1% of the administered dose is recovered in the urine as anagrelide, and approximately 3% and 16-20% of the administered dose is recovered as 3-hydroxy-anagrelide and RL603, respectively.
- Anagrelide and 3-hydroxy-anagrelide are eliminated with plasma half-lives of approximately 1.5 and 2.5 hours, respectively. Anagrelide and 3-hydroxy-anagrelide do not accumulate in plasma when the clinical dose regimens are administered.
- Aspirin : In two pharmacodynamic interaction studies in healthy subjects, co-administration of single-dose anagrelide 1 mg and aspirin 900 mg or repeat-dose anagrelide 1 mg once daily and aspirin 75 mg once daily showed greater ex vivo anti-platelet aggregation effects than administration of aspirin alone. Co-administered anagrelide 1mg and aspirin 900mg single-doses had no effect on bleeding time, prothrombin time (PT) or activated partial thromboplastin time (aPTT).
- Digoxin or warfarin: In vivo interaction studies in humans have demonstrated that anagrelide does not affect the pharmacokinetic properties of digoxin or warfarin, nor does digoxin or warfarin affect the pharmacokinetic properties of anagrelide.
- Pediatric: Dose-normalized Cmax and AUC of anagrelide were higher in children and adolescents (age range 7-16 years) with essential thrombocythemia, by 17% and 56%, respectively, than in adult patients (19-57 years).
- Geriatric: Cmax and AUC of anagrelide were 36% and 61% higher, respectively, in elderly patients (age range 65-75 years), than in younger adults (age range 22-50 years), but Cmax and AUC of the active metabolite, 3-hydroxy anagrelide, were 42% and 37% lower, respectively, in the elderly patients.
- Renal Impairment: Pharmacokinetic study at a single dose of 1 mg anagrelide in subjects with severe renal impairment (creatinine clearance <30 mL/min) showed no significant effects on the pharmacokinetics of anagrelide.
- Hepatic Impairment: A pharmacokinetic study at a single dose of 1 mg anagrelide in subjects with moderate hepatic impairment (Child Pugh score 7-9) showed a 2-fold increase in mean anagrelide Cmax and an 8-fold increase in total exposure (AUC) to anagrelide compared with healthy subjects. Additionally, subjects with moderate hepatic impairment showed 24% lower mean 3-hydroxy-anagrelide Cmax and 77% higher mean 3-hydroxy-anagrelide AUC compared to healthy subjects.
## Nonclinical Toxicology
- In a two year rat carcinogenicity study a higher incidence of uterine adenocarcinoma, relative to controls, was observed in females receiving 30 mg/kg/day (at least 174 times human AUC exposure after a 1mg twice daily dose). Adrenal phaeochromocytomas were increased relative to controls in males receiving 3 mg/kg/day and above, and in females receiving 10 mg/kg/day and above (at least 10 and 18 times respectively human AUC exposure after a 1 mg twice daily dose).
- Anagrelide hydrochloride was not mutagenic in the bacterial mutagenesis (Ames) assay or the mouse lymphoma cell (L5178Y, TK+/-) forward mutation assay, and was not clastogenic in the in vitro chromosome aberration assay using human lymphocytes or the in vivo mouse micronucleus test.
- Anagrelide hydrochloride at oral doses up to 240 mg/kg/day (233 times the recommended human dose of 10 mg/day based on body surface area) had no effect on fertility and reproductive function of male rats. However, in fertility studies in female rats, oral doses of 30 mg/kg/day (360 mg/m2/day, 29 times the recommended maximum human dose based on body surface area) or higher resulted in increased pre- and post-implantation loss and a decrease in the number of live embryos.
- In the 2-year rat study, a significant increase in non-neoplastic lesions was observed in anagrelide treated males and females in the adrenal (medullary hyperplasia), heart (myocardial hypertrophy and chamber distension), kidney (hydronephrosis, tubular dilation and urothelial hyperplasia) and bone (femur enostosis). Vascular effects were observed in tissues of the pancreas (arteritis/periarteritis, intimal proliferation and medial hypertrophy), kidney (arteritis/periarteritis, intimal proliferation and medial hypertrophy), sciatic nerve (vascular mineralization), and testes (tubular atrophy and vascular infarct) in anagrelide treated males.
# Clinical Studies
- A total of 942 patients with myeloproliferative neoplasms including 551 patients with Essential Thrombocythemia (ET), 117 patients with Polycythemia Vera (PV), 178 patients with Chronic Myelogenous Leukemia (CML), and 96 patients with other myeloproliferative neoplasms (OMPN), were treated with AGRYLIN in three clinical trials. Patients with OMPN included 87 patients who had Myeloid Metaplasia with Myelofibrosis (MMM), and 9 patients who had unclassified myeloproliferative neoplasms.
- Patients were enrolled in clinical trials if their platelet count was ≥ 900,000/µL on two occasions or ≥ 650,000/µL on two occasions with documentation of symptoms associated with thrombocythemia. The mean duration of anagrelide therapy for ET, PV, CML, and OMPN patients was 65, 67, 40, and 44 weeks, respectively; 23% of patients received treatment for 2 years. Patients were treated with AGRYLIN starting at doses of 0.5-2.0 mg every 6 hours. The dose was increased if the platelet count was still high, but to no more than 12 mg each day. Efficacy was defined as reduction of platelet count to or near physiologic levels (150,000-400,000/µL). The criteria for defining subjects as "responders" were reduction in platelets for at least 4 weeks to ≤600,000/µL, or by at least 50% from baseline value. Subjects treated for less than 4 weeks were not considered evaluable. The results are depicted graphically below:
- AGRYLIN was effective in phlebotomized patients as well as in patients treated with other concomitant therapies including hydroxyurea, aspirin, interferon, radioactive phosphorus, and alkylating agents.
- An open label safety and PK/PD study was conducted in 18 pediatric patients 7-16 years of age (8 patients 7-11 years of age and 10 patients 12-16 years of age, mean age of 12 years; 8 males and 10 females) with thrombocythemia secondary to ET as compared to 17 adult patients (mean age of 66 years, 9 males and 8 females). Prior to entry on to the study, 17 of 18 pediatric patients and 12 of 17 adult patients had received anagrelide treatment for an average of 2 years. The median starting total daily dose, determined by retrospective chart review, for pediatric and adult patients with ET who had received anagrelide prior to study entry was 1mg for each of the three age groups (7-11 and 12-16 year old patients and adults). The starting dose for 6 anagrelide-naive patients at study entry was 0.5 mg once daily. At study completion, the median total daily maintenance doses were similar across age groups, median of 1.75 mg for patients of 7-11 years of age, 2.25 mg in patients 12-16 years of age, and 1.5 mg for adults.
# How Supplied
- AGRYLIN is available as:
- 0.5 mg, opaque, white capsules imprinted "Imprint 063" in black ink: NDC 54092-063-01 = bottle of 100
## Storage
- Store at 25°C (77°F) excursions permitted to 15-30°C (59-86°F), . Store in a light resistant container.
# Images
## Drug Images
## Package and Label Display Panel
### PRINCIPAL DISPLAY PANEL
### Ingredients and Appearance
# Patient Counseling Information
- Dose: Tell the patient that their dose will be adjusted on a weekly basis until they are on a dose that lowers their platelets to an appropriate level. This will also help the patient to adjust to common side effects. Tell the patient to contact their doctor if they experience tolerability issues, so the dose or dosing frequency can be adjusted .
- Cardiovascular effects: Tell the patient to contact a doctor immediately if they experience chest pain, palpitations, or feel their heartbeat is irregular.
- Risk of bleeding: Warn the patient that concomitant aspirin (or other medicines that affect blood clotting) may increase the risk of bleeding. Tell the patient to contact a doctor immediately if they experience signs or symptoms of bleeding (e.g. vomit blood, pass bloody or black stools) or experience unexplained bruising/bruise more easily than usual
# Precautions with Alcohol
- Alcohol-Anagrelide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Agrylin®
# Look-Alike Drug Names
There is limited information regarding Anagrelide Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Anagrelide
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rabin Bista, M.B.B.S. [2]
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# Overview
Anagrelide is a platelet reducing agent that is FDA approved for the treatment of thrombocythemia, secondary to myeloproliferative neoplasms. Common adverse reactions include .
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- AGRYLIN Capsules are indicated for the treatment of patients with thrombocythemia, secondary to myeloproliferative neoplasms, to reduce the elevated platelet count and the risk of thrombosis and to ameliorate associated symptoms including thrombo-hemorrhagic events
### Dosage
- Adults: The recommended starting dosage of AGRYLIN is 0.5 mg four times daily or 1 mg twice daily.
- Pediatric Patients: The recommended starting dosage of AGRYLIN is 0.5 mg daily.
- Continue the starting dose for at least one week and then titrate to reduce and maintain the platelet count below 600,000/µL, and ideally between 150,000/µL and 400,000/µL. The dose increment should not exceed 0.5 mg/day in any one week. Dosage should not exceed 10 mg/day or 2.5 mg in a single dose. Most patients will experience an adequate response at a dose of 1.5 to 3.0 mg/day. Monitor platelet counts weekly during titration then monthly or as necessary.
- In patients with moderate hepatic impairment (Child Pugh score 7-9) start AGRYLIN therapy at a dose of 0.5 mg/day and monitor frequently for cardiovascular events. Patients with moderate hepatic impairment who have tolerated AGRYLIN therapy for one week may have their dose increased. The dose increase increment should not exceed 0.5 mg/day in any one week. Avoid use of AGRYLIN in patients with severe hepatic impairment.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Anagrelide in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Anagrelide in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
### Dosage
- The recommended starting dosage of AGRYLIN is 0.5 mg daily.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Anagrelide in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Anagrelide in pediatric patients.
# Contraindications
- none
# Warnings
- Torsades de pointes and ventricular tachycardia have been reported with anagrelide. Obtain a pre-treatment cardiovascular examination including an ECG in all patients. During treatment with AGRYLIN monitor patients for cardiovascular effects and evaluate as necessary.
- Anagrelide increases the QTc interval of the electrocardiogram and increases the heart rate in healthy volunteers .
- Do not use AGRYLIN in patients with known risk factors for QT interval prolongation, such as congenital long QT syndrome, a known history of acquired QTc prolongation, medicinal products that can prolong QTc interval and hypokalemia
- Hepatic impairment increases anagrelide exposure and could increase the risk of QTc prolongation. Monitor patients with hepatic impairment for QTc prolongation and other cardiovascular adverse reactions. The potential risks and benefits of anagrelide therapy in a patient with mild and moderate hepatic impairment should be assessed before treatment is commenced. Reduce AGRYLIN dose in patients with moderate hepatic impairment. Use of AGRYLIN in patients with severe hepatic impairment has not been studied.
- In patients with heart failure, bradyarrhythmias, or electrolyte abnormalities, consider periodic monitoring with electrocardiogram.
- Anagrelide is a phosphodiesterase 3 (PDE3) inhibitor and may cause vasodilation, tachycardia, palpitations, and congestive heart failure. Other drugs that inhibit PDE3 have caused decreased survival when compared with placebo in patients with Class III-IV congestive heart failure.
- In patients with cardiac disease, use AGRYLIN only when the benefits outweigh the risks.
- Use of concomitant anagrelide and aspirin increased major hemorrhagic events in a postmarketing study. Assess the potential risks and benefits for concomitant use of anagrelide with aspirin, since bleeding risks may be increased. Monitor patients for bleeding, including those receiving concomitant therapy with other drugs known to cause bleeding (e.g., anticoagulants, PDE3 inhibitors, NSAIDs, antiplatelet agents, selective serotonin reuptake inhibitors).
- Interstitial lung diseases (including allergic alveolitis, eosinophilic pneumonia and interstitial pneumonitis) have been reported to be associated with the use of anagrelide in post-marketing reports. Most cases presented with progressive dyspnea with lung infiltrations. The time of onset ranged from 1 week to several years after initiating anagrelide. If suspected, discontinue AGRYLIN and evaluate. Symptoms may improve after discontinuation
# Adverse Reactions
## Clinical Trials Experience
### Clinical Trial Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- In three single-arm clinical studies, 942 patients diagnosed with myeloproliferative neoplasms of varying etiology (ET: 551; PV: 117; OMPN: 274) were exposed to anagrelide with a mean duration of approximately 65 weeks. Serious adverse reactions reported in these patients included the following: congestive heart failure, myocardial infarction, cardiomyopathy, cardiomegaly, complete heart block, atrial fibrillation, cerebrovascular accident, pericardial effusion, pleural effusion, pulmonary infiltrates, pulmonary fibrosis, pulmonary hypertension, and pancreatitis. Of the 942 patients treated with anagrelide, 161 (17%) were discontinued from the study because of adverse reactions or abnormal laboratory test results. The most common adverse reactions for treatment discontinuation were headache, diarrhea, edema, palpitations, and abdominal pain.
- The most frequently reported adverse reactions to anagrelide (in 5% or greater of 942 patients with myeloproliferative neoplasms) in clinical trials were listed in Table 1.
- General disorders and administration site conditions: Flu symptoms, chills.
- Cardiac Disorders: Arrhythmia, angina pectoris, heart failure, syncope.
- Vascular disorders: Hemorrhage, hypertension, postural hypotension, vasodilatation.
- Gastrointestinal disorders: Constipation, gastrointestinal hemorrhage, gastritis.
- Blood and lymphatic system disorders: Anemia, thrombocytopenia, ecchymosis.
- Hepatobiliary disorders: Elevated liver enzymes.
- Musculoskeletal and connective tissue disorders: Arthralgia, myalgia.
- Psychiatric disorders: Depression, confusion, nervousness.
- Nervous system disorders: Somnolence, insomnia, amnesia, migraine headache.
- Respiratory, thoracic and mediastinal disorders: Epistaxis, pneumonia.
- Skin and subcutaneous tissue disorders: Alopecia.
- Eye disorders: Abnormal vision, diplopia.
- Ear and labyrinth disorders: Tinnitus
- Renal and urinary disorders: Hematuria, renal failure.
- The frequency of adverse events observed in pediatric patients was similar to adult patients. The most common adverse events observed in pediatric patients were fever, epistaxis, headache, and fatigue during the 3-month anagrelide treatment in the study. Episodes of increased pulse and decreased systolic or diastolic blood pressure beyond the normal ranges in the absence of clinical symptoms were observed. Adverse events that had been reported in these pediatric patients prior to the study and were considered to be related to anagrelide treatment based on retrospective review were; palpitations, headache, nausea, vomiting, abdominal pain, back pain, anorexia, fatigue, and muscle cramps.
## Postmarketing Experience
- The following adverse reactions have been identified during post-marketing use of AGRYLIN. 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 torsades de pointes, ventricular tachycardia, interstitial lung diseases (including allergic alveolitis, eosinophilic pneumonia and interstitial pneumonitis), tubulointerstitial nephritis and clinically significant hepatotoxicity (including symptomatic ALT and AST elevations and elevations greater than three times the ULN) have been reported.
- Other adverse events in pediatric patients reported in spontaneous reports and literature reviews include anemia, cutaneous photosensitivity and elevated leukocyte count.
# Drug Interactions
- Do not use AGRYLIN in patients taking medications that may prolong QT interval (including, but not limited to, chloroquine, clarithromycin, haloperidol, methadone, moxifloxacin, amiodarone, disopyramide, procainamide and pimozide).
- Anagrelide is a phosphodiesterase 3 (PDE3) inhibitor. The effects of drug products with similar properties such as inotropes and other PDE3 inhibitors (e.g., cilostazol, milrinone) should be avoided.
- Co-administration of single-dose or repeat-dose anagrelide and aspirin showed greater ex vivo anti-platelet aggregation effects than administration of aspirin alone. Results from an observational study in patients with essential thrombocythemia suggest the rate of major hemorrhagic events (MHEs) in patients treated with anagrelide is higher than in those subjects treated with another cytoreductive treatment. The majority of the major hemorrhagic events occurred in patients who were also receiving concomitant anti-aggregatory treatment (primarily, aspirin). Therefore, the potential risks of the concomitant use of anagrelide with aspirin should be assessed, particularly in patients with a high risk profile for hemorrhage, before treatment is initiated .
- Monitor patients for bleeding, particularly those receiving concomitant therapy with other drugs known to cause bleeding (e.g., anticoagulants, PDE3 inhibitors, NSAIDs, antiplatelet agents, selective serotonin reuptake inhibitors).
- CYP1A2 inhibitors: Anagrelide and its active metabolite are primarily metabolized by CYP1A2. Drugs that inhibit CYP1A2 (e.g., fluvoxamine, ciprofloxacin) could increase the exposure of anagrelide. Monitor patients for cardiovascular events and titrate doses accordingly when CYP1A2 inhibitors are co-administered.
- CYP1A2 inducers: CYP1A2 inducers could decrease the exposure of anagrelide. Patients taking concomitant CYP1A2 inducers (e.g., omeprazole) may need to have their dose titrated to compensate for the decrease in anagrelide exposure.
- CYP1A2 substrates: Anagrelide demonstrates limited inhibitory activity towards CYP1A2 in vitro and may alter the exposure of concomitant CYP1A2 substrates (e.g. theophylline, fluvoxamine, ondansetron).
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- There are no adequate and well-controlled studies with AGRYLIN in pregnant women. In animal embryo-fetal studies, delayed development (delayed skeletal ossification and reduced body weight) was observed in rats administered anagrelide hydrochloride during organogenesis at doses substantially higher than the maximum clinical dose of 10 mg/day. AGRYLIN should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Anagrelide hydrochloride was administered orally to pregnant rats and rabbits during the period of organogenesis at doses up to 900 mg/kg/day in rats and up to 20 mg/kg/day in rabbits (875 and 39 times, respectively, the maximum clinical dose of 10 mg/day based on body surface area). In rats, developmental delays were observed including reductions in fetal weight at 300 and 900 mg/kg/day and delays in skeletal ossification at doses of 100 mg/kg/day and higher. The dose of 100 mg/kg/day (600 mg/m2/day) in rats is approximately 97 times the maximum clinical dose based on body surface area. No adverse embryo-fetal effects were detected in rabbits at the highest dose of 20 mg/kg/day (39 times the maximal clinical dose based on body surface area).
- In a pre- and post-natal study conducted in female rats, anagrelide hydrochloride at oral doses of 60 mg/kg/day (58 times the maximum clinical dose based on body surface area) or higher produced delay or blockage of parturition, deaths of non-delivering pregnant dams and their fully developed fetuses, and increased mortality in the pups born.
- In a placental transfer study, a single oral dose of [14C]-anagrelide hydrochloride was administered to pregnant rats on gestation Day 17. Drug-related radioactivity was detected in maternal and fetal tissue.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Anagrelide in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Anagrelide during labor and delivery.
### Nursing Mothers
Risk Summary
- It is not known whether anagrelide is excreted in human milk. Anagrelide or its metabolites have been detected in the milk of lactating rats. Because many drugs are excreted into human milk and because of the potential for serious adverse reaction in nursing infants from anagrelide, 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.
- In a rat milk secretion study, a single oral dose of [14C]-anagrelide hydrochloride was administered to lactating female rats on postnatal Day 10. Drug-related radioactivity was detected in the maternal milk and blood.
### Pediatric Use
- Experience with AGRYLIN in pediatric patients was based on an open label safety and PK/PD study conducted in 18 pediatric patients aged 7-16 years with thrombocytopenia secondary to ET.
- There were no apparent trends or differences in the types of adverse events observed between the pediatric patients compared with those of the adult patients
### Geriatic Use
- Of the 942 subjects in clinical studies of AGRYLIN, 42.1% were 65 years and over, while 14.9% were 75 years 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 response 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 Anagrelide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Anagrelide with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Anagrelide in patients with renal impairment.
### Hepatic Impairment
- Hepatic metabolism is the major route of anagrelide clearance. Exposure to anagrelide is increased 8-fold in patients with moderate hepatic impairment and dose reduction is required. Use of AGRYLIN in patients with severe hepatic impairment has not been studied. The potential risks and benefits of anagrelide therapy in a patient with mild and moderate hepatic impairment should be assessed before treatment is commenced. Assess hepatic function before and during anagrelide treatment
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Anagrelide in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Anagrelide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
- Intravenous
### Monitoring
- AGRYLIN therapy requires clinical monitoring, including complete blood counts, assessment of hepatic and renal function, and electrolytes.
- To prevent the occurrence of thrombocytopenia, monitor platelet counts every two days during the first week of treatment and at least weekly thereafter until the maintenance dosage is reached. Typically, platelet counts begin to respond within 7 to 14 days at the proper dosage. In the clinical trials, the time to complete response, defined as platelet count ≤ 600,000/µL, ranged from 4 to 12 weeks. In the event of dosage interruption or treatment withdrawal, the rebound in platelet count is variable, but platelet counts typically will start to rise within 4 days and return to baseline levels in one to two weeks, possibly rebounding above baseline values. Monitor platelet counts frequently.
# IV Compatibility
There is limited information regarding IV Compatibility of Anagrelide in the drug label.
# Overdosage
- At higher than recommended doses, this medicine has been shown to cause hypotension. There have been postmarketing case reports of intentional overdose with anagrelide hydrochloride. Reported symptoms include sinus tachycardia and vomiting. Symptoms resolved with supportive management. Platelet reduction from anagrelide therapy is dose-related; therefore, thrombocytopenia, which can potentially cause bleeding, is expected from overdosage.
- In case of overdosage, close clinical supervision of the patient is required; this especially includes monitoring of the platelet count for thrombocytopenia. Dosage should be stopped, as appropriate, until the platelet count returns to within the normal range.
# Pharmacology
## Mechanism of Action
- The precise mechanism by which anagrelide reduces blood platelet count is unknown. In cell culture studies, anagrelide suppressed expression of transcription factors including GATA-1 and FOG-1 required for megakaryocytopoiesis, ultimately leading to reduced platelet production.
## Structure
- AGRYLIN (anagrelide hydrochloride) is a platelet-reducing agent. Its chemical name is 6,7-dichloro-1,5-dihydroimidazo[2,1-b]quinazolin-2(3H)-one monohydrochloride monohydrate. The molecular formula is C10H7Cl2N3O∙HCl∙H2O which corresponds to a molecular weight of 310.55. The structural formula is:
## Pharmacodynamics
- In blood withdrawn from normal volunteers treated with anagrelide, a disruption was found in the postmitotic phase of megakaryocyte development and a reduction in megakaryocyte size and ploidy. At therapeutic doses, anagrelide does not produce significant changes in white cell counts or coagulation parameters, and may have a small, but clinically insignificant effect on red cell parameters. The active metabolite, 3-hydroxy anagrelide, has similar potency and efficacy to that of anagrelide in the platelet lowering effect; however, exposure (measured by plasma AUC) to 3-hydroxy anagrelide is approximately 2-fold higher compared to anagrelide. Anagrelide and 3-hydroxy anagrelide inhibit cyclic AMP phosphodiesterase 3 (PDE3) and 3-hydroxy anagrelide is approximately forty times more potent than anagrelide (IC50s = 0.9 and 36nM, respectively). PDE3 inhibition does not alter platelet production. PDE3 inhibitors, as a class can inhibit platelet aggregation. However, significant inhibition of platelet aggregation is observed only at doses of anagrelide higher than those typically required to reduce platelet count. PDE3 inhibitors have cardiovascular (CV) effects including vasodilation, positive inotropy and chronotropy.
- The effect of anagrelide dose (0.5 mg and 2.5 mg single doses) on the heart rate and QTc interval prolongation potential was evaluated in a double-blind, randomized, placebo- and active-controlled, cross-over study in 60 healthy adult men and women.
- A dose-related increase in heart rate was observed, with the maximum increase occurring around the time of maximal drug concentration (0.5 – 4 hours). The maximum change in mean heart rate occurred at 2 hours after administration and was +7.8 beats per minute (bpm) for 0.5 mg and +29.1 bpm for 2.5 mg.
- Dose-related increase in mean QTc was observed. The maximum mean (95% upper confidence bound) change in QTcI (individual subject correction) from placebo after baseline-correction was 7.0 (9.8) ms and 13.0 (15.7) ms following anagrelide doses of 0.5 mg and 2.5 mg, respectively.
## Pharmacokinetics
- Dose proportionality has been found in the dose range 0.5 mg to 2.5 mg.
- Following oral administration of AGRYLIN, at least 70% is absorbed from the gastrointestinal tract. In fasted subjects, anagrelide peak plasma concentrations occur within about 1 hour after administration.
- Pharmacokinetic data obtained from healthy volunteers comparing the pharmacokinetics of anagrelide in the fed and fasted states showed that administration of a 1 mg dose of anagrelide with food decreased the Cmax by 14%, but increased the AUC by 20%. Food decreased the Cmax of the active metabolite 3-hydroxy-anagrelide by 29%, although it had no effect on the AUC.
- Anagrelide is primarily metabolized by CYP1A2 to the active metabolite, 3-hydroxy-anagrelide, which is subsequently metabolized by CYP1A2 to the inactive metabolite, RL603. Less than 1% of the administered dose is recovered in the urine as anagrelide, and approximately 3% and 16-20% of the administered dose is recovered as 3-hydroxy-anagrelide and RL603, respectively.
- Anagrelide and 3-hydroxy-anagrelide are eliminated with plasma half-lives of approximately 1.5 and 2.5 hours, respectively. Anagrelide and 3-hydroxy-anagrelide do not accumulate in plasma when the clinical dose regimens are administered.
- Aspirin : In two pharmacodynamic interaction studies in healthy subjects, co-administration of single-dose anagrelide 1 mg and aspirin 900 mg or repeat-dose anagrelide 1 mg once daily and aspirin 75 mg once daily showed greater ex vivo anti-platelet aggregation effects than administration of aspirin alone. Co-administered anagrelide 1mg and aspirin 900mg single-doses had no effect on bleeding time, prothrombin time (PT) or activated partial thromboplastin time (aPTT).
- Digoxin or warfarin: In vivo interaction studies in humans have demonstrated that anagrelide does not affect the pharmacokinetic properties of digoxin or warfarin, nor does digoxin or warfarin affect the pharmacokinetic properties of anagrelide.
- Pediatric: Dose-normalized Cmax and AUC of anagrelide were higher in children and adolescents (age range 7-16 years) with essential thrombocythemia, by 17% and 56%, respectively, than in adult patients (19-57 years).
- Geriatric: Cmax and AUC of anagrelide were 36% and 61% higher, respectively, in elderly patients (age range 65-75 years), than in younger adults (age range 22-50 years), but Cmax and AUC of the active metabolite, 3-hydroxy anagrelide, were 42% and 37% lower, respectively, in the elderly patients.
- Renal Impairment: Pharmacokinetic study at a single dose of 1 mg anagrelide in subjects with severe renal impairment (creatinine clearance <30 mL/min) showed no significant effects on the pharmacokinetics of anagrelide.
- Hepatic Impairment: A pharmacokinetic study at a single dose of 1 mg anagrelide in subjects with moderate hepatic impairment (Child Pugh score 7-9) showed a 2-fold increase in mean anagrelide Cmax and an 8-fold increase in total exposure (AUC) to anagrelide compared with healthy subjects. Additionally, subjects with moderate hepatic impairment showed 24% lower mean 3-hydroxy-anagrelide Cmax and 77% higher mean 3-hydroxy-anagrelide AUC compared to healthy subjects.
## Nonclinical Toxicology
- In a two year rat carcinogenicity study a higher incidence of uterine adenocarcinoma, relative to controls, was observed in females receiving 30 mg/kg/day (at least 174 times human AUC exposure after a 1mg twice daily dose). Adrenal phaeochromocytomas were increased relative to controls in males receiving 3 mg/kg/day and above, and in females receiving 10 mg/kg/day and above (at least 10 and 18 times respectively human AUC exposure after a 1 mg twice daily dose).
- Anagrelide hydrochloride was not mutagenic in the bacterial mutagenesis (Ames) assay or the mouse lymphoma cell (L5178Y, TK+/-) forward mutation assay, and was not clastogenic in the in vitro chromosome aberration assay using human lymphocytes or the in vivo mouse micronucleus test.
- Anagrelide hydrochloride at oral doses up to 240 mg/kg/day (233 times the recommended human dose of 10 mg/day based on body surface area) had no effect on fertility and reproductive function of male rats. However, in fertility studies in female rats, oral doses of 30 mg/kg/day (360 mg/m2/day, 29 times the recommended maximum human dose based on body surface area) or higher resulted in increased pre- and post-implantation loss and a decrease in the number of live embryos.
- In the 2-year rat study, a significant increase in non-neoplastic lesions was observed in anagrelide treated males and females in the adrenal (medullary hyperplasia), heart (myocardial hypertrophy and chamber distension), kidney (hydronephrosis, tubular dilation and urothelial hyperplasia) and bone (femur enostosis). Vascular effects were observed in tissues of the pancreas (arteritis/periarteritis, intimal proliferation and medial hypertrophy), kidney (arteritis/periarteritis, intimal proliferation and medial hypertrophy), sciatic nerve (vascular mineralization), and testes (tubular atrophy and vascular infarct) in anagrelide treated males.
# Clinical Studies
- A total of 942 patients with myeloproliferative neoplasms including 551 patients with Essential Thrombocythemia (ET), 117 patients with Polycythemia Vera (PV), 178 patients with Chronic Myelogenous Leukemia (CML), and 96 patients with other myeloproliferative neoplasms (OMPN), were treated with AGRYLIN in three clinical trials. Patients with OMPN included 87 patients who had Myeloid Metaplasia with Myelofibrosis (MMM), and 9 patients who had unclassified myeloproliferative neoplasms.
- Patients were enrolled in clinical trials if their platelet count was ≥ 900,000/µL on two occasions or ≥ 650,000/µL on two occasions with documentation of symptoms associated with thrombocythemia. The mean duration of anagrelide therapy for ET, PV, CML, and OMPN patients was 65, 67, 40, and 44 weeks, respectively; 23% of patients received treatment for 2 years. Patients were treated with AGRYLIN starting at doses of 0.5-2.0 mg every 6 hours. The dose was increased if the platelet count was still high, but to no more than 12 mg each day. Efficacy was defined as reduction of platelet count to or near physiologic levels (150,000-400,000/µL). The criteria for defining subjects as "responders" were reduction in platelets for at least 4 weeks to ≤600,000/µL, or by at least 50% from baseline value. Subjects treated for less than 4 weeks were not considered evaluable. The results are depicted graphically below:
- AGRYLIN was effective in phlebotomized patients as well as in patients treated with other concomitant therapies including hydroxyurea, aspirin, interferon, radioactive phosphorus, and alkylating agents.
- An open label safety and PK/PD study was conducted in 18 pediatric patients 7-16 years of age (8 patients 7-11 years of age and 10 patients 12-16 years of age, mean age of 12 years; 8 males and 10 females) with thrombocythemia secondary to ET as compared to 17 adult patients (mean age of 66 years, 9 males and 8 females). Prior to entry on to the study, 17 of 18 pediatric patients and 12 of 17 adult patients had received anagrelide treatment for an average of 2 years. The median starting total daily dose, determined by retrospective chart review, for pediatric and adult patients with ET who had received anagrelide prior to study entry was 1mg for each of the three age groups (7-11 and 12-16 year old patients and adults). The starting dose for 6 anagrelide-naive patients at study entry was 0.5 mg once daily. At study completion, the median total daily maintenance doses were similar across age groups, median of 1.75 mg for patients of 7-11 years of age, 2.25 mg in patients 12-16 years of age, and 1.5 mg for adults.
# How Supplied
- AGRYLIN is available as:
- 0.5 mg, opaque, white capsules imprinted "Imprint 063" in black ink: NDC 54092-063-01 = bottle of 100
## Storage
- Store at 25°C (77°F) excursions permitted to 15-30°C (59-86°F), [See USP Controlled Room Temperature]. Store in a light resistant container.
# Images
## Drug Images
## Package and Label Display Panel
### PRINCIPAL DISPLAY PANEL
### Ingredients and Appearance
# Patient Counseling Information
- Dose: Tell the patient that their dose will be adjusted on a weekly basis until they are on a dose that lowers their platelets to an appropriate level. This will also help the patient to adjust to common side effects. Tell the patient to contact their doctor if they experience tolerability issues, so the dose or dosing frequency can be adjusted .
- Cardiovascular effects: Tell the patient to contact a doctor immediately if they experience chest pain, palpitations, or feel their heartbeat is irregular.
- Risk of bleeding: Warn the patient that concomitant aspirin (or other medicines that affect blood clotting) may increase the risk of bleeding. Tell the patient to contact a doctor immediately if they experience signs or symptoms of bleeding (e.g. vomit blood, pass bloody or black stools) or experience unexplained bruising/bruise more easily than usual
# Precautions with Alcohol
- Alcohol-Anagrelide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Agrylin®[1]
# Look-Alike Drug Names
There is limited information regarding Anagrelide Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Anagrelide | |
6ad6259f9d073ae95adc91f31df73e9ea946f672 | wikidoc | Anal canal | Anal canal
# Overview
The anal canal is the terminal part of the large intestine.
It is situated between the rectum and anus, below the level of the pelvic diaphragm. It lies in the anal triangle of perineum in between the right and left ischiorectal fossae.
In humans it is approximately 2.5 to 4 cm long, extending from the anorectal junction to the anus. It is directed downwards and backwards. It is surrounded by inner involuntary and outer voluntary sphincters which keep the lumen closed in the form of an anteroposterior slit.
It is differentiated from the rectum by the transition of the internal surface from endodermal to skinlike ectodermal tissue.
# Additional images
- Anatomy of the anus and rectum
- Left Levator ani from within.
- The interior of the anal cami and lower part of the rectum.
- Median sagittal section of male pelvis.
- Median sagittal section of female pelvis. | Anal canal
# Overview
Template:Infobox Anatomy
The anal canal is the terminal part of the large intestine.
It is situated between the rectum and anus, below the level of the pelvic diaphragm. It lies in the anal triangle of perineum in between the right and left ischiorectal fossae.
In humans it is approximately 2.5 to 4 cm long, extending from the anorectal junction to the anus. It is directed downwards and backwards. It is surrounded by inner involuntary and outer voluntary sphincters which keep the lumen closed in the form of an anteroposterior slit.
It is differentiated from the rectum by the transition of the internal surface from endodermal to skinlike ectodermal tissue.
# Additional images
- Anatomy of the anus and rectum
- Left Levator ani from within.
- The interior of the anal cami and lower part of the rectum.
- Median sagittal section of male pelvis.
- Median sagittal section of female pelvis. | https://www.wikidoc.org/index.php/Anal_canal | |
f83062bfbd64d0cbe3f8710b036bd08aa2b26458 | wikidoc | Anandamide | Anandamide
Anandamide, also known as N-arachidonoylethanolamine or AEA, is an endogenous cannabinoid neurotransmitter. It was isolated and its structure was first described by Czech analytical chemist Lumír Ondřej Hanuš and American molecular pharmacologist William Anthony Devane in the Laboratory of Raphael Mechoulam, at the Hebrew University in Jerusalem, Israel in 1992. The name is taken from the Sanskrit word ananda, which means "bliss, delight", and amide. It is synthesized from N-arachidonoyl phosphatidylethanolamine by multiple pathways. It is degraded primarily by the fatty acid amide hydrolase (FAAH) enzyme, which converts anandamide into ethanolamine and arachidonic acid. As such, inhibitors of FAAH lead to elevated anandamide levels and are being pursued for therapeutic use.
# Physiological functions
Anandamide's effects can be either central, in the brain, or peripheral, in other parts of the body. These distinct effects are mediated primarily by CB1 cannabinoid receptors in the central nervous system, and CB2 cannabinoid receptors in the periphery. The latter are mainly involved in functions of the immune system. Cannabinoid receptors were originally discovered as being sensitive to Δ9-tetrahydrocannabinol (Δ9-THC, commonly called THC), which is the primary psychoactive cannabinoid found in cannabis. The discovery of anandamide came from research into CB1 and CB2, as it was inevitable that a naturally occurring (endogenous) chemical would be found to affect these receptors.
Moreover, anandamide is thought to be an endogenous ligand for vanilloid receptors (which are involved in the transduction of acute and inflammatory pain signals), activating the receptor in a PKC-dependent (protein kinase C-dependent) manner.
Anandamide has been shown to be involved in working memory. Studies are under way to explore what role anandamide plays in human behavior, such as eating and sleep patterns, and pain relief.
Anandamide is also important for implantation of the early stage embryo in its blastocyst form into the uterus. Therefore cannabinoids such as Δ9-THC might interfere with the earliest stages of human pregnancy. Peak plasma anandamide occurs at ovulation and positively correlates with peak estradiol and gonadotrophin levels, suggesting that these may be involved in the regulation of AEA levels.
Anandamide also is important in the regulation of feeding behavior, and the neural generation of motivation and pleasure. In addition, anandamide injected directly into the forebrain reward-related brain structure nucleus accumbens enhances the pleasurable responses of rats to a rewarding sucrose taste, and enhances food intake as well.
A study published in 1998 shows that anandamide inhibits human breast cancer cell proliferation.
# Synthesis and degradation
The human body synthesizes anandamide from N-arachidonoyl phosphatidylethanolamine (NAPE), which is itself made by transferring arachidonic acid from lecithin to the free amine of cephalin through an N-acyltransferase enzyme. Anandamide synthesis from NarPE occurs via multiple pathways and includes enzymes such as phospholipase A2, phospholipase C and NAPE-PLD.
Endogenous anandamide is present at very low levels and has a very short half-life due to the action of the enzyme fatty acid amide hydrolase (FAAH), which breaks it down into free arachidonic acid and ethanolamine. Studies of piglets show that dietary levels of arachidonic acid and other essential fatty acids affect the levels of anandamide and other endocannabinoids in the brain. High fat diet feeding in mice increases levels of anandamide in the liver and increases lipogenesis. This suggests that anandamide may play a role in the development of obesity, at least in rodents.
Paracetamol (or acetaminophen in the U.S.A.) is metabolically combined with arachidonic acid by FAAH to form AM404. This metabolite of paracetamol is a potent agonist at the TRPV1 vanilloid receptor, a weak agonist at both CB1 and CB2 receptors, and an inhibitor of anandamide reuptake. As a result, anandamide levels in the body and brain are elevated. In this fashion, paracetamol acts as a pro-drug for a cannabimimetic metabolite. This action may be partially or fully responsible for the analgesic effects of paracetamol. | Anandamide
Anandamide, also known as N-arachidonoylethanolamine or AEA, is an endogenous cannabinoid neurotransmitter. It was isolated and its structure was first described by Czech analytical chemist Lumír Ondřej Hanuš and American molecular pharmacologist William Anthony Devane in the Laboratory of Raphael Mechoulam, at the Hebrew University in Jerusalem, Israel in 1992. The name is taken from the Sanskrit word ananda, which means "bliss, delight", and amide.[1][2] It is synthesized from N-arachidonoyl phosphatidylethanolamine by multiple pathways.[3] It is degraded primarily by the fatty acid amide hydrolase (FAAH) enzyme, which converts anandamide into ethanolamine and arachidonic acid. As such, inhibitors of FAAH lead to elevated anandamide levels and are being pursued for therapeutic use.[4][5]
# Physiological functions
Anandamide's effects can be either central, in the brain, or peripheral, in other parts of the body. These distinct effects are mediated primarily by CB1 cannabinoid receptors in the central nervous system, and CB2 cannabinoid receptors in the periphery. The latter are mainly involved in functions of the immune system. Cannabinoid receptors were originally discovered as being sensitive to Δ9-tetrahydrocannabinol (Δ9-THC, commonly called THC), which is the primary psychoactive cannabinoid found in cannabis. The discovery of anandamide came from research into CB1 and CB2, as it was inevitable that a naturally occurring (endogenous) chemical would be found to affect these receptors.
Moreover, anandamide is thought to be an endogenous ligand for vanilloid receptors (which are involved in the transduction of acute and inflammatory pain signals), activating the receptor in a PKC-dependent (protein kinase C-dependent) manner.[citation needed]
Anandamide has been shown to be involved in working memory.[6] Studies are under way to explore what role anandamide plays in human behavior, such as eating and sleep patterns, and pain relief.
Anandamide is also important for implantation of the early stage embryo in its blastocyst form into the uterus. Therefore cannabinoids such as Δ9-THC might interfere with the earliest stages of human pregnancy.[7] Peak plasma anandamide occurs at ovulation and positively correlates with peak estradiol and gonadotrophin levels, suggesting that these may be involved in the regulation of AEA levels.[8]
Anandamide also is important in the regulation of feeding behavior, and the neural generation of motivation and pleasure. In addition, anandamide injected directly into the forebrain reward-related brain structure nucleus accumbens enhances the pleasurable responses of rats to a rewarding sucrose taste, and enhances food intake as well.[9]
A study published in 1998 shows that anandamide inhibits human breast cancer cell proliferation.[10]
# Synthesis and degradation
The human body synthesizes anandamide from N-arachidonoyl phosphatidylethanolamine (NAPE), which is itself made by transferring arachidonic acid from lecithin to the free amine of cephalin through an N-acyltransferase enzyme.[11][12] Anandamide synthesis from NarPE occurs via multiple pathways and includes enzymes such as phospholipase A2, phospholipase C and NAPE-PLD. [3]
Endogenous anandamide is present at very low levels and has a very short half-life due to the action of the enzyme fatty acid amide hydrolase (FAAH), which breaks it down into free arachidonic acid and ethanolamine. Studies of piglets show that dietary levels of arachidonic acid and other essential fatty acids affect the levels of anandamide and other endocannabinoids in the brain.[13] High fat diet feeding in mice increases levels of anandamide in the liver and increases lipogenesis.[14] This suggests that anandamide may play a role in the development of obesity, at least in rodents.
Paracetamol (or acetaminophen in the U.S.A.) is metabolically combined with arachidonic acid by FAAH to form AM404.[15] This metabolite of paracetamol is a potent agonist at the TRPV1 vanilloid receptor, a weak agonist at both CB1 and CB2 receptors, and an inhibitor of anandamide reuptake. As a result, anandamide levels in the body and brain are elevated. In this fashion, paracetamol acts as a pro-drug for a cannabimimetic metabolite. This action may be partially or fully responsible for the analgesic effects of paracetamol.[16][17] | https://www.wikidoc.org/index.php/Anandamide | |
cc8a48cb8f3aca19eda049add0dbbf4f5b376917 | wikidoc | Anatomotor | Anatomotor
The Hill Anatomotor is a Stationary Massage type therapy table
The Stationary-Top Anatomotor gives you massage and spinal mobilization provided by a moveable-top Anatomotor in a 6'3" space. A reciprocating carriage moves the rollers at a speed just under the respiration rate. Unlike other massage tables, the back rollers are always in contact with the patient for a more relaxing and comfortable, deep-kneading massage therapy.
Model ST2 has two sets of back rollers that are spring cushioned and independently adjust in height to treat the kyphotic and lordotic curvatures at different settings. Model Option ST3 has a third set of massage rollers beneficial in treating the outer rib cage and larger patients. Heat and vibration options are available on both models.
The Stationary Anatomotor easily converts to a straight treatment table by inserting the filler block with face cut-out. A spring-recoil action of the filler-block may also be achieved. | Anatomotor
The Hill Anatomotor is a Stationary Massage type therapy table
The Stationary-Top Anatomotor gives you massage and spinal mobilization provided by a moveable-top Anatomotor in a 6'3" space. A reciprocating carriage moves the rollers at a speed just under the respiration rate. Unlike other massage tables, the back rollers are always in contact with the patient for a more relaxing and comfortable, deep-kneading massage therapy.
Model ST2 has two sets of back rollers that are spring cushioned and independently adjust in height to treat the kyphotic and lordotic curvatures at different settings. Model Option ST3 has a third set of massage rollers beneficial in treating the outer rib cage and larger patients. Heat and vibration options are available on both models.
The Stationary Anatomotor easily converts to a straight treatment table by inserting the filler block with face cut-out. A spring-recoil action of the filler-block may also be achieved. | https://www.wikidoc.org/index.php/Anatomotor | |
2a45f54d0ef790517834c06a044f7d626c3c3bb1 | wikidoc | Andropause | Andropause
# Overview
Andropause may or may not actually exist as a clinical phenomenon. Its proponents claim it is a biological change experienced by men during their mid-life, and is often inaccurately compared to the female menopause. It would perhaps be more reasonable to speak of a steady age-related decline in testosterone levels in men, since men's reproductive systems slowly and gradually decline with age, but do not stop working altogether in mid-life, as women's do. It is also not clear how much this supposedly universal male phenomenon can be related to a psychological mid-life crisis, and to overall negative bodily changes in mid-life due not only to aging, but also to the accumulated effects of a lack of exercise, poor diet and so on.
Andropause is also known as androgen decline in the aging male (ADAM), late onset hypogonadism (LOH) and testosterone deficiency syndrome (TDS). There is no cut off age at which andropause starts as there is variability among men in terms of age of onset.
Endocrine Society Guideline and the European Association of Urology Recommendations defines andropause as the following: TDS/LOH is a clinical and biochemical syndrome associated with advancing age and characterized by symptoms and a deficiency in serum testosterone levels. It may result in significant detriment in the quality of life and adversely affect the function of multiple organ systems.
# Historical Perspective
Much of the current interest in this alleged phenomenon has been fueled by the book Male Menopause, written by Jed Diamond. It should be noted that Diamond is neither an MD nor a PhD. According to the book's author, andropause (another term for "male menopause") is a change of life in middle-aged men, which has hormonal, physical, psychological, interpersonal, social, sexual, and spiritual aspects. Diamond claims that this change occurs in all men, generally between the ages of 40 and 55, though it can occur as early as 35 or as late as 65.
The term "male menopause" is a misnomer, as men don’t have menstrual periods, and therefore cannot stop having them. Unlike women, men's reproductive systems do not cease to work completely in mid-life; some men continue to father children late into their lives (at age 90 or older). But Diamond claims that, in terms of other life impacts, women’s and men’s experience are somewhat similar phenomena.
The concept of andropause is perhaps more widely accepted in Australia and some parts of Europe than it is in the United States. In the U.S., many clinicians believe that, since men can continue to reproduce into old age, and do not show the same dramatic drops in hormone levels characteristic of menopause in women, andropause is nonexistent. Others feel that andropause is real, but is synonymous with hypogonadism or low testosterone levels .
# Pathophysiology
- Aging affects the hypothalamus- pituitary- gonadal axis and causes a decrease in the production of gonadotropin releasing hormone (GnRH) by the hypothalamus and a decrease in the production of LH by the pituitary.
- Aging is associated with decrease in the number Leydig cells as well as decrease in their sensitivity to LH resulting in decrease production of testosterone.
- Age related changes in androgen receptor, a ligand inducible transcription factor, has been reported to be associated with less androgenic effects of the testosterone.
# Epidemiology and Demographics
The prevalence of andropause has not been accurately reported. According to the Massachusetts Male Aging Study (MMAS) has estimated the crude prevalence of andropause in American men between 40 and 69 years old to be around 481,000 new cases per year.
# Screening
Several questionnaires have been developed as a screening tool for andropause. These questionnaires include the following:
- St. Louis University’s ADAM
- Aging Male Survey (AMS)
- Massachusetts Male Aging Study questionnaire (MMAS)
# Symptoms
The impact of low levels of testosterone has been previously reported. Heller and Myers identified symptoms of what they labeled the "male climacteric" including loss of libido and potency, nervousness, depression, impaired memory, the inability to concentrate, fatigue, insomnia, hot flushes, and sweating. Heller and Myers found that their subjects had lower than normal levels of testosterone, and that symptoms improved dramatically when patients were given replacement doses of testosterone.
Testosterone deficiency has also been linked to metabolic syndrome and mood disturbances mainly depression.
# Diagnosis
The diagnosis of andropause is difficult since the clinical diagnosis alone or biochemical assays alone are not sufficient. When symptoms of andropause are clinically present along with low or borderline-low free testosterone levels, the diagnosis can be established. According to Morley et al, the diagnosis requires a positive response to testosterone treatment along with the initial clinical and biochemical diagnostic clues..
The biochemical diagnostic clues include measuring the free testosterone level. It is important that the measurement is done in the morning due to the variability of testosterone levels associated with the circadian rhythm. The testosterone measurement should be repeated in two weeks due to week to week variability.
# Treatment
Several intervention strategies have been found to be effective . These include:
- Hormone replacement therapy,
- Exercise, dietary changes, stress reduction,
- Couple counseling, career refocusing, and spiritual support,
- Chemical dependency treatment, sexual compulsivity treatment,
- Treatment for depression,
- Finding and engaging one’s “calling” in the second half of life. | Andropause
Template:Search infobox
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Andropause may or may not actually exist as a clinical phenomenon. Its proponents claim it is a biological change experienced by men during their mid-life, and is often inaccurately compared to the female menopause. It would perhaps be more reasonable to speak of a steady age-related decline in testosterone levels in men, since men's reproductive systems slowly and gradually decline with age, but do not stop working altogether in mid-life, as women's do. It is also not clear how much this supposedly universal male phenomenon can be related to a psychological mid-life crisis, and to overall negative bodily changes in mid-life due not only to aging, but also to the accumulated effects of a lack of exercise, poor diet and so on.
Andropause is also known as androgen decline in the aging male (ADAM), late onset hypogonadism (LOH) and testosterone deficiency syndrome (TDS). There is no cut off age at which andropause starts as there is variability among men in terms of age of onset.
Endocrine Society Guideline and the European Association of Urology Recommendations defines andropause as the following: TDS/LOH is a clinical and biochemical syndrome associated with advancing age and characterized by symptoms and a deficiency in serum testosterone levels. It may result in significant detriment in the quality of life and adversely affect the function of multiple organ systems.[1]
# Historical Perspective
Much of the current interest in this alleged phenomenon has been fueled by the book Male Menopause, written by Jed Diamond[2]. It should be noted that Diamond is neither an MD nor a PhD. According to the book's author, andropause (another term for "male menopause") is a change of life in middle-aged men, which has hormonal, physical, psychological, interpersonal, social, sexual, and spiritual aspects. Diamond claims that this change occurs in all men, generally between the ages of 40 and 55, though it can occur as early as 35 or as late as 65.
The term "male menopause" is a misnomer, as men don’t have menstrual periods, and therefore cannot stop having them. Unlike women, men's reproductive systems do not cease to work completely in mid-life; some men continue to father children late into their lives (at age 90 or older[3]). But Diamond claims that, in terms of other life impacts, women’s and men’s experience are somewhat similar phenomena.[4][5][6]
The concept of andropause is perhaps more widely accepted in Australia and some parts of Europe than it is in the United States[7]. In the U.S., many clinicians believe that, since men can continue to reproduce into old age, and do not show the same dramatic drops in hormone levels characteristic of menopause in women, andropause is nonexistent. Others feel that andropause is real, but is synonymous with hypogonadism or low testosterone levels [8].
# Pathophysiology
- Aging affects the hypothalamus- pituitary- gonadal axis and causes a decrease in the production of gonadotropin releasing hormone (GnRH) by the hypothalamus[9] and a decrease in the production of LH by the pituitary[10].
- Aging is associated with decrease in the number Leydig cells as well as decrease in their sensitivity to LH resulting in decrease production of testosterone.[11]
- Age related changes in androgen receptor, a ligand inducible transcription factor, has been reported to be associated with less androgenic effects of the testosterone.[12]
# Epidemiology and Demographics
The prevalence of andropause has not been accurately reported. According to the Massachusetts Male Aging Study (MMAS) has estimated the crude prevalence of andropause in American men between 40 and 69 years old to be around 481,000 new cases per year.[1]
# Screening
Several questionnaires have been developed as a screening tool for andropause. These questionnaires include the following:
- St. Louis University’s ADAM[13][14]
- Aging Male Survey (AMS)[15]
- Massachusetts Male Aging Study questionnaire (MMAS)[16]
# Symptoms
The impact of low levels of testosterone has been previously reported. Heller and Myers[17] identified symptoms of what they labeled the "male climacteric" including loss of libido and potency, nervousness, depression, impaired memory, the inability to concentrate, fatigue, insomnia, hot flushes, and sweating. Heller and Myers found that their subjects had lower than normal levels of testosterone, and that symptoms improved dramatically when patients were given replacement doses of testosterone.
Testosterone deficiency has also been linked to metabolic syndrome[18] and mood disturbances mainly depression[19].
# Diagnosis
The diagnosis of andropause is difficult since the clinical diagnosis alone or biochemical assays alone are not sufficient. When symptoms of andropause are clinically present along with low or borderline-low free testosterone levels, the diagnosis can be established. According to Morley et al, the diagnosis requires a positive response to testosterone treatment along with the initial clinical and biochemical diagnostic clues.[20].
The biochemical diagnostic clues include measuring the free testosterone level. It is important that the measurement is done in the morning due to the variability of testosterone levels associated with the circadian rhythm[21]. The testosterone measurement should be repeated in two weeks due to week to week variability[22].
# Treatment
Several intervention strategies have been found to be effective[23] [24] [25][26]. These include:
- Hormone replacement therapy,
- Exercise, dietary changes, stress reduction,
- Couple counseling, career refocusing, and spiritual support,
- Chemical dependency treatment, sexual compulsivity treatment,
- Treatment for depression,
- Finding and engaging one’s “calling” in the second half of life. | https://www.wikidoc.org/index.php/Andropause | |
28154107e0fee11e4a4b24176a39041f0df32f7f | wikidoc | Anetoderma | Anetoderma
# Overview
Anetoderma (also known as "Anetoderma maculosa," "Anetoderma maculosa cutis," "Atrophia maculosa cutis," and "Macular atrophy") is a localized laxity of the skin with herniation or outpouching resulting from abnormal dermal elastic tissue.
# Classification
Anetoderma comes in three types:
- Primary anetoderma
Jadassohn–Pellizzari anetoderma is a benign condition with focal loss of dermal elastic tissue. Jadassohn-Pellizzari is one of two major classifications of primary anetoderma, the other being Schweninger–Buzzi anetoderma. The difference between the two is that Jadassohn–Pellizzari anetoderma is preceded by inflammatory lesions.
Schweninger–Buzzi anetoderma is a cutaneous condition characterized by loss of dermal elastic tissue.
- Jadassohn–Pellizzari anetoderma is a benign condition with focal loss of dermal elastic tissue. Jadassohn-Pellizzari is one of two major classifications of primary anetoderma, the other being Schweninger–Buzzi anetoderma. The difference between the two is that Jadassohn–Pellizzari anetoderma is preceded by inflammatory lesions.
- Schweninger–Buzzi anetoderma is a cutaneous condition characterized by loss of dermal elastic tissue.
- Secondary anetoderma
- Familial anetoderma
# Diagnosis
## Physcial Examination
### Skin
- Anetoderma Jadassohn Pellizari. Adapted from Dermatology Atlas.
- Anetoderma Jadassohn Pellizari. Adapted from Dermatology Atlas.
- Anetoderma Jadassohn Pellizari. Adapted from Dermatology Atlas.
- Anetoderma Jadassohn Pellizari. Adapted from Dermatology Atlas.
- Anetoderma Jadassohn Pellizari. Adapted from Dermatology Atlas.
- Anetoderma Jadassohn Pellizari. Adapted from Dermatology Atlas.
- Anetoderma Jadassohn Pellizari. Adapted from Dermatology Atlas.
- Anetoderma Jadassohn Pellizari. Adapted from Dermatology Atlas.
- Anetoderma Jadassohn Pellizari. Adapted from Dermatology Atlas.
- Anetoderma Jadassohn Pellizari. Adapted from Dermatology Atlas.
- Anetoderma Jadassohn Pellizari. Adapted from Dermatology Atlas.
- Anetoderma Jadassohn Pellizari. Adapted from Dermatology Atlas.
- Anetoderma Jadassohn Pellizari. Adapted from Dermatology Atlas.
- Anetoderma Jadassohn Pellizari. Adapted from Dermatology Atlas.
- Anetoderma Jadassohn Pellizari. Adapted from Dermatology Atlas.
- Anetoderma Jadassohn Pellizari. Adapted from Dermatology Atlas.
- Anetoderma Jadassohn Pellizari. Adapted from Dermatology Atlas.
- Anetoderma Jadassohn Pellizari. Adapted from Dermatology Atlas. | Anetoderma
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Anetoderma (also known as "Anetoderma maculosa,"[1] "Anetoderma maculosa cutis,"[1] "Atrophia maculosa cutis,"[1] and "Macular atrophy"[2]) is a localized laxity of the skin with herniation or outpouching resulting from abnormal dermal elastic tissue.[2]
# Classification
Anetoderma comes in three types:
- Primary anetoderma
Jadassohn–Pellizzari anetoderma is a benign condition with focal loss of dermal elastic tissue.[3] Jadassohn-Pellizzari is one of two major classifications of primary anetoderma, the other being Schweninger–Buzzi anetoderma. The difference between the two is that Jadassohn–Pellizzari anetoderma is preceded by inflammatory lesions.[1]
Schweninger–Buzzi anetoderma is a cutaneous condition characterized by loss of dermal elastic tissue.[1]
- Jadassohn–Pellizzari anetoderma is a benign condition with focal loss of dermal elastic tissue.[3] Jadassohn-Pellizzari is one of two major classifications of primary anetoderma, the other being Schweninger–Buzzi anetoderma. The difference between the two is that Jadassohn–Pellizzari anetoderma is preceded by inflammatory lesions.[1]
- Schweninger–Buzzi anetoderma is a cutaneous condition characterized by loss of dermal elastic tissue.[1]
- Secondary anetoderma
- Familial anetoderma
# Diagnosis
## Physcial Examination
### Skin
- Anetoderma Jadassohn Pellizari. Adapted from Dermatology Atlas.[4]
- Anetoderma Jadassohn Pellizari. Adapted from Dermatology Atlas.[4]
- Anetoderma Jadassohn Pellizari. Adapted from Dermatology Atlas.[4]
- Anetoderma Jadassohn Pellizari. Adapted from Dermatology Atlas.[4]
- Anetoderma Jadassohn Pellizari. Adapted from Dermatology Atlas.[4]
- Anetoderma Jadassohn Pellizari. Adapted from Dermatology Atlas.[4]
- Anetoderma Jadassohn Pellizari. Adapted from Dermatology Atlas.[4]
- Anetoderma Jadassohn Pellizari. Adapted from Dermatology Atlas.[4]
- Anetoderma Jadassohn Pellizari. Adapted from Dermatology Atlas.[4]
- Anetoderma Jadassohn Pellizari. Adapted from Dermatology Atlas.[4]
- Anetoderma Jadassohn Pellizari. Adapted from Dermatology Atlas.[4]
- Anetoderma Jadassohn Pellizari. Adapted from Dermatology Atlas.[4]
- Anetoderma Jadassohn Pellizari. Adapted from Dermatology Atlas.[4]
- Anetoderma Jadassohn Pellizari. Adapted from Dermatology Atlas.[4]
- Anetoderma Jadassohn Pellizari. Adapted from Dermatology Atlas.[4]
- Anetoderma Jadassohn Pellizari. Adapted from Dermatology Atlas.[4]
- Anetoderma Jadassohn Pellizari. Adapted from Dermatology Atlas.[4]
- Anetoderma Jadassohn Pellizari. Adapted from Dermatology Atlas.[4] | https://www.wikidoc.org/index.php/Anetoderma | |
4ce7b083c62568885306cd1f0b959034caa5af73 | wikidoc | Aneuploidy | Aneuploidy
# Overview
Aneuploidy is a change in the number of chromosomes that can lead to a chromosomal disorder. The most recognized forms of aneuploidy are the trisomy diseases of Down syndrome and Edwards syndrome. Trisomy may not necessarily be present in all cells in an individual. It may be detected in just a specific tissue or within different cells in a tissue. When the presence of chromosomal abnormalities occurs differentially within an individual, it is called chromosomal mosaicism. In general, as we would expect, individuals who are mosaic for a chromosome change tend to have a less severe form of the syndrome present than full trisomy individuals. Critical examples of mosaicism are found in leukemia cases, specifically; chronic lymphocytic leukemia (CLL) which is a trisomy of chromosome 12 and acute myeloid leukemia (AML) prognosis which is a trisomy of chromosome 8. Aneuploidy is common in cancerous cells.
# Commonly observed forms
## Monosomy
Monosomy is the presence of only one chromosome from a pair in a cell's nucleus. Partial monosomy occurs when only a portion of the chromosome has one copy, while the rest has two copies.
### Human monosomy
Human genetic disorders arising from monosomy are:
- X0-Only one X chromosome instead of the usual two (XX) seen in a normal female, also known as Turner syndrome
- Cri du chat syndrome -- (French for "cry of the cat" after the distinctive noise by affected persons' malformed larynx) a partial monosomy caused by a deletion of the end of the short p (from the word petit, French for small) arm of chromosome 5
- 1p36 Deletion Syndrome -- a partial monosomy caused by a deletion at the end of the short p arm of chromosome 1
## Disomy
A disomy is the presence of a pair of chromosomes. For diploid organisms, such as humans, it is the normal condition. For organisms that are normally triploid or above, disomy is an aneuploidy. It can also refer to cells that are normally haploid, such as gametes.
Uniparental disomy, the disomy refers to two copies of the chromosome from one of the parents (with no contribution from the other parent).
## Trisomy
A trisomy is the presence of three, instead of the normal two, chromosomes of a particular numbered type in an organism. Thus the presence of an extra chromosome 21 is called trisomy 21.
Full trisomy of an individual occurs due to non-disjunction during meiosis I or meiosis II of gametogenesis resulting in 24 vice 23 chromosomes in a reproductive cell (sperm or egg). Thus, after fertilization, the resulting fetus has 47 chromosomes vice the typical 46. The most common forms of autosomal trisomy are trisomy of chromosome 21 which results in Down syndrome and trisomy of chromosome 18 which results in Edwards syndrome. In rare cases, a fetus with trisomy of chromosome 13 can survive. Trisomy 13 is called Patau syndrome. Autosomal trisomy is frequently associated with severe congenital abnormalities, mental retardation and shortened life expectancy.
A partial trisomy occurs when part of an extra chromosome is attached to one of the other chromosomes, or if one of the chromosomes has two copies of part of its chromosome. A mosaic trisomy is a condition where extra chromosomal material exists in only some of the organism's cells.
### Human trisomy
A trisomy can occur with any chromosome. Most trisomies, like most other abnormalities in chromosome number, result in distinctive and serious birth defects. Mostly, the causes are autosomal and sex chromosomal nondisjunction. Most trisomies result in spontaneous abortion; the most common types that survive to birth in humans are:
Autosomal nondisjunction
- Trisomy 21 (Down syndrome)
- Trisomy 18 (Edwards syndrome)
- Trisomy 13 (Patau syndrome)
- Trisomy 12 (A prognostic indicator of Chronic Lymphocytic Leukemia)
- Trisomy 9
- Trisomy 8 (Warkany syndrome 2)
Trisomy 16 is the most common trisomy in humans, occurring in more than 1% of pregnancies. This condition, however, usually results in spontaneous miscarriage in the first trimester. The most common trisomy in viable births is Trisomy 21.
Sex-chromosomal nondisjunction
Aneuploidy of sex chromosomes can also occur. The presence of extra X chromosome(s) causes Klinefelter syndrome in men and Triple X syndrome in women, while monosomy X (45, X) gives rise to women with Turner syndrome.
- XXX (Triple X syndrome)
- XXY (Klinefelter's syndrome)
- XYY (XYY syndrome)
## Tetrasomy and pentasomy
A tetrasomy and a pentasomy are the presence of a respectively four or five copies of a chromosome. Although very rare, reported examples of tetrasomy and pentasomy in humans include the karyotypes XXXX (XXXX syndrome), XXXY, XXYY, XYYY, XXXXX, XXXXY, XXXYY, XXYYY and XYYYY.
# Mechanisms
- Nondisjunction usually occurs as the result of a weakened mitotic checkpoint, as these checkpoints tend to arrest or delay cell division until all components of the cell are ready to enter the next phase. If a checkpoint is weakened, the cell may fail to 'notice' that a chromosome pair is not lined up on the mitotic plate, for example. In such a case, most chromosomes would separate normally (with one chromatid ending up in each cell), while others could fail to separate at all. This would generate a daughter cell lacking a copy and a daughter cell with an extra copy.
- Completely inactive mitotic checkpoints may cause non-disjunction at multiple chromosomes, possibly all. Such a scenario could result in each daughter cell possessing a disjunct set of genetic material.
- Merotelic attachment occurs when one kinetochore is attached to both mitotic spindle poles. One daughter cell would have a normal complement of chromosomes, the second would lack one. A third daughter cell may end up with the 'missing' chromosome.
- Multipolar spindle: more than two spindle poles form. Such a mitotic division would result in one daughter cell for each spindle pole; each cell may possess an unpredictable complement of chromosomes.
- Monopolar spindle: only a single spindle pole forms. This produces a single daughter cell with its copy number doubled.
- A tetraploid intermediate may be produced as the end result of the monopolar spindle mechanism. In such a case, the cell has double the copy number of a normal cell, and produces double the number of spindle poles as well. This results in four daughter cells with an unpredictable complement of chromosomes, but in the normal copy number.
# Detection
Several prenatal tests can be performed on an expectant mother to detect aneuploidy in the fetus. Fetal cells from the amniotic fluid or chorionic villus are collected and analyzed by one of several techniques which include Fluorescence In Situ Hybridization (FISH) karyotyping, Quantitative Polymerase Chain Reaction (PCR) of Short Tandem Repeats, Quantitative Fluorescence PCR (QF-PCR), Quantitative Real-time PCR (RT-PCR) dosage analysis, Quantitative Mass Spectrometry of Single Nucleotide Polymorphisms, and Comparative Genomic Hybridization (CGH). A program for detecting aneuploidy by short tandem repeat fragments is SoftGenetics GeneMarker® software.
Pregnant women over the age of 35 are screened for trisomy caused syndromes in the fetus because the risk of these syndromes increases as the mother ages. During the procedure whereby cells are collected for analysis, maternal cells can be mixed in with fetal cells. This phenomenon is called Maternal Cell Contamination (MCC).
# Sources
- This article incorporates public domain text from The U.S. National Library of Medicine.
- Sex chromosome tetrasomy and pentasomy. PMID 7567329 | Aneuploidy
Template:Search infobox
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Aneuploidy is a change in the number of chromosomes that can lead to a chromosomal disorder. The most recognized forms of aneuploidy are the trisomy diseases of Down syndrome and Edwards syndrome. Trisomy may not necessarily be present in all cells in an individual. It may be detected in just a specific tissue or within different cells in a tissue. When the presence of chromosomal abnormalities occurs differentially within an individual, it is called chromosomal mosaicism. In general, as we would expect, individuals who are mosaic for a chromosome change tend to have a less severe form of the syndrome present than full trisomy individuals. Critical examples of mosaicism are found in leukemia cases, specifically; chronic lymphocytic leukemia (CLL) which is a trisomy of chromosome 12 and acute myeloid leukemia (AML) prognosis which is a trisomy of chromosome 8. Aneuploidy is common in cancerous cells.
# Commonly observed forms
## Monosomy
Monosomy is the presence of only one chromosome from a pair in a cell's nucleus. Partial monosomy occurs when only a portion of the chromosome has one copy, while the rest has two copies.
### Human monosomy
Human genetic disorders arising from monosomy are:
- X0-Only one X chromosome instead of the usual two (XX) seen in a normal female, also known as Turner syndrome
- Cri du chat syndrome -- (French for "cry of the cat" after the distinctive noise by affected persons' malformed larynx) a partial monosomy caused by a deletion of the end of the short p (from the word petit, French for small) arm of chromosome 5
- 1p36 Deletion Syndrome -- a partial monosomy caused by a deletion at the end of the short p arm of chromosome 1
## Disomy
A disomy is the presence of a pair of chromosomes. For diploid organisms, such as humans, it is the normal condition. For organisms that are normally triploid or above, disomy is an aneuploidy. It can also refer to cells that are normally haploid, such as gametes.
Uniparental disomy, the disomy refers to two copies of the chromosome from one of the parents (with no contribution from the other parent).
## Trisomy
A trisomy is the presence of three, instead of the normal two, chromosomes of a particular numbered type in an organism. Thus the presence of an extra chromosome 21 is called trisomy 21.
Full trisomy of an individual occurs due to non-disjunction during meiosis I or meiosis II of gametogenesis resulting in 24 vice 23 chromosomes in a reproductive cell (sperm or egg). Thus, after fertilization, the resulting fetus has 47 chromosomes vice the typical 46. The most common forms of autosomal trisomy are trisomy of chromosome 21 which results in Down syndrome and trisomy of chromosome 18 which results in Edwards syndrome. In rare cases, a fetus with trisomy of chromosome 13 can survive. Trisomy 13 is called Patau syndrome. Autosomal trisomy is frequently associated with severe congenital abnormalities, mental retardation and shortened life expectancy.
A partial trisomy occurs when part of an extra chromosome is attached to one of the other chromosomes, or if one of the chromosomes has two copies of part of its chromosome. A mosaic trisomy is a condition where extra chromosomal material exists in only some of the organism's cells.
### Human trisomy
A trisomy can occur with any chromosome. Most trisomies, like most other abnormalities in chromosome number, result in distinctive and serious birth defects. Mostly, the causes are autosomal and sex chromosomal nondisjunction. Most trisomies result in spontaneous abortion; the most common types that survive to birth in humans are:
Autosomal nondisjunction
- Trisomy 21 (Down syndrome)
- Trisomy 18 (Edwards syndrome)
- Trisomy 13 (Patau syndrome)
- Trisomy 12 (A prognostic indicator of Chronic Lymphocytic Leukemia)
- Trisomy 9
- Trisomy 8 (Warkany syndrome 2)
Trisomy 16 is the most common trisomy in humans, occurring in more than 1% of pregnancies. This condition, however, usually results in spontaneous miscarriage in the first trimester. The most common trisomy in viable births is Trisomy 21.
Sex-chromosomal nondisjunction
Aneuploidy of sex chromosomes can also occur. The presence of extra X chromosome(s) causes Klinefelter syndrome in men and Triple X syndrome in women, while monosomy X (45, X) gives rise to women with Turner syndrome.
- XXX (Triple X syndrome)
- XXY (Klinefelter's syndrome)
- XYY (XYY syndrome)
## Tetrasomy and pentasomy
A tetrasomy and a pentasomy are the presence of a respectively four or five copies of a chromosome. Although very rare, reported examples of tetrasomy and pentasomy in humans include the karyotypes XXXX (XXXX syndrome), XXXY, XXYY, XYYY, XXXXX, XXXXY, XXXYY, XXYYY and XYYYY.
# Mechanisms
- Nondisjunction usually occurs as the result of a weakened mitotic checkpoint, as these checkpoints tend to arrest or delay cell division until all components of the cell are ready to enter the next phase. If a checkpoint is weakened, the cell may fail to 'notice' that a chromosome pair is not lined up on the mitotic plate, for example. In such a case, most chromosomes would separate normally (with one chromatid ending up in each cell), while others could fail to separate at all. This would generate a daughter cell lacking a copy and a daughter cell with an extra copy.
- Completely inactive mitotic checkpoints may cause non-disjunction at multiple chromosomes, possibly all. Such a scenario could result in each daughter cell possessing a disjunct set of genetic material.
- Merotelic attachment occurs when one kinetochore is attached to both mitotic spindle poles. One daughter cell would have a normal complement of chromosomes, the second would lack one. A third daughter cell may end up with the 'missing' chromosome.
- Multipolar spindle: more than two spindle poles form. Such a mitotic division would result in one daughter cell for each spindle pole; each cell may possess an unpredictable complement of chromosomes.
- Monopolar spindle: only a single spindle pole forms. This produces a single daughter cell with its copy number doubled.
- A tetraploid intermediate may be produced as the end result of the monopolar spindle mechanism. In such a case, the cell has double the copy number of a normal cell, and produces double the number of spindle poles as well. This results in four daughter cells with an unpredictable complement of chromosomes, but in the normal copy number.
# Detection
Several prenatal tests can be performed on an expectant mother to detect aneuploidy in the fetus. Fetal cells from the amniotic fluid or chorionic villus are collected and analyzed by one of several techniques which include Fluorescence In Situ Hybridization (FISH) karyotyping, Quantitative Polymerase Chain Reaction (PCR) of Short Tandem Repeats, Quantitative Fluorescence PCR (QF-PCR), Quantitative Real-time PCR (RT-PCR) dosage analysis, Quantitative Mass Spectrometry of Single Nucleotide Polymorphisms, and Comparative Genomic Hybridization (CGH). A program for detecting aneuploidy by short tandem repeat fragments is SoftGenetics GeneMarker® software.
Pregnant women over the age of 35 are screened for trisomy caused syndromes in the fetus because the risk of these syndromes increases as the mother ages. During the procedure whereby cells are collected for analysis, maternal cells can be mixed in with fetal cells. This phenomenon is called Maternal Cell Contamination (MCC).
# Sources
- This article incorporates public domain text from The U.S. National Library of Medicine.
- Sex chromosome tetrasomy and pentasomy. PMID 7567329 | https://www.wikidoc.org/index.php/Aneuploid | |
24efe5d519b17cdf85d1464c8fc896d001107fda | wikidoc | Angiogenin | Angiogenin
Angiogenin (Ang) also known as ribonuclease 5 is a small 123 amino acid protein that in humans is encoded by the ANG gene. Angiogenin is a potent stimulator of new blood vessels through the process of angiogenesis. Ang hydrolyzes cellular RNA, resulting in modulated levels of protein synthesis and interacts with DNA causing a promoter-like increase in the expression of rRNA. Ang is associated with cancer and neurological disease through angiogenesis and through activating gene expression that suppresses apoptosis.
# Function
Angiogenin is a key protein implicated in angiogenesis in normal and tumor growth. Angiogenin interacts with endothelial and smooth muscle cells resulting in cell migration, invasion, proliferation and formation of tubular structures. Ang binds to actin of both smooth muscle and endothelial cells to form complexes that activate proteolytic cascades which upregulate the production of proteases and plasmin that degrade the laminin and fibronectin layers of the basement membrane. Degradation of the basement membrane and extracellular matrix allows the endothelial cells to penetrate and migrate into the perivascular tissue. Signal transduction pathways activated by Ang interactions at the cellular membrane of endothelial cells produce extracellular signal-related kinase1/2 (ERK1/2) and protein kinase B/Akt. Activation of these proteins leads to invasion of the basement membrane and cell proliferation associated with further angiogenesis. The most important step in the angiogenesis process is the translocation of Ang to the cell nucleus. Once Ang has been translocated to the nucleus, it enhances rRNA transcription by binding to the CT-rich (CTCTCTCTCTCTCTCTCCCTC) angiogenin binding element (ABE) within the upstream intergenic region of rDNA, which subsequently activates other angiogenic factors that induce angiogenesis.
However, angiogenin is unique among the many proteins that are involved in angiogenesis in that it is also an enzyme with an amino acid sequence 33% identical to that of bovine pancreatic ribonuclease (RNase) A. Ang has the same general catalytic properties as RNase A, it cleaves preferentially on the 3' side of pyrimidines and follows a transphosphorylation/hydrolysis mechanism. Although angiogenin contains many of the same catalytic residues as RNase A, it cleaves standard RNA substrates 105–106 times less efficiently than does RNase A. The reason for this inefficiency is due to the 117 residue consisting of a glutamine, which blocks the catalytic site. Removal of this residue through mutation increases the ribonuclease activity between 11 and 30 fold. Despite this apparent weakness, the enzymatic activity of Ang appears to be essential for biological activity: replacements of important catalytic site residues (Histidine13 and Histidine 114) invariably diminish both the ribonuclease activity toward tRNA by 10,000 fold and almost abolishes angiogenesis activities completely.
# Disease
## Cancer
Ang has a prominent role in the pathology of cancer due to its functions in angiogenesis and cell survival. Since Ang possesses angiogenic activity, it makes Ang a possible candidate in therapeutic treatments of cancer. Studies of Ang and tumor relationships provide evidence for a connection between the two. The translocation of Ang to the nucleus causes an upregulation of transcriptional rRNA, while knockdown strains of Ang cause downregulation. The presence of Ang inhibitors that block translocation resulted in a decrease of tumor growth and overall angiogenesis. HeLa cells translocate Ang to the nucleus independent of cell density. In human umbilical vein endothelial cells (HUVECs), translocation of Ang to the nucleus stops after cells reach a specific density, while in HeLa cells translocation continued past that point. Inhibition of Ang affects the ability of HeLa cells to proliferate, which proposes an effective target for possible therapies.
## Neurodegenerative diseases
Due to the ability of Ang to protect motoneurons (MNs), causal links between Ang mutations and Amyotrophic lateral sclerosis (ALS) are likely. The angiogenic factors associated with Ang may protect the central nervous system and MNs directly. Experiments with wild type Ang found that it slows MN degeneration in mice that had developed ALS, providing evidence for further development of Ang protein therapy in ALS treatment. Angiogenin expression in Parkinson's disease is dramatically decreased in the presence of alpha-synuclein (α-syn) aggregations. Exogenous angiogenin applied to dopamine-producing cells leads to the phosphorylation of PKB/AKT and the activation of this complex inhibits cleavage of caspase 3 and apoptosis when cells are exposed to a Parkinson's-like inducing substance.
# Gene
Alternative splicing results in two transcript variants encoding the same protein. This gene and the gene that encodes ribonuclease, RNase A family, 4 share promoters and 5' exons. Each gene splices to a unique downstream exon that contains its complete coding region. | Angiogenin
Angiogenin (Ang) also known as ribonuclease 5 is a small 123 amino acid protein that in humans is encoded by the ANG gene.[1] Angiogenin is a potent stimulator of new blood vessels through the process of angiogenesis. Ang hydrolyzes cellular RNA, resulting in modulated levels of protein synthesis and interacts with DNA causing a promoter-like increase in the expression of rRNA.[2][3] Ang is associated with cancer and neurological disease through angiogenesis and through activating gene expression that suppresses apoptosis.[2][4][5]
# Function
Angiogenin is a key protein implicated in angiogenesis in normal and tumor growth. Angiogenin interacts with endothelial and smooth muscle cells resulting in cell migration, invasion, proliferation and formation of tubular structures.[1] Ang binds to actin of both smooth muscle and endothelial cells to form complexes that activate proteolytic cascades which upregulate the production of proteases and plasmin that degrade the laminin and fibronectin layers of the basement membrane.[2] Degradation of the basement membrane and extracellular matrix allows the endothelial cells to penetrate and migrate into the perivascular tissue.[1] Signal transduction pathways activated by Ang interactions at the cellular membrane of endothelial cells produce extracellular signal-related kinase1/2 (ERK1/2) and protein kinase B/Akt.[1] Activation of these proteins leads to invasion of the basement membrane and cell proliferation associated with further angiogenesis. The most important step in the angiogenesis process is the translocation of Ang to the cell nucleus. Once Ang has been translocated to the nucleus, it enhances rRNA transcription by binding to the CT-rich (CTCTCTCTCTCTCTCTCCCTC) angiogenin binding element (ABE) within the upstream intergenic region of rDNA, which subsequently activates other angiogenic factors that induce angiogenesis.[1][3][6]
However, angiogenin is unique among the many proteins that are involved in angiogenesis in that it is also an enzyme with an amino acid sequence 33% identical to that of bovine pancreatic ribonuclease (RNase) A.[1] Ang has the same general catalytic properties as RNase A, it cleaves preferentially on the 3' side of pyrimidines and follows a transphosphorylation/hydrolysis mechanism.[7] Although angiogenin contains many of the same catalytic residues as RNase A, it cleaves standard RNA substrates 105–106 times less efficiently than does RNase A.[7] The reason for this inefficiency is due to the 117 residue consisting of a glutamine, which blocks the catalytic site.[8] Removal of this residue through mutation increases the ribonuclease activity between 11 and 30 fold.[8] Despite this apparent weakness, the enzymatic activity of Ang appears to be essential for biological activity: replacements of important catalytic site residues (Histidine13 and Histidine 114) invariably diminish both the ribonuclease activity toward tRNA by 10,000 fold and almost abolishes angiogenesis activities completely.[9]
# Disease
## Cancer
Ang has a prominent role in the pathology of cancer due to its functions in angiogenesis and cell survival. Since Ang possesses angiogenic activity, it makes Ang a possible candidate in therapeutic treatments of cancer. Studies of Ang and tumor relationships provide evidence for a connection between the two. The translocation of Ang to the nucleus causes an upregulation of transcriptional rRNA, while knockdown strains of Ang cause downregulation.[1] The presence of Ang inhibitors that block translocation resulted in a decrease of tumor growth and overall angiogenesis.[1][10] HeLa cells translocate Ang to the nucleus independent of cell density. In human umbilical vein endothelial cells (HUVECs), translocation of Ang to the nucleus stops after cells reach a specific density, while in HeLa cells translocation continued past that point.[11] Inhibition of Ang affects the ability of HeLa cells to proliferate, which proposes an effective target for possible therapies.
## Neurodegenerative diseases
Due to the ability of Ang to protect motoneurons (MNs), causal links between Ang mutations and Amyotrophic lateral sclerosis (ALS) are likely. The angiogenic factors associated with Ang may protect the central nervous system and MNs directly.[1] Experiments with wild type Ang found that it slows MN degeneration in mice that had developed ALS, providing evidence for further development of Ang protein therapy in ALS treatment.[10] Angiogenin expression in Parkinson's disease is dramatically decreased in the presence of alpha-synuclein (α-syn) aggregations. Exogenous angiogenin applied to dopamine-producing cells leads to the phosphorylation of PKB/AKT and the activation of this complex inhibits cleavage of caspase 3 and apoptosis when cells are exposed to a Parkinson's-like inducing substance.[12]
# Gene
Alternative splicing results in two transcript variants encoding the same protein. This gene and the gene that encodes ribonuclease, RNase A family, 4 share promoters and 5' exons. Each gene splices to a unique downstream exon that contains its complete coding region.[13] | https://www.wikidoc.org/index.php/Angiogenin | |
b81f16d819ee3f9e22e907fa57aeb0922aae6832 | wikidoc | Angiomotin | Angiomotin
Angiomotin (AMOT) is a protein that in humans is encoded by the AMOT gene. It belongs to the motin family of angiostatin binding proteins, which includes angiomotin, angiomotin-like 1 (AMOTL1) and angiomotin-like 2 (AMOTL2) characterized by coiled-coil domains at N-terminus and consensus PDZ-binding domain at the C-terminus. Angiomotin is expressed predominantly in endothelial cells of capillaries as well as angiogenic tissues such as placenta and solid tumor.
# Discovery
Angiomotin was discovered in 2001 by screening a placenta yeast two-hybrid cDNA library for angiostatin-binding peptides, using a construct encoding the kringle domains 1-4 of angiostatin.
# Gene location
AMOT gene is located on human chromosome X:112,021,794-112,066,354, containing 3252 nucleotides in coding sequence as 11 exons.
# Protein structure
Two splice isoforms are known for angiomotin: p80 and p130. The alternative splicing is somewhat tissue specific. Cells expressing p130 contained more actin than those expressing p80. p80 is not the product of cleavage of p130, as p130 contains no potential proteolytic cleavage site for such conversion.
Angiomotin p80 is a 72.54 kD protein of 675 residues, characterized by conserved N-terminal coiled coil domains and C-terminal PDZ binding motifs, with angiostatin binding domain (ABD) located in the central region. It is hypothesized that the ABD is extracellular, while the coiled-coil and the PDZ binding domain are intracellular. The PDZ-binding motif of angiomotin serves as a protein recognition site and deletion of as few as three amino acids from the C-terminal results in complete loss of pro-migratory activity, and endothelial cells expressing such mutant angiomotin failed to migrate or form tubes.
Angiomotin p130 differs from p80 by having an N-ternimal cytoplasmic extension of 409 amino acids rich in glutamine, which mediates the binding of p130 to F-actin and tight cell-cell junctions. This binding remains after destabilizing actin with cytochalasin B.
Like other surface-associated proteins that can bind plasminogen and its derivatives, angiomotin does not appear to have a signal sequence, thus its association with the cell surface may be via protein–protein interaction usually referred to as non-classic secretion.
# Function
## Role in cell motility and angiogenesis
Expression of angiomotin p80 in endothelial cells increases the random migration of endothelial cells, as well as the migration of endothelial cells toward growth factors, e.g. bFGF, VEGF and LPA etc. Angiomotin also mediates tube formation of endothelial cells. Angiomotin promotes angiogenesis by both stimulating cell spreading and stabilizing established tubes, e.g. in mouse aortic endothelial (MAE) cells the tubes remained stable for over 30 days, while control tubes started to regress after 3 days. In the presence of angiostatin, endothelial cells expressing angiomotin p80 exhibit reduction in migration as well as reduction in tubules formation in vitro. These observations are consistent with the localization of angiomotin in the leading edge of migrating cells. Angiostatin therefore, is an inhibitor of angiomotin.
Angiomotin p80 locates and binds angiostatin on the cell surface. In primary endothelial of Chinese hamster ovary, it localizes to cell-cell junction, recruits ZO-1 and interacts with MAGI-1. It may play a role in the assembly of endothelial cell-cell junctions, as well.
Angiomotin p130 does not promote cell migration, nor responds to angiostatin. It localizes to cell-cell junction like p80 and regulates paracellular permeability. Its N-terminal domain localizes to actin fibers and stabilizes them, and this effect is not affected by angiostatin. Transfection of p130 angiomotin into MAE cells results in change in cell shape, increased average cell size and stress fiber formation. So p80 is involved in cell migration and expressed during migratory phase. While p130 controls cell shape by interaction with actin, and is expressed during the period of blood vessel stabilization and maturation. The relative expression levels of p80 and p130 regulate a switch between a migratory and a non-migratory cell phenotype, where homo-oligomerization of p80 and hetero-oligomerization of both isoforms are critical for this regulation.
## Role in Hippo signaling pathway
AMOT, AMOTL1 and AMOTL2 play critical roles in the Hippo signaling pathway by regulating the subcellular localization of the co-activators YAP (Yes-associated protein) and TAZ (transcriptional co-activator with PDZ-binding motif), and activating LATS2 through a novel conserved domain. The activity of YAP and TAZ can be restricted through their interaction with AMOT and AMOTL1, and such interaction depends on the WW domain of TAZ and the Proline-Proline-x–Tyrosine motif at the N-terminus of AMOT.
In position-dependent Hippo signaling, where the outer and inner cells are polar and nonpolar respectively, AMOT and AMOTL2 are essential for Hippo pathway activation and appropriate cell fate specification. In the nonpolar inner cells, AMOT localizes to adherens junctions (AJs), and Ser-176 at the N-terminal domain is phosphorylated by LATS downstream of GPCR signaling, which inhibits actin binding activity and stabilizes the AMOT-LATS interaction to activate the Hippo pathway. Thus, AMOT is a direct substrate of LATS and its phosphorylation at Ser-176 inhibits cell migration and angiogenesis. In the outer cells, the cell polarity sequesters AMOT from basolateral adherens junctions to apical domains, thereby suppressing Hippo signaling. It is therefore proposed AMOT acts as a molecular switch for Hippo pathway and links F-actin with LATS activity.
Along the Hippo pathway, AMOT's binding to Merlin releases its auto-inhibition and promotes Merlin's binding to LATS1/2. Phosphorylation of Ser-518 outside the Merlin's auto-inhibitory tail prevents binding and thus inhibits Hippo pathway kinase activation. USP9x regulates the ubiquitin-mediated turnover of AMOT, and the deubiquitylation of AMOT results in its stabilization and lower YAP/TAZ activity.
# Cancer research
A DNA vaccination targeting angiomotin generated antibodies that detected AMOT on the endothelial cell surface, which inhibited migration. It blocked angiogenesis and prevented growth of transplanted tumors for up to 150 days in vivo. A combination of DNA vaccines encoding AMOT and the extracellular and transmembrane domains of the human EGF receptor 2 (Her-2)/neu oncogene inhibited breast cancer progression and impaired tumor vascularization in Her-2/neu transgenic mice, showing DNA vaccination targeting AMOT may be used to mimic the effect of angiostatin and no toxicity or impairment of normal blood vessels was detected.
In human breast cancer tissues, AMOT is highly expressed compared with control, and its level is associated with other angiogenesis markers. AMOT links to the proliferation and invasion of breast tumours and the long-term survival of the patients, and could be a potential target for therapy.
For melanoma, AMOT binds a variant of soluble cell adhesion molecule (sCD146) in endothelial progenitor cells (EPC). Silencing AMOT in EPC inhibits the angiogenic effect of sCD146, e.g. EPC migration, proliferation, and capacity to form capillary-like structures in Matrigel. | Angiomotin
Angiomotin (AMOT) is a protein that in humans is encoded by the AMOT gene.[1][2][3][4] It belongs to the motin family of angiostatin binding proteins, which includes angiomotin, angiomotin-like 1 (AMOTL1) and angiomotin-like 2 (AMOTL2) characterized by coiled-coil domains at N-terminus and consensus PDZ-binding domain at the C-terminus.[3] Angiomotin is expressed predominantly in endothelial cells of capillaries as well as angiogenic tissues such as placenta and solid tumor.[5]
# Discovery
Angiomotin was discovered in 2001 by screening a placenta yeast two-hybrid cDNA library for angiostatin-binding peptides, using a construct encoding the kringle domains 1-4 of angiostatin.[1]
# Gene location
AMOT gene is located on human chromosome X:112,021,794-112,066,354, containing 3252 nucleotides in coding sequence as 11 exons.[6]
# Protein structure
Two splice isoforms are known for angiomotin: p80 and p130. The alternative splicing is somewhat tissue specific. Cells expressing p130 contained more actin than those expressing p80. p80 is not the product of cleavage of p130, as p130 contains no potential proteolytic cleavage site for such conversion.[7]
Angiomotin p80 is a 72.54 kD protein of 675 residues,[8] characterized by conserved N-terminal coiled coil domains and C-terminal PDZ binding motifs, with angiostatin binding domain (ABD) located in the central region. It is hypothesized that the ABD is extracellular, while the coiled-coil and the PDZ binding domain are intracellular.[2] The PDZ-binding motif of angiomotin serves as a protein recognition site and deletion of as few as three amino acids from the C-terminal results in complete loss of pro-migratory activity, and endothelial cells expressing such mutant angiomotin failed to migrate or form tubes.[9]
Angiomotin p130 differs from p80 by having an N-ternimal cytoplasmic extension of 409 amino acids rich in glutamine, which mediates the binding of p130 to F-actin and tight cell-cell junctions. This binding remains after destabilizing actin with cytochalasin B.[7]
Like other surface-associated proteins that can bind plasminogen and its derivatives, angiomotin does not appear to have a signal sequence, thus its association with the cell surface may be via protein–protein interaction usually referred to as non-classic secretion.[5]
# Function
## Role in cell motility and angiogenesis
Expression of angiomotin p80 in endothelial cells increases the random migration of endothelial cells, as well as the migration of endothelial cells toward growth factors, e.g. bFGF, VEGF and LPA etc. Angiomotin also mediates tube formation of endothelial cells.[1][9] Angiomotin promotes angiogenesis by both stimulating cell spreading and stabilizing established tubes, e.g. in mouse aortic endothelial (MAE) cells the tubes remained stable for over 30 days, while control tubes started to regress after 3 days.[10] In the presence of angiostatin, endothelial cells expressing angiomotin p80 exhibit reduction in migration as well as reduction in tubules formation in vitro. These observations are consistent with the localization of angiomotin in the leading edge of migrating cells. Angiostatin therefore, is an inhibitor of angiomotin.
Angiomotin p80 locates and binds angiostatin on the cell surface. In primary endothelial of Chinese hamster ovary, it localizes to cell-cell junction, recruits ZO-1 and interacts with MAGI-1. It may play a role in the assembly of endothelial cell-cell junctions, as well.[2]
Angiomotin p130 does not promote cell migration, nor responds to angiostatin. It localizes to cell-cell junction like p80 and regulates paracellular permeability. Its N-terminal domain localizes to actin fibers and stabilizes them, and this effect is not affected by angiostatin. Transfection of p130 angiomotin into MAE cells results in change in cell shape, increased average cell size and stress fiber formation. So p80 is involved in cell migration and expressed during migratory phase. While p130 controls cell shape by interaction with actin, and is expressed during the period of blood vessel stabilization and maturation.[7][11] The relative expression levels of p80 and p130 regulate a switch between a migratory and a non-migratory cell phenotype, where homo-oligomerization of p80 and hetero-oligomerization of both isoforms are critical for this regulation.[11]
## Role in Hippo signaling pathway
AMOT, AMOTL1 and AMOTL2 play critical roles in the Hippo signaling pathway by regulating the subcellular localization of the co-activators YAP (Yes-associated protein) and TAZ (transcriptional co-activator with PDZ-binding motif),[12] and activating LATS2 through a novel conserved domain.[13] The activity of YAP and TAZ can be restricted through their interaction with AMOT and AMOTL1, and such interaction depends on the WW domain of TAZ and the Proline-Proline-x–Tyrosine motif at the N-terminus of AMOT.[14]
In position-dependent Hippo signaling, where the outer and inner cells are polar and nonpolar respectively, AMOT and AMOTL2 are essential for Hippo pathway activation and appropriate cell fate specification. In the nonpolar inner cells, AMOT localizes to adherens junctions (AJs), and Ser-176 at the N-terminal domain is phosphorylated by LATS downstream of GPCR signaling, which inhibits actin binding activity and stabilizes the AMOT-LATS interaction to activate the Hippo pathway. Thus, AMOT is a direct substrate of LATS and its phosphorylation at Ser-176 inhibits cell migration and angiogenesis. In the outer cells, the cell polarity sequesters AMOT from basolateral adherens junctions to apical domains, thereby suppressing Hippo signaling.[15][16] It is therefore proposed AMOT acts as a molecular switch for Hippo pathway and links F-actin with LATS activity.[17]
Along the Hippo pathway, AMOT's binding to Merlin releases its auto-inhibition and promotes Merlin's binding to LATS1/2. Phosphorylation of Ser-518 outside the Merlin's auto-inhibitory tail prevents binding and thus inhibits Hippo pathway kinase activation.[18] USP9x regulates the ubiquitin-mediated turnover of AMOT, and the deubiquitylation of AMOT results in its stabilization and lower YAP/TAZ activity.[19]
# Cancer research
A DNA vaccination targeting angiomotin generated antibodies that detected AMOT on the endothelial cell surface, which inhibited migration. It blocked angiogenesis and prevented growth of transplanted tumors for up to 150 days in vivo. A combination of DNA vaccines encoding AMOT and the extracellular and transmembrane domains of the human EGF receptor 2 (Her-2)/neu oncogene inhibited breast cancer progression and impaired tumor vascularization in Her-2/neu transgenic mice, showing DNA vaccination targeting AMOT may be used to mimic the effect of angiostatin and no toxicity or impairment of normal blood vessels was detected.[20]
In human breast cancer tissues, AMOT is highly expressed compared with control, and its level is associated with other angiogenesis markers. AMOT links to the proliferation and invasion of breast tumours and the long-term survival of the patients, and could be a potential target for therapy.[21][22]
For melanoma, AMOT binds a variant of soluble cell adhesion molecule (sCD146) in endothelial progenitor cells (EPC). Silencing AMOT in EPC inhibits the angiogenic effect of sCD146, e.g. EPC migration, proliferation, and capacity to form capillary-like structures in Matrigel.[23] | https://www.wikidoc.org/index.php/Angiomotin | |
1d6c473da3e5cc327ab61e5282e00711e73cfe72 | wikidoc | Angiopathy | Angiopathy
Angiopathy is the generic term for a disease of the blood vessels (arteries, veins, and capillaries). The best known and most prevalent angiopathy is the diabetic angiopathy, a complication that may occur in chronic diabetes.
There are two types of angiopathy: macroangiopathy and microangiopathy. In macroangiopathy, fat and blood clots build up in the large blood vessels, stick to the vessel walls, and block the flow of blood. In microangiopathy, the walls of the smaller blood vessels become so thick and weak that they bleed, leak protein, and slow the flow of blood through the body. The decrease of blood flow through stenosis or clot formation impair the flow of oxygen to cells and biological tissues (called ischemia) and lead to their death (necrosis and gangrene, which in turn may require amputation). Thus, tissues which are very sensitive to oxygen levels, such as the retina, develop microangiopathy and may cause blindness (so-called proliferative diabetic retinopathy). Damage to nerve cells may cause peripheral neuropathy, and to kidney cells, diabetic nephropathy (Kimmelstiel-Wilson syndrome).
Macroangiopathy, on the other hand, may cause other complications, such as ischemic heart disease, stroke and peripheral vascular disease which contributes to the diabetic foot ulcers and the risk of amputation.
Diabetes mellitus is the most common cause of adult kidney failure worldwide. It also the most common cause of amputation in the US, usually toes and feet, often as a result of gangrene, and almost always as a result of peripheral vascular disease. Retinal damage (from microangiopathy) makes it the most common cause of blindness among non-elderly adults in the US.
"Diabetic dermopathy" is a manifestation of diabetic angiopathy. It is often found on the shin.
There is also Neuropathy; also associated with diabetes mellitus; type 1 and 2. | Angiopathy
Template:DiseaseDisorder infobox
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Angiopathy is the generic term for a disease of the blood vessels (arteries, veins, and capillaries). The best known and most prevalent angiopathy is the diabetic angiopathy, a complication that may occur in chronic diabetes.
There are two types of angiopathy: macroangiopathy and microangiopathy. In macroangiopathy, fat and blood clots build up in the large blood vessels, stick to the vessel walls, and block the flow of blood. In microangiopathy, the walls of the smaller blood vessels become so thick and weak that they bleed, leak protein, and slow the flow of blood through the body. The decrease of blood flow through stenosis or clot formation impair the flow of oxygen to cells and biological tissues (called ischemia) and lead to their death (necrosis and gangrene, which in turn may require amputation). Thus, tissues which are very sensitive to oxygen levels, such as the retina, develop microangiopathy and may cause blindness (so-called proliferative diabetic retinopathy). Damage to nerve cells may cause peripheral neuropathy, and to kidney cells, diabetic nephropathy (Kimmelstiel-Wilson syndrome).
Macroangiopathy, on the other hand, may cause other complications, such as ischemic heart disease, stroke and peripheral vascular disease which contributes to the diabetic foot ulcers and the risk of amputation.
Diabetes mellitus is the most common cause of adult kidney failure worldwide. It also the most common cause of amputation in the US, usually toes and feet, often as a result of gangrene, and almost always as a result of peripheral vascular disease. Retinal damage (from microangiopathy) makes it the most common cause of blindness among non-elderly adults in the US.
"Diabetic dermopathy" is a manifestation of diabetic angiopathy. It is often found on the shin.
There is also Neuropathy; also associated with diabetes mellitus; type 1 and 2. | https://www.wikidoc.org/index.php/Angiopathy | |
d2ceb16da106a13ea3cdeb4b3683029860cf5dcd | wikidoc | Anglerfish | Anglerfish
Anglerfish are bony fish in the order Lophiiformes, named for their characteristic mode of predation, wherein a fleshy growth from the fish's head (the esca) acts as a lure; this is considered analogous to angling.
Anglerfish are both pelagic and benthic fishes of the abyss (e.g. Ceratiidae) and the continental shelf (e.g. the frogfishes Antennariidae and the monkfish/goosefish Lophiidae) respectively. They occur worldwide. Pelagic forms are most laterally compressed whereas the benthic forms are often extremely dorse-ventrally compressed (depressed) often with large upward pointing mouths.
# Predation
The fish are named for their characteristic method of predation. Anglerfish typically have three long filaments sprouting from the middle of the head; these are the detached and modified three first spines of the anterior dorsal fin. In most anglerfish species, the longest filament is the first (the illicium). This first spine protrudes above the fish's eyes, and terminates in an irregular growth of flesh (the esca) at the tip of the spine. The spine is movable in all directions, and the esca can be wiggled so as to resemble a prey animal, and thus to act as bait to lure other predators close enough for the anglerfish to devour them whole. The jaws are triggered in automatic reflex by contact with the tentacle.
Deep sea anglerfish live mainly in the oceans' aphotic zones, where the water is too deep for sufficient sunlight to penetrate for photosynthesis to occur, therefore their predation relies on the "lure" being bioluminescent (via bacterial symbiosis).
The wide mouth extends all around the anterior circumference of the head, and both jaws are armed with bands of long pointed teeth, which are inclined inwards, and can be depressed so as to offer no impediment to an object gliding towards the stomach, but to prevent its escape from the mouth. The anglerfish is able to distend both its jaw and its stomach (its bones are thin and flexible) to enormous size, allowing it to swallow prey up to twice as large as its entire body.
Some benthic (bottom-dwelling) forms have arm-like pectoral fins which the fish use to walk along the ocean floor. The pectoral and ventral fins are so articulated as to perform the functions of feet, enabling the fish to move, or rather to walk, on the bottom of the sea, where it generally hides itself in the sand or amongst seaweed. All around its head and also along the body the skin bears fringed appendages resembling short fronds of seaweed, a structure which, combined with the extraordinary faculty of assimilating the colour of the body to its surroundings, assists this fish greatly in concealing itself in places which it selects on account of the abundance of prey.
# Reproduction
Anglerfishes of the suborder Ceratioidea employ an unusual mating method. Since individuals are presumably locally rare and encounters doubly so, finding a mate is problematic. When scientists first started capturing ceratioid anglerfish, they noticed that all of the specimens were females. These individuals were a few inches in size and almost all of them had what appeared to be parasites attached to them. It turned out that these "parasites" were the remains of male ceratioids.
At birth, male ceratioids are already equipped with extremely well developed olfactory organs that detect scents in the water. When he is mature, the male's digestive system degenerates, making him incapable of feeding independently, which necessitates his quickly finding a female anglerfish or else dying. The sensitive olfactory organs help the male to detect the pheromones that signal the proximity of a female anglerfish. When he finds a female, he bites into her skin, and releases an enzyme that digests the skin of his mouth and her body, fusing the pair down to the blood-vessel level. The male then atrophies into nothing more than a pair of gonads, which release sperm in response to hormones in the female's bloodstream indicating egg release. This extreme sexual dimorphism ensures that, when the female is ready to spawn, she has a mate immediately available.
The spawn of the anglerfish of the genus Lophius consists of a thin sheet of transparent gelatinous material 2 or 3 feet wide and 25 to 30 feet long. The eggs in this sheet are in a single layer, each in its own little cavity. The spawn is free in the sea. The larvae are free-swimming and have the pelvic fins elongated into filaments. Such an egg sheet is rare in fishes.
# Consumption
One family Lophiidae is of commercial interest with fisheries found in the in north-western Europe, eastern North America, Africa and the Far East. In Europe and North America, the tail meat of fish of the genus Lophius (known as goosefish (North America) or monkfish (British Isles)), is widely used in cooking and is often compared to lobster tail in taste and texture. It is therefore sometimes referred to as "poor man's lobster."
The anglerfish is a culinary speciality in certain Asian countries. In Japan, each fish sells for as much as US$150; the liver alone, being a great delicacy, can cost US$100.
# Threats
North-west European Lophius sp. are listed by the ICES as "outside safe biological limits." | Anglerfish
Anglerfish are bony fish in the order Lophiiformes[1], named for their characteristic mode of predation, wherein a fleshy growth from the fish's head (the esca) acts as a lure; this is considered analogous to angling.
Anglerfish are both pelagic and benthic fishes of the abyss (e.g. Ceratiidae) and the continental shelf (e.g. the frogfishes Antennariidae and the monkfish/goosefish Lophiidae) respectively. They occur worldwide. Pelagic forms are most laterally compressed whereas the benthic forms are often extremely dorse-ventrally compressed (depressed) often with large upward pointing mouths.
# Predation
The fish are named for their characteristic method of predation. Anglerfish typically have three long filaments sprouting from the middle of the head; these are the detached and modified three first spines of the anterior dorsal fin. In most anglerfish species, the longest filament is the first (the illicium). This first spine protrudes above the fish's eyes, and terminates in an irregular growth of flesh (the esca) at the tip of the spine. The spine is movable in all directions, and the esca can be wiggled so as to resemble a prey animal, and thus to act as bait to lure other predators close enough for the anglerfish to devour them whole. The jaws are triggered in automatic reflex by contact with the tentacle.
Deep sea anglerfish live mainly in the oceans' aphotic zones, where the water is too deep for sufficient sunlight to penetrate for photosynthesis to occur, therefore their predation relies on the "lure" being bioluminescent (via bacterial symbiosis).
The wide mouth extends all around the anterior circumference of the head, and both jaws are armed with bands of long pointed teeth, which are inclined inwards, and can be depressed so as to offer no impediment to an object gliding towards the stomach, but to prevent its escape from the mouth. The anglerfish is able to distend both its jaw and its stomach (its bones are thin and flexible) to enormous size, allowing it to swallow prey up to twice as large as its entire body.
Some benthic (bottom-dwelling) forms have arm-like pectoral fins which the fish use to walk along the ocean floor. The pectoral and ventral fins are so articulated as to perform the functions of feet, enabling the fish to move, or rather to walk, on the bottom of the sea, where it generally hides itself in the sand or amongst seaweed. All around its head and also along the body the skin bears fringed appendages resembling short fronds of seaweed, a structure which, combined with the extraordinary faculty of assimilating the colour of the body to its surroundings, assists this fish greatly in concealing itself in places which it selects on account of the abundance of prey.
# Reproduction
Anglerfishes of the suborder Ceratioidea employ an unusual mating method. Since individuals are presumably locally rare and encounters doubly so, finding a mate is problematic. When scientists first started capturing ceratioid anglerfish, they noticed that all of the specimens were females. These individuals were a few inches in size and almost all of them had what appeared to be parasites attached to them. It turned out that these "parasites" were the remains of male ceratioids.
At birth, male ceratioids are already equipped with extremely well developed olfactory organs that detect scents in the water. When he is mature, the male's digestive system degenerates, making him incapable of feeding independently, which necessitates his quickly finding a female anglerfish or else dying. The sensitive olfactory organs help the male to detect the pheromones that signal the proximity of a female anglerfish. When he finds a female, he bites into her skin, and releases an enzyme that digests the skin of his mouth and her body, fusing the pair down to the blood-vessel level. The male then atrophies into nothing more than a pair of gonads, which release sperm in response to hormones in the female's bloodstream indicating egg release. This extreme sexual dimorphism ensures that, when the female is ready to spawn, she has a mate immediately available.[2]
The spawn of the anglerfish of the genus Lophius consists of a thin sheet of transparent gelatinous material 2 or 3 feet wide and 25 to 30 feet long. The eggs in this sheet are in a single layer, each in its own little cavity. The spawn is free in the sea. The larvae are free-swimming and have the pelvic fins elongated into filaments. Such an egg sheet is rare in fishes.
# Consumption
One family Lophiidae is of commercial interest with fisheries found in the in north-western Europe, eastern North America, Africa and the Far East. In Europe and North America, the tail meat of fish of the genus Lophius (known as goosefish (North America) or monkfish (British Isles)), is widely used in cooking and is often compared to lobster tail in taste and texture. It is therefore sometimes referred to as "poor man's lobster."[citation needed]
The anglerfish is a culinary speciality in certain Asian countries. In Japan, each fish sells for as much as US$150; the liver alone, being a great delicacy, can cost US$100.[citation needed]
# Threats
North-west European Lophius sp. are listed by the ICES as "outside safe biological limits."[3] | https://www.wikidoc.org/index.php/Anglerfish | |
716c3e8f1f69826a0c92fd7288ffb5efd00aebae | wikidoc | Anisocoria | Anisocoria
Anisocoria is a condition characterized by an unequal size of the pupils.
# Causes
To a certain extent, this is normal. Anisocoria to a mild degree (generally 0.3 to 0.5 mm) can be found in about 20% of people. This form is termed "simple anisocoria." When pathological, it may be seen in a variety of nervous system pathologies such as Wernicke-Korsakoff syndrome.
In the absence of any deformities of the iris or eyeball proper, anisocoria is usually the result of a defect in efferent nervous pathways controlling the pupil traveling in the oculomotor nerve (parasympathetic fibers) or the sympathetic pathways. Physical lesions and drugs causing anisocoria will do so via disruption of these pathways.
Some examples of drugs which may affect the pupils include pilocarpine, cocaine, tropicamide and scopolamine.
Additionally, dilation of the pupil is termed mydriasis and constriction of the pupil is termed miosis.
# Complete Differential Diagnosis of Anisocoria
In alphabetical order
- Adie's Syndrome
- Alcohol intoxication
- Aniridia
- Argyll-Robertson Pupil
- Arsenic poisoning
- Botulism
- Brain tumor
- Cavernous sinus thrombosis
- Cerebral aneurysm
- Congenital
- Degenerative neurologic disorders
- Diabetes Mellitus
- Diphtheria
- Drugs
- Encephalitis
- Herpes Zoster
- Horner's Syndrome
- Injury to the iris
- Internal carotid artery aneurysm
- Intracranial hemorrhage
- Iridocyclitis
- Ischemia
- Keratitis
- Lead poisoning
- Meningitis
- Multiple Sclerosis
- Narrow Angle Glaucoma
- Neoplastic
- Neurofibromatosis
- Ocular prosthesis
- Retinal disease
- Syphilis
- Syringomyelia
- Tabes Dorsalis
- Trauma
- Tuberculosis
# Interpretation
Clinically, it is important to establish which of the two pupils is behaving abnormally.
- If the smaller of the two pupils is the abnormal one, dimming the ambient light will not cause it to dilate, in which case a defect in sympathetic fibers is suspected, as seen in Horner's syndrome.
- Alternatively, if the abnormal pupil is the larger one, it will fail to contract in response to light, raising suspicion for a parasympathetic nerve defect, possibly an oculomotor nerve palsy.
A relative afferent pupillary defect or RAPD also known as a Marcus Gunn pupil does not cause anisocoria.
When anisocoria occurs and the examiner is unsure whether the abnormal pupil is the constricted or dilated one, if a one-sided ptosis is present then the abnormally sized pupil can be presumed to be the one on the side of the ptosis. | Anisocoria
Template:Search infobox
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Anisocoria is a condition characterized by an unequal size of the pupils.
# Causes
To a certain extent, this is normal. Anisocoria to a mild degree (generally 0.3 to 0.5 mm) can be found in about 20% of people. This form is termed "simple anisocoria." When pathological, it may be seen in a variety of nervous system pathologies such as Wernicke-Korsakoff syndrome.
In the absence of any deformities of the iris or eyeball proper, anisocoria is usually the result of a defect in efferent nervous pathways controlling the pupil traveling in the oculomotor nerve (parasympathetic fibers) or the sympathetic pathways. Physical lesions and drugs causing anisocoria will do so via disruption of these pathways.
Some examples of drugs which may affect the pupils include pilocarpine, cocaine, tropicamide and scopolamine.
Additionally, dilation of the pupil is termed mydriasis and constriction of the pupil is termed miosis.
# Complete Differential Diagnosis of Anisocoria
In alphabetical order [1] [2]
- Adie's Syndrome
- Alcohol intoxication
- Aniridia
- Argyll-Robertson Pupil
- Arsenic poisoning
- Botulism
- Brain tumor
- Cavernous sinus thrombosis
- Cerebral aneurysm
- Congenital
- Degenerative neurologic disorders
- Diabetes Mellitus
- Diphtheria
- Drugs
- Encephalitis
- Herpes Zoster
- Horner's Syndrome
- Injury to the iris
- Internal carotid artery aneurysm
- Intracranial hemorrhage
- Iridocyclitis
- Ischemia
- Keratitis
- Lead poisoning
- Meningitis
- Multiple Sclerosis
- Narrow Angle Glaucoma
- Neoplastic
- Neurofibromatosis
- Ocular prosthesis
- Retinal disease
- Syphilis
- Syringomyelia
- Tabes Dorsalis
- Trauma
- Tuberculosis
# Interpretation
Clinically, it is important to establish which of the two pupils is behaving abnormally.
- If the smaller of the two pupils is the abnormal one, dimming the ambient light will not cause it to dilate, in which case a defect in sympathetic fibers is suspected, as seen in Horner's syndrome.
- Alternatively, if the abnormal pupil is the larger one, it will fail to contract in response to light, raising suspicion for a parasympathetic nerve defect, possibly an oculomotor nerve palsy.
A relative afferent pupillary defect or RAPD also known as a Marcus Gunn pupil does not cause anisocoria.
When anisocoria occurs and the examiner is unsure whether the abnormal pupil is the constricted or dilated one, if a one-sided ptosis is present then the abnormally sized pupil can be presumed to be the one on the side of the ptosis. | https://www.wikidoc.org/index.php/Anicosoria | |
cae0fa7331bff2c9e4f8e4e8f4dd81487cea9a25 | wikidoc | Piperidine | Piperidine
Piperidine is an organic compound with the molecular formula C5H11N. It is a heterocyclic amine with a six-membered ring containing five carbon atoms and one nitrogen atom. It is a clear liquid with a pepper-like odor.
The piperidine structural motif is present in numerous natural alkaloids such as piperine and quinine, and is the main active chemical agent in black pepper and relatives (Piper sp.), hence the name. Piperidine is also a structural element of many pharmaceutical drugs such as raloxifene, minoxidil, thioridazine and mesoridazine.
Piperidine is listed as a Table II precursor under the United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances due to its use (peaking in the 1970s) in the clandestine manufacture of PCP (also known as angel dust).
Piperidine is often used as a solvent for its mild basic properties, most notably in Fmoc-strategy solid phase peptide synthesis.
The major industrial application of piperidine is for the production of dipiperidinyl dithium tetrasulfide, which is used as a rubber vulcanization accelerator.
Piperidine is naturally found in fire ant venom, and is the cause of the burning sensation associated with the bite of these insects.
Piperidine is also commonly used in chemical degradation reactions, such as the DNA sequencing method invented by Walter Gilbert in 1977, for cleavage of particular modified nucleotides. Piperidine is also commonly used as a strong base for the deprotection of amino acids in solid-phase peptide synthesis.
# Use in pharmaceutical drugs
Many pharmaceutical drugs contain a piperidine ring because the group tends to impart pharmacokinetics such as water solubility and bioavailability. Examples of drugs that contain piperidines include mesoridazine, thioridazine, haloperidol, droperidol, PCP, benperidol, and risperidone.
Most piperidines induce the liver enzyme CYP2D6, resulting in faster metabolism of e.g. many beta-blockers and antiarrhythmics. | Piperidine
Template:Chembox new
Piperidine is an organic compound with the molecular formula C5H11N. It is a heterocyclic amine with a six-membered ring containing five carbon atoms and one nitrogen atom. It is a clear liquid with a pepper-like odor.
The piperidine structural motif is present in numerous natural alkaloids such as piperine and quinine, and is the main active chemical agent in black pepper and relatives (Piper sp.), hence the name. Piperidine is also a structural element of many pharmaceutical drugs such as raloxifene, minoxidil, thioridazine and mesoridazine.
Piperidine is listed as a Table II precursor under the United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances[1] due to its use (peaking in the 1970s) in the clandestine manufacture of PCP (also known as angel dust).
Piperidine is often used as a solvent for its mild basic properties, most notably in Fmoc-strategy solid phase peptide synthesis.
The major industrial application of piperidine is for the production of dipiperidinyl dithium tetrasulfide, which is used as a rubber vulcanization accelerator.
Piperidine is naturally found in fire ant venom, and is the cause of the burning sensation associated with the bite of these insects.
Piperidine is also commonly used in chemical degradation reactions, such as the DNA sequencing method invented by Walter Gilbert in 1977, for cleavage of particular modified nucleotides. Piperidine is also commonly used as a strong base for the deprotection of amino acids in solid-phase peptide synthesis.
# Use in pharmaceutical drugs
Many pharmaceutical drugs contain a piperidine ring because the group tends to impart pharmacokinetics such as water solubility and bioavailability. Examples of drugs that contain piperidines include mesoridazine, thioridazine, haloperidol, droperidol, PCP, benperidol, and risperidone.
Most piperidines induce the liver enzyme CYP2D6, resulting in faster metabolism of e.g. many beta-blockers and antiarrhythmics. | https://www.wikidoc.org/index.php/Anilidopiperidine | |
c45a3a44844ebb549f43700f3fff17a854ae29ac | wikidoc | Animal fat | Animal fat
Animal fats are rendered tissue fats that can be obtained from a variety of animals.
# Human nutrition
Animal fats are often claimed to be unhealthy owing to their association with high cholesterol levels in the blood. Animal fat contains some cholesterol and saturated fat. Elevated blood cholesterol levels have been linked to heart disease, there is not necessarily a relationship between cholesterol intake and blood cholesterol level.
Some sources of animal fat include blubber, cod liver oil, lard pork fat, beef tallow, schmaltz or chicken fat.
# Pet nutrition
In pet nutrition it is the source of animal fat that has concerned food manufacturers. AAFCO states that animal fat is "obtained from the tissues of mammals and/or poultry in the commercial processes of rendering or extracting. It consists predominantly of glyceride esters of fatty acids and contains no additions of free fatty acids. If an antioxidant is used, the common name or names must be indicated, followed by the words "used as a preservative". In actuality the animal source is not specified or required to give the origin of slaughtered animals. The rendered animals can be obtained from any source. There is no control over quality or contamination and any animal can be used including dead, diseased, disabled, or dying prior to slaughter.
# Caloric Equivalent
100 grams of animal fat (bacon grease) contains 3750 kJ, or 900 kcal (4000 kcal/lb). | Animal fat
Animal fats are rendered tissue fats that can be obtained from a variety of animals.
# Human nutrition
Animal fats are often claimed to be unhealthy owing to their association with high cholesterol levels in the blood. Animal fat contains some cholesterol and saturated fat. Elevated blood cholesterol levels have been linked to heart disease, there is not necessarily a relationship between cholesterol intake and blood cholesterol level.
Some sources of animal fat include blubber, cod liver oil, lard pork fat, beef tallow, schmaltz or chicken fat.
# Pet nutrition
In pet nutrition it is the source of animal fat that has concerned food manufacturers. AAFCO states that animal fat is "obtained from the tissues of mammals and/or poultry in the commercial processes of rendering or extracting. It consists predominantly of glyceride esters of fatty acids and contains no additions of free fatty acids. If an antioxidant is used, the common name or names must be indicated, followed by the words "used as a preservative". In actuality the animal source is not specified or required to give the origin of slaughtered animals. The rendered animals can be obtained from any source. There is no control over quality or contamination and any animal can be used including dead, diseased, disabled, or dying prior to slaughter.[1]
# Caloric Equivalent
100 grams of animal fat (bacon grease) contains 3750 kJ, or 900 kcal (4000 kcal/lb). [2] | https://www.wikidoc.org/index.php/Animal_fat | |
b599705caa176c431f90c4b1191cf8c0ee8d738d | wikidoc | Anna Freud | Anna Freud
Anna Freud (December 3, 1895 - October 9, 1982) was the sixth and last child of Sigmund and Martha Freud. Born in Vienna, she followed the path of her father and contributed to the newly born field of psychoanalysis. Compared to her father, Anna Freud's work emphasized the importance of the ego, and its ability to be trained socially.
# The Vienna years
Anna did not have a very close bond with her mother and had difficulties getting along with her siblings, specifically with her sister Sophie Freud. Sophie, who was the prettiest child, represented a threat in the struggle for the affection of their father. Apart from this rivalry between the two sisters, Anna had some other difficulties growing up. Out of correspondence between father and daughter, it can be concluded today that Anna suffered from a depression which caused eating disorders. The relationship between Anna and her father was different from the rest of her family; they were very close. She was a lively child with a reputation for mischief. Freud wrote to his friend Wilhelm Fliess in 1899: "Anna has become downright beautiful through naughtiness... ", Sigmund was very proud of his daughter. It was found that he mentioned her in his diaries more than others in the family.
Anna began school in 1901, later on Anna would say that she didn’t learn much in school but all the more from her father and his guests at home. This way she picked up languages as Hebrew, German, English, French and Italian. At the age of 15, she started reading her father’s work. At a young age she started to tell her father her dreams and he would publish them in his book Interpretation of Dreams. Anna finished her education at the Cottage Lyceum in Vienna in 1912. Suffering from a depression, she was very insecure about what to do in the future. Subsequently, she went to Italy to stay with her grandmother.
In 1914, she started teaching at her old school, the Cottage Lyceum. In 1918 her father started psychoanalysis on her and she became seriously involved with this new profession. Her analysis was completed in 1922 and thereupon she presented the paper "Beating Fantasies and Daydreams" to the Vienna Psychoanalytical Society, subsequently becoming a member. In 1923 she began her own psychoanalytical practice with children and two years later she was teaching at the Vienna Psychoanalytic Training Institute on the technique of child analysis. From 1925 until 1934 she was the Secretary of the International Psychoanalytical Association while she continued child analysis and seminars and conferences on the subject. In 1935 Anna became director of the Vienna Psychoanalytical Training Institute and in the following year she published her influential study of the "ways and means by which the ego wards off displeasure and anxiety", The Ego and the Mechanisms of Defence. It became a founding work of ego psychology and established Anna’s reputation as a pioneering theoretician.
# 1938 and later: Anna in London
In 1938 the Freuds had to flee from Austria as a consequence of the Nazis' continuous harassment of Jews in Vienna. Her father's health was getting bad due to a severe jaw cancer infection, so she had to organize the family's emigration to London. Here she continued her work and took care of her father, who finally died in the autumn of 1939.
When Anna arrived in London, a conflict emerged between her and Melanie Klein regarding developmental theories of children. This conflict threatened to split the British Psycho-analytical Society, but ended in training courses given from two different points of view.
The war gave Anna opportunity to observe the effect of deprivation of parental care on children. She set up a centre for young war victims, called "The Hampstead War Nursery". Here the children got foster care although mothers were encouraged to visit as often as possible. The underlying idea was to give children the opportunity to form attachments by providing continuity of relationships. This was continued, after the war, at the Bulldogs Bank home, which was an orphanage, run by colleagues of Anna and was taking care of children who survive concentration camps. Based on these observations Anna published a series of studies with her lifelong friend, Dorothy Burlingham on the impact of stress on children and the ability to find substitute affections among peers when parents cannot give them.
In 1947 Anna Freud and Kate Friedlaender established the Hampstead Child Therapy Courses. Five years later, a children's clinic was added. Here they worked with Anna's theory of the developmental lines. Furthermore Anna started lecturing on child psychology. Until then Child analysis had remained a quite uncharted territory. Siegfried Bernfeld and August Aichorn, who both had practical experience of dealing with children, mentored her in this.
From the 1950s until the end of her life Anna Freud travelled regularly to the United States to lecture, to teach and to visit friends. During the 1970s she was concerned with the problems of emotionally deprived and socially disadvantaged children, and she studied deviations and delays in development. At Yale Law School she taught seminars on crime and the family: this led to a transatlantic collaboration with Joseph Goldstein and Albert Solnit on children and the law, published as Beyond the Best Interests of the Child(1973).
Anna Freud died in London on October 9, 1982. She was cremated at Golders Green Crematorium and her ashes placed in a marble shelf next to her parents' ancient Greek funeral urn. Her lifelong friend Dorothy Burlingham and several other members of the Freud family also rest there.
One year after Anna Freud's death a publication of her collected works appeared. She was mentioned as "a passionate and inspirational teacher" and in 1984 the Hampstead Clinic was renamed the Anna Freud Centre. Furthermore her home in London for forty years was in 1986, as she had wished, transformed into the Freud Museum, dedicated to her father and the psychoanalytical society.
# Major contributions to psychoanalysis
Anna Freud moved away from the classical position of her father, who was concentrating on the unconscious Id (a perspective she found to be restrictive) and instead emphasized the importance of the ego, the constant struggle and conflict it is experiencing by the need to answer contradicting wishes, desires, values and demands of reality. By this, she established the importance of the ego functions and the concept of defense mechanisms.
Focusing on research, observation and treatment of children, Freud established a group of prominent child developmental analysts (which included Erik Erikson, Edith Jacobson and Margaret Mahler) who noticed that children's symptoms were ultimately analogue to personality disorders among adults and thus often related to developmental stages. At that time, these ideas were revolutionary and Anna provided us with a comprehensive developmental theory and the concept of developmental lines, which combined her father's important drive model with more recent object relations theories of development, which emphasize the importance of parents in child development processes.
As such, the formation of the fields of child psychoanalysis and child developmental psychology can be attributed to Anna Freud.
Anna Freud furthermore developed different techniques of assessment and treatment of children disorders, thereby contributing to our understanding of anxiety and depression as significant problems among children.
# Anna Freud about essential personal qualities in Psychoanalysts
"Dear John ...,
You asked me what I consider essential personal qualities in a future psychoanalyst. The answer is comparatively simple. If you want to be a real psychoanalyst you have to have a great love of the truth, scientific truth as well as personal truth, and you have to place this appreciation of truth higher than any discomfort at meeting unpleasant facts, whether they belong to the world outside or to your own inner person.
Further, I think that a psychoanalyst should have...interests...beyond the limits of the medical field...in facts that belong to sociology, religion, literature, , history,...his outlook on...his patient will remain too narrow. This point contains...the necessary preparations beyond the requirements made on candidates of psychoanalysis in the institutes. You ought to be a great reader and become acquainted with the literature of many countries and cultures. In the great literary figures you will find people who know at least as much of human nature as the psychiatrists and psychologists try to do.
Does that answer your question?"
# Notes
- ↑ from a letter written by Anna Freud. The International Journal of Psycho-Analysis And Bulletin of the International Psycho-Analytical Association, Volume 49 1968, Article of Heinz Kohut HEINZ KOHUT: The evaluation of applicants for psychoanalytic training Pages 548-554 (P. S.552, 553)
- ^ The Century Of The Self
# Publications by Anna Freud:
- Freud, Anna (1966-1980). The Writings of Anna Freud: 8 Volumes. New York: IUP. (These volumes include most of Anna Freud's papers.)
Vol. 1. Introduction to Psychoanalysis: Lectures for Child Analysts and Teachers (1922-1935)
Vol. 2. Ego and the Mechanisms of Defense (1936)
Vol. 3. Infants Without Families Reports on the Hampstead Nurseries by Anna Freud
Vol. 4. Indications for Child Analysis and Other Papers (1945-1956)
Vol. 5. Research at the Hampstead Child-Therapy Clinic and Other Papers: (1956-1965)
Vol. 6. Normality and Pathology in Childhood: Assessments of Development (1965)
Vol. 7. Problems of Psychoanalytic Training, Diagnosis, and the Technique of Therapy (1966-1970)
Vol. 8. Psychoanalytic Psychology of Normal Development
- Vol. 1. Introduction to Psychoanalysis: Lectures for Child Analysts and Teachers (1922-1935)
- Vol. 2. Ego and the Mechanisms of Defense (1936)
- Vol. 3. Infants Without Families Reports on the Hampstead Nurseries by Anna Freud
- Vol. 4. Indications for Child Analysis and Other Papers (1945-1956)
- Vol. 5. Research at the Hampstead Child-Therapy Clinic and Other Papers: (1956-1965)
- Vol. 6. Normality and Pathology in Childhood: Assessments of Development (1965)
- Vol. 7. Problems of Psychoanalytic Training, Diagnosis, and the Technique of Therapy (1966-1970)
- Vol. 8. Psychoanalytic Psychology of Normal Development
# Biographies
- Coles, Robert (1992). Anna Freud: The Dream of Psychoanalysis. Reading, Mass.: Addison-Wesley. ISBN 0-201-57707-0..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}
- Peters, Uwe Henrik (1985). Anna Freud: A Life Dedicated to Children. New York: Schocken Books. ISBN 0-8052-3910-3.
- Young-Bruehl, Elisabeth (1988). Anna Freud: A Biography. New York: Summit Books. ISBN 0-671-61696-X. | Anna Freud
Template:Psychoanalysis
Anna Freud (December 3, 1895 - October 9, 1982) was the sixth and last child of Sigmund and Martha Freud. Born in Vienna, she followed the path of her father and contributed to the newly born field of psychoanalysis. Compared to her father, Anna Freud's work emphasized the importance of the ego, and its ability to be trained socially.
# The Vienna years
Anna did not have a very close bond with her mother and had difficulties getting along with her siblings, specifically with her sister Sophie Freud. Sophie, who was the prettiest child, represented a threat in the struggle for the affection of their father. Apart from this rivalry between the two sisters, Anna had some other difficulties growing up. Out of correspondence between father and daughter, it can be concluded today that Anna suffered from a depression which caused eating disorders. The relationship between Anna and her father was different from the rest of her family; they were very close. She was a lively child with a reputation for mischief. Freud wrote to his friend Wilhelm Fliess in 1899: "Anna has become downright beautiful through naughtiness... ", Sigmund was very proud of his daughter. It was found that he mentioned her in his diaries more than others in the family.
Anna began school in 1901, later on Anna would say that she didn’t learn much in school but all the more from her father and his guests at home. This way she picked up languages as Hebrew, German, English, French and Italian. At the age of 15, she started reading her father’s work. At a young age she started to tell her father her dreams and he would publish them in his book Interpretation of Dreams. Anna finished her education at the Cottage Lyceum in Vienna in 1912. Suffering from a depression, she was very insecure about what to do in the future. Subsequently, she went to Italy to stay with her grandmother.
In 1914, she started teaching at her old school, the Cottage Lyceum. In 1918 her father started psychoanalysis on her and she became seriously involved with this new profession. Her analysis was completed in 1922 and thereupon she presented the paper "Beating Fantasies and Daydreams" to the Vienna Psychoanalytical Society, subsequently becoming a member. In 1923 she began her own psychoanalytical practice with children and two years later she was teaching at the Vienna Psychoanalytic Training Institute on the technique of child analysis. From 1925 until 1934 she was the Secretary of the International Psychoanalytical Association while she continued child analysis and seminars and conferences on the subject. In 1935 Anna became director of the Vienna Psychoanalytical Training Institute and in the following year she published her influential study of the "ways and means by which the ego wards off displeasure and anxiety", The Ego and the Mechanisms of Defence. It became a founding work of ego psychology and established Anna’s reputation as a pioneering theoretician.
# 1938 and later: Anna in London
In 1938 the Freuds had to flee from Austria as a consequence of the Nazis' continuous harassment of Jews in Vienna. Her father's health was getting bad due to a severe jaw cancer infection, so she had to organize the family's emigration to London. Here she continued her work and took care of her father, who finally died in the autumn of 1939.
When Anna arrived in London, a conflict emerged between her and Melanie Klein regarding developmental theories of children. This conflict threatened to split the British Psycho-analytical Society, but ended in training courses given from two different points of view.
The war gave Anna opportunity to observe the effect of deprivation of parental care on children. She set up a centre for young war victims, called "The Hampstead War Nursery". Here the children got foster care although mothers were encouraged to visit as often as possible. The underlying idea was to give children the opportunity to form attachments by providing continuity of relationships. This was continued, after the war, at the Bulldogs Bank home, which was an orphanage, run by colleagues of Anna and was taking care of children who survive concentration camps. Based on these observations Anna published a series of studies with her lifelong friend, Dorothy Burlingham on the impact of stress on children and the ability to find substitute affections among peers when parents cannot give them.
In 1947 Anna Freud and Kate Friedlaender established the Hampstead Child Therapy Courses. Five years later, a children's clinic was added. Here they worked with Anna's theory of the developmental lines. Furthermore Anna started lecturing on child psychology. Until then Child analysis had remained a quite uncharted territory. Siegfried Bernfeld and August Aichorn, who both had practical experience of dealing with children, mentored her in this.
From the 1950s until the end of her life Anna Freud travelled regularly to the United States to lecture, to teach and to visit friends. During the 1970s she was concerned with the problems of emotionally deprived and socially disadvantaged children, and she studied deviations and delays in development. At Yale Law School she taught seminars on crime and the family: this led to a transatlantic collaboration with Joseph Goldstein and Albert Solnit on children and the law, published as Beyond the Best Interests of the Child(1973).
Anna Freud died in London on October 9, 1982. She was cremated at Golders Green Crematorium and her ashes placed in a marble shelf next to her parents' ancient Greek funeral urn. Her lifelong friend Dorothy Burlingham and several other members of the Freud family also rest there.
One year after Anna Freud's death a publication of her collected works appeared. She was mentioned as "a passionate and inspirational teacher" and in 1984 the Hampstead Clinic was renamed the Anna Freud Centre. Furthermore her home in London for forty years was in 1986, as she had wished, transformed into the Freud Museum, dedicated to her father and the psychoanalytical society.
# Major contributions to psychoanalysis
Anna Freud moved away from the classical position of her father, who was concentrating on the unconscious Id (a perspective she found to be restrictive) and instead emphasized the importance of the ego, the constant struggle and conflict it is experiencing by the need to answer contradicting wishes, desires, values and demands of reality. By this, she established the importance of the ego functions and the concept of defense mechanisms.
Focusing on research, observation and treatment of children, Freud established a group of prominent child developmental analysts (which included Erik Erikson, Edith Jacobson and Margaret Mahler) who noticed that children's symptoms were ultimately analogue to personality disorders among adults and thus often related to developmental stages. At that time, these ideas were revolutionary and Anna provided us with a comprehensive developmental theory and the concept of developmental lines, which combined her father's important drive model with more recent object relations theories of development, which emphasize the importance of parents in child development processes.
As such, the formation of the fields of child psychoanalysis and child developmental psychology can be attributed to Anna Freud.
Anna Freud furthermore developed different techniques of assessment and treatment of children disorders, thereby contributing to our understanding of anxiety and depression as significant problems among children.
# Anna Freud about essential personal qualities in Psychoanalysts
"Dear John ...,
You asked me what I consider essential personal qualities in a future psychoanalyst. The answer is comparatively simple. If you want to be a real psychoanalyst you have to have a great love of the truth, scientific truth as well as personal truth, and you have to place this appreciation of truth higher than any discomfort at meeting unpleasant facts, whether they belong to the world outside or to your own inner person.
Further, I think that a psychoanalyst should have...interests...beyond the limits of the medical field...in facts that belong to sociology, religion, literature, ,[and] history,...[otherwise]his outlook on...his patient will remain too narrow. This point contains...the necessary preparations beyond the requirements made on candidates of psychoanalysis in the institutes. You ought to be a great reader and become acquainted with the literature of many countries and cultures. In the great literary figures you will find people who know at least as much of human nature as the psychiatrists and psychologists try to do.
Does that answer your question?"
[1]
# Notes
- ↑ from a letter written by Anna Freud. The International Journal of Psycho-Analysis And Bulletin of the International Psycho-Analytical Association, Volume 49 1968, Article of Heinz Kohut HEINZ KOHUT: The evaluation of applicants for psychoanalytic training Pages 548-554 (P. S.552, 553)
- ^ The Century Of The Self
# Publications by Anna Freud:
- Freud, Anna (1966-1980). The Writings of Anna Freud: 8 Volumes. New York: IUP. (These volumes include most of Anna Freud's papers.)
Vol. 1. Introduction to Psychoanalysis: Lectures for Child Analysts and Teachers (1922-1935)
Vol. 2. Ego and the Mechanisms of Defense (1936)
Vol. 3. Infants Without Families Reports on the Hampstead Nurseries by Anna Freud
Vol. 4. Indications for Child Analysis and Other Papers (1945-1956)
Vol. 5. Research at the Hampstead Child-Therapy Clinic and Other Papers: (1956-1965)
Vol. 6. Normality and Pathology in Childhood: Assessments of Development (1965)
Vol. 7. Problems of Psychoanalytic Training, Diagnosis, and the Technique of Therapy (1966-1970)
Vol. 8. Psychoanalytic Psychology of Normal Development
- Vol. 1. Introduction to Psychoanalysis: Lectures for Child Analysts and Teachers (1922-1935)
- Vol. 2. Ego and the Mechanisms of Defense (1936)
- Vol. 3. Infants Without Families Reports on the Hampstead Nurseries by Anna Freud
- Vol. 4. Indications for Child Analysis and Other Papers (1945-1956)
- Vol. 5. Research at the Hampstead Child-Therapy Clinic and Other Papers: (1956-1965)
- Vol. 6. Normality and Pathology in Childhood: Assessments of Development (1965)
- Vol. 7. Problems of Psychoanalytic Training, Diagnosis, and the Technique of Therapy (1966-1970)
- Vol. 8. Psychoanalytic Psychology of Normal Development
# Biographies
- Coles, Robert (1992). Anna Freud: The Dream of Psychoanalysis. Reading, Mass.: Addison-Wesley. ISBN 0-201-57707-0..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}
- Peters, Uwe Henrik (1985). Anna Freud: A Life Dedicated to Children. New York: Schocken Books. ISBN 0-8052-3910-3.
- Young-Bruehl, Elisabeth (1988). Anna Freud: A Biography. New York: Summit Books. ISBN 0-671-61696-X.
# External links
- Life and Work of Anna Freud
- Anna Freud Centre
- International Psychoanalytical Association
- Biography of Anna Freud
- Lost Girl by Doug Davis
cs:Anna Freud
de:Anna Freud
et:Anna Freud
eo:Anna Freud
it:Anna Freud
he:אנה פרויד
nl:Anna Freud
sk:Anna Freudová
fi:Anna Freud
sv:Anna Freud | https://www.wikidoc.org/index.php/Anna_Freud | |
92ac4ec1a42443e5513904015fdce98e9f0162b6 | wikidoc | Annexin A1 | Annexin A1
Annexin A1, also known as lipocortin I, is a protein that is encoded by the ANXA1 gene in humans.
# Function
Annexin A1 belongs to the annexin family of Ca2+-dependent phospholipid-binding proteins that have a molecular weight of approximately 35,000 to 40,000 and are preferentially located on the cytosolic face of the plasma membrane. Annexin A1 protein has an apparent relative molecular mass of 40 kDa with phospholipase A2 inhibitory activity.
# Clinical significance
## Effect on innate and adaptive immunity
Glucocorticoids (such as budesonide, cortisol, and beclomethasone) are a class of endogenous or synthetic anti-inflammatory steroid hormones that bind to the glucocorticoid receptor (GR), which is present in almost every vertebrate animal cell. They are used in medicine to treat diseases caused by an overactive immune system, including allergies, asthma, autoimmune diseases, and sepsis. Because they suppress inflammatory pathways, long-term use of glucocorticoid drugs can lead to side-effects such as immunodeficiency and adrenal insufficiency.
The main mechanism of glucocorticoids' anti-inflammatory effects is to increase the synthesis and function of annexin A1. Annexin A1 both suppresses phospholipase A2, thereby blocking eicosanoid production, and inhibits various leukocyte inflammatory events (epithelial adhesion, emigration, chemotaxis, phagocytosis, respiratory burst, etc.). In other words, glucocorticoids not only suppress immune response, but also inhibit the two main products of inflammation, prostaglandins and leukotrienes. They inhibit prostaglandin synthesis at the level of phospholipase A2 as well as at the level of cyclooxygenase/PGE isomerase (COX-1 and COX-2), the latter effect being much like that of NSAIDs, potentiating the anti-inflammatory effect.
In resting conditions, human and mouse immune cells such as neutrophils, monocytes, and macrophages contain high levels of annexin A1 in their cytoplasm. Following cell activation (for example, by neutrophil adhesion to endothelial-cell monolayers), annexin A1 is promptly mobilized to the cell surface and secreted. Annexin A1 promotes neutrophil detachment and apoptosis, and phagocytosis of apoptotic neutrophils by macrophages. On the other hand, it reduces the tendency of neutrophils to penetrate the endothelium of blood vessels. In vitro and in vivo analyses show that exogenous and endogenous annexin A1 counter-regulate the activities of innate immune cells, particularly extravasation and the generation of proinflammatory mediators, which ensures that a sufficient level of activation is reached but not exceeded.
Annexin A1 has important opposing properties during innate and adaptive immune responses: it inhibits innate immune cells and promotes T-cell activation. The activation of T cells results in the release of annexin A1 and the expression of its receptor. This pathway seems to fine-tune the strength of TCR signalling. Higher expression of annexin A1 during pathological conditions could increase the strength of TCR signalling through the mitogen-activated protein kinase signalling pathway, thereby causing a state of hyperactivation of T cells.
## Inflammation
Since phospholipase A2 is required for the biosynthesis of the potent mediators of inflammation, prostaglandins, and leukotrienes, annexin A1 may have potential anti-inflammatory activity.
Glucocorticoids stimulate production of lipocortin. In this way, synthesis of eicosanoids are inhibited.
## Cancer
Annexin A1 has been of interest for use as a potential anticancer drug. Upon induction by modified NSAIDS and other potent anti-inflammatory drugs, annexin A1 inhibits the NF-κB signal transduction pathway, which is exploited by cancerous cells to proliferate and avoid apoptosis. ANXA1 inhibits the activation of NF-κB by binding to the p65 subunit.
### Leukemia
The gene for annexin A1 (ANXA1) is upregulated in hairy cell leukemia. ANXA1 protein expression is specific to hairy cell leukemia. Detection of ANXA1 (by immunocytochemical means) reportedly provides a simple, highly sensitive, and specific assay for the diagnosis of hairy cell leukemia.
### Breast cancer
Altered annexin A1 expression levels through modulation of the immune system effects the initiation and spread of breast cancer, but the association is complex and conclusions of published studies often conflict.
Exposure of MCF-7 breast cancer cells to high physiological levels (up to 100 nM) of estrogen lead to an up-regulation of annexin A1 expression partially through the activation of CREB, and dependent on activation of the estrogen receptor alpha. Treatment of MCF-7 cells with physiological levels of estrogen (1 nM) induced proliferation while high pregnancy levels of estrogen (100 nM) induced a growth arrest of MCF-7 cells. Silencing of ANXA1 with specific siRNA reverses the estrogen-dependent proliferation as well as growth arrest. ANXA1 is lost in clinical breast cancer, indicating that the anti-proliferative protective function of ANXA1 against high levels of estrogen may be lost in breast cancer. This data suggests that ANXA1 may act as a tumor suppressor gene and modulate the proliferative functions of estrogens.
Annexin A1 protects against DNA damage induced by heat in breast cancer cells, adding to the evidence that it has tumor suppressive and protective activities. When ANXA1 is silenced or lost in cancer, cells are more prone to DNA damage, indicating its unidentified diverse role in genome maintenance or integrity.
Annexin A1 has also been shown to be associated with treatment resistance. ARID1A loss activates annexin A1 expression, which is required for drug resistance (mTOR inhibitor or trastuzumab) through its activation of AKT. | Annexin A1
Annexin A1, also known as lipocortin I, is a protein that is encoded by the ANXA1 gene in humans.[1]
# Function
Annexin A1 belongs to the annexin family of Ca2+-dependent phospholipid-binding proteins that have a molecular weight of approximately 35,000 to 40,000 and are preferentially located on the cytosolic face of the plasma membrane. Annexin A1 protein has an apparent relative molecular mass of 40 kDa with phospholipase A2 inhibitory activity.[2]
# Clinical significance
## Effect on innate and adaptive immunity
Glucocorticoids (such as budesonide, cortisol, and beclomethasone) are a class of endogenous or synthetic anti-inflammatory steroid hormones that bind to the glucocorticoid receptor (GR), which is present in almost every vertebrate animal cell. They are used in medicine to treat diseases caused by an overactive immune system, including allergies, asthma, autoimmune diseases, and sepsis.[3] Because they suppress inflammatory pathways, long-term use of glucocorticoid drugs can lead to side-effects such as immunodeficiency and adrenal insufficiency.
The main mechanism of glucocorticoids' anti-inflammatory effects is to increase the synthesis and function of annexin A1.[4] Annexin A1 both suppresses phospholipase A2, thereby blocking eicosanoid production, and inhibits various leukocyte inflammatory events (epithelial adhesion, emigration, chemotaxis, phagocytosis, respiratory burst, etc.). In other words, glucocorticoids not only suppress immune response, but also inhibit the two main products of inflammation, prostaglandins and leukotrienes. They inhibit prostaglandin synthesis at the level of phospholipase A2 as well as at the level of cyclooxygenase/PGE isomerase (COX-1 and COX-2),[5] the latter effect being much like that of NSAIDs, potentiating the anti-inflammatory effect.
In resting conditions, human and mouse immune cells such as neutrophils, monocytes, and macrophages contain high levels of annexin A1 in their cytoplasm. Following cell activation (for example, by neutrophil adhesion to endothelial-cell monolayers), annexin A1 is promptly mobilized to the cell surface and secreted. Annexin A1 promotes neutrophil detachment and apoptosis, and phagocytosis of apoptotic neutrophils by macrophages. On the other hand, it reduces the tendency of neutrophils to penetrate the endothelium of blood vessels. In vitro and in vivo analyses show that exogenous and endogenous annexin A1 counter-regulate the activities of innate immune cells, particularly extravasation and the generation of proinflammatory mediators, which ensures that a sufficient level of activation is reached but not exceeded.[4]
Annexin A1 has important opposing properties during innate and adaptive immune responses: it inhibits innate immune cells and promotes T-cell activation. The activation of T cells results in the release of annexin A1 and the expression of its receptor. This pathway seems to fine-tune the strength of TCR signalling. Higher expression of annexin A1 during pathological conditions could increase the strength of TCR signalling through the mitogen-activated protein kinase signalling pathway, thereby causing a state of hyperactivation of T cells.[4]
## Inflammation
Since phospholipase A2 is required for the biosynthesis of the potent mediators of inflammation, prostaglandins, and leukotrienes, annexin A1 may have potential anti-inflammatory activity.[2]
Glucocorticoids stimulate production of lipocortin.[6] In this way, synthesis of eicosanoids are inhibited.
## Cancer
Annexin A1 has been of interest for use as a potential anticancer drug. Upon induction by modified NSAIDS and other potent anti-inflammatory drugs, annexin A1 inhibits the NF-κB signal transduction pathway, which is exploited by cancerous cells to proliferate and avoid apoptosis. ANXA1 inhibits the activation of NF-κB by binding to the p65 subunit.[7]
### Leukemia
The gene for annexin A1 (ANXA1) is upregulated in hairy cell leukemia. ANXA1 protein expression is specific to hairy cell leukemia. Detection of ANXA1 (by immunocytochemical means) reportedly provides a simple, highly sensitive, and specific assay for the diagnosis of hairy cell leukemia.[8]
### Breast cancer
Altered annexin A1 expression levels through modulation of the immune system effects the initiation and spread of breast cancer, but the association is complex and conclusions of published studies often conflict.[9]
Exposure of MCF-7 breast cancer cells to high physiological levels (up to 100 nM) of estrogen lead to an up-regulation of annexin A1 expression partially through the activation of CREB, and dependent on activation of the estrogen receptor alpha. Treatment of MCF-7 cells with physiological levels of estrogen (1 nM) induced proliferation while high pregnancy levels of estrogen (100 nM) induced a growth arrest of MCF-7 cells. Silencing of ANXA1 with specific siRNA reverses the estrogen-dependent proliferation as well as growth arrest. ANXA1 is lost in clinical breast cancer, indicating that the anti-proliferative protective function of ANXA1 against high levels of estrogen may be lost in breast cancer. This data suggests that ANXA1 may act as a tumor suppressor gene and modulate the proliferative functions of estrogens.[10]
Annexin A1 protects against DNA damage induced by heat in breast cancer cells, adding to the evidence that it has tumor suppressive and protective activities. When ANXA1 is silenced or lost in cancer, cells are more prone to DNA damage, indicating its unidentified diverse role in genome maintenance or integrity.[11]
Annexin A1 has also been shown to be associated with treatment resistance. ARID1A loss activates annexin A1 expression, which is required for drug resistance (mTOR inhibitor or trastuzumab) through its activation of AKT.[12][13] | https://www.wikidoc.org/index.php/Annexin_A1 | |
d4bc4d658ac2acf8cd2b84d3d5fe6c0fb359ba78 | wikidoc | Annexin A2 | Annexin A2
Annexin A2 also known as annexin II is a protein that in humans is encoded by the ANXA2 gene.
Annexin 2 is involved in diverse cellular processes such as cell motility (especially that of the epithelial cells), linkage of membrane-associated protein complexes to the actin cytoskeleton, endocytosis, fibrinolysis, ion channel formation, and cell matrix interactions.
It is a calcium-dependent phospholipid-binding protein whose function is to help organize exocytosis of intracellular proteins to the extracellular domain. Annexin II is a pleiotropic protein meaning that its function is dependent on place and time in the body.
# Gene
The ANXA2 gene, located at 15q22.2, has three pseudogenes located on chromosomes 4, 9 and 10, respectively. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene.
# Function
This protein is a member of the annexin family. Members of this calcium-dependent phospholipid-binding protein family play a role in the regulation of cellular growth and in signal transduction pathways. This protein functions as an autocrine factor which heightens osteoclast formation and bone resorption. Epigenetic regulation of Annexin A2 has been identified as a key determinant of mesenchymal transformation in brain tumors.
Annexin A2 has been proposed to function inside the cell in sorting of endosomes and outside the cell in anticoagulant reactions.
# Interactions
Annexin A2 has been shown to interact with Prohibitin, CEACAM1, S100A10, PCNA, complement Factor H, and a number of viral factors including the HPV16 minor capsid protein L2. | Annexin A2
Annexin A2 also known as annexin II is a protein that in humans is encoded by the ANXA2 gene.[1]
Annexin 2 is involved in diverse cellular processes such as cell motility (especially that of the epithelial cells), linkage of membrane-associated protein complexes to the actin cytoskeleton, endocytosis, fibrinolysis, ion channel formation, and cell matrix interactions.
It is a calcium-dependent phospholipid-binding protein whose function is to help organize exocytosis of intracellular proteins to the extracellular domain. Annexin II is a pleiotropic protein meaning that its function is dependent on place and time in the body.
# Gene
The ANXA2 gene, located at 15q22.2, has three pseudogenes located on chromosomes 4, 9 and 10, respectively. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene.[2]
# Function
This protein is a member of the annexin family. Members of this calcium-dependent phospholipid-binding protein family play a role in the regulation of cellular growth and in signal transduction pathways. This protein functions as an autocrine factor which heightens osteoclast formation and bone resorption.[2] Epigenetic regulation of Annexin A2 has been identified as a key determinant of mesenchymal transformation in brain tumors.[3]
Annexin A2 has been proposed to function inside the cell in sorting of endosomes and outside the cell in anticoagulant reactions.
# Interactions
Annexin A2 has been shown to interact with Prohibitin,[4] CEACAM1,[5] S100A10,[6][7] PCNA,[8] complement Factor H,[9] and a number of viral factors including the HPV16 minor capsid protein L2.[10][11] | https://www.wikidoc.org/index.php/Annexin_A2 | |
890082f2a19643f4500043699282594607cf504e | wikidoc | Annexin A3 | Annexin A3
Annexin A3 is a protein that in humans is encoded by the ANXA3 gene.
It is abnormally expressed in fetuses of both IVF and ICSI, which may contribute to the increase risk of birth defects in these ART.
This gene encodes a member of the annexin family. Members of this calcium-dependent phospholipid-binding protein family play a role in the regulation of cellular growth and in signal transduction pathways. This protein functions in the inhibition of phospholipase A2 and cleavage of inositol 1,2-cyclic phosphate to form inositol 1-phosphate. This protein may also play a role in anti-coagulation. | Annexin A3
Annexin A3 is a protein that in humans is encoded by the ANXA3 gene.[1][2]
It is abnormally expressed in fetuses of both IVF and ICSI, which may contribute to the increase risk of birth defects in these ART.[3]
This gene encodes a member of the annexin family. Members of this calcium-dependent phospholipid-binding protein family play a role in the regulation of cellular growth and in signal transduction pathways. This protein functions in the inhibition of phospholipase A2 and cleavage of inositol 1,2-cyclic phosphate to form inositol 1-phosphate. This protein may also play a role in anti-coagulation.[2] | https://www.wikidoc.org/index.php/Annexin_A3 | |
865439656874442501e45a56de365a2a041bc949 | wikidoc | Annexin A5 | Annexin A5
Annexin A5 (or annexin V) is a cellular protein in the annexin group. In flow cytometry, annexin V is commonly used to detect apoptotic cells by its ability to bind to phosphatidylserine, a marker of apoptosis when it is on the outer leaflet of the plasma membrane. The function of the protein is unknown; however, annexin A5 has been proposed to play a role in the inhibition of blood coagulation by competing for phosphatidylserine binding sites with prothrombin and also to inhibit the activity of phospholipase A1. These properties have been found by in vitro experiments.
# Pathology
Antibodies directed against annexin A5 are found in patients with a disease called the antiphospholipid syndrome (APS), a thrombophilic disease associated with autoantibodies against phospholipid compounds.
Annexin A5 forms a shield around negatively charged phospholipid molecules. The formation of an annexin A5 shield blocks the entry of phospholipids into coagulation (clotting) reactions. In the antiphospholipid antibody syndrome, the formation of the shield is disrupted by antibodies. Without the shield, there is an increased quantity of phospholipid molecules on cell membranes, speeding up coagulation reactions and causing the blood-clotting characteristic of the antiphospholipid antibody syndrome.
Annexin A5 showed upregulation in papillary thyroid carcinoma.
# Laboratory use
Annexin A5 is used as a non-quantitative probe to detect cells that have expressed phosphatidylserine (PS) on the cell surface, an event found in apoptosis as well as other forms of cell death. Platelets also expose PS and PE on their surface when activated, which serves as binding site for various coagulation factors.
The annexin A5 affinity assay typically uses a conjugate of annexin V and a fluorescent or enzymatic label, biotin or other tags, or a radioelement, in a suitable buffer (annexin V binding to aminophospholipids is Ca2+ dependent). The assay combines annexin V staining of PS and PE membrane events with the staining of DNA in the cell nucleus with propidium iodide (PI) or 7-Aminoactinomycin D (AAD-7), distinguishing viable cells from apoptotic cells and necrotic cells. Detection occurs by flow cytometry or a fluorescence microscope.
# Interactions
Annexin A5 has been shown to interact with Kinase insert domain receptor and Integrin, beta 5. | Annexin A5
Annexin A5 (or annexin V) is a cellular protein in the annexin group. In flow cytometry, annexin V is commonly used to detect apoptotic cells by its ability to bind to phosphatidylserine, a marker of apoptosis when it is on the outer leaflet of the plasma membrane. The function of the protein is unknown; however, annexin A5 has been proposed to play a role in the inhibition of blood coagulation by competing for phosphatidylserine binding sites with prothrombin and also to inhibit the activity of phospholipase A1. These properties have been found by in vitro experiments.
# Pathology
Antibodies directed against annexin A5 are found in patients with a disease called the antiphospholipid syndrome (APS), a thrombophilic disease associated with autoantibodies against phospholipid compounds.
Annexin A5 forms a shield around negatively charged phospholipid molecules. The formation of an annexin A5 shield blocks the entry of phospholipids into coagulation (clotting) reactions. In the antiphospholipid antibody syndrome, the formation of the shield is disrupted by antibodies. Without the shield, there is an increased quantity of phospholipid molecules on cell membranes, speeding up coagulation reactions and causing the blood-clotting characteristic of the antiphospholipid antibody syndrome.
Annexin A5 showed upregulation in papillary thyroid carcinoma.[1]
# Laboratory use
Annexin A5 is used as a non-quantitative probe to detect cells that have expressed phosphatidylserine (PS) on the cell surface, an event found in apoptosis as well as other forms of cell death.[2][3][4] Platelets also expose PS and PE on their surface when activated, which serves as binding site for various coagulation factors.
The annexin A5 affinity assay typically uses a conjugate of annexin V and a fluorescent or enzymatic label, biotin or other tags, or a radioelement, in a suitable buffer (annexin V binding to aminophospholipids is Ca2+ dependent). The assay combines annexin V staining of PS and PE membrane events with the staining of DNA in the cell nucleus with propidium iodide (PI) or 7-Aminoactinomycin D (AAD-7), distinguishing viable cells from apoptotic cells and necrotic cells.[5] Detection occurs by flow cytometry or a fluorescence microscope.
# Interactions
Annexin A5 has been shown to interact with Kinase insert domain receptor[6] and Integrin, beta 5.[7] | https://www.wikidoc.org/index.php/Annexin_A5 | |
e3c81a6c49481897c412939dc8a00864bd951bbf | wikidoc | Annexin A6 | Annexin A6
Annexin A6 is a protein that in humans is encoded by the ANXA6 gene.
# Function
Annexin VI belongs to a family of calcium-dependent membrane and phospholipid binding proteins. Although their functions are still not clearly defined, several members of the annexin family have been implicated in membrane-related events along exocytotic and endocytotic pathways. The annexin VI gene is approximately 60 kbp long and contains 26 exons. It encodes a protein of about 68 kDa that consists of eight 68-amino acid repeats separated by linking sequences of variable lengths. It is highly similar to human annexins I and II sequences, each of which contain four such repeats. Exon 21 of annexin VI is alternatively spliced, giving rise to two isoforms that differ by a 6-amino acid insertion at the start of the seventh repeat. Annexin VI has been implicated in mediating the endosome aggregation and vesicle fusion in secreting epithelia during exocytosis.
# Model organisms
Model organisms have been used in the study of ANXA6 function. A conditional knockout mouse line, called Anxa6tm1a(EUCOMM)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the Wellcome Trust Sanger Institute.
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty six tests were carried out on mutant mice and one significant abnormality was observed: female homozygous mutant animals had an increased susceptibility to Citrobacter infection.
# Interactions
ANXA6 has been shown to interact with RAS p21 protein activator 1. | Annexin A6
Annexin A6 is a protein that in humans is encoded by the ANXA6 gene.[1]
# Function
Annexin VI belongs to a family of calcium-dependent membrane and phospholipid binding proteins. Although their functions are still not clearly defined, several members of the annexin family have been implicated in membrane-related events along exocytotic and endocytotic pathways. The annexin VI gene is approximately 60 kbp long and contains 26 exons. It encodes a protein of about 68 kDa that consists of eight 68-amino acid repeats separated by linking sequences of variable lengths. It is highly similar to human annexins I and II sequences, each of which contain four such repeats. Exon 21 of annexin VI is alternatively spliced, giving rise to two isoforms that differ by a 6-amino acid insertion at the start of the seventh repeat. Annexin VI has been implicated in mediating the endosome aggregation and vesicle fusion in secreting epithelia during exocytosis.[2]
# Model organisms
Model organisms have been used in the study of ANXA6 function. A conditional knockout mouse line, called Anxa6tm1a(EUCOMM)Wtsi[9][10] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the Wellcome Trust Sanger Institute.[11][12][13]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[7][14] Twenty six tests were carried out on mutant mice and one significant abnormality was observed: female homozygous mutant animals had an increased susceptibility to Citrobacter infection.[7]
# Interactions
ANXA6 has been shown to interact with RAS p21 protein activator 1.[15] | https://www.wikidoc.org/index.php/Annexin_A6 | |
310e32f8556b3c512066eef9a715b09ed1186112 | wikidoc | Annexin A9 | Annexin A9
Annexin A9 is a protein that in humans is encoded by the ANXA9 gene.
# Function
The annexins are a family of calcium-dependent phospholipid-binding proteins. Members of the annexin family contain 4 internal repeat domains, each of which includes a type II calcium-binding site. The calcium-binding sites are required for annexins to aggregate and cooperatively bind anionic phospholipids and extracellular matrix proteins. This gene encodes a divergent member of the annexin protein family in which all four homologous type II calcium-binding sites in the conserved tetrad core contain amino acid substitutions that ablate their function. However, structural analysis suggests that the conserved putative ion channel formed by the tetrad core is intact.
# Model organisms
Model organisms have been used in the study of ANXA9 function. A conditional knockout mouse line called Anxa9tm1b(EUCOMM)Wtsi was generated at the Wellcome Trust Sanger Institute. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Additional screens performed: - In-depth immunological phenotyping - in-depth bone and cartilage phenotyping | Annexin A9
Annexin A9 is a protein that in humans is encoded by the ANXA9 gene.[1][2][3]
# Function
The annexins are a family of calcium-dependent phospholipid-binding proteins. Members of the annexin family contain 4 internal repeat domains, each of which includes a type II calcium-binding site. The calcium-binding sites are required for annexins to aggregate and cooperatively bind anionic phospholipids and extracellular matrix proteins. This gene encodes a divergent member of the annexin protein family in which all four homologous type II calcium-binding sites in the conserved tetrad core contain amino acid substitutions that ablate their function. However, structural analysis suggests that the conserved putative ion channel formed by the tetrad core is intact.[3]
# Model organisms
Model organisms have been used in the study of ANXA9 function. A conditional knockout mouse line called Anxa9tm1b(EUCOMM)Wtsi was generated at the Wellcome Trust Sanger Institute.[4] Male and female animals underwent a standardized phenotypic screen[5] to determine the effects of deletion.[6][7][8][9] Additional screens performed: - In-depth immunological phenotyping[10] - in-depth bone and cartilage phenotyping[11] | https://www.wikidoc.org/index.php/Annexin_A9 | |
c44bf68236ab5e856dd10571d1ace13489404c5b | wikidoc | Anorgasmia | Anorgasmia
Synonyms and keywords: Female orgasmic disorder
# Overview
Anorgasmia (often related to delayed ejaculation in males) is a form of sexual dysfunction sometimes classified as a psychiatric disorder in which the patient cannot achieve orgasm, even with "adequate" stimulation. However, it can also be caused by medical problems such as diabetic neuropathy, multiple sclerosis, pelvic trauma, hormonal imbalances, total hysterectomy, spinal cord injury and cardiovascular disease. Anorgasmia is far more common in females than in males and is especially rare in younger men.
A common cause of anorgasmia, in both men and women, is the use of anti-depressants, particularly selective serotonin reuptake inhibitors (SSRIs). Though reporting of anorgasmia as a side-effect of SSRIs is not precise, it is estimated that 15-50% of users of such medications are affected by this condition. The chemical amantadine has been shown to relieve SSRI-induced anorgasmia in some, but not all, people.
# Classification
## Primary anorgasmia
Primary anorgasmia is a condition where one has never experienced an orgasm. This is significantly more common in women, although it can occur in men who lack the gladipudendal reflexes.
Women with this condition can sometimes achieve a relatively low level of sexual excitement and may think of intercourse or other sexual activities as pleasant despite their inability to orgasm. They may get most of their reward from touching, holding, kissing, caressing, attention, and approval. However, women who regularly achieve high levels of sexual response without orgasmic release of tension may find the experience frustrating. Emotional irritability, restlessness, and pelvic pain or a heavy pelvic sensation may occur because of vascular engorgement.
Women who have not yet had an orgasm usually have some combination
-f the following:
- Sociocultural inhibitions that interfere with normal sexual response.
- Unresolved feelings towards a traumatic sexual experience as in sexual abuse or rape.
- A lack of knowledge about sex and sexuality, which interferes with normal sexual development.
- A lack of opportunity to practice in a safe, secure, socially acceptable, and a private atmosphere (only two partaking) in a situation that offers approval and support.
- A partner who has primary or secondary difficulty in achieving an erection.
- Dyspareunia, or painful intercourse.
- Genital mutilation ("female circumcision") that removes part or all of the clitoris, scars the genital area, or constricts the opening to the vagina. Often, vaginal intercourse is painful not only because of scarring from this procedure but also because of associated infection.
Often, though, there is no obvious reason why orgasm is unobtainable. Regardless of having a caring, skilled partner, having adequate time and privacy, and having no medical issues which would affect sexual satisfaction, some women are unable to orgasm. This situation is extremely frustrating because with no discernible cause, a plausible solution is difficult to discover.Template:Facts
In many contexts, many people have been able to find effective relief from anorgasmia despite a physical factor through a mental process of conditioning, as such hypnosis can have a positive impact. Primary male anorgasmia is very uncommon, and thus has been studied very little.
## Secondary anorgasmia
Secondary anorgasmia is the loss of the ability to have orgasms. The cause may be alcoholism, depression, grief, pelvic surgery or injuries, certain medications, illness, estrogen deprivation associated with menopause or an event that has violated the patient's sexual value system.
Secondary anorgasmia is close to 50% among males undergoing prostatectomy; 80% among radical prostatectomies. This is a serious adverse result because radical prostatectomies are usually given to younger males who are expected to live more than 10 years. At more advanced ages, the prostate is more unlikely to grow during that person's remaining lifetime. This is generally caused by damage to the primary nerves serving the penile area, which pass near the prostate gland. Removal of the prostate frequently damages or even completely removes these nerves, making sexual response unreasonably difficult.
Due to the existence of these nerves in the prostate, surgeons performing sex reassignment surgery on transsexual male to female patients avoid removing the prostate. This leaves the nerves that will then lead to the newly-formed clitoris, and decreases the chances that the patient will not respond to clitoral stimulation after surgery. Additionally, by leaving the prostate in the patient, the surgeon allows it to be situated close to the wall of the newly-formed vagina, which may potentially increase stimulation during vaginal intercourse after the procedure.
## Situational anorgasmia
Women who are orgasmic in some situations may not be in others. A woman may have an orgasm from one type of stimulation but not from another. Or a woman may achieve orgasm with one partner but not another, or have an orgasm only under certain conditions or only with a certain type or amount of foreplay. These common variations are within the range of normal sexual expression.
Doctors believe that a woman with situational anorgasmia should be encouraged to explore alone and with her partner those factors that may affect whether or not she is orgasmic, such as fatigue, emotional concerns, feeling pressured to have sex when she is not interested, or her partner's sexual dysfunction.
The same doctors believe that family plannings should consider recommending the female-above position for penile-vaginal intercourse, as it may allow for greater stimulation of the clitoris by the penis or symphysis pubis or both, and it allows the woman better control of movement. Bridging is the combining of a successful method for sexual stimulation with a desired technique so that the body learns to associate orgasm with that technique. If, for example, the woman is readily orgasmic with manual stimulation but not with penile-vaginal thrusting, she is encouraged to combine those two regularly until her body has learned to associate high levels of excitement and orgasm with penile-vaginal thrusting.Template:Facts
## Random anorgasmia
Some women are orgasmic but not in enough instances to satisfy their sense of what is appropriate or desirable. Often such women have trouble momentarily giving up control and allowing themselves to respond fully. Therapy can be aimed at helping them give up the need to keep their sexual feelings under control at all times.
# Differential Diagnosis Of Female Orgasmic Disorder
- Other medical condition
- Multiple sclerosis
- Spinal cord injury
- Interpersonal factors
- Intimate partner violence
- Severe relationship distress
- Nonsexual mental disorders
- Other sexual dysfunctions
- Substance/medication-induced sexual dysfunction
# Epidemiology and Demographics Of Female Orgasmic Disorder
## Prevalence
The prevalence of female orgasmic disorder is 10,000-42,000 per 100,000 (10%-42%) in women.
# Risk Factors Of Female Orgasmic Disorder
- Genetic Predisposition
- Multiple sclerosis
- Medical conditions
- Medications
- Mental health
- Physical health
- Psychological factors
- Anxiety
- Concerns about pregnancy
- Pelvic nerve damage
- Relationship problems
- Socioculturalfactors
- spinal cord injury
- Selective serotonin reuptake inhibitors
- Vulvovaginal atrophy
# Diagnostic Criteria
## DSM-V Diagnostic Criteria for Female Orgasmic Disorder
# Treatment
Effective treatment for anorgasmia depends on the cause. In the case of a women suffering from psychological sexual trauma or inhibition, psychosexual counselling might be advisable and could be obtained through GP referral.
Women suffering from anorgasmia with no obvious psychological cause would need to be examined by their GP to check for absence of disease. Blood tests would also need to be done (full blood count, liver function, oestradiol/estradiol, total testosterone, SHBG, FSH/LH, prolactin, thyroid function, lipids and fasting blood sugar) to check for other conditions such as diabetes, lack of ovulation, low thyroid function or hormone imbalances. They would then need to be referred to a consultant specialising in female sexual dysfunction. There are very few such consultants in the UK (their details can be obtained from the Sexual Dysfunction Association).
Just as with erectile dysfunction in men lack of sexual function in women may be treated with hormones to correct imbalances, clitoral vacuum pump devices or medication to improve blood flow and sexual sensation. | Anorgasmia
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2]
Synonyms and keywords: Female orgasmic disorder
# Overview
Anorgasmia (often related to delayed ejaculation in males) is a form of sexual dysfunction sometimes classified as a psychiatric disorder in which the patient cannot achieve orgasm, even with "adequate" stimulation. However, it can also be caused by medical problems such as diabetic neuropathy, multiple sclerosis, pelvic trauma, hormonal imbalances, total hysterectomy, spinal cord injury and cardiovascular disease. Anorgasmia is far more common in females than in males and is especially rare in younger men.
A common cause of anorgasmia, in both men and women, is the use of anti-depressants, particularly selective serotonin reuptake inhibitors (SSRIs). Though reporting of anorgasmia as a side-effect of SSRIs is not precise, it is estimated that 15-50% of users of such medications are affected by this condition[citation needed]. The chemical amantadine has been shown to relieve SSRI-induced anorgasmia in some, but not all, people.
# Classification
## Primary anorgasmia
Primary anorgasmia is a condition where one has never experienced an orgasm. This is significantly more common in women, although it can occur in men who lack the gladipudendal reflexes.
Women with this condition can sometimes achieve a relatively low level of sexual excitement and may think of intercourse or other sexual activities as pleasant despite their inability to orgasm. They may get most of their reward from touching, holding, kissing, caressing, attention, and approval. However, women who regularly achieve high levels of sexual response without orgasmic release of tension may find the experience frustrating. Emotional irritability, restlessness, and pelvic pain or a heavy pelvic sensation may occur because of vascular engorgement.
Women who have not yet had an orgasm usually have some combination
of the following:[citation needed]
- Sociocultural inhibitions that interfere with normal sexual response.
- Unresolved feelings towards a traumatic sexual experience as in sexual abuse or rape.
- A lack of knowledge about sex and sexuality, which interferes with normal sexual development.
- A lack of opportunity to practice in a safe, secure, socially acceptable, and a private atmosphere (only two partaking) in a situation that offers approval and support.
- A partner who has primary or secondary difficulty in achieving an erection.
- Dyspareunia, or painful intercourse.
- Genital mutilation ("female circumcision") that removes part or all of the clitoris, scars the genital area, or constricts the opening to the vagina. Often, vaginal intercourse is painful not only because of scarring from this procedure but also because of associated infection.
Often, though, there is no obvious reason why orgasm is unobtainable. Regardless of having a caring, skilled partner, having adequate time and privacy, and having no medical issues which would affect sexual satisfaction, some women are unable to orgasm. This situation is extremely frustrating because with no discernible cause, a plausible solution is difficult to discover.Template:Facts
In many contexts, many people have been able to find effective relief from anorgasmia despite a physical factor through a mental process of conditioning, as such hypnosis can have a positive impact.[citation needed] Primary male anorgasmia is very uncommon, and thus has been studied very little.[citation needed]
## Secondary anorgasmia
Secondary anorgasmia is the loss of the ability to have orgasms.[dubious – discuss] The cause may be alcoholism, depression, grief, pelvic surgery or injuries, certain medications, illness, estrogen deprivation associated with menopause or an event that has violated the patient's sexual value system.
Secondary anorgasmia is close to 50% among males undergoing prostatectomy;[1] 80% among radical prostatectomies.[2] This is a serious adverse result because radical prostatectomies are usually given to younger males who are expected to live more than 10 years. At more advanced ages, the prostate is more unlikely to grow during that person's remaining lifetime.[3] This is generally caused by damage to the primary nerves serving the penile area, which pass near the prostate gland. Removal of the prostate frequently damages or even completely removes these nerves, making sexual response unreasonably difficult.[4]
Due to the existence of these nerves in the prostate, surgeons performing sex reassignment surgery on transsexual male to female patients avoid removing the prostate. This leaves the nerves that will then lead to the newly-formed clitoris, and decreases the chances that the patient will not respond to clitoral stimulation after surgery. Additionally, by leaving the prostate in the patient, the surgeon allows it to be situated close to the wall of the newly-formed vagina, which may potentially increase stimulation during vaginal intercourse after the procedure.
## Situational anorgasmia
Women who are orgasmic in some situations may not be in others. A woman may have an orgasm from one type of stimulation but not from another. Or a woman may achieve orgasm with one partner but not another, or have an orgasm only under certain conditions or only with a certain type or amount of foreplay. These common variations are within the range of normal sexual expression.
Doctors believe[citation needed] that a woman with situational anorgasmia should be encouraged to explore alone and with her partner those factors that may affect whether or not she is orgasmic, such as fatigue, emotional concerns, feeling pressured to have sex when she is not interested, or her partner's sexual dysfunction.
The same doctors believe[citation needed] that family plannings should consider recommending the female-above position for penile-vaginal intercourse, as it may allow for greater stimulation of the clitoris by the penis or symphysis pubis or both, and it allows the woman better control of movement. Bridging is the combining of a successful method for sexual stimulation with a desired technique so that the body learns to associate orgasm with that technique. If, for example, the woman is readily orgasmic with manual stimulation but not with penile-vaginal thrusting, she is encouraged to combine those two regularly until her body has learned to associate high levels of excitement and orgasm with penile-vaginal thrusting.Template:Facts
## Random anorgasmia
Some women are orgasmic but not in enough instances to satisfy their sense of what is appropriate or desirable. Often such women have trouble momentarily giving up control and allowing themselves to respond fully. Therapy can be aimed at helping them give up the need to keep their sexual feelings under control at all times.
# Differential Diagnosis Of Female Orgasmic Disorder
- Other medical condition
- Multiple sclerosis
- Spinal cord injury
- Interpersonal factors
- Intimate partner violence
- Severe relationship distress
- Nonsexual mental disorders
- Other sexual dysfunctions
- Substance/medication-induced sexual dysfunction[3]
# Epidemiology and Demographics Of Female Orgasmic Disorder
## Prevalence
The prevalence of female orgasmic disorder is 10,000-42,000 per 100,000 (10%-42%) in women.[3]
# Risk Factors Of Female Orgasmic Disorder
- Genetic Predisposition
- Multiple sclerosis
- Medical conditions
- Medications
- Mental health
- Physical health
- Psychological factors
- Anxiety
- Concerns about pregnancy
- Pelvic nerve damage
- Relationship problems
- Socioculturalfactors
- spinal cord injury
- Selective serotonin reuptake inhibitors
- Vulvovaginal atrophy[3]
# Diagnostic Criteria
## DSM-V Diagnostic Criteria for Female Orgasmic Disorder[3]
# Treatment
Effective treatment for anorgasmia depends on the cause. In the case of a women suffering from psychological sexual trauma or inhibition, psychosexual counselling might be advisable and could be obtained through GP referral.
Women suffering from anorgasmia with no obvious psychological cause would need to be examined by their GP to check for absence of disease. Blood tests would also need to be done (full blood count, liver function, oestradiol/estradiol, total testosterone, SHBG, FSH/LH, prolactin, thyroid function, lipids and fasting blood sugar) to check for other conditions such as diabetes, lack of ovulation, low thyroid function or hormone imbalances. They would then need to be referred to a consultant specialising in female sexual dysfunction. There are very few such consultants in the UK (their details can be obtained from the Sexual Dysfunction Association).
Just as with erectile dysfunction in men lack of sexual function in women may be treated with hormones to correct imbalances, clitoral vacuum pump devices or medication to improve blood flow and sexual sensation. | https://www.wikidoc.org/index.php/Anorgasmia | |
c77133857d8470f9d463ac5c858a1fe08132e38a | wikidoc | Disulfiram | Disulfiram
# 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
Disulfiram is an alcohol antagonist that is FDA approved for the treatment of alcoholism. There is a Black Box Warning for this drug as shown here. Common adverse reactions include dermatitis and garlic-like or metallic aftertaste.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Disulfiram is an aid in the management of selected chronic alcohol patients who want to remain in a state of enforced sobriety so that supportive and psychotherapeutic treatment may be applied to best advantage.
- Disulfiram is not a cure for alcoholism. When used alone, without proper motivation and supportive therapy, it is unlikely that it will have any substantive effect on the drinking pattern of the chronic alcoholic.
- Disulfiram should never be administered until the patient has abstained from alcohol for at least 12 hours.
- Initial Dosage Schedule
- In the first phase of treatment, a maximum of 500 mg daily is given in a single dose for one to two weeks. Although usually taken in the morning, disulfiram may be taken on retiring by patients who experience a sedative effect. Alternatively, to minimize, or eliminate, the sedative effect, dosage may be adjusted downward.
- Maintenance Regimen
- The average maintenance dose is 250 mg daily (range, 125 to 500 mg), it should not exceed 500 mg daily.
- Note: Occasionally patients, while seemingly on adequate maintenance doses of disulfiram, report that they are able to drink alcoholic beverages with impunity and without any symptomatology. All appearances to the contrary, such patients must be presumed to be disposing of their tablets in some manner without actually taking them. Until such patients have been observed reliably taking their daily disulfiram tablets (preferably crushed and well mixed with liquid), it cannot be concluded that disulfiram is ineffective.
- Duration of Therapy
- The daily, uninterrupted administration of disulfiram must be continued until the patient is fully recovered socially and a basis for permanent self-control is established. Depending on the individual patient, maintenance therapy may be required for months or even years.
- Trial with Alcohol
- During early experience with disulfiram, it was thought advisable for each patient to have at least one supervised alcohol-drug reaction. More recently, the test reaction has been largely abandoned. Furthermore, such a test reaction should never be administered to a patient over 50 years of age. A clear, detailed and convincing description of the reaction is felt to be sufficient in most cases.
- However, where a test reaction is deemed necessary, the suggested procedure is as follows:
- After the first one to two weeks’ therapy with 500 mg daily, a drink of 15 mL (1/2 oz) of 100 proof whiskey, or equivalent, is taken slowly. This test dose of alcoholic beverage may be repeated once only, so that the total dose does not exceed 30 mL (1 oz) of whiskey. Once a reaction develops, no more alcohol should be consumed. Such tests should be carried out only when the patient is hospitalized, or comparable supervision and facilities, including oxygen, are available.
- Management of Disulfiram-Alcohol Reaction
- In severe reactions, whether caused by an excessive test dose or by the patient’s unsupervised ingestion of alcohol, supportive measures to restore blood pressure and treat shock should be instituted. Other recommendations include: oxygen, carbogen (95% oxygen and 5% carbon dioxide), vitamin C intravenously in massive doses (1 g) and ephedrine sulfate. Antihistamines have also been used intravenously. Potassium levels should be monitored, particularly in patients on digitalis, since hypokalemia has been reported.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Disulfiram in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Disulfiram in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Disulfiram in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Disulfiram in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Disulfiram in pediatric patients.
# Contraindications
- Patients who are receiving or have recently received metronidazole, paraldehyde, alcohol, or alcohol-containing preparations, e.g., cough syrups, tonics and the like, should not be given disulfiram.
- Disulfiram is contraindicated in the presence of severe myocardial disease or coronary occlusion, psychoses, and hypersensitivity to disulfiram or to other thiuram derivatives used in pesticides and rubber vulcanization.
# Warnings
- The Disulfiram-Alcohol Reaction
- Disulfiram plus alcohol, even small amounts, produce flushing, throbbing in head and neck, throbbing headache, respiratory difficulty, nausea, copious vomiting, sweating, thirst, chest pain, palpitation, dyspnea, hyperventilation, tachycardia, hypotension, syncope, marked uneasiness, weakness, vertigo, blurred vision, and confusion. In severe reactions there may be respiratory depression, cardiovascular collapse, arrhythmias, myocardial infarction, acute congestive heart failure, unconsciousness, convulsions, and death.
- The intensity of the reaction varies with each individual, but is generally proportional to the amounts of disulfiram and alcohol ingested. Mild reactions may occur in the sensitive individual when the blood alcohol concentration is increased to as little as 5 to 10 mg per 100 mL. Symptoms are fully developed at 50 mg per 100 mL, and unconsciousness usually results when the blood alcohol level reaches 125 to 150 mg.
- The duration of the reaction varies from 30 to 60 minutes, to several hours in the more severe cases, or as long as there is alcohol in the blood.
- Concomitant Conditions
- Because of the possibility of an accidental disulfiram-alcohol reaction, disulfiram should be used with extreme caution in patients with any of the following conditions: diabetes mellitus, hypothyroidism, epilepsy, cerebral damage, chronic and acute nephritis, hepatic cirrhosis or insufficiency.
- The patient must be fully informed of the disulfiram-alcohol reaction. He must be strongly cautioned against surreptitious drinking while taking the drug, and he must be fully aware of the possible consequences. He should be warned to avoid alcohol in disguised forms, i.e., in sauces, vinegars, cough mixtures, and even in aftershave lotions and back rubs. He should also be warned that reactions may occur with alcohol up to 14 days after ingesting disulfiram.
### Precautions
- Patients with a history of rubber contact dermatitis should be evaluated for hypersensitivity to thiuram derivatives before receiving disulfiram.
- Alcoholism may accompany or be followed by dependence on narcotics or sedatives. Barbiturates and disulfiram have been administered concurrently without untoward effects; the possibility of initiating a new abuse should be considered.
- Hepatic toxicity including hepatic failure resulting in transplantation or death have been reported. Severe and sometimes fatal hepatitis associated with disulfiram therapy may develop even after many months of therapy. Hepatic toxicity has occurred in patients with or without prior history of abnormal liver function. Patients should be advised to immediately notify their physician of any early symptoms of hepatitis, such as fatigue, weakness, malaise, anorexia, nausea, vomiting, jaundice, or dark urine.
- Baseline and follow-up liver function tests (10 to 14 days) are suggested to detect any hepatic dysfunction that may result with disulfiram therapy. In addition, a complete blood count and serum chemistries, including liver function tests, should be monitored.
- Patients taking disulfiram tablets should not be exposed to ethylene dibromide or its vapors. This precaution is based on preliminary results of animal research currently in progress that suggest a toxic interaction between inhaled ethylene dibromide and ingested disulfiram resulting in a higher incidence of tumors and mortality in rats. A correlation between this finding and humans, however, has not been demonstrated.
# Adverse Reactions
## Clinical Trials Experience
- Optic neuritis, peripheral neuritis, polyneuritis, and peripheral neuropathy may occur following administration of disulfiram.
- Multiple cases of hepatitis, including both cholestatic and fulminant hepatitis, as well as hepatic failure resulting in transplantation or death, have been reported with administration of disulfiram.
- Occasional skin eruptions are, as a rule, readily controlled by concomitant administration of an antihistaminic drug.
- In a small number of patients, a transient mild drowsiness, fatigability, impotence, headache, acneform eruptions, allergic dermatitis, or a metallic or garlic-like aftertaste may be experienced during the first two weeks of therapy. These complaints usually disappear spontaneously with the continuation of therapy, or with reduced dosage.
- Psychotic reactions have been noted, attributable in most cases to high dosage, combined toxicity (with metronidazole or isoniazid), or to the unmasking of underlying psychoses in patients stressed by the withdrawal of alcohol.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Disulfiram in the drug label.
# Drug Interactions
- Disulfiram appears to decrease the rate at which certain drugs are metabolized and therefore may increase the blood levels and the possibility of clinical toxicity of drugs given concomitantly.
- Disulfiram should be used with caution in those patients receiving phenytoin and its congeners, since the concomitant administration of these two drugs can lead to phenytoin intoxication. Prior to administering disulfiram to a patient on phenytoin therapy, a baseline phenytoin serum level should be obtained. Subsequent to initiation of disulfiram therapy, serum levels of phenytoin should be determined on different days for evidence of an increase or for a continuing rise in levels. Increased phenytoin levels should be treated with appropriate dosage adjustment.
- It may be necessary to adjust the dosage of oral anticoagulants upon beginning or stopping disulfiram, since disulfiram may prolong prothrombin time.
- Patients taking isoniazid when disulfiram is given should be observed for the appearance of unsteady gait or marked changes in mental status, the disulfiram should be discontinued if such signs appear.
- In rats, simultaneous ingestion of disulfiram and nitrite in the diet for 78 weeks has been reported to cause tumors, and it has been suggested that disulfiram may react with nitrites in the rat stomach to form a nitrosamine, which is tumorigenic. Disulfiram alone in the rat’s diet did not lead to such tumors. The relevance of this finding to humans is not known at this time.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category
- The safe use of this drug in pregnancy has not been established. Therefore, disulfiram should be used during pregnancy only when, in the judgement of the physician, the probable benefits outweigh the possible risks.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Disulfiram in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Disulfiram during labor and delivery.
### Nursing Mothers
- It is not known whether this drug is excreted in human milk. Since many drugs are so excreted, disulfiram should not be given to nursing mothers.
### Pediatric Use
- Safety and effectiveness in pediatric patients have not been established.
### Geriatic Use
- A determination has not been made whether controlled clinical studies of disulfiram included sufficient numbers of subjects aged 65 and over to define a difference in response 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 Disulfiram with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Disulfiram with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Disulfiram in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Disulfiram in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Disulfiram in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Disulfiram in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- Baseline and follow-up liver function tests (10 to 14 days) are suggested to detect any hepatic dysfunction that may result with disulfiram therapy. In addition, a complete blood count and serum chemistries, including liver function tests, should be monitored.
# IV Compatibility
There is limited information regarding IV Compatibility of Disulfiram in the drug label.
# Overdosage
## Chronic Overdose
There is limited information regarding Chronic Overdose of Disulfiram in the drug label.
# Pharmacology
## Mechanism of Action
- Disulfiram produces a sensitivity to alcohol which results in a highly unpleasant reaction when the patient under treatment ingests even small amounts of alcohol.
- Disulfiram blocks the oxidation of alcohol at the acetaldehyde stage. During alcohol metabolism following disulfiram intake, the concentration of acetaldehyde occurring in the blood may be 5 to 10 times higher than that found during metabolism of the same amount of alcohol alone.
- Accumulation of acetaldehyde in the blood produces a complex of highly unpleasant symptoms referred to hereinafter as the disulfiram-alcohol reaction. This reaction, which is proportional to the dosage of both disulfiram and alcohol, will persist as long as alcohol is being metabolized. Disulfiram does not appear to influence the rate of alcohol elimination from the body.
## Structure
- Disulfiram, USP is an alcohol antagonist drug.
- Chemical name
- bis(diethylthiocarbamoyl) disulfide.
- Structural Formula
- Disulfiram, USP occurs as a white to off-white, odorless, and almost tasteless powder, soluble in water to the extent of about 20 mg in 100 mL, and in alcohol to the extent of about 3.8 g in 100 mL.
- Each tablet for oral administration contains 250 mg or 500 mg disulfiram, USP. Tablets also contain colloidal silicon dioxide, lactose anhydrous, magnesium stearate, microcrystalline cellulose, sodium starch glycolate, and stearic acid
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Disulfiram in the drug label.
## Pharmacokinetics
- Disulfiram is absorbed slowly from the gastrointestinal tract and is eliminated slowly from the body. One (or even two) weeks after a patient has taken his last dose of disulfiram, ingestion of alcohol may produce unpleasant symptoms.
- Prolonged administration of disulfiram does not produce tolerance; the longer a patient remains on therapy, the more exquisitely sensitive he becomes to alcohol.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Disulfiram in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Disulfiram in the drug label.
# How Supplied
- Disulfiram Tablets USP
- 250 mg:
- White, round, unscored, biconvex tablets, debossed with “OP” over “706” on one side and plain on the other side.
- Available in bottles of 100 tablets.
- 500 mg:
- White, round, scored tablets, debossed with “OP” over “707” on one side and scored on the other side.
- Available in bottles of 100 tablets.
- Store at 20° to 25°C (68° to 77°F).
- Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).
- KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN.
## Storage
There is limited information regarding Disulfiram 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 Disulfiram in the drug label.
# Precautions with Alcohol
- Disulfiram produces a sensitivity to alcohol which results in a highly unpleasant reaction when the patient under treatment ingests even small amounts of alcohol.
# Brand Names
- ANTABUSE®
# Look-Alike Drug Names
There is limited information regarding Disulfiram Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Disulfiram
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Black Box Warning
# Overview
Disulfiram is an alcohol antagonist that is FDA approved for the treatment of alcoholism. There is a Black Box Warning for this drug as shown here. Common adverse reactions include dermatitis and garlic-like or metallic aftertaste.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Disulfiram is an aid in the management of selected chronic alcohol patients who want to remain in a state of enforced sobriety so that supportive and psychotherapeutic treatment may be applied to best advantage.
- Disulfiram is not a cure for alcoholism. When used alone, without proper motivation and supportive therapy, it is unlikely that it will have any substantive effect on the drinking pattern of the chronic alcoholic.
- Disulfiram should never be administered until the patient has abstained from alcohol for at least 12 hours.
- Initial Dosage Schedule
- In the first phase of treatment, a maximum of 500 mg daily is given in a single dose for one to two weeks. Although usually taken in the morning, disulfiram may be taken on retiring by patients who experience a sedative effect. Alternatively, to minimize, or eliminate, the sedative effect, dosage may be adjusted downward.
- Maintenance Regimen
- The average maintenance dose is 250 mg daily (range, 125 to 500 mg), it should not exceed 500 mg daily.
- Note: Occasionally patients, while seemingly on adequate maintenance doses of disulfiram, report that they are able to drink alcoholic beverages with impunity and without any symptomatology. All appearances to the contrary, such patients must be presumed to be disposing of their tablets in some manner without actually taking them. Until such patients have been observed reliably taking their daily disulfiram tablets (preferably crushed and well mixed with liquid), it cannot be concluded that disulfiram is ineffective.
- Duration of Therapy
- The daily, uninterrupted administration of disulfiram must be continued until the patient is fully recovered socially and a basis for permanent self-control is established. Depending on the individual patient, maintenance therapy may be required for months or even years.
- Trial with Alcohol
- During early experience with disulfiram, it was thought advisable for each patient to have at least one supervised alcohol-drug reaction. More recently, the test reaction has been largely abandoned. Furthermore, such a test reaction should never be administered to a patient over 50 years of age. A clear, detailed and convincing description of the reaction is felt to be sufficient in most cases.
- However, where a test reaction is deemed necessary, the suggested procedure is as follows:
- After the first one to two weeks’ therapy with 500 mg daily, a drink of 15 mL (1/2 oz) of 100 proof whiskey, or equivalent, is taken slowly. This test dose of alcoholic beverage may be repeated once only, so that the total dose does not exceed 30 mL (1 oz) of whiskey. Once a reaction develops, no more alcohol should be consumed. Such tests should be carried out only when the patient is hospitalized, or comparable supervision and facilities, including oxygen, are available.
- Management of Disulfiram-Alcohol Reaction
- In severe reactions, whether caused by an excessive test dose or by the patient’s unsupervised ingestion of alcohol, supportive measures to restore blood pressure and treat shock should be instituted. Other recommendations include: oxygen, carbogen (95% oxygen and 5% carbon dioxide), vitamin C intravenously in massive doses (1 g) and ephedrine sulfate. Antihistamines have also been used intravenously. Potassium levels should be monitored, particularly in patients on digitalis, since hypokalemia has been reported.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Disulfiram in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Disulfiram in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Disulfiram in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Disulfiram in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Disulfiram in pediatric patients.
# Contraindications
- Patients who are receiving or have recently received metronidazole, paraldehyde, alcohol, or alcohol-containing preparations, e.g., cough syrups, tonics and the like, should not be given disulfiram.
- Disulfiram is contraindicated in the presence of severe myocardial disease or coronary occlusion, psychoses, and hypersensitivity to disulfiram or to other thiuram derivatives used in pesticides and rubber vulcanization.
# Warnings
- The Disulfiram-Alcohol Reaction
- Disulfiram plus alcohol, even small amounts, produce flushing, throbbing in head and neck, throbbing headache, respiratory difficulty, nausea, copious vomiting, sweating, thirst, chest pain, palpitation, dyspnea, hyperventilation, tachycardia, hypotension, syncope, marked uneasiness, weakness, vertigo, blurred vision, and confusion. In severe reactions there may be respiratory depression, cardiovascular collapse, arrhythmias, myocardial infarction, acute congestive heart failure, unconsciousness, convulsions, and death.
- The intensity of the reaction varies with each individual, but is generally proportional to the amounts of disulfiram and alcohol ingested. Mild reactions may occur in the sensitive individual when the blood alcohol concentration is increased to as little as 5 to 10 mg per 100 mL. Symptoms are fully developed at 50 mg per 100 mL, and unconsciousness usually results when the blood alcohol level reaches 125 to 150 mg.
- The duration of the reaction varies from 30 to 60 minutes, to several hours in the more severe cases, or as long as there is alcohol in the blood.
- Concomitant Conditions
- Because of the possibility of an accidental disulfiram-alcohol reaction, disulfiram should be used with extreme caution in patients with any of the following conditions: diabetes mellitus, hypothyroidism, epilepsy, cerebral damage, chronic and acute nephritis, hepatic cirrhosis or insufficiency.
- The patient must be fully informed of the disulfiram-alcohol reaction. He must be strongly cautioned against surreptitious drinking while taking the drug, and he must be fully aware of the possible consequences. He should be warned to avoid alcohol in disguised forms, i.e., in sauces, vinegars, cough mixtures, and even in aftershave lotions and back rubs. He should also be warned that reactions may occur with alcohol up to 14 days after ingesting disulfiram.
### Precautions
- Patients with a history of rubber contact dermatitis should be evaluated for hypersensitivity to thiuram derivatives before receiving disulfiram.
- Alcoholism may accompany or be followed by dependence on narcotics or sedatives. Barbiturates and disulfiram have been administered concurrently without untoward effects; the possibility of initiating a new abuse should be considered.
- Hepatic toxicity including hepatic failure resulting in transplantation or death have been reported. Severe and sometimes fatal hepatitis associated with disulfiram therapy may develop even after many months of therapy. Hepatic toxicity has occurred in patients with or without prior history of abnormal liver function. Patients should be advised to immediately notify their physician of any early symptoms of hepatitis, such as fatigue, weakness, malaise, anorexia, nausea, vomiting, jaundice, or dark urine.
- Baseline and follow-up liver function tests (10 to 14 days) are suggested to detect any hepatic dysfunction that may result with disulfiram therapy. In addition, a complete blood count and serum chemistries, including liver function tests, should be monitored.
- Patients taking disulfiram tablets should not be exposed to ethylene dibromide or its vapors. This precaution is based on preliminary results of animal research currently in progress that suggest a toxic interaction between inhaled ethylene dibromide and ingested disulfiram resulting in a higher incidence of tumors and mortality in rats. A correlation between this finding and humans, however, has not been demonstrated.
# Adverse Reactions
## Clinical Trials Experience
- Optic neuritis, peripheral neuritis, polyneuritis, and peripheral neuropathy may occur following administration of disulfiram.
- Multiple cases of hepatitis, including both cholestatic and fulminant hepatitis, as well as hepatic failure resulting in transplantation or death, have been reported with administration of disulfiram.
- Occasional skin eruptions are, as a rule, readily controlled by concomitant administration of an antihistaminic drug.
- In a small number of patients, a transient mild drowsiness, fatigability, impotence, headache, acneform eruptions, allergic dermatitis, or a metallic or garlic-like aftertaste may be experienced during the first two weeks of therapy. These complaints usually disappear spontaneously with the continuation of therapy, or with reduced dosage.
- Psychotic reactions have been noted, attributable in most cases to high dosage, combined toxicity (with metronidazole or isoniazid), or to the unmasking of underlying psychoses in patients stressed by the withdrawal of alcohol.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Disulfiram in the drug label.
# Drug Interactions
- Disulfiram appears to decrease the rate at which certain drugs are metabolized and therefore may increase the blood levels and the possibility of clinical toxicity of drugs given concomitantly.
- Disulfiram should be used with caution in those patients receiving phenytoin and its congeners, since the concomitant administration of these two drugs can lead to phenytoin intoxication. Prior to administering disulfiram to a patient on phenytoin therapy, a baseline phenytoin serum level should be obtained. Subsequent to initiation of disulfiram therapy, serum levels of phenytoin should be determined on different days for evidence of an increase or for a continuing rise in levels. Increased phenytoin levels should be treated with appropriate dosage adjustment.
- It may be necessary to adjust the dosage of oral anticoagulants upon beginning or stopping disulfiram, since disulfiram may prolong prothrombin time.
- Patients taking isoniazid when disulfiram is given should be observed for the appearance of unsteady gait or marked changes in mental status, the disulfiram should be discontinued if such signs appear.
- In rats, simultaneous ingestion of disulfiram and nitrite in the diet for 78 weeks has been reported to cause tumors, and it has been suggested that disulfiram may react with nitrites in the rat stomach to form a nitrosamine, which is tumorigenic. Disulfiram alone in the rat’s diet did not lead to such tumors. The relevance of this finding to humans is not known at this time.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category
- The safe use of this drug in pregnancy has not been established. Therefore, disulfiram should be used during pregnancy only when, in the judgement of the physician, the probable benefits outweigh the possible risks.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Disulfiram in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Disulfiram during labor and delivery.
### Nursing Mothers
- It is not known whether this drug is excreted in human milk. Since many drugs are so excreted, disulfiram should not be given to nursing mothers.
### Pediatric Use
- Safety and effectiveness in pediatric patients have not been established.
### Geriatic Use
- A determination has not been made whether controlled clinical studies of disulfiram included sufficient numbers of subjects aged 65 and over to define a difference in response 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 Disulfiram with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Disulfiram with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Disulfiram in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Disulfiram in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Disulfiram in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Disulfiram in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- Baseline and follow-up liver function tests (10 to 14 days) are suggested to detect any hepatic dysfunction that may result with disulfiram therapy. In addition, a complete blood count and serum chemistries, including liver function tests, should be monitored.
# IV Compatibility
There is limited information regarding IV Compatibility of Disulfiram in the drug label.
# Overdosage
## Chronic Overdose
There is limited information regarding Chronic Overdose of Disulfiram in the drug label.
# Pharmacology
## Mechanism of Action
- Disulfiram produces a sensitivity to alcohol which results in a highly unpleasant reaction when the patient under treatment ingests even small amounts of alcohol.
- Disulfiram blocks the oxidation of alcohol at the acetaldehyde stage. During alcohol metabolism following disulfiram intake, the concentration of acetaldehyde occurring in the blood may be 5 to 10 times higher than that found during metabolism of the same amount of alcohol alone.
- Accumulation of acetaldehyde in the blood produces a complex of highly unpleasant symptoms referred to hereinafter as the disulfiram-alcohol reaction. This reaction, which is proportional to the dosage of both disulfiram and alcohol, will persist as long as alcohol is being metabolized. Disulfiram does not appear to influence the rate of alcohol elimination from the body.
## Structure
- Disulfiram, USP is an alcohol antagonist drug.
- Chemical name
- bis(diethylthiocarbamoyl) disulfide.
- Structural Formula
- Disulfiram, USP occurs as a white to off-white, odorless, and almost tasteless powder, soluble in water to the extent of about 20 mg in 100 mL, and in alcohol to the extent of about 3.8 g in 100 mL.
- Each tablet for oral administration contains 250 mg or 500 mg disulfiram, USP. Tablets also contain colloidal silicon dioxide, lactose anhydrous, magnesium stearate, microcrystalline cellulose, sodium starch glycolate, and stearic acid
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Disulfiram in the drug label.
## Pharmacokinetics
- Disulfiram is absorbed slowly from the gastrointestinal tract and is eliminated slowly from the body. One (or even two) weeks after a patient has taken his last dose of disulfiram, ingestion of alcohol may produce unpleasant symptoms.
- Prolonged administration of disulfiram does not produce tolerance; the longer a patient remains on therapy, the more exquisitely sensitive he becomes to alcohol.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Disulfiram in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Disulfiram in the drug label.
# How Supplied
- Disulfiram Tablets USP
- 250 mg:
- White, round, unscored, biconvex tablets, debossed with “OP” over “706” on one side and plain on the other side.
- Available in bottles of 100 tablets.
- 500 mg:
- White, round, scored tablets, debossed with “OP” over “707” on one side and scored on the other side.
- Available in bottles of 100 tablets.
- Store at 20° to 25°C (68° to 77°F).
- Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).
- KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN.
## Storage
There is limited information regarding Disulfiram 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 Disulfiram in the drug label.
# Precautions with Alcohol
- Disulfiram produces a sensitivity to alcohol which results in a highly unpleasant reaction when the patient under treatment ingests even small amounts of alcohol.
# Brand Names
- ANTABUSE®[1]
# Look-Alike Drug Names
There is limited information regarding Disulfiram Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Antabuse | |
81def7a1cac6d84353a435d45f00707eacc019c7 | wikidoc | Antalarmin | Antalarmin
# Overview
Antalarmin is a drug which acts as a CRF-1 antagonist.
Corticotropin releasing factor (CRF), also known as Corticotropin releasing hormone, is an endogenous peptide hormone which is released in response to various triggers such as chronic stress and drug addiction. This then triggers the release of corticotropin (ACTH), another hormone which is involved in the physiological response to stress. Chronic release of CRF and ACTH is believed to be directly or indirectly involved in many of the harmful physiological effects of chronic stress, such as excessive glucocorticoid release, stomach ulcers, anxiety, depression, and development of high blood pressure and consequent cardiovascular problems.
Antalarmin is a non-peptide drug which blocks the CRF-1 receptor, and consequently reduces the release of ACTH in response to chronic stress. This has been demonstrated in animals to reduce the behavioural responses to stressful situations, and it is proposed that antalarmin itself, or more likely newer CRF antagonist drugs still under development, could be useful for reducing the adverse health consequences of chronic stress in humans, as well as having possible uses in the treatment of conditions such as anxiety, depression and drug addiction.
Results so far have had limited success, with various CRF antagonists being tested, which showed some antidepressant effects, but failed to produce an effect comparable with conventional antidepressant drugs. However more positive results were seen when antalarmin was combined with an SSRI antidepressant, suggesting a potential for synergistic effect. Encouraging results have also been observed using antalarmin as a potential treatment for anxiety and stress-induced hypertension.
Chronic antalarmin treatment also showed antiinflammatory effects and has been suggested as having potential uses in the treatment of inflammatory conditions such as arthritis, as well as stress-induced gastrointestinal ulcers and irritable bowel syndrome.
Mixed results have been seen in research into the use of antalarmin and other CRF-1 antagonists in the treatment of drug addiction disorders. Tests of antalarmin on cocaine use in cocaine-addicted monkeys produced only slight reductions of use that were not statistically significant, however in tests on cocaine-addicted rats, antalarmin did prevent dose escalation with prolonged use, suggesting that it might stabilise cocaine use and prevent it increasing over time, although without consistently reducing it.
Antalarmin also showed positive effects in reducing withdrawal syndrome from chronic opioid use, and significantly reduced self-administration of ethanol in ethanol-addicted rodents.
# See Also
- Pexacerfont
- Corticotropin releasing hormone antagonist | Antalarmin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Antalarmin is a drug which acts as a CRF-1 antagonist.
Corticotropin releasing factor (CRF), also known as Corticotropin releasing hormone, is an endogenous peptide hormone which is released in response to various triggers such as chronic stress and drug addiction. This then triggers the release of corticotropin (ACTH), another hormone which is involved in the physiological response to stress. Chronic release of CRF and ACTH is believed to be directly or indirectly involved in many of the harmful physiological effects of chronic stress, such as excessive glucocorticoid release, stomach ulcers, anxiety, depression, and development of high blood pressure and consequent cardiovascular problems.[1]
Antalarmin is a non-peptide drug which blocks the CRF-1 receptor, and consequently reduces the release of ACTH in response to chronic stress.[2] This has been demonstrated in animals to reduce the behavioural responses to stressful situations,[3] and it is proposed that antalarmin itself, or more likely newer CRF antagonist drugs still under development,[4] could be useful for reducing the adverse health consequences of chronic stress in humans, as well as having possible uses in the treatment of conditions such as anxiety, depression and drug addiction.[5]
Results so far have had limited success, with various CRF antagonists being tested, which showed some antidepressant effects, but failed to produce an effect comparable with conventional antidepressant drugs.[6] However more positive results were seen when antalarmin was combined with an SSRI antidepressant, suggesting a potential for synergistic effect.[7] Encouraging results have also been observed using antalarmin as a potential treatment for anxiety[8][9] and stress-induced hypertension.[10]
Chronic antalarmin treatment also showed antiinflammatory effects and has been suggested as having potential uses in the treatment of inflammatory conditions such as arthritis,[11] as well as stress-induced gastrointestinal ulcers[12] and irritable bowel syndrome.[13][14]
Mixed results have been seen in research into the use of antalarmin and other CRF-1 antagonists in the treatment of drug addiction disorders. Tests of antalarmin on cocaine use in cocaine-addicted monkeys produced only slight reductions of use that were not statistically significant,[15] however in tests on cocaine-addicted rats, antalarmin did prevent dose escalation with prolonged use, suggesting that it might stabilise cocaine use and prevent it increasing over time, although without consistently reducing it.[16]
Antalarmin also showed positive effects in reducing withdrawal syndrome from chronic opioid use,[17] and significantly reduced self-administration of ethanol in ethanol-addicted rodents.[18][19][20]
# See Also
- Pexacerfont
- Corticotropin releasing hormone antagonist
# External Links
Tox Battery Prepares Antalarmin for Clin Trials | https://www.wikidoc.org/index.php/Antalarmin | |
11fbfcbffaefa0e59042c32e7e3783202db7a2e1 | wikidoc | Clonazepam | Clonazepam
# 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
Clonazepam is a benzodiazepine that is FDA approved for the treatment of lennox-gastaut syndrome, (petit mal variant), akinetic and myoclonic seizures, panic disorder, with or without agoraphobia. Common adverse reactions include ataxia, coordination problem, dizziness, somnolence, behavior problem, upper respiratory infection, fatigue.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Seizure Disorders
- Dosing information
- Adults
- Initial dose: not exceed 1.5 mg PO tid. Dosage may be increased in increments of 0.5 mg to 1 mg every 3 days until seizures are adequately controlled or until side effects preclude any further increase. Maintenance dosage must be individualized for each patient depending upon response. Maximum recommended daily dose is 20 mg.
- The use of multiple anticonvulsants may result in an increase of depressant adverse effects. This should be considered before adding clonazepam tablets to an existing anticonvulsant regimen.
- Geriatric Patients
- There is no clinical trial experience with clonazepam tablets in seizure disorder patients 65 years of age and older. In general, elderly patients should be started on low doses of clonazepam tablets and observed closely
### Panic disorder
- Dosing införmation
- Adults
- Initial dose: 0.25 mg bid. An increase to the target dose for most patients of 1 mg/day may be made after 3 days.
- Recommended dose: 1 mg/day is based on the results from a fixed dose study in which the optimal effect was seen at 1 mg/day. Higher doses of 2 mg/day, 3 mg/day and 4 mg/day in that study were less effective than the 1 mg/day dose and were associated with more adverse effects.
- Maximum dosage: 4 mg/day, and in those instances, the dose may be increased in increments of 0.125 mg to 0.25 mg bid every 3 days until panic disorder is controlled or until side effects make further increases undesired. To reduce the inconvenience of somnolence, administration of one dose at bedtime may be desirable.
- Treatment should be discontinued gradually, with a decrease of 0.125 mg bid every 3 days, until the drug is completely withdrawn.
- There is no body of evidence available to answer the question of how long the patient treated with clonazepam should remain on it. Therefore, the physician who elects to use clonazepam tablets for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient.
- Geriatric Patients
- There is no clinical trial experience with clonazepam tablets in panic disorder patients 65 years of age and older. In general, elderly patients should be started on low doses of clonazepam tablets and observed closely.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of clonazepam in adult patients.
### Non–Guideline-Supported Use
### Restless Leg Syndrome
- Dosing information
- 0.5 to 2 mg at bedtime
### Sleep Walking Disorder
- Dosing information
- 0.25 to 2 mg at bedtime
### Social Phobia
- Dosing information
- 1 to 2.5 mg daily
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
### Seizure Disorder
- Dosing information
- Lonazepam tablets are administered orally. In order to minimize drowsiness, the initial dose for infants and children (up to 10 years of age or 30 kg of body weight) should be between 0.01 mg/kg/day and 0.03 mg/kg/day but not to exceed 0.05 mg/kg/day given in two or three divided doses. Dosage should be increased by no more than 0.25 mg to 0.5 mg every third day until a daily maintenance dose of 0.1 mg/kg to 0.2 mg/kg of body weight has been reached, unless seizures are controlled or side effects preclude further increase. Whenever possible, the daily dose should be divided into three equal doses. If doses are not equally divided, the largest dose should be given before retiring.
### Panic Disorder
- Dosing information
- There is no clinical trial experience with clonazepam tablets in panic disorder patients under 18 years of age.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of clonazepam in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of clonazepam in pediatric patients.
# Contraindications
Clonazepam should not be used in patients with a history of sensitivity to benzodiazepines, nor in patients with clinical or biochemical evidence of significant liver disease. It may be used in patients with open angle glaucoma who are receiving appropriate therapy but is contraindicated in acute narrow angle glaucoma.
# Warnings
Interference with Cognitive and Motor Performance
Since clonazepam produces CNS depression, patients receiving this drug should be cautioned against engaging in hazardous occupations requiring mental alertness, such as operating machinery or driving a motor vehicle. They should also be warned about the concomitant use of alcohol or other CNS-depressant drugs during clonazepam therapy.
Suicidal Behavior and Ideation
Antiepileptic drugs (AEDs), including clonazepam, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43% compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.
The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed.
Table 1 shows absolute and relative risk by indication for all evaluated AEDs.
The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.
Anyone considering prescribing clonazepam or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.
### Pregnancy Risks
Data from several sources raise concerns about the use of clonazepam during pregnancy.
Animal Findings
In three studies in which clonazepam was administered orally to pregnant rabbits at doses of 0.2 mg/kg/day, 1 mg/kg/day, 5 mg/kg/day or 10 mg/kg/day (low dose approximately 0.2 times the maximum recommended human dose of 20 mg/day for seizure disorders and equivalent to the maximum dose of 4 mg/day for panic disorder, on a mg/m2 basis) during the period of organogenesis, a similar pattern of malformations (cleft palate, open eyelid, fused sternebrae and limb defects) was observed in a low, non-dose-related incidence in exposed litters from all dosage groups. Reductions in maternal weight gain occurred at dosages of 5 mg/kg/day or greater and reduction in embryo-fetal growth occurred in one study at a dosage of 10 mg/kg/day. No adverse maternal or embryo-fetal effects were observed in mice and rats following administration during organogenesis of oral doses up to 15 mg/kg/day or 40 mg/kg/day, respectively (4 and 20 times the maximum recommended human dose of 20 mg/day for seizure disorders and 20 and 100 times the maximum dose of 4 mg/day for panic disorder, respectively, on a mg/m2 basis).
General Concerns and Considerations about Anticonvulsants
Recent reports suggest an association between the use of anticonvulsant drugs by women with epilepsy and an elevated incidence of birth defects in children born to these women. Data are more extensive with respect to diphenylhydantoin and phenobarbital, but these are also the most commonly prescribed anticonvulsants; less systematic or anecdotal reports suggest a possible similar association with the use of all known anticonvulsant drugs.
In children of women treated with drugs for epilepsy, reports suggesting an elevated incidence of birth defects cannot be regarded as adequate to prove a definite cause and effect relationship. There are intrinsic methodologic problems in obtaining adequate data on drug teratogenicity in humans; the possibility also exists that other factors, (e.g., genetic factors or the epileptic condition itself), may be more important than drug therapy in leading to birth defects. The great majority of mothers on anticonvulsant medication deliver normal infants. It is important to note that anticonvulsant drugs should not be discontinued in patients in whom the drug is administered to prevent seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life. In individual cases where the severity and frequency of the seizure disorder are such that the removal of medication does not pose a serious threat to the patient, discontinuation of the drug may be considered prior to and during pregnancy; however, it cannot be said with any confidence that even mild seizures do not pose some hazards to the developing embryo or fetus.
General Concerns about Benzodiazepines
An increased risk of congenital malformations associated with the use of benzodiazepine drugs has been suggested in several studies.
There may also be non-teratogenic risks associated with the use of benzodiazepines during pregnancy. There have been reports of neonatal flaccidity, respiratory and feeding difficulties, and hypothermia in children born to mothers who have been receiving benzodiazepines late in pregnancy. In addition, children born to mothers receiving benzodiazepines late in pregnancy may be at some risk of experiencing withdrawal symptoms during the postnatal period.
Advice Regarding the use of Clonazepam in Women of Childbearing Potential
In general, the use of clonazepam in women of childbearing potential, and more specifically during known pregnancy, should be considered only when the clinical situation warrants the risk to the fetus.
The specific considerations addressed above regarding the use of anticonvulsants for epilepsy in women of childbearing potential should be weighed in treating or counseling these women.
Because of experience with other members of the benzodiazepine class, clonazepam is assumed to be capable of causing an increased risk of congenital abnormalities when administered to a pregnant woman during the first trimester. Because use of these drugs is rarely a matter of urgency in the treatment of panic disorder, their use during the first trimester should almost always be avoided. The possibility that a woman of childbearing potential may be pregnant at the time of institution of therapy should be considered. 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. Patients should also be advised that if they become pregnant during therapy or intend to become pregnant, they should communicate with their physician about the desirability of discontinuing the drug.
### Withdrawal Symptoms
Withdrawal symptoms of the barbiturate type have occurred after the discontinuation of benzodiazepines
# PRECAUTIONS
## General
Worsening of Seizures
When used in patients in whom several different types of seizure disorders coexist, clonazepam may increase the incidence or precipitate the onset of generalized tonic-clonic seizures (grand mal). This may require the addition of appropriate anticonvulsants or an increase in their dosages. The concomitant use of valproic acid and clonazepam may produce absence status.
Laboratory Testing during Long-Term Therapy
Periodic blood counts and liver function tests are advisable during long-term therapy with clonazepam.
Risks of Abrupt Withdrawal
The abrupt withdrawal of clonazepam, particularly in those patients on long-term, high-dose therapy, may precipitate status epilepticus. Therefore, when discontinuing clonazepam, gradual withdrawal is essential. While clonazepam is being gradually withdrawn, the simultaneous substitution of another anticonvulsant may be indicated.
Caution in Renally Impaired Patients
Metabolites of clonazepam are excreted by the kidneys; to avoid their excess accumulation, caution should be exercised in the administration of the drug to patients with impaired renal function.
Hypersalivation
Clonazepam may produce an increase in salivation. This should be considered before giving the drug to patients who have difficulty handling secretions. Because of this and the possibility of respiratory depression, clonazepam should be used with caution in patients with chronic respiratory diseases.
# Adverse Reactions
## Clinical Trials Experience
The adverse experiences for clonazepam are provided separately for patients with seizure disorders and with panic disorder.
Seizure Disorders
The most frequently occurring side effects of clonazepam are referable to CNS depression. Experience in treatment of seizures has shown that drowsiness has occurred in approximately 50% of patients and ataxia in approximately 30%. In some cases, these may diminish with time; behavior problems have been noted in approximately 25% of patients. Others, listed by system, are:
Neurologic: abnormal eye movements, aphonia, choreiform movements, coma, diplopia, dysarthria, dysdiadochokinesis, “glassy-eyed” appearance, headache, hemiparesis, hypotonia, nystagmus, respiratory depression, slurred speech, tremor, vertigo
Psychiatric: confusion, depression, amnesia, hallucinations, hysteria, increased libido, insomnia, psychosis (the behavior effects are more likely to occur in patients with a history of psychiatric disturbances).
The following paradoxical reactions have been observed: excitability, irritability, aggressive behavior, agitation, nervousness, hostility, anxiety, sleep disturbances, nightmares and vivid dreams
Respiratory: chest congestion, rhinorrhea, shortness of breath, hypersecretion in upper respiratory passages
Cardiovascular: palpitations
Dermatologic: hair loss, hirsutism, skin rash, ankle and facial edema
Gastrointestinal: anorexia, coated tongue, constipation, diarrhea, dry mouth, encopresis, gastritis, increased appetite, nausea, sore gums
Genitourinary: dysuria, enuresis, nocturia, urinary retention
Musculoskeletal: muscle weakness, pains
Miscellaneous: dehydration, general deterioration, fever, lymphadenopathy, weight loss or gain
Hematopoietic: anemia, leukopenia, thrombocytopenia, eosinophilia
Hepatic: hepatomegaly, transient elevations of serum transaminases and alkaline phosphatase
Panic disorder
Adverse events during exposure to clonazepam were obtained by spontaneous report and recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of events into a smaller number of standardized event categories. In the tables and tabulations that follow, CIGY dictionary terminology has been used to classify reported adverse events, except in certain cases in which redundant terms were collapsed into more meaningful terms, as noted below.
The stated frequencies of adverse events represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed. An event was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation.
Adverse Findings Observed in Short-Term, Placebo Controlled Trials
Adverse Events Associated With Discontinuation of Treatment
Overall, the incidence of discontinuation due to adverse events was 17% in clonazepam compared to 9% for placebo in the combined data of two 6- to 9-week trials. The most common events (≥1%) associated with discontinuation and a dropout rate twice or greater for clonazepam than that of placebo included the following:
Adverse Events Occurring at an Incidence of 1% or More Among Clonazepam-Treated Patients:
Table 3 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse events that occurred during acute therapy of panic disorder from a pool of two 6- to 9-week trials. Events reported in 1% or more of patients treated with clonazepam (doses ranging from 0.5 mg/day to 4 mg/day) and for which the incidence was greater than that in placebo-treated patients are included.
The prescriber should be aware that the figures in Table 3 cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and non drug factors to the side effect incidence in the population studied.
Treatment-Emergent Depressive Symptoms
In the pool of two short-term placebo-controlled trials, adverse events classified under the preferred term “depression” were reported in 7% of clonazepam-treated patients compared to 1% of placebo-treated patients, without any clear pattern of dose relatedness. In these same trials, adverse events classified under the preferred term “depression” were reported as leading to discontinuation in 4% of clonazepam-treated patients compared to 1% of placebo-treated patients. While these findings are noteworthy, Hamilton Depression Rating Scale (HAM-D) data collected in these trials revealed a larger decline in HAM-D scores in the clonazepam group than the placebo group suggesting that clonazepam-treated patients were not experiencing a worsening or emergence of clinical depression.
Other Adverse Events Observed During the Pre marketing Evaluation of Clonazepam in panic disorder
Following is a list of modified CIGY terms that reflect treatment-emergent adverse events reported by patients treated with clonazepam at multiple doses during clinical trials. All reported events are included except those already listed in Table 3 or elsewhere in labeling, those events for which a drug cause was remote, those event terms which were so general as to be uninformative, and events reported only once and which did not have a substantial probability of being acutely life-threatening. It is important to emphasize that, although the events occurred during treatment with clonazepam, they were not necessarily caused by it.
Events are further categorized by body system and listed in order of decreasing frequency. These adverse events were reported infrequently, which is defined as occurring in 1/100 to 1/1,000 patients.
Body as a Whole: weight increase, accident, weight decrease, wound, edema, fever, shivering, abrasions, ankle edema, edema foot, edema periorbital, injury, malaise, pain, cellulitis, inflammation localized
Cardiovascular Disorders: chest pain, hypotension postural
Central and Peripheral Nervous System Disorders: migraine, paresthesia, drunkenness, feeling of enuresis, paresis, tremor, burning skin, falling, head fullness, hoarseness, hyperactivity, hypoesthesia, tongue thick, twitching
Gastrointestinal System Disorders: abdominal discomfort, gastrointestinal inflammation, stomach upset, toothache, flatulence, pyrosis, saliva increased, tooth disorder, bowel movements frequent, pain pelvic, dyspepsia, hemorrhoids
Hearing and Vestibular Disorders: vertigo, otitis, earache, motion sickness
Heart Rate and Rhythm Disorders: palpitation
Metabolic and Nutritional Disorders: thirst, gout
Musculoskeletal System Disorders: back pain, fracture traumatic, sprains and strains, pain leg, pain nape, cramps muscle, cramps leg, pain ankle, pain shoulder, tendinitis, arthralgia, hypertonia, lumbago, pain feet, pain jaw, pain knee, swelling knee
Platelet, Bleeding and Clotting Disorders: bleeding dermal
Psychiatric Disorders: insomnia, organic disinhibition, anxiety, depersonalization, dreaming excessive, libido loss, appetite increased, libido increased, reactions decreased, aggressive reaction, apathy, attention lack, excitement, feeling mad, hunger abnormal, illusion, nightmares, sleep disorders, suicide ideation, yawning
Reproductive Disorders, Female: breast pain, menstrual irregularity
Reproductive Disorders, Male: ejaculation decreased
Resistance Mechanism Disorders: infection mycotic, infection viral, infection streptococcal, herpes simplex infection, infectious mononucleosis, moniliasis
Respiratory System Disorders: sneezing excessive, asthmatic attack, dyspnea, nosebleed, pneumonia, pleurisy
Skin and Appendages Disorders: acne flare, alopecia, xeroderma, dermatitis contact, flushing, pruritus, pustular reaction, skin burns, skin disorder
Special Senses Other, Disorders: taste loss
Urinary System Disorders: dysuria, cystitis, polyuria, urinary incontinence, bladder dysfunction, urinary retention, urinary tract bleeding, urine discoloration
Vascular (Extracardiac) Disorders: thrombophlebitis leg
Vision Disorders: eye irritation, visual disturbance, diplopia, eye twitching, styes, visual field defect, xerophthalmia
## Postmarketing Experience
FDA package insert for clonazepam contains no information regarding post marketing experience.
# Drug Interactions
There is limited information regarding Clonazepam Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
To provide information regarding the effects of in utero exposure to clonazepam, physicians are advised to recommend that pregnant patients taking clonazepam enroll in the NAAED Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on this registry can also be found at the website /.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Clonazepam in women who are pregnant.
### Labor and Delivery
The effect of clonazepam on labor and delivery in humans has not been specifically studied; however, perinatal complications have been reported in children born to mothers who have been receiving benzodiazepines late in pregnancy, including findings suggestive of either excess benzodiazepine exposure or of withdrawal phenomena.
### Nursing Mothers
Mothers receiving clonazepam should not breastfeed their infants.
### Pediatric Use
Because of the possibility that adverse effects on physical or mental development could become apparent only after many years, a benefit-risk consideration of the long-term use of clonazepam is important in pediatric patients being treated for seizure disorder .
Safety and effectiveness in pediatric patients with panic disorder below the age of 18 have not been established.
### Geriatic Use
Clinical studies of clonazepam 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.
Because clonazepam undergoes hepatic metabolism, it is possible that liver disease will impair clonazepam elimination. Metabolites of clonazepam are excreted by the kidneys; to avoid their excess accumulation, caution should be exercised in the administration of the drug to patients with impaired renal function. Because elderly patients are more likely to have decreased hepatic and/or renal function, care should be taken in dose selection, and it may be useful to assess hepatic and/or renal function at the time of dose selection.
Sedating drugs may cause confusion and over-sedation in the elderly; elderly patients generally should be started on low doses of clonazepam and observed closely.
### Gender
There is no FDA guidance on the use of Clonazepam with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Clonazepam with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Clonazepam in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Clonazepam in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Clonazepam in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Clonazepam in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Oral
### Monitoring
FDA package insert for clonazepam contains no information regarding drug monitoring.
# IV Compatibility
There is limited information about the IV compatibility.
# Overdosage
FDA package insert for clonazepam contains no information regarding Overdose.
# Pharmacology
## Mechanism of Action
The precise mechanism by which clonazepam exerts its antiseizure and antipanic effects is unknown, although it is believed to be related to its ability to enhance the activity of gamma aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system.
## Structure
Clonazepam tablets USP, for oral administration, contain 0.5 mg, 1 mg or 2 mg clonazepam. In addition, each tablet also contains the following inactive ingredients: corn starch, lactose anhydrous, magnesium stearate and microcrystalline cellulose with the following colorants: 0.5 mg - D&C yellow No. 10 aluminum lake; 1 mg - FD&C blue No. 1 aluminum lake.
Chemically, clonazepam is 5-(2-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has a molecular weight of 315.72 and the following structural formula:
## Pharmacodynamics
The precise mechanism by which clonazepam exerts its antiseizure and antipanic effects is unknown, although it is believed to be related to its ability to enhance the activity of gamma aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system. Convulsions produced in rodents by pentylenetetrazol or, to a lesser extent, electrical stimulation are antagonized, as are convulsions produced by photic stimulation in susceptible baboons. A taming effect in aggressive primates, muscle weakness and hypnosis are also produced. In humans, clonazepam is capable of suppressing the spike and wave discharge in absence seizures (petit mal) and decreasing the frequency, amplitude, duration and spread of discharge in minor motor seizures.
## Pharmacokinetics
Clonazepam is rapidly and completely absorbed after oral administration. The absolute bioavailability of clonazepam is about 90%. Maximum plasma concentrations of clonazepam are reached within 1 to 4 hours after oral administration. Clonazepam is approximately 85% bound to plasma proteins. Clonazepam is highly metabolized, with less than 2% unchanged clonazepam being excreted in the urine. Biotransformation occurs mainly by reduction of the 7-nitro group to the 4-amino derivative. This derivative can be acetylated, hydroxylated and glucuronidated. Cytochrome P-450, including CYP3A, may play an important role in clonazepam reduction and oxidation. The elimination half-life of clonazepam is typically 30 to 40 hours. Clonazepam pharmacokinetics are dose-independent throughout the dosing range. There is no evidence that clonazepam induces its own metabolism or that of other drugs in humans.
Pharmacokinetics in Demographic Subpopulations and in Disease States
Controlled studies examining the influence of gender and age on clonazepam pharmacokinetics have not been conducted, nor have the effects of renal or liver disease on clonazepam pharmacokinetics been studied. Because clonazepam undergoes hepatic metabolism, it is possible that liver disease will impair clonazepam elimination. Thus, caution should be exercised when administering clonazepam to these patients.
## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies have not been conducted with clonazepam.
The data currently available are not sufficient to determine the genotoxic potential of clonazepam.
In a two-generation fertility study in which clonazepam was given orally to rats at 10 mg/kg/day and 100 mg/kg/day (low dose approximately 5 times and 24 times the maximum recommended human dose of 20 mg/day for seizure disorder and 4 mg/day for panic disorder, respectively, on a mg/m2 basis), there was a decrease in the number of pregnancies and in the number of offspring surviving until weaning.
# Clinical Studies
FDA package insert for clonazepam contains no information regarding Clinical studies.
# How Supplied
Clonazepam Tablets USP for oral administration are available as:
0.5 mg: Round, light yellow, biconvex tablet, debossed “E” over “63” on one side and bisected on the other side and supplied as:
NDC 0185-0063-01 bottles of 100
NDC 0185-0063-05 bottles of 500
NDC 0185-0063-10 bottles of 1000
1 mg: Round, light blue, biconvex tablet, debossed “E” over “64” on one side and bisected on the other side and supplied as:
NDC 0185-0064-01 bottles of 100
NDC 0185-0064-05 bottles of 500
NDC 0185-0064-10 bottles of 1000
2 mg: Round, white, biconvex tablet, debossed “E” over “65” on one side and bisected on the other side and supplied as:
NDC 0185-0065-01 bottles of 100
NDC 0185-0065-05 bottles of 500
NDC 0185-0065-10 bottles of 1000
## Storage
Store at 20° to 25°C (68° to 77°F) .
Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure, as required.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
A clonazepam medication guide must be given to the patient each time clonazepam is dispensed, as required by law.
Patients should be instructed to take clonazepam only as prescribed.
Physicians are advised to discuss the following issues with patients for whom they prescribe clonazepam.
# Precautions with Alcohol
Patients should be advised to avoid alcohol while taking clonazepam.
# Brand Names
- Klonopin
- Klonopin Wafers
# Look-Alike Drug Names
clonazepam - cloBAZam
clonazepam - cloNIDine
clonazepam - cloNIDine hydrochloride
clonazepam - cloZApine
clonazepam - LORazepam
Klonopin - cloNIDine hydrochloride
Klonopin - cloNIDine
# Drug Shortage Status
# Price | Clonazepam
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2];Aparna Vuppala, M.B.B.S. [3]
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# Overview
Clonazepam is a benzodiazepine that is FDA approved for the treatment of lennox-gastaut syndrome, (petit mal variant), akinetic and myoclonic seizures, panic disorder, with or without agoraphobia. Common adverse reactions include ataxia, coordination problem, dizziness, somnolence, behavior problem, upper respiratory infection, fatigue.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Seizure Disorders
- Dosing information
- Adults
- Initial dose: not exceed 1.5 mg PO tid. Dosage may be increased in increments of 0.5 mg to 1 mg every 3 days until seizures are adequately controlled or until side effects preclude any further increase. Maintenance dosage must be individualized for each patient depending upon response. Maximum recommended daily dose is 20 mg.
- The use of multiple anticonvulsants may result in an increase of depressant adverse effects. This should be considered before adding clonazepam tablets to an existing anticonvulsant regimen.
- Geriatric Patients
- There is no clinical trial experience with clonazepam tablets in seizure disorder patients 65 years of age and older. In general, elderly patients should be started on low doses of clonazepam tablets and observed closely
### Panic disorder
- Dosing införmation
- Adults
- Initial dose: 0.25 mg bid. An increase to the target dose for most patients of 1 mg/day may be made after 3 days.
- Recommended dose: 1 mg/day is based on the results from a fixed dose study in which the optimal effect was seen at 1 mg/day. Higher doses of 2 mg/day, 3 mg/day and 4 mg/day in that study were less effective than the 1 mg/day dose and were associated with more adverse effects.
- Maximum dosage: 4 mg/day, and in those instances, the dose may be increased in increments of 0.125 mg to 0.25 mg bid every 3 days until panic disorder is controlled or until side effects make further increases undesired. To reduce the inconvenience of somnolence, administration of one dose at bedtime may be desirable.
- Treatment should be discontinued gradually, with a decrease of 0.125 mg bid every 3 days, until the drug is completely withdrawn.
- There is no body of evidence available to answer the question of how long the patient treated with clonazepam should remain on it. Therefore, the physician who elects to use clonazepam tablets for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient.
- Geriatric Patients
- There is no clinical trial experience with clonazepam tablets in panic disorder patients 65 years of age and older. In general, elderly patients should be started on low doses of clonazepam tablets and observed closely.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of clonazepam in adult patients.
### Non–Guideline-Supported Use
### Restless Leg Syndrome
- Dosing information
- 0.5 to 2 mg at bedtime[1]
### Sleep Walking Disorder
- Dosing information
- 0.25 to 2 mg at bedtime[2]
### Social Phobia
- Dosing information
- 1 to 2.5 mg daily [3]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
### Seizure Disorder
- Dosing information
- Lonazepam tablets are administered orally. In order to minimize drowsiness, the initial dose for infants and children (up to 10 years of age or 30 kg of body weight) should be between 0.01 mg/kg/day and 0.03 mg/kg/day but not to exceed 0.05 mg/kg/day given in two or three divided doses. Dosage should be increased by no more than 0.25 mg to 0.5 mg every third day until a daily maintenance dose of 0.1 mg/kg to 0.2 mg/kg of body weight has been reached, unless seizures are controlled or side effects preclude further increase. Whenever possible, the daily dose should be divided into three equal doses. If doses are not equally divided, the largest dose should be given before retiring.
### Panic Disorder
- Dosing information
- There is no clinical trial experience with clonazepam tablets in panic disorder patients under 18 years of age.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of clonazepam in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of clonazepam in pediatric patients.
# Contraindications
Clonazepam should not be used in patients with a history of sensitivity to benzodiazepines, nor in patients with clinical or biochemical evidence of significant liver disease. It may be used in patients with open angle glaucoma who are receiving appropriate therapy but is contraindicated in acute narrow angle glaucoma.
# Warnings
Interference with Cognitive and Motor Performance
Since clonazepam produces CNS depression, patients receiving this drug should be cautioned against engaging in hazardous occupations requiring mental alertness, such as operating machinery or driving a motor vehicle. They should also be warned about the concomitant use of alcohol or other CNS-depressant drugs during clonazepam therapy.
Suicidal Behavior and Ideation
Antiepileptic drugs (AEDs), including clonazepam, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43% compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.
The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed.
Table 1 shows absolute and relative risk by indication for all evaluated AEDs.
The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.
Anyone considering prescribing clonazepam or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.
### Pregnancy Risks
Data from several sources raise concerns about the use of clonazepam during pregnancy.
Animal Findings
In three studies in which clonazepam was administered orally to pregnant rabbits at doses of 0.2 mg/kg/day, 1 mg/kg/day, 5 mg/kg/day or 10 mg/kg/day (low dose approximately 0.2 times the maximum recommended human dose of 20 mg/day for seizure disorders and equivalent to the maximum dose of 4 mg/day for panic disorder, on a mg/m2 basis) during the period of organogenesis, a similar pattern of malformations (cleft palate, open eyelid, fused sternebrae and limb defects) was observed in a low, non-dose-related incidence in exposed litters from all dosage groups. Reductions in maternal weight gain occurred at dosages of 5 mg/kg/day or greater and reduction in embryo-fetal growth occurred in one study at a dosage of 10 mg/kg/day. No adverse maternal or embryo-fetal effects were observed in mice and rats following administration during organogenesis of oral doses up to 15 mg/kg/day or 40 mg/kg/day, respectively (4 and 20 times the maximum recommended human dose of 20 mg/day for seizure disorders and 20 and 100 times the maximum dose of 4 mg/day for panic disorder, respectively, on a mg/m2 basis).
General Concerns and Considerations about Anticonvulsants
Recent reports suggest an association between the use of anticonvulsant drugs by women with epilepsy and an elevated incidence of birth defects in children born to these women. Data are more extensive with respect to diphenylhydantoin and phenobarbital, but these are also the most commonly prescribed anticonvulsants; less systematic or anecdotal reports suggest a possible similar association with the use of all known anticonvulsant drugs.
In children of women treated with drugs for epilepsy, reports suggesting an elevated incidence of birth defects cannot be regarded as adequate to prove a definite cause and effect relationship. There are intrinsic methodologic problems in obtaining adequate data on drug teratogenicity in humans; the possibility also exists that other factors, (e.g., genetic factors or the epileptic condition itself), may be more important than drug therapy in leading to birth defects. The great majority of mothers on anticonvulsant medication deliver normal infants. It is important to note that anticonvulsant drugs should not be discontinued in patients in whom the drug is administered to prevent seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life. In individual cases where the severity and frequency of the seizure disorder are such that the removal of medication does not pose a serious threat to the patient, discontinuation of the drug may be considered prior to and during pregnancy; however, it cannot be said with any confidence that even mild seizures do not pose some hazards to the developing embryo or fetus.
General Concerns about Benzodiazepines
An increased risk of congenital malformations associated with the use of benzodiazepine drugs has been suggested in several studies.
There may also be non-teratogenic risks associated with the use of benzodiazepines during pregnancy. There have been reports of neonatal flaccidity, respiratory and feeding difficulties, and hypothermia in children born to mothers who have been receiving benzodiazepines late in pregnancy. In addition, children born to mothers receiving benzodiazepines late in pregnancy may be at some risk of experiencing withdrawal symptoms during the postnatal period.
Advice Regarding the use of Clonazepam in Women of Childbearing Potential
In general, the use of clonazepam in women of childbearing potential, and more specifically during known pregnancy, should be considered only when the clinical situation warrants the risk to the fetus.
The specific considerations addressed above regarding the use of anticonvulsants for epilepsy in women of childbearing potential should be weighed in treating or counseling these women.
Because of experience with other members of the benzodiazepine class, clonazepam is assumed to be capable of causing an increased risk of congenital abnormalities when administered to a pregnant woman during the first trimester. Because use of these drugs is rarely a matter of urgency in the treatment of panic disorder, their use during the first trimester should almost always be avoided. The possibility that a woman of childbearing potential may be pregnant at the time of institution of therapy should be considered. 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. Patients should also be advised that if they become pregnant during therapy or intend to become pregnant, they should communicate with their physician about the desirability of discontinuing the drug.
### Withdrawal Symptoms
Withdrawal symptoms of the barbiturate type have occurred after the discontinuation of benzodiazepines
# PRECAUTIONS
## General
Worsening of Seizures
When used in patients in whom several different types of seizure disorders coexist, clonazepam may increase the incidence or precipitate the onset of generalized tonic-clonic seizures (grand mal). This may require the addition of appropriate anticonvulsants or an increase in their dosages. The concomitant use of valproic acid and clonazepam may produce absence status.
Laboratory Testing during Long-Term Therapy
Periodic blood counts and liver function tests are advisable during long-term therapy with clonazepam.
Risks of Abrupt Withdrawal
The abrupt withdrawal of clonazepam, particularly in those patients on long-term, high-dose therapy, may precipitate status epilepticus. Therefore, when discontinuing clonazepam, gradual withdrawal is essential. While clonazepam is being gradually withdrawn, the simultaneous substitution of another anticonvulsant may be indicated.
Caution in Renally Impaired Patients
Metabolites of clonazepam are excreted by the kidneys; to avoid their excess accumulation, caution should be exercised in the administration of the drug to patients with impaired renal function.
Hypersalivation
Clonazepam may produce an increase in salivation. This should be considered before giving the drug to patients who have difficulty handling secretions. Because of this and the possibility of respiratory depression, clonazepam should be used with caution in patients with chronic respiratory diseases.
# Adverse Reactions
## Clinical Trials Experience
The adverse experiences for clonazepam are provided separately for patients with seizure disorders and with panic disorder.
Seizure Disorders
The most frequently occurring side effects of clonazepam are referable to CNS depression. Experience in treatment of seizures has shown that drowsiness has occurred in approximately 50% of patients and ataxia in approximately 30%. In some cases, these may diminish with time; behavior problems have been noted in approximately 25% of patients. Others, listed by system, are:
Neurologic: abnormal eye movements, aphonia, choreiform movements, coma, diplopia, dysarthria, dysdiadochokinesis, “glassy-eyed” appearance, headache, hemiparesis, hypotonia, nystagmus, respiratory depression, slurred speech, tremor, vertigo
Psychiatric: confusion, depression, amnesia, hallucinations, hysteria, increased libido, insomnia, psychosis (the behavior effects are more likely to occur in patients with a history of psychiatric disturbances).
The following paradoxical reactions have been observed: excitability, irritability, aggressive behavior, agitation, nervousness, hostility, anxiety, sleep disturbances, nightmares and vivid dreams
Respiratory: chest congestion, rhinorrhea, shortness of breath, hypersecretion in upper respiratory passages
Cardiovascular: palpitations
Dermatologic: hair loss, hirsutism, skin rash, ankle and facial edema
Gastrointestinal: anorexia, coated tongue, constipation, diarrhea, dry mouth, encopresis, gastritis, increased appetite, nausea, sore gums
Genitourinary: dysuria, enuresis, nocturia, urinary retention
Musculoskeletal: muscle weakness, pains
Miscellaneous: dehydration, general deterioration, fever, lymphadenopathy, weight loss or gain
Hematopoietic: anemia, leukopenia, thrombocytopenia, eosinophilia
Hepatic: hepatomegaly, transient elevations of serum transaminases and alkaline phosphatase
Panic disorder
Adverse events during exposure to clonazepam were obtained by spontaneous report and recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of events into a smaller number of standardized event categories. In the tables and tabulations that follow, CIGY dictionary terminology has been used to classify reported adverse events, except in certain cases in which redundant terms were collapsed into more meaningful terms, as noted below.
The stated frequencies of adverse events represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed. An event was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation.
Adverse Findings Observed in Short-Term, Placebo Controlled Trials
Adverse Events Associated With Discontinuation of Treatment
Overall, the incidence of discontinuation due to adverse events was 17% in clonazepam compared to 9% for placebo in the combined data of two 6- to 9-week trials. The most common events (≥1%) associated with discontinuation and a dropout rate twice or greater for clonazepam than that of placebo included the following:
Adverse Events Occurring at an Incidence of 1% or More Among Clonazepam-Treated Patients:
Table 3 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse events that occurred during acute therapy of panic disorder from a pool of two 6- to 9-week trials. Events reported in 1% or more of patients treated with clonazepam (doses ranging from 0.5 mg/day to 4 mg/day) and for which the incidence was greater than that in placebo-treated patients are included.
The prescriber should be aware that the figures in Table 3 cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and non drug factors to the side effect incidence in the population studied.
Treatment-Emergent Depressive Symptoms
In the pool of two short-term placebo-controlled trials, adverse events classified under the preferred term “depression” were reported in 7% of clonazepam-treated patients compared to 1% of placebo-treated patients, without any clear pattern of dose relatedness. In these same trials, adverse events classified under the preferred term “depression” were reported as leading to discontinuation in 4% of clonazepam-treated patients compared to 1% of placebo-treated patients. While these findings are noteworthy, Hamilton Depression Rating Scale (HAM-D) data collected in these trials revealed a larger decline in HAM-D scores in the clonazepam group than the placebo group suggesting that clonazepam-treated patients were not experiencing a worsening or emergence of clinical depression.
Other Adverse Events Observed During the Pre marketing Evaluation of Clonazepam in panic disorder
Following is a list of modified CIGY terms that reflect treatment-emergent adverse events reported by patients treated with clonazepam at multiple doses during clinical trials. All reported events are included except those already listed in Table 3 or elsewhere in labeling, those events for which a drug cause was remote, those event terms which were so general as to be uninformative, and events reported only once and which did not have a substantial probability of being acutely life-threatening. It is important to emphasize that, although the events occurred during treatment with clonazepam, they were not necessarily caused by it.
Events are further categorized by body system and listed in order of decreasing frequency. These adverse events were reported infrequently, which is defined as occurring in 1/100 to 1/1,000 patients.
Body as a Whole: weight increase, accident, weight decrease, wound, edema, fever, shivering, abrasions, ankle edema, edema foot, edema periorbital, injury, malaise, pain, cellulitis, inflammation localized
Cardiovascular Disorders: chest pain, hypotension postural
Central and Peripheral Nervous System Disorders: migraine, paresthesia, drunkenness, feeling of enuresis, paresis, tremor, burning skin, falling, head fullness, hoarseness, hyperactivity, hypoesthesia, tongue thick, twitching
Gastrointestinal System Disorders: abdominal discomfort, gastrointestinal inflammation, stomach upset, toothache, flatulence, pyrosis, saliva increased, tooth disorder, bowel movements frequent, pain pelvic, dyspepsia, hemorrhoids
Hearing and Vestibular Disorders: vertigo, otitis, earache, motion sickness
Heart Rate and Rhythm Disorders: palpitation
Metabolic and Nutritional Disorders: thirst, gout
Musculoskeletal System Disorders: back pain, fracture traumatic, sprains and strains, pain leg, pain nape, cramps muscle, cramps leg, pain ankle, pain shoulder, tendinitis, arthralgia, hypertonia, lumbago, pain feet, pain jaw, pain knee, swelling knee
Platelet, Bleeding and Clotting Disorders: bleeding dermal
Psychiatric Disorders: insomnia, organic disinhibition, anxiety, depersonalization, dreaming excessive, libido loss, appetite increased, libido increased, reactions decreased, aggressive reaction, apathy, attention lack, excitement, feeling mad, hunger abnormal, illusion, nightmares, sleep disorders, suicide ideation, yawning
Reproductive Disorders, Female: breast pain, menstrual irregularity
Reproductive Disorders, Male: ejaculation decreased
Resistance Mechanism Disorders: infection mycotic, infection viral, infection streptococcal, herpes simplex infection, infectious mononucleosis, moniliasis
Respiratory System Disorders: sneezing excessive, asthmatic attack, dyspnea, nosebleed, pneumonia, pleurisy
Skin and Appendages Disorders: acne flare, alopecia, xeroderma, dermatitis contact, flushing, pruritus, pustular reaction, skin burns, skin disorder
Special Senses Other, Disorders: taste loss
Urinary System Disorders: dysuria, cystitis, polyuria, urinary incontinence, bladder dysfunction, urinary retention, urinary tract bleeding, urine discoloration
Vascular (Extracardiac) Disorders: thrombophlebitis leg
Vision Disorders: eye irritation, visual disturbance, diplopia, eye twitching, styes, visual field defect, xerophthalmia
## Postmarketing Experience
FDA package insert for clonazepam contains no information regarding post marketing experience.
# Drug Interactions
There is limited information regarding Clonazepam Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
To provide information regarding the effects of in utero exposure to clonazepam, physicians are advised to recommend that pregnant patients taking clonazepam enroll in the NAAED Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on this registry can also be found at the website http://www.aedpregnancyregistry.org/.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Clonazepam in women who are pregnant.
### Labor and Delivery
The effect of clonazepam on labor and delivery in humans has not been specifically studied; however, perinatal complications have been reported in children born to mothers who have been receiving benzodiazepines late in pregnancy, including findings suggestive of either excess benzodiazepine exposure or of withdrawal phenomena.
### Nursing Mothers
Mothers receiving clonazepam should not breastfeed their infants.
### Pediatric Use
Because of the possibility that adverse effects on physical or mental development could become apparent only after many years, a benefit-risk consideration of the long-term use of clonazepam is important in pediatric patients being treated for seizure disorder .
Safety and effectiveness in pediatric patients with panic disorder below the age of 18 have not been established.
### Geriatic Use
Clinical studies of clonazepam 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.
Because clonazepam undergoes hepatic metabolism, it is possible that liver disease will impair clonazepam elimination. Metabolites of clonazepam are excreted by the kidneys; to avoid their excess accumulation, caution should be exercised in the administration of the drug to patients with impaired renal function. Because elderly patients are more likely to have decreased hepatic and/or renal function, care should be taken in dose selection, and it may be useful to assess hepatic and/or renal function at the time of dose selection.
Sedating drugs may cause confusion and over-sedation in the elderly; elderly patients generally should be started on low doses of clonazepam and observed closely.
### Gender
There is no FDA guidance on the use of Clonazepam with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Clonazepam with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Clonazepam in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Clonazepam in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Clonazepam in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Clonazepam in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Oral
### Monitoring
FDA package insert for clonazepam contains no information regarding drug monitoring.
# IV Compatibility
There is limited information about the IV compatibility.
# Overdosage
FDA package insert for clonazepam contains no information regarding Overdose.
# Pharmacology
## Mechanism of Action
The precise mechanism by which clonazepam exerts its antiseizure and antipanic effects is unknown, although it is believed to be related to its ability to enhance the activity of gamma aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system.
## Structure
Clonazepam tablets USP, for oral administration, contain 0.5 mg, 1 mg or 2 mg clonazepam. In addition, each tablet also contains the following inactive ingredients: corn starch, lactose anhydrous, magnesium stearate and microcrystalline cellulose with the following colorants: 0.5 mg - D&C yellow No. 10 aluminum lake; 1 mg - FD&C blue No. 1 aluminum lake.
Chemically, clonazepam is 5-(2-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has a molecular weight of 315.72 and the following structural formula:
## Pharmacodynamics
The precise mechanism by which clonazepam exerts its antiseizure and antipanic effects is unknown, although it is believed to be related to its ability to enhance the activity of gamma aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system. Convulsions produced in rodents by pentylenetetrazol or, to a lesser extent, electrical stimulation are antagonized, as are convulsions produced by photic stimulation in susceptible baboons. A taming effect in aggressive primates, muscle weakness and hypnosis are also produced. In humans, clonazepam is capable of suppressing the spike and wave discharge in absence seizures (petit mal) and decreasing the frequency, amplitude, duration and spread of discharge in minor motor seizures.
## Pharmacokinetics
Clonazepam is rapidly and completely absorbed after oral administration. The absolute bioavailability of clonazepam is about 90%. Maximum plasma concentrations of clonazepam are reached within 1 to 4 hours after oral administration. Clonazepam is approximately 85% bound to plasma proteins. Clonazepam is highly metabolized, with less than 2% unchanged clonazepam being excreted in the urine. Biotransformation occurs mainly by reduction of the 7-nitro group to the 4-amino derivative. This derivative can be acetylated, hydroxylated and glucuronidated. Cytochrome P-450, including CYP3A, may play an important role in clonazepam reduction and oxidation. The elimination half-life of clonazepam is typically 30 to 40 hours. Clonazepam pharmacokinetics are dose-independent throughout the dosing range. There is no evidence that clonazepam induces its own metabolism or that of other drugs in humans.
Pharmacokinetics in Demographic Subpopulations and in Disease States
Controlled studies examining the influence of gender and age on clonazepam pharmacokinetics have not been conducted, nor have the effects of renal or liver disease on clonazepam pharmacokinetics been studied. Because clonazepam undergoes hepatic metabolism, it is possible that liver disease will impair clonazepam elimination. Thus, caution should be exercised when administering clonazepam to these patients.
## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies have not been conducted with clonazepam.
The data currently available are not sufficient to determine the genotoxic potential of clonazepam.
In a two-generation fertility study in which clonazepam was given orally to rats at 10 mg/kg/day and 100 mg/kg/day (low dose approximately 5 times and 24 times the maximum recommended human dose of 20 mg/day for seizure disorder and 4 mg/day for panic disorder, respectively, on a mg/m2 basis), there was a decrease in the number of pregnancies and in the number of offspring surviving until weaning.
# Clinical Studies
FDA package insert for clonazepam contains no information regarding Clinical studies.
# How Supplied
Clonazepam Tablets USP for oral administration are available as:
0.5 mg: Round, light yellow, biconvex tablet, debossed “E” over “63” on one side and bisected on the other side and supplied as:
NDC 0185-0063-01 bottles of 100
NDC 0185-0063-05 bottles of 500
NDC 0185-0063-10 bottles of 1000
1 mg: Round, light blue, biconvex tablet, debossed “E” over “64” on one side and bisected on the other side and supplied as:
NDC 0185-0064-01 bottles of 100
NDC 0185-0064-05 bottles of 500
NDC 0185-0064-10 bottles of 1000
2 mg: Round, white, biconvex tablet, debossed “E” over “65” on one side and bisected on the other side and supplied as:
NDC 0185-0065-01 bottles of 100
NDC 0185-0065-05 bottles of 500
NDC 0185-0065-10 bottles of 1000
## Storage
Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].
Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure, as required.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
A clonazepam medication guide must be given to the patient each time clonazepam is dispensed, as required by law.
Patients should be instructed to take clonazepam only as prescribed.
Physicians are advised to discuss the following issues with patients for whom they prescribe clonazepam.
# Precautions with Alcohol
Patients should be advised to avoid alcohol while taking clonazepam.
# Brand Names
- Klonopin
- Klonopin Wafers
# Look-Alike Drug Names
clonazepam - cloBAZam
clonazepam - cloNIDine
clonazepam - cloNIDine hydrochloride
clonazepam - cloZApine
clonazepam - LORazepam
Klonopin - cloNIDine hydrochloride
Klonopin - cloNIDine[5]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Antelepsin | |
2746210d521dee19fe7423ab69199b2f8b5a423e | wikidoc | Fontanelle | Fontanelle
In human anatomy, a fontanelle (or fontanel) is one of two "soft spots" on a newborn human's skull. There are, however, two more fontanelles of interest, the mastoid fontanelle, and the sphenoidal fontanelle.
Fontanelles are soft spots on a baby's head which, during birth, enable the soft bony plates of the skull to flex, allowing the head to pass through the birth canal. Fontanelles are usually completely hardened by a child's second birthday, and will eventually form the sutures of the neurocranium.
The skull of a newborn consists of five main bones: two frontal bones, two parietal bones, and one occipital bone. These are joined by fibrous sutures, which allow movement that facilitates childbirth and brain growth.
At birth, the skull features a small posterior fontanelle, an open area covered by a tough membrane, where the two parietal bones adjoin the occipital bone (at the lambda). This fontanelle usually closes during the first several months of an infant's life.
There is also a much larger, diamond-shaped anterior fontanelle where the two frontal and two parietal bones abut. This fontanelle remains open until the child is about two years of age. In cleidocranial dysostosis it is often late in closing or never closes.
The anterior fontanelle is useful clinically. Examination of an infant includes palpating the anterior fontanelle. A sunken fontanelle indicates dehydration, whereas a very tense or bulging anterior fontanelle indicates raised intracranial pressure.
Parents may worry that their infant may be more prone to injury at the fontanelles. In fact, although they may colloquially be called "soft-spots", the membrane covering the fontanelles is extremely tough and difficult to penetrate.
The fontanelles allow the infant brain to be imaged using ultrasonography. Once they are closed, most of the brain is inaccessible to ultrasound imaging, as the bony skull presents an acoustic barrier. | Fontanelle
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
In human anatomy, a fontanelle (or fontanel) is one of two "soft spots" on a newborn human's skull. There are, however, two more fontanelles of interest, the mastoid fontanelle, and the sphenoidal fontanelle.
Fontanelles are soft spots on a baby's head which, during birth, enable the soft bony plates of the skull to flex, allowing the head to pass through the birth canal. Fontanelles are usually completely hardened by a child's second birthday, and will eventually form the sutures of the neurocranium.
The skull of a newborn consists of five main bones: two frontal bones, two parietal bones, and one occipital bone. These are joined by fibrous sutures, which allow movement that facilitates childbirth and brain growth.
At birth, the skull features a small posterior fontanelle, an open area covered by a tough membrane, where the two parietal bones adjoin the occipital bone (at the lambda). This fontanelle usually closes during the first several months of an infant's life.
There is also a much larger, diamond-shaped anterior fontanelle where the two frontal and two parietal bones abut. This fontanelle remains open until the child is about two years of age. In cleidocranial dysostosis it is often late in closing or never closes.
The anterior fontanelle is useful clinically. Examination of an infant includes palpating the anterior fontanelle. A sunken fontanelle indicates dehydration, whereas a very tense or bulging anterior fontanelle indicates raised intracranial pressure.
Parents may worry that their infant may be more prone to injury at the fontanelles. In fact, although they may colloquially be called "soft-spots", the membrane covering the fontanelles is extremely tough and difficult to penetrate.
The fontanelles allow the infant brain to be imaged using ultrasonography. Once they are closed, most of the brain is inaccessible to ultrasound imaging, as the bony skull presents an acoustic barrier. | https://www.wikidoc.org/index.php/Anterior_fontanel | |
18a8b2fce5af10cca5fb33a0af4afc7a14855967 | wikidoc | Cerebellum | Cerebellum
# Overview
The cerebellum (Latin: "little brain") is a region of the brain that plays an important role in the integration of sensory perception and motor output. Many neural pathways link the cerebellum with the motor cortex—which sends information to the muscles causing them to move—and the spinocerebellar tract—which provides feedback on the position of the body in space (proprioception). The cerebellum integrates these pathways, using the constant feedback on body position to fine-tune motor movements.
Because of this 'updating' function of the cerebellum, lesions within it are not so debilitating as to cause paralysis, but rather present as feedback deficits resulting in disorders in fine movement, equilibrium, posture, and motor learning. Initial observations by physiologists during the 18th century indicated that patients with cerebellar damage show problems with motor coordination and movement. Research into cerebellar function during the early to mid 19th century was done via lesion and ablation studies in animals. Research physiologists noted that such lesions led to animals with strange movements, awkward gait, and muscular weakness. These observations and studies led to the conclusion that the cerebellum was a motor control structure. However, modern research shows that the cerebellum has a broader role in a number of key cognitive functions, including attention and the processing of language, music, and other sensory temporal stimuli.
# General features
The cerebellum is located in the inferior posterior portion of the head (the hindbrain), directly dorsal to the pons, and inferior to the occipital lobe (Figs. 1 and 3). Because of its large number of tiny granule cells, the cerebellum contains nearly 50% of all neurons in the brain, but it only takes up 10% of total brain volume. The cerebellum receives nearly 200 million input fibers; in contrast, the optic nerve is composed of a mere one million fibers.
The cerebellum is divided into two large hemispheres, much like the cerebrum, and contains ten smaller lobules. The cytoarchitecture (cellular organization) of the cerebellum is highly uniform, with connections organized into a rough, three-dimensional array of perpendicular circuit elements. This organizational uniformity makes the nerve circuitry relatively easy to study. To envision this "perpendicular array," one might imagine a tree-lined street with wires running straight through the branches of one tree to the next.
# Development and evolution
During the early stages of embryonic development, the brain starts to form in three distinct segments: the prosencephalon, mesencephalon, and rhombencephalon. The rhombencephalon is the most caudal (toward the tail) segment of the embryonic brain; it is from this segment that the cerebellum develops. Along the embryonic rhombencephalic segment develop eight swellings, called rhombomeres. The cerebellum arises from two rhombomeres located in the alar plate of the neural tube, a structure that eventually forms the brain and spinal cord. The specific rhombomeres from which the cerebellum forms are rhombomere 1 (Rh.1) caudally (near the tail) and the "isthmus" rostrally (near the front).
Two primary regions are thought to give rise to the neurons that make up the cerebellum. The first region is the ventricular zone in the roof of the fourth ventricle. This area produces Purkinje cells and deep cerebellar nuclear neurons. These cells are the primary output neurons of the cerebellar cortex and cerebellum. The second germinal zone (cellular birthplace) is known as the external granular layer. This layer of cells—found on the exterior the cerebellum—produces the granule neurons. Once born, the granule neurons migrate from this exterior layer to form an inner layer known as the internal granule layer. The external granular layer ceases to exist in the mature cerebellum, leaving only granule cells in the internal granule layer. The cerebellar white matter may be a third germinal zone in the cerebellum; however, its function as a germinal zone is controversial.
The cerebellum is of archipalliar phylogenetic origin. The pallium is a term for gray matter that forms the cortex. The archipallium is the one of the most evolutionarily primitive brain regions. The circuits in the cerebellar cortex look similar across all classes of vertebrates, including fish, reptiles, birds, and mammals (e.g., Fig. 2). This has been taken as evidence that the cerebellum performs functions important to all vertebrate species.
# Anatomy
The cerebellum contains similar gray and white matter divisions as the cerebrum. Embedded within the white matter—which is known as the arbor vitae (Tree of Life) in the cerebellum due to its branched, treelike appearance—are four deep cerebellar nuclei. Three gross phylogenetic segments are largely grouped by general function. The three cortical layers contain various cellular types that often create various feedback and feedforward loops. Oxygenated blood is supplied by three arterial branches off the basilar and vertebral arteries.
## Divisions
The cerebellum can be divided according to three different criteria: gross anatomical, phyologenetical, and functional.
### Gross anatomical divisions
On gross inspection, three lobes can be distinguished in the cerebellum: the flocculonodular lobe, the anterior lobe (rostral to the "primary fissure"), and the posterior lobe (dorsal to the "primary fissure"). The latter two can be further divided in a midline cerebellar vermis and lateral cerebellar hemispheres.
### Phylogenetic and functional divisions
The cerebellum can also be divided in three parts based on both phylogenetic criteria (the evolutionary age of each part) and on functional criteria (the incoming and outgoing connections each part has and the role played in normal cerebellar function). From the phylogenetically oldest to the newest, the three parts are:
Much of what is understood about the functions of the cerebellum stems from careful documentation of the effects of focal lesions in human patients who have suffered from injury or disease or through animal lesion research.
## Deep nuclei
The four deep cerebellar nuclei are in the center of the cerebellum, embedded in the white matter. These nuclei receive inhibitory (GABAergic) inputs from Purkinje cells in the cerebellar cortex and excitatory (glutamatergic) inputs from mossy fiber pathways. Most output fibers of the cerebellum originate from these nuclei. One exception is that fibers from the flocculonodular lobe synapse directly on vestibular nuclei without first passing through the deep cerebellar nuclei. The vestibular nuclei in the brainstem are analogous structures to the deep nuclei, since they receive both mossy fiber and Purkinje cell inputs.
From lateral to medial, the four deep cerebellar nuclei are the dentate, emboliform, globose, and fastigial. An easy mnemonic device to remember these names and positions relative to their position from the midline is the phrase "Don't Eat Greasy Food", where each letter indicates the lateral to medial location in the cerebellar white matter. Some animals do not have distinct emboliform and globose nuclei, instead having a single, fused nucleus interpositus (interposed nucleus). In animals with distinct emboliform and globose nuclei, the term interposed nucleus is often used to refer collectively to these two nuclei.
In general, each pair of deep nuclei is associated with a corresponding region of cerebellar surface anatomy. The dentate nuclei are deep within the lateral hemispheres, the interposed nuclei are located in the paravermal (intermediate) zone, and the fastigial nuclei are in the vermis. These structural relationships are generally maintained in the neuronal connections between the nuclei and associated cerebellar cortex, with the dentate nucleus receiving most of its connections from the lateral hemispheres, the interposed nuclei receiving inputs mostly from the paravermis, and the fastigial nucleus receiving primarily afferents from the vermis.
## Cortical layers
There are three layers to the cerebellar cortex; from outer to inner layer, these are the molecular, Purkinje, and granular layers. The function of the cerebellar cortex is essentially to modulate information flowing through the deep nuclei. The microcircuitry of the cerebellum is schematized in Figure 5. Mossy and climbing fibers carry sensorimotor information into the deep nuclei, which in turn pass it on to various premotor areas, thus regulating the gain and timing of motor actions. Mossy and climbing fibers also feed this information into the cerebellar cortex, which performs various computations, resulting in the regulation of Purkinje cell firing. Purkinje neurons feed back into the deep nuclei via a potent inhibitory synapse. This synapse regulates the extent to which mossy and climbing fibers activate the deep nuclei, and thus control the ultimate effect of the cerebellum on motor function. The synaptic strength of almost every synapse in the cerebellar cortex has been shown to undergo synaptic plasticity. This allows the circuitry of the cerebellar cortex to continuously adjust and fine-tune the output of the cerebellum, forming the basis of some types of motor learning and coordination. Each layer in the cerebellar cortex contains the various cell types that comprise this circuitry.
### Granular layer
The innermost layer contains the cell bodies of two types of cells: the numerous and tiny granule cells, and the larger Golgi cells. Mossy fibers enter the granular layer from their main point of origin, the pontine nuclei. These fibers form excitatory synapses with the granule cells and the cells of the deep cerebellar nuclei. The granule cells send their T-shaped axons—known as parallel fibers—up into the superficial molecular layer, where they form hundreds of thousands of synapses with Purkinje cell dendrites. The human cerebellum contains on the order of 60 to 80 billion granule cells, making this single cell type by far the most numerous neuron in the brain (roughly 70% of all neurons in the brain and spinal cord, combined). Golgi cells provide inhibitory feedback to granule cells, forming a synapse with them and projecting an axon into the molecular layer.
### Purkinje layer
The middle layer contains only one type of cell body—that of the large Purkinje cell. Purkinje cells are the primary integrative neurons of the cerebellar cortex and provide its sole output. Purkinje cell dendrites are large arbors with hundreds of spiny branches reaching up into the molecular layer (Fig. 6). These dendritic arbors are flat—nearly all of them lie in planes—with neighboring Purkinje arbors in parallel planes. Each parallel fiber from the granule cells runs orthogonally through these arbors, like a wire passing through many layers. Purkinje neurons are GABAergic—meaning they have inhibitory synapses—with the neurons of the deep cerebellar and vestibular nuclei in the brainstem. Each Purkinje cell receives excitatory input from 100,000 to 200,000 parallel fibers. Parallel fibers are said to be responsible for the simple (all or nothing, amplitude invariant) spiking of the Purkinje cell.
Purkinje cells also receive input from the inferior olivary nucleus via climbing fibers. A good mnemonic for this interaction is the phrase "climb the other olive tree", given that climbing fibers originate from the contralateral inferior olive. In striking contrast to the 100,000-plus inputs from parallel fibers, each Purkinje cell receives input from exactly one climbing fiber; but this single fiber "climbs" the dendrites of the Purkinje cell, winding around them and making a large number of synapses as it goes. The net input is so strong that a single action potential from a climbing fiber is capable of producing a "complex spike" in the Purkinje cell: a burst of several spikes in a row, with diminishing amplitude, followed by a pause during which simple spikes are suppressed.
### Molecular layer
This outermost layer of the cerebellar cortex contains two types of inhibitory interneurons: the stellate and basket cells. It also contains the dendritic arbors of Purkinje neurons and parallel fiber tracts from the granule cells. Both stellate and basket cells form GABAergic synapses onto Purkinje cell dendrites.
## Peduncles
Similarly, the cerebellum follows the trend of "threes", with three major input and output peduncles (fiber bundles). These are the superior (brachium conjunctivum), middle (brachium pontis), and inferior (restiform body) cerebellar peduncles.
There are three sources of input to the cerebellum, in two categories consisting of mossy and climbing fibers, respectively. Mossy fibers can originate from the pontine nuclei, which are clusters of neurons located in the pons that carry information from the contralateral cerebral cortex. They may also arise within the spinocerebellar tract whose origin is located in the ipsilateral spinal cord. Most of the output from the cerebellum initially synapses onto the deep cerebellar nuclei before exiting via the three peduncles. The most notable exception is the direct inhibition of the vestibular nuclei by Purkinje cells.
## Blood supply
Three arteries supply blood to the cerebellum (Fig. 7): the superior cerebellar artery (SCA), anterior inferior cerebellar artery (AICA), and posterior inferior cerebellar artery (PICA).
### Superior cerebellar artery
The SCA branches off the lateral portion of the basilar artery, just inferior to its bifurcation into the posterior cerebral artery. Here it wraps posteriorly around the pons (to which it also supplies blood) before reaching the cerebellum. The SCA supplies blood to most of the cerebellar cortex, the cerebellar nuclei, and the middle and superior cerebellar peduncles.
### Anterior inferior cerebellar artery
The AICA branches off the lateral portion of the basilar artery, just superior to the junction of the vertebral arteries. From its origin, it branches along the inferior portion of the pons at the cerebellopontine angle before reaching the cerebellum. This artery supplies blood to the anterior portion of the inferior cerebellum, and to the facial (CN VII) and vestibulocochlear nerves (CN VIII).
Obstruction of the AICA can cause paresis, paralysis, and loss of sensation in the face; it can also cause hearing impairment. Moreover, it could cause an infarct of the cerebellopontine angle. This could lead to hyperacusia (dysfunction of the stapedius muscle, innervated by CN VII) and vertigo (wrong interpretation from the vestibular semi-circular canal's endolymph acceleration caused by alteration of CN VIII).
### Posterior inferior cerebellar artery
The PICA branches off the lateral portion of the vertebral arteries just inferior to their junction with the basilar artery. Before reaching the inferior surface of the cerebellum, the PICA sends branches into the medulla, supplying blood to several cranial nerve nuclei. In the cerebellum, the PICA supplies blood to the posterior inferior portion of the cerebellum, the inferior cerebellar peduncle, the nucleus ambiguus, the vagus motor nucleus, the spinal trigeminal nucleus, the solitary nucleus, and the vestibulocochlear nuclei.
# Dysfunction
Ataxia is a complex of symptoms, generally involving a lack of coordination, that is often found in disease processes affecting the cerebellum. To identify cerebellar problems, the neurological examination includes assessment of gait (a broad-based gait being indicative of ataxia), finger-pointing tests and assessment of posture. Structural abnormalities of the cerebellum (hemorrhage, infarction, neoplasm, degeneration) may be identified on cross-sectional imaging. Magnetic resonance imaging is the modality of choice, as computed tomography is insufficiently sensitive for detecting structural abnormalities of the cerebellum.
# Theories about cerebellar function
Two main theories address the function of the cerebellum, both dealing with motor coordination. One claims that the cerebellum functions as a regulator of the "timing of movements". This has emerged from studies of patients whose timed movements are disrupted.
The second, "Tensor Network Theory" provides a mathematical model of transformation of sensory (covariant) space-time coordinates into motor (contravariant) coordinates by cerebellar neuronal networks.
Like many controversies in the physical sciences, there is evidence supporting each of the above hypotheses. Studies of motor learning in the vestibulo-ocular reflex and eyeblink conditioning demonstrate that the timing and amplitude of learned movements are encoded by the cerebellum.
Many synaptic plasticity mechanisms have been found throughout the cerebellum. The Marr-Albus model mostly attributes motor learning to a single plasticity mechanism: the long-term depression of parallel fiber synapses. The Tensor Network Theory of sensorimotor transformations by the cerebellum has also been experimentally supported.
With the advent of more sophisticated neuroimaging techniques such as positron emission tomography (PET),
and fMRI,
numerous diverse functions are now at least partially attributed to the cerebellum. What was once thought to be primarily a motor/sensory integration region is now proving to be involved in many diverse cognitive functions. Paradoxically, despite the importance of this region and the heterogeneous role it plays in motor and sensory functions, people who have lost their entire cerebellum through disease, injury, or surgery can live reasonably normal lives.
# Cerebellar modeling
As mentioned in the preceding section, there have been many attempts to model the cerebellar function.
The insights provided by the models have also led to extrapolations in the domains of artificial intelligence methodologies, especially neural networks. Some of the notable achievements have been Cerebellatron ,
Cerebellar Model Associative Memory or CMAC networks,
and SpikeFORCE for robotic movement control,
and "Tensor Network Theory".
# Additional images
- Computed tomography of head, with cerebellum visible at lower part.
- Lobes
- Diencephalon
- Scheme showing the connections of the several parts of the brain.
- Upper surface of the cerebellum.
- Under surface of the cerebellum.
- Sagittal section of the cerebellum, near the junction of the vermis with the hemisphere.
- Dissection showing the projection fibers of the cerebellum.
- Dissection showing the course of the cerebrospinal fibers.
- Diagram showing the positions of the three principal subarachnoid cisternæ.
- Human cerebellum anterior view
- Human brain midsagittal view | Cerebellum
Template:Infobox Brain
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
The cerebellum (Latin: "little brain") is a region of the brain that plays an important role in the integration of sensory perception and motor output. Many neural pathways link the cerebellum with the motor cortex—which sends information to the muscles causing them to move—and the spinocerebellar tract—which provides feedback on the position of the body in space (proprioception). The cerebellum integrates these pathways, using the constant feedback on body position to fine-tune motor movements.
Because of this 'updating' function of the cerebellum, lesions within it are not so debilitating as to cause paralysis, but rather present as feedback deficits resulting in disorders in fine movement, equilibrium, posture, and motor learning. Initial observations by physiologists during the 18th century indicated that patients with cerebellar damage show problems with motor coordination and movement. Research into cerebellar function during the early to mid 19th century was done via lesion and ablation studies in animals. Research physiologists noted that such lesions led to animals with strange movements, awkward gait, and muscular weakness. These observations and studies led to the conclusion that the cerebellum was a motor control structure.[1] However, modern research shows that the cerebellum has a broader role in a number of key cognitive functions, including attention and the processing of language, music, and other sensory temporal stimuli.
# General features
The cerebellum is located in the inferior posterior portion of the head (the hindbrain), directly dorsal to the pons, and inferior to the occipital lobe (Figs. 1 and 3). Because of its large number of tiny granule cells, the cerebellum contains nearly 50% of all neurons in the brain, but it only takes up 10% of total brain volume. The cerebellum receives nearly 200 million input fibers; in contrast, the optic nerve is composed of a mere one million fibers.
The cerebellum is divided into two large hemispheres, much like the cerebrum, and contains ten smaller lobules. The cytoarchitecture (cellular organization) of the cerebellum is highly uniform, with connections organized into a rough, three-dimensional array of perpendicular circuit elements. This organizational uniformity makes the nerve circuitry relatively easy to study. To envision this "perpendicular array," one might imagine a tree-lined street with wires running straight through the branches of one tree to the next.
# Development and evolution
During the early stages of embryonic development, the brain starts to form in three distinct segments: the prosencephalon, mesencephalon, and rhombencephalon. The rhombencephalon is the most caudal (toward the tail) segment of the embryonic brain; it is from this segment that the cerebellum develops. Along the embryonic rhombencephalic segment develop eight swellings, called rhombomeres. The cerebellum arises from two rhombomeres located in the alar plate of the neural tube, a structure that eventually forms the brain and spinal cord. The specific rhombomeres from which the cerebellum forms are rhombomere 1 (Rh.1) caudally (near the tail) and the "isthmus" rostrally (near the front).[2]
Two primary regions are thought to give rise to the neurons that make up the cerebellum. The first region is the ventricular zone in the roof of the fourth ventricle. This area produces Purkinje cells and deep cerebellar nuclear neurons. These cells are the primary output neurons of the cerebellar cortex and cerebellum. The second germinal zone (cellular birthplace) is known as the external granular layer. This layer of cells—found on the exterior the cerebellum—produces the granule neurons. Once born, the granule neurons migrate from this exterior layer to form an inner layer known as the internal granule layer. The external granular layer ceases to exist in the mature cerebellum, leaving only granule cells in the internal granule layer. The cerebellar white matter may be a third germinal zone in the cerebellum; however, its function as a germinal zone is controversial.
The cerebellum is of archipalliar phylogenetic origin. The pallium is a term for gray matter that forms the cortex. The archipallium is the one of the most evolutionarily primitive brain regions. The circuits in the cerebellar cortex look similar across all classes of vertebrates, including fish, reptiles, birds, and mammals (e.g., Fig. 2). This has been taken as evidence that the cerebellum performs functions important to all vertebrate species.
# Anatomy
The cerebellum contains similar gray and white matter divisions as the cerebrum. Embedded within the white matter—which is known as the arbor vitae (Tree of Life) in the cerebellum due to its branched, treelike appearance—are four deep cerebellar nuclei. Three gross phylogenetic segments are largely grouped by general function. The three cortical layers contain various cellular types that often create various feedback and feedforward loops. Oxygenated blood is supplied by three arterial branches off the basilar and vertebral arteries.
## Divisions
The cerebellum can be divided according to three different criteria: gross anatomical, phyologenetical, and functional.
### Gross anatomical divisions
On gross inspection, three lobes can be distinguished in the cerebellum: the flocculonodular lobe, the anterior lobe (rostral to the "primary fissure"), and the posterior lobe (dorsal to the "primary fissure"). The latter two can be further divided in a midline cerebellar vermis and lateral cerebellar hemispheres.
### Phylogenetic and functional divisions
The cerebellum can also be divided in three parts based on both phylogenetic criteria (the evolutionary age of each part) and on functional criteria (the incoming and outgoing connections each part has and the role played in normal cerebellar function). From the phylogenetically oldest to the newest, the three parts are:
Much of what is understood about the functions of the cerebellum stems from careful documentation of the effects of focal lesions in human patients who have suffered from injury or disease or through animal lesion research.
## Deep nuclei
The four deep cerebellar nuclei are in the center of the cerebellum, embedded in the white matter. These nuclei receive inhibitory (GABAergic) inputs from Purkinje cells in the cerebellar cortex and excitatory (glutamatergic) inputs from mossy fiber pathways. Most output fibers of the cerebellum originate from these nuclei. One exception is that fibers from the flocculonodular lobe synapse directly on vestibular nuclei without first passing through the deep cerebellar nuclei. The vestibular nuclei in the brainstem are analogous structures to the deep nuclei, since they receive both mossy fiber and Purkinje cell inputs.
From lateral to medial, the four deep cerebellar nuclei are the dentate, emboliform, globose, and fastigial. An easy mnemonic device to remember these names and positions relative to their position from the midline is the phrase "Don't Eat Greasy Food", where each letter indicates the lateral to medial location in the cerebellar white matter. Some animals do not have distinct emboliform and globose nuclei, instead having a single, fused nucleus interpositus (interposed nucleus). In animals with distinct emboliform and globose nuclei, the term interposed nucleus is often used to refer collectively to these two nuclei.
In general, each pair of deep nuclei is associated with a corresponding region of cerebellar surface anatomy. The dentate nuclei are deep within the lateral hemispheres, the interposed nuclei are located in the paravermal (intermediate) zone, and the fastigial nuclei are in the vermis. These structural relationships are generally maintained in the neuronal connections between the nuclei and associated cerebellar cortex, with the dentate nucleus receiving most of its connections from the lateral hemispheres, the interposed nuclei receiving inputs mostly from the paravermis, and the fastigial nucleus receiving primarily afferents from the vermis.
## Cortical layers
There are three layers to the cerebellar cortex; from outer to inner layer, these are the molecular, Purkinje, and granular layers. The function of the cerebellar cortex is essentially to modulate information flowing through the deep nuclei. The microcircuitry of the cerebellum is schematized in Figure 5. Mossy and climbing fibers carry sensorimotor information into the deep nuclei, which in turn pass it on to various premotor areas, thus regulating the gain and timing of motor actions. Mossy and climbing fibers also feed this information into the cerebellar cortex, which performs various computations, resulting in the regulation of Purkinje cell firing. Purkinje neurons feed back into the deep nuclei via a potent inhibitory synapse. This synapse regulates the extent to which mossy and climbing fibers activate the deep nuclei, and thus control the ultimate effect of the cerebellum on motor function. The synaptic strength of almost every synapse in the cerebellar cortex has been shown to undergo synaptic plasticity. This allows the circuitry of the cerebellar cortex to continuously adjust and fine-tune the output of the cerebellum, forming the basis of some types of motor learning and coordination. Each layer in the cerebellar cortex contains the various cell types that comprise this circuitry.
### Granular layer
The innermost layer contains the cell bodies of two types of cells: the numerous and tiny granule cells, and the larger Golgi cells. Mossy fibers enter the granular layer from their main point of origin, the pontine nuclei. These fibers form excitatory synapses with the granule cells and the cells of the deep cerebellar nuclei. The granule cells send their T-shaped axons—known as parallel fibers—up into the superficial molecular layer, where they form hundreds of thousands of synapses with Purkinje cell dendrites. The human cerebellum contains on the order of 60 to 80 billion granule cells, making this single cell type by far the most numerous neuron in the brain (roughly 70% of all neurons in the brain and spinal cord, combined). Golgi cells provide inhibitory feedback to granule cells, forming a synapse with them and projecting an axon into the molecular layer.
### Purkinje layer
The middle layer contains only one type of cell body—that of the large Purkinje cell. Purkinje cells are the primary integrative neurons of the cerebellar cortex and provide its sole output. Purkinje cell dendrites are large arbors with hundreds of spiny branches reaching up into the molecular layer (Fig. 6). These dendritic arbors are flat—nearly all of them lie in planes—with neighboring Purkinje arbors in parallel planes. Each parallel fiber from the granule cells runs orthogonally through these arbors, like a wire passing through many layers. Purkinje neurons are GABAergic—meaning they have inhibitory synapses—with the neurons of the deep cerebellar and vestibular nuclei in the brainstem. Each Purkinje cell receives excitatory input from 100,000 to 200,000 parallel fibers. Parallel fibers are said to be responsible for the simple (all or nothing, amplitude invariant) spiking of the Purkinje cell.
Purkinje cells also receive input from the inferior olivary nucleus via climbing fibers. A good mnemonic for this interaction is the phrase "climb the other olive tree", given that climbing fibers originate from the contralateral inferior olive. In striking contrast to the 100,000-plus inputs from parallel fibers, each Purkinje cell receives input from exactly one climbing fiber; but this single fiber "climbs" the dendrites of the Purkinje cell, winding around them and making a large number of synapses as it goes. The net input is so strong that a single action potential from a climbing fiber is capable of producing a "complex spike" in the Purkinje cell: a burst of several spikes in a row, with diminishing amplitude, followed by a pause during which simple spikes are suppressed.
### Molecular layer
This outermost layer of the cerebellar cortex contains two types of inhibitory interneurons: the stellate and basket cells. It also contains the dendritic arbors of Purkinje neurons and parallel fiber tracts from the granule cells. Both stellate and basket cells form GABAergic synapses onto Purkinje cell dendrites.
## Peduncles
Similarly, the cerebellum follows the trend of "threes", with three major input and output peduncles (fiber bundles). These are the superior (brachium conjunctivum), middle (brachium pontis), and inferior (restiform body) cerebellar peduncles.
There are three sources of input to the cerebellum, in two categories consisting of mossy and climbing fibers, respectively. Mossy fibers can originate from the pontine nuclei, which are clusters of neurons located in the pons that carry information from the contralateral cerebral cortex. They may also arise within the spinocerebellar tract whose origin is located in the ipsilateral spinal cord. Most of the output from the cerebellum initially synapses onto the deep cerebellar nuclei before exiting via the three peduncles. The most notable exception is the direct inhibition of the vestibular nuclei by Purkinje cells.
## Blood supply
Three arteries supply blood to the cerebellum (Fig. 7): the superior cerebellar artery (SCA), anterior inferior cerebellar artery (AICA), and posterior inferior cerebellar artery (PICA).
### Superior cerebellar artery
The SCA branches off the lateral portion of the basilar artery, just inferior to its bifurcation into the posterior cerebral artery. Here it wraps posteriorly around the pons (to which it also supplies blood) before reaching the cerebellum. The SCA supplies blood to most of the cerebellar cortex, the cerebellar nuclei, and the middle and superior cerebellar peduncles.
### Anterior inferior cerebellar artery
The AICA branches off the lateral portion of the basilar artery, just superior to the junction of the vertebral arteries. From its origin, it branches along the inferior portion of the pons at the cerebellopontine angle before reaching the cerebellum. This artery supplies blood to the anterior portion of the inferior cerebellum, and to the facial (CN VII) and vestibulocochlear nerves (CN VIII).
Obstruction of the AICA can cause paresis, paralysis, and loss of sensation in the face; it can also cause hearing impairment. Moreover, it could cause an infarct of the cerebellopontine angle. This could lead to hyperacusia (dysfunction of the stapedius muscle, innervated by CN VII) and vertigo (wrong interpretation from the vestibular semi-circular canal's endolymph acceleration caused by alteration of CN VIII).
### Posterior inferior cerebellar artery
The PICA branches off the lateral portion of the vertebral arteries just inferior to their junction with the basilar artery. Before reaching the inferior surface of the cerebellum, the PICA sends branches into the medulla, supplying blood to several cranial nerve nuclei. In the cerebellum, the PICA supplies blood to the posterior inferior portion of the cerebellum, the inferior cerebellar peduncle, the nucleus ambiguus, the vagus motor nucleus, the spinal trigeminal nucleus, the solitary nucleus, and the vestibulocochlear nuclei.
# Dysfunction
Template:Seemain
Ataxia is a complex of symptoms, generally involving a lack of coordination, that is often found in disease processes affecting the cerebellum. To identify cerebellar problems, the neurological examination includes assessment of gait (a broad-based gait being indicative of ataxia), finger-pointing tests and assessment of posture.[1] Structural abnormalities of the cerebellum (hemorrhage, infarction, neoplasm, degeneration) may be identified on cross-sectional imaging. Magnetic resonance imaging is the modality of choice, as computed tomography is insufficiently sensitive for detecting structural abnormalities of the cerebellum.[4]
# Theories about cerebellar function
Two main theories address the function of the cerebellum, both dealing with motor coordination. One claims that the cerebellum functions as a regulator of the "timing of movements". This has emerged from studies of patients whose timed movements are disrupted.[5]
The second, "Tensor Network Theory" provides a mathematical model of transformation of sensory (covariant) space-time coordinates into motor (contravariant) coordinates by cerebellar neuronal networks.[6][7]
Like many controversies in the physical sciences, there is evidence supporting each of the above hypotheses. Studies of motor learning in the vestibulo-ocular reflex and eyeblink conditioning demonstrate that the timing and amplitude of learned movements are encoded by the cerebellum.[8]
Many synaptic plasticity mechanisms have been found throughout the cerebellum. The Marr-Albus model mostly attributes motor learning to a single plasticity mechanism: the long-term depression of parallel fiber synapses. The Tensor Network Theory of sensorimotor transformations by the cerebellum has also been experimentally supported.[9][10]
With the advent of more sophisticated neuroimaging techniques such as positron emission tomography (PET),[11]
and fMRI,[12]
numerous diverse functions are now at least partially attributed to the cerebellum. What was once thought to be primarily a motor/sensory integration region is now proving to be involved in many diverse cognitive functions. Paradoxically, despite the importance of this region and the heterogeneous role it plays in motor and sensory functions, people who have lost their entire cerebellum through disease, injury, or surgery can live reasonably normal lives.
# Cerebellar modeling
As mentioned in the preceding section, there have been many attempts to model the cerebellar function.[13]
The insights provided by the models have also led to extrapolations in the domains of artificial intelligence methodologies, especially neural networks. Some of the notable achievements have been Cerebellatron ,[14]
Cerebellar Model Associative Memory or CMAC networks,
and SpikeFORCE for robotic movement control,[15]
and "Tensor Network Theory".[16]
# Additional images
- Computed tomography of head, with cerebellum visible at lower part.
- Lobes
- Diencephalon
- Scheme showing the connections of the several parts of the brain.
- Upper surface of the cerebellum.
- Under surface of the cerebellum.
- Sagittal section of the cerebellum, near the junction of the vermis with the hemisphere.
- Dissection showing the projection fibers of the cerebellum.
- Dissection showing the course of the cerebrospinal fibers.
- Diagram showing the positions of the three principal subarachnoid cisternæ.
- Human cerebellum anterior view
- Human brain midsagittal view | https://www.wikidoc.org/index.php/Anterior_lobe | |
2e2e4144d5e58eebe69ede241cbbf6bc43332590 | wikidoc | Anthracene | Anthracene
# Overview
Anthracene is a solid polycyclic aromatic hydrocarbon consisting of three fused benzene rings derived from coal-tar. Anthracene is used in the artificial production of the red dye alizarin. It is also used in wood preservatives, insecticides, and coating materials. Anthracene is colorless but exhibits a blue (400-500 nm peak) fluorescence under ultraviolet light.
# Synthesis
A classic method for the preparation of anthracene in the laboratory is by cyclodehydration of o-methyl- or o-methylene-substituted diarylketones in the so-called Elbs reaction (named for the German chemist Karl Elbs).
# Reactions
Anthracene has the ability to photodimerize with irradiation by UV light. This results in considerable changes in the physical properties of the material.
The dimer is connected by two covalent bonds resulting from the cycloaddition. The dimer reverts to anthracene thermally or with UV irradiation below 300 nm. The reversible bonding and photochromic properties of anthracenes is the basis of many potential applications using poly and monosubstituted anthracene derivatives. The reaction is sensitive to oxygen.
In most other reactions of anthracene, the central ring is also targeted, as it is the most highly reactive. Electrophilic substitution occurs at the "9" and "10" positions of the center ring, and oxidation of anthracene occurs readily, giving anthraquinone, C14H8O2 (below).
# Uses
Anthracene can also have a hydroxyl group to form 1-hydroxyanthracene and 2-hydroxyanthracene, homologous to phenol and napthol, and hydroxyanthracene is also called anthrol, and anthracenol.
Hydroxyanthracene derivatives are pharmacologically active, and are contained in aloe for example.
Anthracene is an organic semiconductor.
Anthracene is used as a scintillator for detectors of high energy photons, electrons and alpha particles. Plastics such as polyvinyltolulene can be doped with Anthracene to produce a plastic scintillator that is approximately water equivalent for use in radiation therapy dosimetry. Anthracenes emission spectrum peaks at between 400 nm and 440 nm. | Anthracene
Template:Chembox new
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Anthracene is a solid polycyclic aromatic hydrocarbon consisting of three fused benzene rings derived from coal-tar. Anthracene is used in the artificial production of the red dye alizarin. It is also used in wood preservatives, insecticides, and coating materials. Anthracene is colorless but exhibits a blue (400-500 nm peak) fluorescence under ultraviolet light.
# Synthesis
A classic method for the preparation of anthracene in the laboratory is by cyclodehydration of o-methyl- or o-methylene-substituted diarylketones in the so-called Elbs reaction (named for the German chemist Karl Elbs).
# Reactions
Anthracene has the ability to photodimerize with irradiation by UV light. This results in considerable changes in the physical properties of the material.
The dimer is connected by two covalent bonds resulting from the [4+4] cycloaddition. The dimer reverts to anthracene thermally or with UV irradiation below 300 nm. The reversible bonding and photochromic properties of anthracenes is the basis of many potential applications using poly and monosubstituted anthracene derivatives. The reaction is sensitive to oxygen.
In most other reactions of anthracene, the central ring is also targeted, as it is the most highly reactive. Electrophilic substitution occurs at the "9" and "10" positions of the center ring, and oxidation of anthracene occurs readily, giving anthraquinone, C14H8O2 (below).
# Uses
Anthracene can also have a hydroxyl group to form 1-hydroxyanthracene and 2-hydroxyanthracene, homologous to phenol and napthol, and hydroxyanthracene is also called anthrol, and anthracenol.[1][2]
Hydroxyanthracene derivatives are pharmacologically active, and are contained in aloe for example.[3][4]
Anthracene is an organic semiconductor.
Anthracene is used as a scintillator for detectors of high energy photons, electrons and alpha particles. Plastics such as polyvinyltolulene can be doped with Anthracene to produce a plastic scintillator that is approximately water equivalent for use in radiation therapy dosimetry. Anthracenes emission spectrum peaks at between 400 nm and 440 nm. | https://www.wikidoc.org/index.php/Anthracene | |
3a19ff5f0d1f784afd387325ec0907dffe87800c | wikidoc | Anti-aging | Anti-aging
# Introduction
Anti-aging addresses how to prevent, slow, or reverse the effects of aging and help people live longer, healthier, happier lives. It includes scientific research and applications in genetic engineering, tissue engineering, and other medical advances, e.g., finding treatments and cures for Alzheimer’s disease. It includes anti-aging psychology, e.g., coping skills for resiliently handling change, stress, and aging. Life extension is the part of anti-aging focused on living as long as possible.
The anti-aging marketplace includes nutrition, physical fitness, skin care, hormone replacements, vitamins, supplements, and herbs. Alternative medicine and holistic approaches have often been an incubator for approaches initially shunned by traditional medicine.
Leading sources of anti-aging information include the Life Extension Foundation (focusing on research and supplements), the American Academy of Anti-Aging Medicine (focusing on anti-aging physicians and cutting edge treatments), Andrew Weil (focusing on alternative medicine, holistic health, and herbal supplements), the Chopra Center for Wellbeing (focusing on mind-body medicine and integrating Eastern and Western medicine), and the Ageless Lifestyles Institute (focusing on anti-aging psychology).
# History
Anti-aging pursuits date back at least to ancient Egypt. While the religion and pyramids focused on the afterlife, a lot of attention was given to herbs and remedies to promote beauty and longevity. Over the centuries scientists and alchemists tried to find cures and potions. These included drinking, eating, or injecting substances such as gold, testicles, and transplanting monkey gonads. Many cultures such as India and China developed long traditions of herbs, foods, diets, and health practices to foster anti-aging.
There are many legends of magic places that give life, e.g., Ponce de León’s search for the “Fountain of Youth.” In 1933 British novelist James Hilton’s book Lost Horizon described Shangri-la – an ageless paradise somewhere in the Himalayan mountains near the Tibet-China border. Despite Shangri-la being a fictional place, expeditions have tried to find it.
Gerontologists have tended to paint a bleak picture of aging being all downhill with increasing loss of skills, functions, and quality of life. Women’s movements leaders, e.g., Betty Friedan’s book The Fountain of Youth and books like Gail Sheehy’s Passages helped paint a more positive, generative template for aging.
Around 2000 research started identifying strengths that go with aging. Daniel Mroczek, Ph.D., found that older people report being happier than younger people. At ages 18-27 only 28% reported being very happy. The percentage goes up with each age bracket with the bracket 68-77 at 38%. The rating dips a little at ages 78-89 to 34%. Other researcher found that seniors tend to be better story tellers and become more agreeable and conscientious with age. Laura Carstensen, Ph.D reports that as we age, we are tend to be more positive and in better control of our emotions.
# Centenarians—What Makes Them the Anti-Aging All Stars?
One way to find what helps people live long healthy lives is to study those who have succeeded. Centenarians have written best selling books, excelled in sports, piloted airplanes, practiced medicine, danced, sculpted, taught in universities, graduated from universities, run for Congress, and even fathered children.
The current documented record holder for longevity was Jeanne Calment, a French woman who lived 122 years and died in 1997. There are reports of older people in some remote villages but there is no documentation to verify the claims (and they live in cultures that give great status to the oldest). Centenarians have become so common, the newest category is “Super Centenarians,” those 110+ years old.
The most definitive research on centenarians is Thomas Perls, MD and Margery’s Living to 100 study of New England centenarians. Interviews with centenarians include Lynn Adler’s Centenarians: The Bonus Years and photographer Liane Enkelis’ incredible photographs and stories in On Being 100. There are quite a few autobiographies and biographies including Jeanne Calment: From Van Gough’s Time to Ours.
Research suggests that centenarians have little in common physically. They are physically active people, most don’t smoke, and they typically maintained about the same body weight through their adult life.
The role of genetics in longevity is complex. A genetic vulnerability to a life threatening disease, e.g., malaria, reduces life expectancy. If a vaccine or cure is developed, the same genes no longer present a problem. With Alzheimer’s disease, for example, those with the certain apo-E gene patterns have a higher risk of developing Alzheimer’s. When scientists develop a cure, Alzheimer’s will no longer compromise the quality and length of life for those who are at risk.
There appear to be genes that foster living longer. Researchers have extended the life of fruit flies by 30% by giving them an extra copy of a gene. Other researchers extended the life of nematodes (microscopic worms) by 500% by removing a gene. It isn’t clear yet why the genetic engineering is extending the lives, but the results are promising.
Danish researchers compared identical and fraternal twins and extrapolated that only 30% of longevity is genetic. That means that 70% is lifestyle and the choices people make. George Valliant, Ph.D., and subsequent researchers have followed Harvard freshman in the classes from 1939-1949 periodically to the present. One especially notable finding was that men who had traits such as optimism and humor as freshmen were less likely to develop chronic illness or die by age 45. The difference was even more pronounced at age 60.
# Current Anti-aging
American life expectancy jumped from 47 in 1900 to 77 in 2007. This is attributed to many factors:
- preventing and curing diseases
medical and pharmaceutical treatment advances
increased affluence, giving people more money to take care of themselves
better education to better understand how to take care of themselves (in 1900 most adult Americans didn’t have an eighth-grade education, now more than 80% of American 25+ years old are high school graduates and 27% have at least a bachelor’s degree)
better sanitation and hygiene
safer, healthier working conditions
- preventing and curing diseases
- medical and pharmaceutical treatment advances
- increased affluence, giving people more money to take care of themselves
- better education to better understand how to take care of themselves (in 1900 most adult Americans didn’t have an eighth-grade education, now more than 80% of American 25+ years old are high school graduates and 27% have at least a bachelor’s degree)
- better sanitation and hygiene
- safer, healthier working conditions
Nutrition has been an extremely controversial area in anti-aging medicine with gurus offering a huge variety of diets to help people stay healthy and live longer. The diets are often contradictory. One of the better validated studies is Dr. Dean Ornish Program for Reducing Heart Disease. Note, however, that the program also places a strong emphasis on exercise, relaxation skills, managing stress, emotional intimacy, and lifestyles. Thus it is not clear to what extent the nutritional program is achieving the results and how big a role the lifestyles components play. One of the few areas of consensus among nutritionists is the importance of keeping stable blood sugar levels, achieved in part by managing the glycemic indexes of food choices.
Some fitness and longevity advocates love grueling sports and activities such as running marathons. This runs the risk of injuries and wear and tear on body parts such as knee joints. Some fitness experts focus on being healthy and fit enough and emphasize a balanced approach. This includes cardiovascular, strength, flexibility, balance, and posture – whether achieved through exercise or sports.
Researchers continue to search for causes and cures for diseases. Tissue engineering is developing ways to grow new tissue, e.g., for burned skin, damaged heart muscle. Tissue engineering includes using stem cells to grow new tissue, organ transplants, and artificial tissue or organs. Nanotechnology, genetic research, and pharmaceutical research are all contributing as well.
Anti-aging medicine has tended to focus on age conscious consumer’s desires to look good, feel good, and live as long as possible. Anti-aging medicine has tended to focus on hormone therapies, supplements, skin care treatments (e.g., skin resurfacing, Botox treatments), and plastic surgery.
Millions of women have use Premarin (synthetic estrogens and made from mare’s urine) to delay or attenuate menopause. In 1991 the Women’s Health Initiative, studied 161,808 postmenopausal women with randomized trials of hormone supplements vs. placebo. It discontinued the study in 2002 because it concluded that on the whole the supplements were doing more harm than good (primarily due to an increased risk of breast cancer). Suzane Sommers has been championing the use of bioidentical hormone replacement for women as more efficacious. She has received a lot of opposition from doctors.
Millions of men are taking testosterone supplements (usually creams or patches) and tens of thousands of Americans are taking Human Growth Hormone (HGH) injections at a cost of $10-12,000 a year. The Internet has more than a hundred website promoting less expensive secretagogues that claim to prompt the body to naturally produce HGH. There is little independent research on HGH secretagogues.
The U.S. now has more than 5,000 health spas generating $5 billion dollars in revenue. Most are day spas that offer relaxation and beauty treatments. Many are including medical treatments as well.
The American Academy of Anti-Aging Medicine is an international professional organization with 18,500 members (primarily anti-aging physicians). It sponsors a journal, publications, and conferences including an annual conference in Las Vegas. The organization’s found, Ronald Klatz, MD, DO says he coined the term anti-aging.
The Life Extension Foundation, is “the world’s largest organization dedicated to finding scientific methods for addressing disease, aging, and death.” It has focused on vitamins and supplements and much of its income is derived from selling vitamins and supplements. The nonprofit organization conducts and funds anti-aging research. It has a track record of ground breaking results and often being ten years ahead of mainstream medicine in it’s recommendations. It takes a strong advocacy posture and is often critical of the practices of mainstream medicine and pharmaceutical companies.
Deepak Chopra, MD. emphasizes the “integration of the best of western medicine with the natural healing traditions of the East.” He is especially interested in meditation, Ayervedic medicine and philosophy, yoga, personal empowerment, and peace. He is a popular speaker, prolific author, and is founder of the Chopra Center for Wellbeing in Carlsbad California.
Andrew Weil, MD is the most prominent leader in alternative medicine, holistic health, and herbal supplements. He gives a balanced approach to optimal health with an emphasis on natural approaches. He is a popular speaker, author, and newsletter editor.
Jack LaLanne is the godfather of physical fitness in the U.S. He says he started the first gym. He had the original fitness program on television, getting millions to exercise with him. He has often celebrated birthdays with prodigious feats such as swimming across a bay while towing dozens of boats. Now in his nineties, LeLanne is still fit, brimming with enthusiasm, and encouraging fitness.
Michael Brickey, Ph.D., is developing anti-aging psychology as a discipline rooted in positive psychology and the psychological factors that promote health and longevity. He focuses on Anti-Aging ABCs™ – attitudes, beliefs and coping skills. He is a popular speaker, author, and newsletter editor.
Roy L. Walford, MD, a “crew member” of the biosphere experiment, championed caloric restriction as a research validated method for extending longevity. An obstacle to widespread adoption is that most Westerners lack the discipline to choose to limit eating to around 1800 calories a day. Dr. Walford died at age 79. His daughter continues his research.
Ping Wu, MD, Ph.D. and Taichi Tzu, Ph.D, for the first time, explained aging, longevity, afterlife based on I-Ching and modern physics. They also experimented and practiced an integrated anti-aging protocol, combining thousand years of oriental wisdom and leading edge sciences, called PingLongevity, consisting of raw natural food diet, caloric restriction, non-traumatic exercises, spiritual development, hormonal balance, and psychological and cosmetic aspects of staying young by look and in heart. Their work is summarized in the book "Asian Longevity Secrets", and in their website www.youngbodymind.com.
# See Also
Life Extension
de:Anti-Aging | Anti-aging
Template:AB
# Introduction
Anti-aging addresses how to prevent, slow, or reverse the effects of aging and help people live longer, healthier, happier lives. It includes scientific research and applications in genetic engineering, tissue engineering, and other medical advances, e.g., finding treatments and cures for Alzheimer’s disease. It includes anti-aging psychology, e.g., coping skills for resiliently handling change, stress, and aging. Life extension is the part of anti-aging focused on living as long as possible.
The anti-aging marketplace includes nutrition, physical fitness, skin care, hormone replacements, vitamins, supplements, and herbs. Alternative medicine and holistic approaches have often been an incubator for approaches initially shunned by traditional medicine.
Leading sources of anti-aging information include the Life Extension Foundation (focusing on research and supplements), the American Academy of Anti-Aging Medicine (focusing on anti-aging physicians and cutting edge treatments), Andrew Weil (focusing on alternative medicine, holistic health, and herbal supplements), the Chopra Center for Wellbeing (focusing on mind-body medicine and integrating Eastern and Western medicine), and the Ageless Lifestyles Institute (focusing on anti-aging psychology).
# History
Anti-aging pursuits date back at least to ancient Egypt. While the religion and pyramids focused on the afterlife, a lot of attention was given to herbs and remedies to promote beauty and longevity. Over the centuries scientists and alchemists tried to find cures and potions. These included drinking, eating, or injecting substances such as gold, testicles, and transplanting monkey gonads. Many cultures such as India and China developed long traditions of herbs, foods, diets, and health practices to foster anti-aging.
There are many legends of magic places that give life, e.g., Ponce de León’s search for the “Fountain of Youth.” In 1933 British novelist James Hilton’s book Lost Horizon described Shangri-la – an ageless paradise somewhere in the Himalayan mountains near the Tibet-China border. Despite Shangri-la being a fictional place, expeditions have tried to find it.
Gerontologists have tended to paint a bleak picture of aging being all downhill with increasing loss of skills, functions, and quality of life. Women’s movements leaders, e.g., Betty Friedan’s book The Fountain of Youth and books like Gail Sheehy’s Passages helped paint a more positive, generative template for aging.
Around 2000 research started identifying strengths that go with aging. Daniel Mroczek, Ph.D., found that older people report being happier than younger people. At ages 18-27 only 28% reported being very happy. The percentage goes up with each age bracket with the bracket 68-77 at 38%. The rating dips a little at ages 78-89 to 34%. Other researcher found that seniors tend to be better story tellers and become more agreeable and conscientious with age. Laura Carstensen, Ph.D reports that as we age, we are tend to be more positive and in better control of our emotions.
# Centenarians—What Makes Them the Anti-Aging All Stars?
One way to find what helps people live long healthy lives is to study those who have succeeded. Centenarians have written best selling books, excelled in sports, piloted airplanes, practiced medicine, danced, sculpted, taught in universities, graduated from universities, run for Congress, and even fathered children.
The current documented record holder for longevity was Jeanne Calment, a French woman who lived 122 years and died in 1997. There are reports of older people in some remote villages but there is no documentation to verify the claims (and they live in cultures that give great status to the oldest). Centenarians have become so common, the newest category is “Super Centenarians,” those 110+ years old.
The most definitive research on centenarians is Thomas Perls, MD and Margery’s Living to 100 study of New England centenarians. Interviews with centenarians include Lynn Adler’s Centenarians: The Bonus Years and photographer Liane Enkelis’ incredible photographs and stories in On Being 100. There are quite a few autobiographies and biographies including Jeanne Calment: From Van Gough’s Time to Ours.
Research suggests that centenarians have little in common physically. They are physically active people, most don’t smoke, and they typically maintained about the same body weight through their adult life.
The role of genetics in longevity is complex. A genetic vulnerability to a life threatening disease, e.g., malaria, reduces life expectancy. If a vaccine or cure is developed, the same genes no longer present a problem. With Alzheimer’s disease, for example, those with the certain apo-E gene patterns have a higher risk of developing Alzheimer’s. When scientists develop a cure, Alzheimer’s will no longer compromise the quality and length of life for those who are at risk.
There appear to be genes that foster living longer. Researchers have extended the life of fruit flies by 30% by giving them an extra copy of a gene. Other researchers extended the life of nematodes (microscopic worms) by 500% by removing a gene. It isn’t clear yet why the genetic engineering is extending the lives, but the results are promising.
Danish researchers compared identical and fraternal twins and extrapolated that only 30% of longevity is genetic. That means that 70% is lifestyle and the choices people make. George Valliant, Ph.D., and subsequent researchers have followed Harvard freshman in the classes from 1939-1949 periodically to the present. One especially notable finding was that men who had traits such as optimism and humor as freshmen were less likely to develop chronic illness or die by age 45. The difference was even more pronounced at age 60.
# Current Anti-aging
American life expectancy jumped from 47 in 1900 to 77 in 2007. This is attributed to many factors:
- preventing and curing diseases
medical and pharmaceutical treatment advances
increased affluence, giving people more money to take care of themselves
better education to better understand how to take care of themselves (in 1900 most adult Americans didn’t have an eighth-grade education, now more than 80% of American 25+ years old are high school graduates and 27% have at least a bachelor’s degree)
better sanitation and hygiene
safer, healthier working conditions
- preventing and curing diseases
- medical and pharmaceutical treatment advances
- increased affluence, giving people more money to take care of themselves
- better education to better understand how to take care of themselves (in 1900 most adult Americans didn’t have an eighth-grade education, now more than 80% of American 25+ years old are high school graduates and 27% have at least a bachelor’s degree)
- better sanitation and hygiene
- safer, healthier working conditions
Nutrition has been an extremely controversial area in anti-aging medicine with gurus offering a huge variety of diets to help people stay healthy and live longer. The diets are often contradictory. One of the better validated studies is Dr. Dean Ornish Program for Reducing Heart Disease. Note, however, that the program also places a strong emphasis on exercise, relaxation skills, managing stress, emotional intimacy, and lifestyles. Thus it is not clear to what extent the nutritional program is achieving the results and how big a role the lifestyles components play. One of the few areas of consensus among nutritionists is the importance of keeping stable blood sugar levels, achieved in part by managing the glycemic indexes of food choices.
Some fitness and longevity advocates love grueling sports and activities such as running marathons. This runs the risk of injuries and wear and tear on body parts such as knee joints. Some fitness experts focus on being healthy and fit enough and emphasize a balanced approach. This includes cardiovascular, strength, flexibility, balance, and posture – whether achieved through exercise or sports.
Researchers continue to search for causes and cures for diseases. Tissue engineering is developing ways to grow new tissue, e.g., for burned skin, damaged heart muscle. Tissue engineering includes using stem cells to grow new tissue, organ transplants, and artificial tissue or organs. Nanotechnology, genetic research, and pharmaceutical research are all contributing as well.
Anti-aging medicine has tended to focus on age conscious consumer’s desires to look good, feel good, and live as long as possible. Anti-aging medicine has tended to focus on hormone therapies, supplements, skin care treatments (e.g., skin resurfacing, Botox treatments), and plastic surgery.
Millions of women have use Premarin (synthetic estrogens and made from mare’s urine) to delay or attenuate menopause. In 1991 the Women’s Health Initiative, studied 161,808 postmenopausal women with randomized trials of hormone supplements vs. placebo. It discontinued the study in 2002 because it concluded that on the whole the supplements were doing more harm than good (primarily due to an increased risk of breast cancer). Suzane Sommers has been championing the use of bioidentical hormone replacement for women as more efficacious. She has received a lot of opposition from doctors.
Millions of men are taking testosterone supplements (usually creams or patches) and tens of thousands of Americans are taking Human Growth Hormone (HGH) injections at a cost of $10-12,000 a year. The Internet has more than a hundred website promoting less expensive secretagogues that claim to prompt the body to naturally produce HGH. There is little independent research on HGH secretagogues.
The U.S. now has more than 5,000 health spas generating $5 billion dollars in revenue. Most are day spas that offer relaxation and beauty treatments. Many are including medical treatments as well.
The American Academy of Anti-Aging Medicine is an international professional organization with 18,500 members (primarily anti-aging physicians). It sponsors a journal, publications, and conferences including an annual conference in Las Vegas. The organization’s found, Ronald Klatz, MD, DO says he coined the term anti-aging.
The Life Extension Foundation, is “the world’s largest organization dedicated to finding scientific methods for addressing disease, aging, and death.” It has focused on vitamins and supplements and much of its income is derived from selling vitamins and supplements. The nonprofit organization conducts and funds anti-aging research. It has a track record of ground breaking results and often being ten years ahead of mainstream medicine in it’s recommendations. It takes a strong advocacy posture and is often critical of the practices of mainstream medicine and pharmaceutical companies.
Deepak Chopra, MD. emphasizes the “integration of the best of western medicine with the natural healing traditions of the East.” He is especially interested in meditation, Ayervedic medicine and philosophy, yoga, personal empowerment, and peace. He is a popular speaker, prolific author, and is founder of the Chopra Center for Wellbeing in Carlsbad California.
Andrew Weil, MD is the most prominent leader in alternative medicine, holistic health, and herbal supplements. He gives a balanced approach to optimal health with an emphasis on natural approaches. He is a popular speaker, author, and newsletter editor.
Jack LaLanne is the godfather of physical fitness in the U.S. He says he started the first gym. He had the original fitness program on television, getting millions to exercise with him. He has often celebrated birthdays with prodigious feats such as swimming across a bay while towing dozens of boats. Now in his nineties, LeLanne is still fit, brimming with enthusiasm, and encouraging fitness.
Michael Brickey, Ph.D., is developing anti-aging psychology as a discipline rooted in positive psychology and the psychological factors that promote health and longevity. He focuses on Anti-Aging ABCs™ – attitudes, beliefs and coping skills. He is a popular speaker, author, and newsletter editor.
Roy L. Walford, MD, a “crew member” of the biosphere experiment, championed caloric restriction as a research validated method for extending longevity. An obstacle to widespread adoption is that most Westerners lack the discipline to choose to limit eating to around 1800 calories a day. Dr. Walford died at age 79. His daughter continues his research.
Ping Wu, MD, Ph.D. and Taichi Tzu, Ph.D, for the first time, explained aging, longevity, afterlife based on I-Ching and modern physics. They also experimented and practiced an integrated anti-aging protocol, combining thousand years of oriental wisdom and leading edge sciences, called PingLongevity, consisting of raw natural food diet, caloric restriction, non-traumatic exercises, spiritual development, hormonal balance, and psychological and cosmetic aspects of staying young by look and in heart. Their work is summarized in the book "Asian Longevity Secrets", and in their website www.youngbodymind.com.
# See Also
Life Extension
de:Anti-Aging
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